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## Science Has A Systemic Problem, Not an Innovation Problem

### Science Has A Systemic Problem, Not an Innovation Problem

Curator: Stephen J. Williams, Ph.D.

A recent email, asking me to submit a survey, got me thinking about the malaise that scientists and industry professionals frequently bemoan: that innovation has been stymied for some reason and all sorts of convuluted processes must be altered to spur this mythical void of great new discoveries…..  and it got me thinking about our current state of science, and what is the perceived issue… and if this desert of innovation actually exists or is more a fundamental problem which we have created.

The email was from an NIH committee asking for opinions on recreating the grant review process …. now this on the same day someone complained to me about a shoddy and perplexing grant review they received.

The following email, which was sent out to multiple researchers, involved in either NIH grant review on both sides, as well as those who had been involved in previous questionnaires and studies on grant review and bias.  The email asked for researchers to fill out a survey on the grant review process, and how to best change it to increase innovation of ideas as well as inclusivity.  In recent years, there have been multiple survey requests on these matters, with multiple confusing procedural changes to grant format and content requirements, adding more administrative burden to scientists.

The email from Center for Scientific Review (one of the divisions a grant will go to before review {they set up review study sections and decide what section a grant should be  assigned to} was as follows:

Update on Simplifying Review Criteria: A Request for Information

https://www.csr.nih.gov/reviewmatters/2022/12/08/update-on-simplifying-review-criteria-a-request-for-information/

NIH has issued a request for information (RFI) seeking feedback on revising and simplifying the peer review framework for research project grant applications. The goal of this effort is to facilitate the mission of scientific peer review – identification of the strongest, highest-impact research. The proposed changes will allow peer reviewers to focus on scientific merit by evaluating 1) the scientific impact, research rigor, and feasibility of the proposed research without the distraction of administrative questions and 2) whether or not appropriate expertise and resources are available to conduct the research, thus mitigating the undue influence of the reputation of the institution or investigator.

Currently, applications for research project grants (RPGs, such as R01s, R03s, R15s, R21s, R34s) are evaluated based on five scored criteria: Significance, Investigators, Innovation, Approach, and Environment (derived from NIH peer review regulations 42 C.F.R. Part 52h.8; see Definitions of Criteria and Considerations for Research Project Grant Critiques for more detail) and a number of additional review criteria such as Human Subject Protections.

NIH gathered input from the community to identify potential revisions to the review framework. Given longstanding and often-heard concerns from diverse groups, CSR decided to form two working groups to the CSR Advisory Council—one on non-clinical trials and one on clinical trials. To inform these groups, CSR published a Review Matters blog, which was cross-posted on the Office of Extramural Research blog, Open Mike. The blog received more than 9,000 views by unique individuals and over 400 comments. Interim recommendations were presented to the CSR Advisory Council in a public forum (March 2020 videoslides; March 2021 videoslides). Final recommendations from the CSRAC (report) were considered by the major extramural committees of the NIH that included leadership from across NIH institutes and centers. Additional background information can be found here. This process produced many modifications and the final proposal presented below. Discussions are underway to incorporate consideration of a Plan for Enhancing Diverse Perspectives (PEDP) and rigorous review of clinical trials RPGs (~10% of RPGs are clinical trials) within the proposed framework.

Simplified Review Criteria

NIH proposes to reorganize the five review criteria into three factors, with Factors 1 and 2 receiving a numerical score. Reviewers will be instructed to consider all three factors (Factors 1, 2 and 3) in arriving at their Overall Impact Score (scored 1-9), reflecting the overall scientific and technical merit of the application.

• Factor 1: Importance of the Research (Significance, Innovation), numerical score (1-9)
• Factor 2: Rigor and Feasibility (Approach), numerical score (1-9)
• Factor 3: Expertise and Resources (Investigator, Environment), assessed and considered in the Overall Impact Score, but not individually scored

Within Factor 3 (Expertise and Resources), Investigator and Environment will be assessed in the context of the research proposed. Investigator(s) will be rated as “fully capable” or “additional expertise/capability needed”. Environment will be rated as “appropriate” or “additional resources needed.” If a need for additional expertise or resources is identified, written justification must be provided. Detailed descriptions of the three factors can be found here.

Now looking at some of the Comments were very illuminating:

I strongly support streamlining the five current main review criteria into three, and the present five additional criteria into two. This will bring clarity to applicants and reduce the workload on both applicants and reviewers. Blinding reviewers to the applicants’ identities and institutions would be a helpful next step, and would do much to reduce the “rich-getting-richer” / “good ole girls and good ole boys” / “big science” elitism that plagues the present review system, wherein pedigree and connections often outweigh substance and creativity.

I support the proposed changes. The shift away from “innovation” will help reduce the tendency to create hype around a proposed research direction. The shift away from Investigator and Environment assessments will help reduce bias toward already funded investigators in large well-known institutions.

As a reviewer for 5 years, I believe that the proposed changes are a step in the right direction, refocusing the review on whether the science SHOULD be done and whether it CAN BE DONE WELL, while eliminating burdensome and unhelpful sections of review that are better handled administratively. I particularly believe that the de-emphasis of innovation (which typically focuses on technical innovation) will improve evaluation of the overall science, and de-emphasis of review of minor technical details will, if implemented correctly, reduce the “downward pull” on scores for approach. The above comments reference blinded reviews, but I did not see this in the proposed recommendations. I do not believe this is a good idea for several reasons: 1) Blinding of the applicant and institution is not likely feasible for many of the reasons others have described (e.g., self-referencing of prior work), 2) Blinding would eliminate the potential to review investigators’ biosketches and budget justifications, which are critically important in review, 3) Making review blinded would make determination of conflicts of interest harder to identify and avoid, 4) Evaluation of “Investigator and Environment” would be nearly impossible.

Most of the Comments were in favor of the proposed changes, however many admitted that it adds additional confusion on top of many administrative changes to formats and content of grant sections.

Being a Stephen Covey devotee, and just have listened to  The Four Principles of Execution, it became more apparent that issues that hinder many great ideas coming into fruition, especially in science, is a result of these systemic or problems in the process, not at the level of individual researchers or small companies trying to get their innovations funded or noticed.  In summary, Dr. Covey states most issues related to the success of any initiative is NOT in the strategic planning, but in the failure to adhere to a few EXECUTION principles.  Primary to these failures of strategic plans is lack of accounting of what Dr. Covey calls the ‘whirlwind’, or those important but recurring tasks that take us away from achieving the wildly important goals.  In addition, lack of  determining lead and lag measures of success hinder such plans.

In this case a lag measure in INNOVATION.  It appears we have created such a whirlwind and focus on lag measures that we are incapable of translating great discoveries into INNOVATION.

In the following post, I will focus on issues relating to Open Access, publishing and dissemination of scientific discovery may be costing us TIME to INNOVATION.  And it appears that there are systemic reasons why we appear stuck in a rut, so to speak.

The first indication is from a paper published by Johan Chu and James Evans in 2021 in PNAS:

### Slowed canonical progress in large fields of science

Chu JSG, Evans JA. Slowed canonical progress in large fields of science. Proc Natl Acad Sci U S A. 2021 Oct 12;118(41):e2021636118. doi: 10.1073/pnas.2021636118. PMID: 34607941; PMCID: PMC8522281

## Abstract

In many academic fields, the number of papers published each year has increased significantly over time. Policy measures aim to increase the quantity of scientists, research funding, and scientific output, which is measured by the number of papers produced. These quantitative metrics determine the career trajectories of scholars and evaluations of academic departments, institutions, and nations. Whether and how these increases in the numbers of scientists and papers translate into advances in knowledge is unclear, however. Here, we first lay out a theoretical argument for why too many papers published each year in a field can lead to stagnation rather than advance. The deluge of new papers may deprive reviewers and readers the cognitive slack required to fully recognize and understand novel ideas. Competition among many new ideas may prevent the gradual accumulation of focused attention on a promising new idea. Then, we show data supporting the predictions of this theory. When the number of papers published per year in a scientific field grows large, citations flow disproportionately to already well-cited papers; the list of most-cited papers ossifies; new papers are unlikely to ever become highly cited, and when they do, it is not through a gradual, cumulative process of attention gathering; and newly published papers become unlikely to disrupt existing work. These findings suggest that the progress of large scientific fields may be slowed, trapped in existing canon. Policy measures shifting how scientific work is produced, disseminated, consumed, and rewarded may be called for to push fields into new, more fertile areas of study.

So the Summary of this paper is

• The authors examined 1.8 billion citations among 90 million papers over 241 subjects
• found the corpus of papers do not lead to turnover of new ideas in a field, but rather the ossification or entrenchment of canonical (or older ideas)
• this is mainly due to older paper cited more frequently than new papers with new ideas, potentially because authors are trying to get their own papers cited more frequently for funding and exposure purposes
• The authors suggest that “fundamental progress may be stymied if quantitative growth of scientific endeavors is not balanced by structures fostering disruptive scholarship and focusing attention of novel ideas”

The authors note that, in most cases, science policy reinforces this “more is better” philosophy”,  where metrics of publication productivity are either number of publications or impact measured by citation rankings.  However, using an analysis of citation changes occurring in large versus smaller fields, it becomes apparent that this process is favoring the older, more established papers and a recirculating of older canonical ideas.

“Rather than resulting in faster turnover of field paradigms, the massive amounts of new publications entrenches the ideas of top-cited papers.”  New ideas are pushed down to the bottom of the citation list and potentially lost in the literature.  The authors suggest that this problem will intensify as the “annual mass” of new publications in each field grows, especially in large fields.  This issue is exacerbated by the deluge on new online ‘open access’ journals, in which authors would focus on citing the more highly cited literature.

We maybe at a critical junction, where if many papers are published in a short time, new ideas will not be considered as carefully as the older ideas.  In addition,

with proliferation of journals and the blurring of journal hierarchies due to online articles-level access can exacerbate this problem

As a counterpoint, the authors do note that even though many molecular biology highly cited articles were done in 1976, there has been extremely much innovation since then however it may take a lot more in experiments and money to gain the level of citations that those papers produced, and hence a lower scientific productivity.

##### This issue is seen in the field of economics as well

Ellison, Glenn. “Is peer review in decline?” Economic Inquiry, vol. 49, no. 3, July 2011, pp. 635+. Gale Academic OneFile, link.gale.com/apps/doc/A261386330/AONE?u=temple_main&sid=bookmark-AONE&xid=f5891002. Accessed 12 Dec. 2022.

Abstract

Over the past decade, there has been a decline in the fraction of papers in top economics journals written by economists from the highest-ranked economics departments. This paper documents this fact and uses additional data on publications and citations to assess various potential explanations. Several observations are consistent with the hypothesis that the Internet improves the ability of high-profile authors to disseminate their research without going through the traditional peer-review process. (JEL A14, 030)

The facts part of this paper documents two main facts:

1. Economists in top-ranked departments now publish very few papers in top field journals. There is a marked decline in such publications between the early 1990s and early 2000s.

2. Comparing the early 2000s with the early 1990s, there is a decline in both the absolute number of papers and the share of papers in the top general interest journals written by Harvard economics department faculty.

Although the second fact just concerns one department, I see it as potentially important to understanding what is happening because it comes at a time when Harvard is widely regarded (I believe correctly) as having ascended to the top position in the profession.

The “decline-of-peer-review” theory I allude to in the title is that the necessity of going through the peer-review process has lessened for high-status authors: in the old days peer-reviewed journals were by far the most effective means of reaching readers, whereas with the growth of the Internet high-status authors can now post papers online and exploit their reputation to attract readers.

Many alternate explanations are possible. I focus on four theories: the decline-in-peer-review theory and three alternatives.

1. The trends could be a consequence of top-school authors’ being crowded out of the top journals by other researchers. Several such stories have an optimistic message, for example, there is more talent entering the profession, old pro-elite biases are being broken down, more schools are encouraging faculty to do cutting-edge research, and the Internet is enabling more cutting-edge research by breaking down informational barriers that had hampered researchers outside the top schools. (2)

2. The trends could be a consequence of the growth of revisions at economics journals discussed in Ellison (2002a, 2002b). In this more pessimistic theory, highly productive researchers must abandon some projects and/or seek out faster outlets to conserve the time now required to publish their most important works.

3. The trends could simply reflect that field journals have declined in quality in some relative sense and become a less attractive place to publish. This theory is meant to encompass also the rise of new journals, which is not obviously desirable or undesirable.

The majority of this paper is devoted to examining various data sources that provide additional details about how economics publishing has changed over the past decade. These are intended both to sharpen understanding of the facts to be explained and to provide tests of auxiliary predictions of the theories. Two main sources of information are used: data on publications and data on citations. The publication data include department-level counts of publications in various additional journals, an individual-level dataset containing records of publications in a subset of journals for thousands of economists, and a very small dataset containing complete data on a few authors’ publication records. The citation data include citations at the paper level for 9,000 published papers and less well-matched data that is used to construct measures of citations to authors’ unpublished works, to departments as a whole, and to various journals.

##### Inside Job or Deep Impact? Extramural Citations and the Influence of Economic Scholarship

Josh Angrist, Pierre Azoulay, Glenn Ellison, Ryan Hill, Susan Feng Lu. Inside Job or Deep Impact? Extramural Citations and the Influence of Economic Scholarship.

JOURNAL OF ECONOMIC LITERATURE

VOL. 58, NO. 1, MARCH 2020

(pp. 3-52)

#### Why Isn’t Innovation Helping Reduce Health Care Costs?

National health care expenditures (NHEs) in the United States continue to grow at rates outpacing the broader economy: Inflation- and population-adjusted NHEs have increased 1.6 percent faster than the gross domestic product (GDP) between 1990 and 2018. US national health expenditure growth as a share of GDP far outpaces comparable nations in the Organization for Economic Cooperation and Development (17.2 versus 8.9 percent).

Multiple recent analyses have proposed that growth in the prices and intensity of US health care services—rather than in utilization rates or demographic characteristics—is responsible for the disproportionate increases in NHEs relative to global counterparts. The consequences of ever-rising costs amid ubiquitous underinsurance in the US include price-induced deferral of care leading to excess morbidity relative to comparable nations.

These patterns exist despite a robust innovation ecosystem in US health care—implying that novel technologies, in isolation, are insufficient to bend the health care cost curve. Indeed, studies have documented that novel technologies directly increase expenditure growth.

Why is our prolific innovation ecosystem not helping reduce costs? The core issue relates to its apparent failure to enhance net productivity—the relative output generated per unit resource required. In this post, we decompose the concept of innovation to highlight situations in which inventions may not increase net productivity. We begin by describing how this issue has taken on increased urgency amid resource constraints magnified by the COVID-19 pandemic. In turn, we describe incentives for the pervasiveness of productivity-diminishing innovations. Finally, we provide recommendations to promote opportunities for low-cost innovation.

### Net Productivity During The COVID-19 Pandemic

The issue of productivity-enhancing innovation is timely, as health care systems have been overwhelmed by COVID-19. Hospitals in Italy, New York City, and elsewhere have lacked adequate capital resources to care for patients with the disease, sufficient liquidity to invest in sorely needed resources, and enough staff to perform all of the necessary tasks.

The critical constraint in these settings is not technology: In fact, the most advanced technology required to routinely treat COVID-19—the mechanical ventilator—was invented nearly 100 years ago in response to polio (the so-called iron lung). Rather, the bottleneck relates to the total financial and human resources required to use the technology—the denominator of net productivity. The clinical implementation of ventilators has been illustrative: Health care workers are still required to operate ventilators on a nearly one-to-one basis, just like in the mid-twentieth century.

High levels of resources required for implementation of health care technologies constrain the scalability of patient care—such as during respiratory disease outbreaks such as COVID-19. Thus, research to reduce health care costs is the same kind of research we urgently require to promote health care access for patients with COVID-19.

### Types Of Innovation And Their Relationship To Expenditure Growth

The widespread use of novel medical technologies has been highlighted as a central driver of NHE growth in the US. We believe that the continued expansion of health care costs is largely the result of innovation that tends to have low productivity (exhibit 1). We argue that these archetypes—novel widgets tacked on to existing workflows to reinforce traditional care models—are exactly the wrong properties to reduce NHEs at the systemic level.

### Exhibit 1: Relative productivity of innovation subtypes

Source: Authors’ analysis.

### Content Versus Process Innovation

Content (also called technical) innovation refers to the creation of new widgets, such as biochemical agents, diagnostic tools, or therapeutic interventions. Contemporary examples of content innovation include specialty pharmaceuticalsmolecular diagnostics, and advanced interventions and imaging.

These may be contrasted with process innovations, which address the organized sequences of activities that implement content. Classically, these include clinical pathways and protocols. They can address the delivery of care for acute conditions, such as central line infections, sepsis, or natural disasters. Alternatively, they can target chronic conditions through initiatives such as team-based management of hypertension and hospital-at-home models for geriatric care. Other processes include hiring staffdelegating labor, and supply chain management.

### Performance-Enhancing Versus Cost-Reducing Innovation

Performance-enhancing innovations frequently create incremental outcome gains in diagnostic characteristics, such as sensitivity or specificity, or in therapeutic characteristics, such as biomarkers for disease status. Their performance gains often lead to higher prices compared to existing alternatives.

Performance-enhancing innovations can be compared to “non-inferior” innovations capable of achieving outcomes approximating those of existing alternatives, but at reduced cost. Industries outside of medicine, such as the computing industry, have relied heavily on the ability to reduce costs while retaining performance.

In health care though, this pattern of innovation is rare. Since passage of the 2010 “Biosimilars” Act aimed at stimulating non-inferior innovation and competition in therapeutics markets, only 17 agents have been approved, and only seven have made it to market. More than three-quarters of all drugs receiving new patents between 2005 and 2015 were “reissues,” meaning they had already been approved, and the new patent reflected changes to the previously approved formula. Meanwhile, the costs of approved drugs have increased over time, at rates between 4 percent and 7 percent annually.

### Sustaining Versus Disruptive Innovation

Competitive market theory suggests that incumbents and disruptors innovate differently. Incumbents seek sustaining innovations capable of perpetuating their dominance, whereas disruptors pursue innovations capable of redefining traditional business models.

In health care, while disruptive innovations hold the potential to reduce overall health expenditures, often they run counter to the capabilities of market incumbents. For example, telemedicine can deliver care asynchronously, remotely, and virtually, but large-scale brick-and-mortar medical facilities invest enormous capital in the delivery of synchronous, in-house, in-person care (incentivized by facility fees).

The connection between incumbent business models and the innovation pipeline is particularly relevant given that 58 percent of total funding for biomedical research in the US is now derived from private entities, compared with 46 percent a decade prior. It follows that the growing influence of eminent private organizations may favor innovations supporting their market dominance—rather than innovations that are societally optimal.

### Incentives And Repercussions Of High-Cost Innovation

Taken together, these observations suggest that innovation in health care is preferentially designed for revenue expansion rather than for cost reduction. While offering incremental improvements in patient outcomes, therefore creating theoretical value for society, these innovations rarely deliver incremental reductions in short- or long-term costs at the health system level.

For example, content-based, performance-enhancing, additive, sustaining innovations tend to add layers of complexity to the health care system—which in turn require additional administration to manage. The net result is employment growth in excess of outcome improvement, leading to productivity losses. This gap leads to continuously increasing overall expenditures in turn passed along to payers and consumers.

Nonetheless, high-cost innovations are incentivized across health care stakeholders (exhibit 2). From the supply side of innovation, for academic researchers, “breakthrough” and “groundbreaking” innovations constitute the basis for career advancement via funding and tenure. This is despite stakeholders’ frequent inability to generalize early successes to become cost-effective in the clinical setting. As previously discussed, the increasing influence of private entities in setting the medical research agenda is also likely to stimulate innovation benefitting single stakeholders rather than the system.

### Exhibit 2: Incentives promoting low-value innovation

Source: Authors’ analysis adapted from Hofmann BM. Too much technology. BMJ. 2015 Feb 16.

From the demand side of innovation (providers and health systems), a combined allure (to provide “cutting-edge” patient care), imperative (to leave “no stone unturned” in patient care), and profit-motive (to amplify fee-for-service reimbursements) spur participation in a “technological arms-race.” The status quo thus remains as Clay Christensen has written: “Our major health care institutions…together overshoot the level of care actually needed or used by the vast majority of patients.”

Christensen’s observations have been validated during the COVID-19 epidemic, as treatment of the disease requires predominantly century-old technology. By continually adopting innovation that routinely overshoots the needs of most patients, layer by layer, health care institutions are accruing costs that quickly become the burden of society writ large.

### Recommendations To Reduce The Costs Of Health Care Innovation

Henry Aaron wrote in 2002 that “…the forces that have driven up costs are, if anything, intensifying. The staggering fecundity of biomedical research is increasing…[and] always raises expenditures.” With NHEs spiraling ever-higher, urgency to “bend the cost curve” is mounting. Yet, since much biomedical innovation targets the “flat of the [productivity] curve,” alternative forms of innovation are necessary.

The shortcomings in net productivity revealed by the COVID-19 pandemic highlight the urgent need for redesign of health care delivery in this country, and reevaluation of the innovation needed to support it. Specifically, efforts supporting process redesign are critical to promote cost-reducing, substitutive innovations that can inaugurate new and disruptive business models.

Process redesign rarely involves novel gizmos, so much as rejiggering the wiring of, and connections between, existing gadgets. It targets operational changes capable of streamlining workflows, rather than technical advancements that complicate them. As described above, precisely these sorts of “frugal innovations” have led to productivity improvements yielding lower costs in other high-technology industries, such as the computing industry.

Shrank and colleagues recently estimated that nearly one-third of NHEs—almost $1 trillion—were due to preventable waste. Four of the six categories of waste enumerated by the authors—failure in care delivery, failure in care coordination, low-value care, and administrative complexity—represent ripe targets for process innovation, accounting for$610 billion in waste annually, according to Shrank.

Health systems adopting process redesign methods such as continuous improvement and value-based management have exhibited outcome enhancement and expense reduction simultaneously. Internal processes addressed have included supply chain reconfiguration, operational redesign, outlier reconciliation, and resource standardization.

Despite the potential of process innovation, focus on this area (often bundled into “health services” or “quality improvement” research) occupies only a minute fraction of wallet- or mind-share in the biomedical research landscape, accounting for 0.3 percent of research dollars in medicine. This may be due to a variety of barriers beyond minimal funding. One set of barriers is academic, relating to negative perceptions around rigor and a lack of outlets in which to publish quality improvement research. To achieve health care cost containment over the long term, this dimension of innovation must be destigmatized relative to more traditional manners of innovation by the funders and institutions determining the conditions of the research ecosystem.

Another set of barriers is financial: Innovations yielding cost reduction are less “reimbursable” than are innovations fashioned for revenue expansion. This is especially the case in a fee-for-service system where reimbursement is tethered to cost, which creates perverse incentives for health care institutions to overlook cost increases. However, institutions investing in low-cost innovation will be well-positioned in a rapidly approaching future of value-based care—in which the solvency of health care institutions will rely upon their ability to provide economically efficient care.

### Innovating For Cost Control Necessitates Frugality Over Novelty

Restraining US NHEs represents a critical step toward health promotion. Innovation for innovation’s sake—that is content-based, incrementally effective, additive, and sustaining—is unlikely to constrain continually expanding NHEs.

In contrast, process innovation offers opportunities to reduce costs while maintaining high standards of patient care. As COVID-19 stress-tests health care systems across the world, the importance of cost control and productivity amplification for patient care has become apparent.

As such, frugality, rather than novelty, may hold the key to health care cost containment. Redesigning the innovation agenda to stem the tide of ever-rising NHEs is an essential strategy to promote widespread access to care—as well as high-value preventive care—in this country. In the words of investors across Silicon Valley: Cost-reducing innovation is no longer a “nice-to-have,” but a “need-to-have” for the future of health and overall well-being this country.

#### So Do We Need A New Way of Disseminating Scientific Information?  Can Curation Help?

We had high hopes for Science 2.0, in particular the smashing of data and knowledge silos. However the digital age along with 2.0 platforms seemed to excaccerbate this somehow. We still are critically short on analysis!

Old Science 1.0 is still the backbone of all scientific discourse, built on the massive amount of experimental and review literature. However this literature was in analog format, and we moved to a more accesible digital open access format for both publications as well as raw data. However as there was a structure for 1.0, like the Dewey decimal system and indexing, 2.0 made science more accesible and easier to search due to the newer digital formats. Yet both needed an organizing structure; for 1.0 that was the scientific method of data and literature organization with libraries as the indexers. In 2.0 this relied on an army mostly of volunteers who did not have much in the way of incentivization to co-curate and organize the findings and massive literature.

The Intenet and the Web is rapidly adopting a new “Web 3.0” format, with decentralized networks, enhanced virtual experiences, and greater interconnection between people. Here we start the discussion what will the move from Science 2.0, where dissemination of scientific findings was revolutionized and piggybacking on Web 2.0 or social media, to a Science 3.0 format. And what will it involve or what paradigms will be turned upside down?

We have discussed this in other posts such as

Will Web 3.0 Do Away With Science 2.0? Is Science Falling Behind?

and

Curation Methodology – Digital Communication Technology to mitigate Published Information Explosion and Obsolescence in Medicine and Life Sciences

For years the pharmaceutical industry has toyed with the idea of making innovation networks and innovation hubs

It has been the main focus of whole conferences

Tales from the Translational Frontier – Four Unique Approaches to Turning Novel Biology into Investable Innovations @BIOConvention #BIO2018

However it still seems these strategies have not worked

Is it because we did not have an Execution plan? Or we did not understand the lead measures for success?

### Other Related Articles on this Open Access Scientific Journal Include:

Old Industrial Revolution Paradigm of Education Needs to End: How Scientific Curation Can Transform Education

Analysis of Utilizing LPBI Group’s Scientific Curation Platform as an Educational Tool: New Paradigm for Student Engagement

Global Alliance for Genomics and Health Issues Guidelines for Data Siloing and Sharing

Multiple Major Scientific Journals Will Fully Adopt Open Access Under Plan S

eScientific Publishing a Case in Point: Evolution of Platform Architecture Methodologies and of Intellectual Property Development (Content Creation by Curation) Business Model

### Will Web 3.0 Do Away With Science 2.0? Is Science Falling Behind?

Curator: Stephen J. Williams, Ph.D.

UPDATED 4/06/2022

A while back (actually many moons ago) I had put on two posts on this site:

Scientific Curation Fostering Expert Networks and Open Innovation: Lessons from Clive Thompson and others

Twitter is Becoming a Powerful Tool in Science and Medicine

Each of these posts were on the importance of scientific curation of findings within the realm of social media and the Web 2.0; a sub-environment known throughout the scientific communities as Science 2.0, in which expert networks collaborated together to produce massive new corpus of knowledge by sharing their views, insights on peer reviewed scientific findings. And through this new media, this process of curation would, in itself generate new ideas and new directions for research and discovery.

The platform sort of looked like the image below:

This system lied above a platform of the original Science 1.0, made up of all the scientific journals, books, and traditional literature:

Previous image source: PeerJ.com

To index the massive and voluminous research and papers beyond the old Dewey Decimal system, a process of curation was mandatory. The dissemination of this was a natural for the new social media however the cost had to be spread out among numerous players. Journals, faced with the high costs of subscriptions and their only way to access this new media as an outlet was to become Open Access, a movement first sparked by journals like PLOS and PeerJ but then begrudingly adopted throughout the landscape. But with any movement or new adoption one gets the Good the Bad and the Ugly (as described in my cited, above, Clive Thompson article). The bad side of Open Access Journals were

1. costs are still assumed by the individual researcher not by the journals
2. the arise of the numerous Predatory Journals

Even PeerJ, in their column celebrating an anniversary of a year’s worth of Open Access success stories, lamented the key issues still facing Open Access in practice

• which included the cost and the rise of predatory journals.

In essence, Open Access and Science 2.0 sprung full force BEFORE anyone thought of a way to defray the costs

### Can Web 3.0 Finally Offer a Way to Right the Issues Facing High Costs of Scientific Publishing?

What is Web 3.0?

From Wikipedia: https://en.wikipedia.org/wiki/Web3

Web 1.0 and Web 2.0 refer to eras in the history of the Internet as it evolved through various technologies and formats. Web 1.0 refers roughly to the period from 1991 to 2004, where most websites were static webpages, and the vast majority of users were consumers, not producers, of content.[6][7] Web 2.0 is based around the idea of “the web as platform”,[8] and centers on user-created content uploaded to social-networking services, blogs, and wikis, among other services.[9] Web 2.0 is generally considered to have begun around 2004, and continues to the current day.[8][10][4]

### Terminology

The term “Web3”, specifically “Web 3.0”, was coined by Ethereum co-founder Gavin Wood in 2014.[1] In 2020 and 2021, the idea of Web3 gained popularity[citation needed]. Particular interest spiked towards the end of 2021, largely due to interest from cryptocurrency enthusiasts and investments from high-profile technologists and companies.[4][5] Executives from venture capital firm Andreessen Horowitz travelled to Washington, D.C. in October 2021 to lobby for the idea as a potential solution to questions about Internet regulation with which policymakers have been grappling.[11]

Web3 is distinct from Tim Berners-Lee‘s 1999 concept for a semantic web, which has also been called “Web 3.0”.[12] Some writers referring to the decentralized concept usually known as “Web3” have used the terminology “Web 3.0”, leading to some confusion between the two concepts.[2][3] Furthermore, some visions of Web3 also incorporate ideas relating to the semantic web.[13][14]

## Concept

Web3 revolves around the idea of decentralization, which proponents often contrast with Web 2.0, wherein large amounts of the web’s data and content are centralized in the fairly small group of companies often referred to as Big Tech.[4]

Specific visions for Web3 differ, but all are heavily based in blockchain technologies, such as various cryptocurrencies and non-fungible tokens (NFTs).[4] Bloomberg described Web3 as an idea that “would build financial assets, in the form of tokens, into the inner workings of almost anything you do online”.[15] Some visions are based around the concepts of decentralized autonomous organizations (DAOs).[16] Decentralized finance (DeFi) is another key concept; in it, users exchange currency without bank or government involvement.[4] Self-sovereign identity allows users to identify themselves without relying on an authentication system such as OAuth, in which a trusted party has to be reached in order to assess identity.[17]

## Reception

Technologists and journalists have described Web3 as a possible solution to concerns about the over-centralization of the web in a few “Big Tech” companies.[4][11] Some have expressed the notion that Web3 could improve data securityscalability, and privacy beyond what is currently possible with Web 2.0 platforms.[14] Bloomberg states that sceptics say the idea “is a long way from proving its use beyond niche applications, many of them tools aimed at crypto traders”.[15] The New York Times reported that several investors are betting $27 billion that Web3 “is the future of the internet”.[18][19] Some companies, including Reddit and Discord, have explored incorporating Web3 technologies into their platforms in late 2021.[4][20] After heavy user backlash, Discord later announced they had no plans to integrate such technologies.[21] The company’s CEO, Jason Citron, tweeted a screenshot suggesting it might be exploring integrating Web3 into their platform. This led some to cancel their paid subscriptions over their distaste for NFTs, and others expressed concerns that such a change might increase the amount of scams and spam they had already experienced on crypto-related Discord servers.[20] Two days later, Citron tweeted that the company had no plans to integrate Web3 technologies into their platform, and said that it was an internal-only concept that had been developed in a company-wide hackathon.[21] Some legal scholars quoted by The Conversation have expressed concerns over the difficulty of regulating a decentralized web, which they reported might make it more difficult to prevent cybercrimeonline harassmenthate speech, and the dissemination of child abuse images.[13] But, the news website also states that, “[decentralized web] represents the cyber-libertarian views and hopes of the past that the internet can empower ordinary people by breaking down existing power structures.” Some other critics of Web3 see the concept as a part of a cryptocurrency bubble, or as an extension of blockchain-based trends that they see as overhyped or harmful, particularly NFTs.[20] Some critics have raised concerns about the environmental impact of cryptocurrencies and NFTs. Others have expressed beliefs that Web3 and the associated technologies are a pyramid scheme.[5] Kevin Werbach, author of The Blockchain and the New Architecture of Trust,[22] said that “many so-called ‘web3’ solutions are not as decentralized as they seem, while others have yet to show they are scalable, secure and accessible enough for the mass market”, adding that this “may change, but it’s not a given that all these limitations will be overcome”.[23] David Gerard, author of Attack of the 50 Foot Blockchain,[24] told The Register that “web3 is a marketing buzzword with no technical meaning. It’s a melange of cryptocurrencies, smart contracts with nigh-magical abilities, and NFTs just because they think they can sell some monkeys to morons”.[25] ##### Below is an article from MarketWatch.com Distributed Ledger series about the different forms and cryptocurrencies involved #### by Frances Yue, Editor of Distributed Ledger, Marketwatch.com Clayton Gardner, co-CEO of crypto investment management firm Titan, told Distributed Ledger that as crypto embraces broader adoption, he expects more institutions to bypass bitcoin and invest in other blockchains, such as Ethereum, Avalanche, and Terra in 2022. which all boast smart-contract features. Bitcoin traditionally did not support complex smart contracts, which are computer programs stored on blockchains, though a major upgrade in November might have unlocked more potential. “Bitcoin was originally seen as a macro speculative asset by many funds and for many it still is,” Gardner said. “If anything solidifies its use case, it’s a store of value. It’s not really used as originally intended, perhaps from a medium of exchange perspective.” For institutions that are looking for blockchains that can “produce utility and some intrinsic value over time,” they might consider some other smart contract blockchains that have been driving the growth of decentralized finance and web 3.0, the third generation of the Internet, according to Gardner. Bitcoin is still one of the most secure blockchains, but I think layer-one, layer-two blockchains beyond Bitcoin, will handle the majority of transactions and activities from NFT (nonfungible tokens) to DeFi,“ Gardner said. “So I think institutions see that and insofar as they want to put capital to work in the coming months, I think that could be where they just pump the capital.” ### Decentralized social media？ The price of Decentralized Social, or DeSo, a cryptocurrency powering a blockchain that supports decentralized social media applications, surged roughly 74% to about$164 from $94, after Deso was listed at Coinbase Pro on Monday, before it fell to about$95, according to CoinGecko.

In the eyes of Nader Al-Naji, head of the DeSo foundation, decentralized social media has the potential to be “a lot bigger” than decentralized finance.

“Today there are only a few companies that control most of what we see online,” Al-Naji told Distributed Ledger in an interview. But DeSo is “creating a lot of new ways for creators to make money,” Al-Naji said.

“If you find a creator when they’re small, or an influencer, you can invest in that, and then if they become bigger and more popular, you make money and they make and they get capital early on to produce their creative work,” according to AI-Naji.

BitClout, the first application that was created by AI-Naji and his team on the DeSo blockchain, had initially drawn controversy, as some found that they had profiles on the platform without their consent, while the application’s users were buying and selling tokens representing their identities. Such tokens are called “creator coins.”

AI-Naji responded to the controversy saying that DeSo now supports more than 200 social-media applications including Bitclout. “I think that if you don’t like those features, you now have the freedom to use any app you want. Some apps don’t have that functionality at all.”

But Before I get to the “selling monkeys to morons” quote,

THE GOOD, THE BAD, AND THE UGLY

#### THE GOOD

My foray into Science 2.0 and then pondering what the movement into a Science 3.0 led me to an article by Dr. Vladimir Teif, who studies gene regulation and the nucleosome, as well as creating a worldwide group of scientists who discuss matters on chromatin and gene regulation in a journal club type format.

Fragile Nucleosome is an international community of scientists interested in chromatin and gene regulation. Fragile Nucleosome is active in several spaces: one is the Discord server where several hundred scientists chat informally on scientific matters. You can join the Fragile Nucleosome Discord server. Another activity of the group is the organization of weekly virtual seminars on Zoom. Our webinars are usually conducted on Wednesdays 9am Pacific time (5pm UK, 6pm Central Europe). Most previous seminars have been recorded and can be viewed at our YouTube channel. The schedule of upcoming webinars is shown below. Our third activity is the organization of weekly journal clubs detailed at a separate page (Fragile Nucleosome Journal Club).

His lab site is at https://generegulation.org/ but had published a paper describing what he felt what the #science2_0 to #science3_0 transition would look like (see his blog page on this at https://generegulation.org/open-science/).

### This concept of science 3.0 he had coined back in 2009.  As Dr Teif had mentioned

So essentially I first introduced this word Science 3.0 in 2009, and since then we did a lot to implement this in practice. The Twitter account @generegulation is also one of examples

### This is curious as we still have an ill defined concept of what #science3_0 would look like but it is a good read nonetheless.

His paper,  entitled “Science 3.0: Corrections to the Science 2.0 paradigm” is on the Cornell preprint server at https://arxiv.org/abs/1301.2522

Abstract

### Science 3.0: Corrections to the Science 2.0 paradigm

The concept of Science 2.0 was introduced almost a decade ago to describe the new generation of online-based tools for researchers allowing easier data sharing, collaboration and publishing. Although technically sound, the concept still does not work as expected. Here we provide a systematic line of arguments to modify the concept of Science 2.0, making it more consistent with the spirit and traditions of science and Internet. Our first correction to the Science 2.0 paradigm concerns the open-access publication models charging fees to the authors. As discussed elsewhere, we show that the monopoly of such publishing models increases biases and inequalities in the representation of scientific ideas based on the author’s income. Our second correction concerns post-publication comments online, which are all essentially non-anonymous in the current Science 2.0 paradigm. We conclude that scientific post-publication discussions require special anonymization systems. We further analyze the reasons of the failure of the current post-publication peer-review models and suggest what needs to be changed in Science 3.0 to convert Internet into a large journal club. [bold face added]
In this paper it is important to note the transition of a science 1.0, which involved hard copy journal publications usually only accessible in libraries to a more digital 2.0 format where data, papers, and ideas could be easily shared among networks of scientists.
As Dr. Teif states, the term “Science 2.0” had been coined back in 2009, and several influential journals including Science, Nature and Scientific American endorsed this term and suggested scientists to move online and their discussions online.  However, even at present there are thousands on this science 2.0 platform, Dr Teif notes the number of scientists subscribed to many Science 2.0 networking groups such as on LinkedIn and ResearchGate have seemingly saturated over the years, with little new members in recent times.
The consensus is that science 2.0 networking is:
1. good because it multiplies the efforts of many scientists, including experts and adds to the scientific discourse unavailable on a 1.0 format
2. that online data sharing is good because it assists in the process of discovery (can see this evident with preprint servers, bio-curated databases, Github projects)
3. open-access publishing is beneficial because free access to professional articles and open-access will be the only publishing format in the future (although this is highly debatable as many journals are holding on to a type of “hybrid open access format” which is not truly open access
4. only sharing of unfinished works and critiques or opinions is good because it creates visibility for scientists where they can receive credit for their expert commentary

### A.  Science 3.0 Still Needs Peer Review

Peer review of scientific findings will always be an imperative in the dissemination of well-done, properly controlled scientific discovery.  As Science 2.0 relies on an army of scientific volunteers, the peer review process also involves an army of scientific experts who give their time to safeguard the credibility of science, by ensuring that findings are reliable and data is presented fairly and properly.  It has been very evident, in this time of pandemic and the rapid increase of volumes of preprint server papers on Sars-COV2, that peer review is critical.  Many of these papers on such preprint servers were later either retracted or failed a stringent peer review process.

Now many journals of the 1.0 format do not generally reward their peer reviewers other than the self credit that researchers use on their curriculum vitaes.  Some journals, like the MDPI journal family, do issues peer reviewer credits which can be used to defray the high publication costs of open access (one area that many scientists lament about the open access movement; where the burden of publication cost lies on the individual researcher).

An issue which is highlighted is the potential for INFORMATION NOISE regarding the ability to self publish on Science 2.0 platforms.

### The NEW BREED was born in 4/2012

An ongoing effort on this platform, https://pharmaceuticalintelligence.com/, is to establish a scientific methodology for curating scientific findings where one the goals is to assist to quell the information noise that can result from the massive amounts of new informatics and data occurring in the biomedical literature.

### B.  Open Access Publishing Model leads to biases and inequalities in the idea selection

The open access publishing model has been compared to the model applied by the advertising industry years ago and publishers then considered the journal articles as “advertisements”.  However NOTHING could be further from the truth.  In advertising the publishers claim the companies not the consumer pays for the ads.  However in scientific open access publishing, although the consumer (libraries) do not pay for access the burden of BOTH the cost of doing the research and publishing the findings is now put on the individual researcher.  Some of these publishing costs can be as high as 4000 USD per article, which is very high for most researchers. However many universities try to refund the publishers if they do open access publishing so it still costs the consumer and the individual researcher, limiting the cost savings to either. However, this sets up a situation in which young researchers, who in general are not well funded, are struggling with the publication costs, and this sets up a bias or inequitable system which rewards the well funded older researchers and bigger academic labs. ### C. Post publication comments and discussion require online hubs and anonymization systems Many recent publications stress the importance of a post-publication review process or system yet, although many big journals like Nature and Science have their own blogs and commentary systems, these are rarely used. In fact they show that there are just 1 comment per 100 views of a journal article on these systems. In the traditional journals editors are the referees of comments and have the ability to censure comments or discourse. The article laments that comments should be easy to do on journals, like how easy it is to make comments on other social sites, however scientists are not offering their comments or opinions on the matter. In a personal experience, a well written commentary goes through editors which usually reject a comment like they were rejecting an original research article. Thus many scientists, I believe, after fashioning a well researched and referenced reply, do not get the light of day if not in the editor’s interests. Therefore the need for anonymity is greatly needed and the lack of this may be the hindrance why scientific discourse is so limited on these types of Science 2.0 platforms. Platforms that have success in this arena include anonymous platforms like Wikipedia or certain closed LinkedIn professional platforms but more open platforms like Google Knowledge has been a failure. A great example on this platform was a very spirited conversation on LinkedIn on genomics, tumor heterogeneity and personalized medicine which we curated from the LinkedIn discussion (unfortunately LinkedIn has closed many groups) seen here: Issues in Personalized Medicine: Discussions of Intratumor Heterogeneity from the Oncology Pharma forum on LinkedIn Issues in Personalized Medicine: Discussions of Intratumor Heterogeneity from the Oncology Pharma forum on LinkedIn In this discussion, it was surprising that over a weekend so many scientists from all over the world contributed to a great discussion on the topic of tumor heterogeneity. But many feel such discussions would be safer if they were anonymized. However then researchers do not get any credit for their opinions or commentaries. A Major problem is how to take the intangible and make them into tangible assets which would both promote the discourse as well as reward those who take their time to improve scientific discussion. #### This is where something like NFTs or a decentralized network may become important! See https://pharmaceuticalintelligence.com/portfolio-of-ip-assets/ UPDATED 5/09/2022 Below is an online @TwitterSpace Discussion we had with some young scientists who are just starting out and gave their thoughts on what SCIENCE 3.0 and the future of dissemination of science might look like, in light of this new Meta Verse. However we have to define each of these terms in light of Science and not just the Internet as merely a decentralized marketplace for commonly held goods. This online discussion was tweeted out and got a fair amount of impressions (60) as well as interactors (50). #### For the recording on both Twitter as well as on an audio format please see below <blockquote class=”twitter-tweet”><p lang=”en” dir=”ltr”>Set a reminder for my upcoming Space! <a href=”https://t.co/7mOpScZfGN”>https://t.co/7mOpScZfGN</a&gt; <a href=”https://twitter.com/Pharma_BI?ref_src=twsrc%5Etfw”>@Pharma_BI</a&gt; <a href=”https://twitter.com/PSMTempleU?ref_src=twsrc%5Etfw”>@PSMTempleU</a&gt; <a href=”https://twitter.com/hashtag/science3_0?src=hash&amp;ref_src=twsrc%5Etfw”>#science3_0</a&gt; <a href=”https://twitter.com/science2_0?ref_src=twsrc%5Etfw”>@science2_0</a></p>&mdash; Stephen J Williams (@StephenJWillia2) <a href=”https://twitter.com/StephenJWillia2/status/1519776668176502792?ref_src=twsrc%5Etfw”>April 28, 2022</a></blockquote> <script async src=”https://platform.twitter.com/widgets.js&#8221; charset=”utf-8″></script> To introduce this discussion first a few startoff material which will fram this discourse ##### The Intenet and the Web is rapidly adopting a new “Web 3.0” format, with decentralized networks, enhanced virtual experiences, and greater interconnection between people. Here we start the discussion what will the move from Science 2.0, where dissemination of scientific findings was revolutionized and piggybacking on Web 2.0 or social media, to a Science 3.0 format. And what will it involve or what paradigms will be turned upside down? Old Science 1.0 is still the backbone of all scientific discourse, built on the massive amount of experimental and review literature. However this literature was in analog format, and we moved to a more accesible digital open access format for both publications as well as raw data. However as there was a structure for 1.0, like the Dewey decimal system and indexing, 2.0 made science more accesible and easier to search due to the newer digital formats. Yet both needed an organizing structure; for 1.0 that was the scientific method of data and literature organization with libraries as the indexers. In 2.0 this relied on an army mostly of volunteers who did not have much in the way of incentivization to co-curate and organize the findings and massive literature. Each version of Science has their caveats: their benefits as well as deficiencies. This curation and the ongoing discussion is meant to solidy the basis for the new format, along with definitions and determination of structure. We had high hopes for Science 2.0, in particular the smashing of data and knowledge silos. However the digital age along with 2.0 platforms seemed to excaccerbate this somehow. We still are critically short on analysis! We really need people and organizations to get on top of this new Web 3.0 or metaverse so the similar issues do not get in the way: namely we need to create an organizing structure (maybe as knowledgebases), we need INCENTIVIZED co-curators, and we need ANALYSIS… lots of it!! Are these new technologies the cure or is it just another headache? There were a few overarching themes whether one was talking about AI, NLP, Virtual Reality, or other new technologies with respect to this new meta verse and a concensus of Decentralized, Incentivized, and Integrated was commonly expressed among the attendees #### The Following are some slides from representative Presentations ### Other article of note on this topic on this Open Access Scientific Journal Include: ### Electronic Scientific AGORA: Comment Exchanges by Global Scientists on Articles published in the Open Access Journal @pharmaceuticalintelligence.com – Four Case Studies eScientific Publishing a Case in Point: Evolution of Platform Architecture Methodologies and of Intellectual Property Development (Content Creation by Curation) Business Model e-Scientific Publishing: The Competitive Advantage of a Powerhouse for Curation of Scientific Findings and Methodology Development for e-Scientific Publishing – LPBI Group, A Case in Point @PharmaceuticalIntelligence.com – A Case Study on the LEADER in Curation of Scientific Findings Real Time Coverage @BIOConvention #BIO2019: Falling in Love with Science: Championing Science for Everyone, Everywhere Old Industrial Revolution Paradigm of Education Needs to End: How Scientific Curation Can Transform Education Read Full Post » ## Crowdsourcing Difficult-to-Collect Epidemiological Data in Pandemics: Lessons from Ebola to the current COVID-19 Pandemic ### Crowdsourcing Difficult-to-Collect Epidemiological Data in Pandemics: Lessons from Ebola to the current COVID-19 Pandemic Curator: Stephen J. Williams, Ph.D. At the onset of the COVID-19 pandemic, epidemiological data from the origin of the Sars-Cov2 outbreak, notably from the Wuhan region in China, was sparse. In fact, official individual patient data rarely become available early on in an outbreak, when that data is needed most. Epidemiological data was just emerging from China as countries like Italy, Spain, and the United States started to experience a rapid emergence of the outbreak in their respective countries. China, made of 31 geographical provinces, is a vast and complex country, with both large urban and rural areas. As a result of this geographical diversity and differences in healthcare coverage across the country, epidemiological data can be challenging. For instance, cancer incidence data for regions and whole country is difficult to calculate as there are not many regional cancer data collection efforts, contrasted with the cancer statistics collected in the United States, which is meticulously collected by cancer registries in each region, state and municipality. Therefore, countries like China must depend on hospital record data and autopsy reports in order to back-extrapolate cancer incidence data. This is the case in some developed countries like Italy where cancer registry is administered by a local government and may not be as extensive (for example in the Napoli region of Italy). Population density China by province. Source https://www.unicef.cn/en/figure-13-population-density-province-2017 Epidemiologists, in areas in which data collection may be challenging, are relying on alternate means of data collection such as using devices connected to the internet-of-things such as mobile devices, or in some cases, social media is becoming useful to obtain health related data. Such as effort to acquire pharmacovigilance data, patient engagement, and oral chemotherapeutic adherence using the social media site Twitter has been discussed in earlier posts: (see below) Twitter is Becoming a Powerful Tool in Science and Medicine at https://pharmaceuticalintelligence.com/2014/11/06/twitter-is-becoming-a-powerful-tool-in-science-and-medicine/ Now epidemiologists are finding crowd-sourced data from social media and social networks becoming useful in collecting COVID-19 related data in those countries where health data collection efforts may be sub-optimal. In a recent paper in The Lancet Digital Health [1], authors Kaiyuan Sun, Jenny Chen, and Cecile Viboud present data from the COVID-19 outbreak in China using information collected over social network sites as well as public news outlets and find strong correlations with later-released government statistics, showing the usefulness in such social and crowd-sourcing strategies to collect pertinent time-sensitive data. In particular, the authors aim was to investigate this strategy of data collection to reduce the time delays between infection and detection, isolation and reporting of cases. The paper is summarized below: Kaiyuan Sun, PhD Jenny Chen, BScn Cécile Viboud, PhD . (2020). Early epidemiological analysis of the coronavirus disease 2019 outbreak based on crowdsourced data: a population-level observational study. The Lancet: Digital Health; Volume 2, Issue 4, E201-E208. ## Summary ### Background As the outbreak of coronavirus disease 2019 (COVID-19) progresses, epidemiological data are needed to guide situational awareness and intervention strategies. Here we describe efforts to compile and disseminate epidemiological information on COVID-19 from news media and social networks. ### Methods In this population-level observational study, we searched DXY.cn, a health-care-oriented social network that is currently streaming news reports on COVID-19 from local and national Chinese health agencies. We compiled a list of individual patients with COVID-19 and daily province-level case counts between Jan 13 and Jan 31, 2020, in China. We also compiled a list of internationally exported cases of COVID-19 from global news media sources (Kyodo News, The Straits Times, and CNN), national governments, and health authorities. We assessed trends in the epidemiology of COVID-19 and studied the outbreak progression across China, assessing delays between symptom onset, seeking care at a hospital or clinic, and reporting, before and after Jan 18, 2020, as awareness of the outbreak increased. All data were made publicly available in real time. ### Findings We collected data for 507 patients with COVID-19 reported between Jan 13 and Jan 31, 2020, including 364 from mainland China and 143 from outside of China. 281 (55%) patients were male and the median age was 46 years (IQR 35–60). Few patients (13 [3%]) were younger than 15 years and the age profile of Chinese patients adjusted for baseline demographics confirmed a deficit of infections among children. Across the analysed period, delays between symptom onset and seeking care at a hospital or clinic were longer in Hubei province than in other provinces in mainland China and internationally. In mainland China, these delays decreased from 5 days before Jan 18, 2020, to 2 days thereafter until Jan 31, 2020 (p=0·0009). Although our sample captures only 507 (5·2%) of 9826 patients with COVID-19 reported by official sources during the analysed period, our data align with an official report published by Chinese authorities on Jan 28, 2020. ### Interpretation News reports and social media can help reconstruct the progression of an outbreak and provide detailed patient-level data in the context of a health emergency. The availability of a central physician-oriented social network facilitated the compilation of publicly available COVID-19 data in China. As the outbreak progresses, social media and news reports will probably capture a diminishing fraction of COVID-19 cases globally due to reporting fatigue and overwhelmed health-care systems. In the early stages of an outbreak, availability of public datasets is important to encourage analytical efforts by independent teams and provide robust evidence to guide interventions. A Few notes on Methodology: • The authors used crowd-sourced reports from DXY.cn, a social network for Chinese physicians, health-care professionals, pharmacies and health-care facilities. This online platform provides real time coverage of the COVID-19 outbreak in China • More data was curated from news media, television and includes time-stamped information on COVID-19 cases • These reports are publicly available, de-identified patient data • No patient consent was needed and no ethics approval was required • Data was collected between January 20, 2020 and January 31,2020 • Sex, age, province of identification, travel history, dates of symptom development was collected • Additional data was collected for other international sites of the pandemic including Cambodia, Canada, France, Germany, Hong Kong, India, Italy, Japan, Malaysia, Nepal, Russia, Singapore, UK, and USA • All patients in database had laboratory confirmation of infection Results • 507 patient data was collected with 153 visited and 152 resident of Wuhan • Reported cases were skewed toward males however the overall population curve is skewed toward males in China • Most cases (26%) were from Beijing (urban area) while an equal amount were from rural areas combined (Shaanzi and Yunnan) • Age distribution of COVID cases were skewed toward older age groups with median age of 45 HOWEVER there were surprisingly a statistically high amount of cases less than 5 years of age • Outbreak progression based on the crowd-sourced patient line was consistent with the data published by the China Center for Disease Control • Median reporting delay in the authors crowd-sourcing data was 5 days • Crowd-sourced data was able to detect apparent rapid growth of newly reported cases during the collection period in several provinces outside of Hubei province, which is consistent with local government data The following graphs show age distribution for China in 2017 and predicted for 2050. projected age distribution China 2050. Source https://chinapower.csis.org/aging-problem/ The authors have previously used this curation of news methodology to analyze the Ebola outbreak[2]. A further use of the crowd-sourced database was availability of travel histories for patients returning from Wuhan and onset of symptoms, allowing for estimation of incubation periods. The following published literature has also used these datasets: Backer JA, Klinkenberg D, Wallinga J: Incubation period of 2019 novel coronavirus (2019-nCoV) infections among travellers from Wuhan, China, 20-28 January 2020. Euro surveillance : bulletin Europeen sur les maladies transmissibles = European communicable disease bulletin 2020, 25(5). Lauer SA, Grantz KH, Bi Q, Jones FK, Zheng Q, Meredith HR, Azman AS, Reich NG, Lessler J: The Incubation Period of Coronavirus Disease 2019 (COVID-19) From Publicly Reported Confirmed Cases: Estimation and Application. Annals of internal medicine 2020, 172(9):577-582. Li Q, Guan X, Wu P, Wang X, Zhou L, Tong Y, Ren R, Leung KSM, Lau EHY, Wong JY et al: Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus-Infected Pneumonia. The New England journal of medicine 2020, 382(13):1199-1207. Dataset is available on the Laboratory for the Modeling of Biological and Socio-technical systems website of Northeastern University at https://www.mobs-lab.org/. References 1. Sun K, Chen J, Viboud C: Early epidemiological analysis of the coronavirus disease 2019 outbreak based on crowdsourced data: a population-level observational study. The Lancet Digital health 2020, 2(4):e201-e208. 2. Cleaton JM, Viboud C, Simonsen L, Hurtado AM, Chowell G: Characterizing Ebola Transmission Patterns Based on Internet News Reports. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2016, 62(1):24-31. Read Full Post » ## Old Industrial Revolution Paradigm of Education Needs to End: How Scientific Curation Can Transform Education ### Old Industrial Revolution Paradigm of Education Needs to End: How Scientific Curation Can Transform Education Curator: Stephen J. Williams, PhD. Dr. Cathy N. Davidson from Duke University gives a talk entitled: Now You See It. Why the Future of Learning Demands a Paradigm Shift In this talk, shown below, Dr. Davidson shows how our current education system has been designed for educating students for the industrial age type careers and skills needed for success in the Industrial Age and how this educational paradigm is failing to prepare students for the challenges they will face in their future careers. Or as Dr. Davidson summarizes Designing education not for your past but for their future As the video is almost an hour I will summarize some of the main points below PLEASE WATCH VIDEO #### Summary of talk Dr. Davidson starts the talk with a thesis: that Institutions tend to preserve the problems they were created to solve. All the current work, teaching paradigms that we use today were created for the last information age (19th century) Our job to to remake the institutions of education work for the future not the one we inherited Four information ages or technologies that radically changed communication 1. advent of writing: B.C. in ancient Mesopotamia allowed us to record and transfer knowledge and ideas 2. movable type – first seen in 10th century China 3. steam powered press – allowed books to be mass produced and available to the middle class. First time middle class was able to have unlimited access to literature 4. internet- ability to publish and share ideas worldwide Interestingly, in the early phases of each of these information ages, the same four complaints about the new technology/methodology of disseminating information was heard • ruins memory • creates a distraction • ruins interpersonal dialogue and authority • reduces complexity of thought She gives an example of Socrates who hated writing and frequently stated that writing ruins memory, creates a distraction, and worst commits ideas to what one writes down which could not be changed or altered and so destroys ‘free thinking’. #### She discusses how our educational institutions are designed for the industrial age. #### The need for collaborative (group) learning AND teaching Designing education not for your past but for the future In other words preparing students for THEIR future not your past and the future careers that do not exist today. In the West we were all taught to answer silently and alone. However in Japan, education is arranged in the han or group think utilizing the best talents of each member in the group. In Japan you are arranged in such groups at an early age. The concept is that each member of the group contributes their unique talent and skill for the betterment of the whole group. The goal is to demonstrate that the group worked well together. see https://educationinjapan.wordpress.com/education-system-in-japan-general/the-han-at-work-community-spirit-begins-in-elementary-school/ for a description of “in the han” In the 19th century in institutions had to solve a problem: how to get people out of the farm and into the factory and/or out of the shop and into the firm Takes a lot of regulation and institutionalization to convince people that independent thought is not the best way in the corporation keywords for an industrial age • timeliness • attention to task • standards, standardization • hierarchy • specialization, expertise • metrics (measures, management) • two cultures: separating curriculum into STEM versus artistic tracts or dividing the world of science and world of art This effort led to a concept used in scientific labor management derived from this old paradigm in education, an educational system controlled and success measured using • grades (A,B,C,D) • multiple choice tests keywords for our age • workflow • multitasking attention • interactive process (Prototype, Feedback) • data mining • collaboration by difference Can using a methodology such as scientific curation affect higher education to achieve this goal of teaching students to collaborate in an interactive process using data mining to create a new workflow for any given problem? Can a methodology of scientific curation be able to affect such changes needed in academic departments to achieve the above goal? This will be the subject of future curations tested using real-world in class examples. However, it is important to first discern that scientific content curation takes material from Peer reviewed sources and other expert-vetted sources. This is unique from other types of content curation in which take from varied sources, some of which are not expert-reviewed, vetted, or possibly ‘fake news’ or highly edited materials such as altered video and audio. In this respect, the expert acts not only as curator but as referee. In addition, collaboration is necessary and even compulsory for the methodology of scientific content curation, portending the curator not as the sole expert but revealing the CONTENT from experts as the main focus for learning and edification. ### Other article of note on this subject in this Open Access Online Scientific Journal include: The above articles will give a good background on this NEW Conceived Methodology of Scientific Curation and its Applicability in various areas such as Medical Publishing, and as discussed below Medical Education. To understand the new paradigm in medical communication and the impact curative networks have or will play in this arena please read the following: Scientific Curation Fostering Expert Networks and Open Innovation: Lessons from Clive Thompson and others This article discusses a history of medical communication and how science and medical communication initially moved from discussions from select individuals to the current open accessible and cooperative structure using Web 2.0 as a platform. Read Full Post » ## In Data Science, A Pioneer Practitioner’s Portfolio of Algorithm-based Decision Support Systems for Operations Management in Several Industrial Verticals: Analytics Designer, Aviva Lev-Ari, PhD, RN ### In Data Science, A Pioneer Practitioner’s Portfolio of Algorithm-based Decision Support Systems for Operations Management in Several Industrial Verticals: Analytics Designer, Aviva Lev-Ari, PhD, RN An overview of Data Science as a discipline is presented in Data Science & Analytics: What do Data Scientists Do in 2020 and a Pioneer Practitioner’s Portfolio of Algorithm-based Decision Support Systems for Operations Management in Several Industrial Verticals On this landscape about IT, The Internet, Analytics, Statistics, Big Data, Data Science and Artificial Intelligence, I am to tell stories on my own pioneering work in data science, Algorithm-based decision support systems design for different organizations in several sectors of the US economy: Images on 12/7/2019 • Startups: 1. TimeØ Group – The leader in Digital Marketplaces Design 2. Concept Five Technologies, Inc. – Commercialization of DoD funded technologies 3. MDSS, Inc. – SAAS in Analytical Services 4. LPBI Group – Pharmaceutical & Media • Top Tier Management Consulting: SRI International, Monitor Group; • OEM: Amdahl Corporation; • Top 6th System Integrator: Perot System Corporation; • FFRDC: MITRE Corporation. • Publishing industry: was Director of Research at McGraw-Hill/CTB. • Northeastern University, Researcher on Cardiovascular Pharmacotherapy at Bouve College of Health Sciences (Independent research guided by Professor of Pharmacology) Type of institutions: • For-Profit corporations: Amdahl Corp, PSC, McGraw-Hill • For-Profit Top Tier Consulting: Monitor Company, Now Deloitte • Not-for-Profit Top Tier Consulting: SRI International • FFRDC: MITRE • Pharmaceutical & Media Start up in eScientific Publishing: LPBI Group: 1. Developers of Curation methodology for e-Articles [N = 5,700], 2. Developers of electronic Table of Contents for e-Books in Medicine [N = 16, https://lnkd.in/ekWGNqA] and 3. Developers of Methodologies for real time press coverage and production of e-Proceedings of Biotech Conferences [N = 70]. Autobiographical Annotations: Tribute to My Professors Pioneering implementations of analytics to business decision making: contributions to domain knowledge conceptualization, research design, methodology development, data modeling and statistical data analysis: Aviva Lev-Ari, UCB, PhD’83; HUJI MA’76 https://pharmaceuticalintelligence.com/2018/05/28/pioneering-implementations-of-analytics-to-business-decision-making-contributions-to-domain-knowledge-conceptualization-research-design-methodology-development-data-modeling-and-statistical-data-a/ ### Recollections of Years at UC, Berkeley, Part 1 and Part 2 • Recollections: Part 1 – My days at Berkeley, 9/1978 – 12/1983 – About my doctoral advisor, Allan Pred, other professors and other peers https://pharmaceuticalintelligence.com/2018/03/15/recollections-my-days-at-berkeley-9-1978-12-1983-about-my-doctoral-advisor-allan-pred-other-professors-and-other-peer/ • Recollections: Part 2 – “While Rolling” is preceded by “While Enrolling” Autobiographical Alumna Recollections of Berkeley – Aviva Lev-Ari, PhD’83 https://pharmaceuticalintelligence.com/2018/05/24/recollections-part-2-while-rolling-is-preceded-by-while-enrolling-autobiographical-alumna-recollections-of-berkeley-aviva-lev-ari-phd83/ Accomplishments The Digital Age Gave Rise to New Definitions – New Benchmarks were born on the World Wide Web for the Intangible Asset of Firm’s Reputation: Pay a Premium for buying e-Reputation Thriving at the Survival Calls during Careers in the Digital Age – An AGE like no Other, also known as, DIGITAL Professional Self Re-Invention: From Academia to Industry – Opportunities for PhDs in the Business Sector of the Economy Was prepared for publication in American Friends of the Hebrew University (AFHU), May 2018 Newsletter, Hebrew University’s HUJI Alumni Spotlight Section. Aviva Lev-Ari’s profile was up on 5/3/2018 on AFHU website under the Alumni Spotlight at https://www.afhu.org/ On 5/11/2018, Excerpts were Published in AFHU e-news. https://us10.campaign-archive.com/?u=5c25136c60d4dfc4d3bb36eee&id=757c5c3aae&e=d09d2b8d72 ### https://www.afhu.org/2018/05/03/aviva-lev-ari/ Read Full Post » ## Analysis of Utilizing LPBI Group’s Scientific Curation Platform as an Educational Tool: New Paradigm for Student Engagement ### Analysis of Utilizing LPBI Group’s Scientific Curation Platform as an Educational Tool: New Paradigm for Student Engagement Author: Stephen J. Williams, Ph.D. Use of LBPI Platform for Educational Purposes Goal: to offer supplemental information for student lessons in an upper level Biology course on Cell Signaling and Cell Motility with emphasis on disease etiology including cancer, neurological disease, and cardiovascular disease. Course: Temple University Department of Biology course Cell Signaling and Motility Spring semester 2019. Forty five students enrolled. Methodology: Each weekly lesson was presented to students as a PowerPoint presentation. After each lesson the powerpoint presentation was originally meant to be disseminated to each class-registered student on the students Canvas account. Canvas is a cloud based Learning Management Software developed by educational technology company Salt Lake City, Utah company Infrastructure, Inc. According to rough figures, Canvas® charges a setup fee and at least30 per user (for a university the size of Temple University: 55,000 students at $30 each = 1.6 million a semester for user fees only). As a result of a technical issue with uploading the first week lesson on this system, I had informed the class that, as an alternative means, class presentation notes and lectures will be posted on the site www.pharmaceuticalintelligence.com as a separate post and searchable on all search engines including Google, Twitter, Yahoo, Bing, Facebook etc. In addition, I had informed the students that supplemental information, from curated posts and articles from our site, would be added to the class lecture post as supplemental information they could use for further reading on the material as well as helpful information and reference for class projects. The posted material was tagged with #TUBiol3373 (university abbreviation, department, course number) and disseminated to various social media platforms using our system. This allowed the students to enter #TUBiol3373 in any search engine to easily find their lecture notes and supplemental information. This gave students access to lectures on a mobile platform which was easily discoverable due to our ability to do search engine optimization. (#TUBiol3373 was among the first search results on most popular search engines). From a technical standpoint, the ease at which posts of this nature can be made as well as the ease of including links to full articles as references as well as media has been noted. Although students seem to navigate the Canvas software with ease, they had noticed many professors have issues or problems with using this software, especially with navigating the software for their needs. LBPI’s platform is an easily updated, accessible, and extensive knowledge system which can alleviate many of these technical issues and provide the added value of incorporating media based instructional material as well as downloadable file and allow the instructor ability to expound on the presented material with commentary. In addition due to the social nature of the platform, feedback can be attained by use of curated site statistics and commentary sections as well as online surveys. Results After the first week, all 45 students used LBPI platform to access these lecture notes with 17 out of 45 continuing to refer to the site during every week (week 1-4) to the class notes. This was evident from our site statistics as well as number of downloads of the material. The students had used the #TUBIol3373 and were directed to the site mainly from search engines Google and Yahoo. In addition, students had also clicked on the links corresponding to supplemental information which I had included, from articles on our site. In addition, because of the ability to incorporate media on our site, additional information including instructional videos and interviews were included in lecture posts, and this material was easily updated on the instructor’s side. Adoption of the additional material from our site was outstanding, as many students had verbally said that the additional material was very useful in their studies. This was also evidenced by site statistics owing to the secondary clicks made from the class lecture post going to additional articles, some not even included as links on the original post. In addition, and more important, students had incorporated many of the information from the additional site articles posted and referenced in their class group projects. At end of semester a survey was emailed to each student to assess the usefulness of such a teaching strategy. Results of the polling are shown below. Results from polling of students of #TUBiol3373 “Cell Signaling & Motility” Class Do you find using a web based platform such as a site like this an easier communication platform for posting lecture notes/added information than a platform like Canvas®? (5 votes)  Answer Votes Percent Yes 2 40% Somewhat but could use some improvement 2 40% No 1 20% Did not use web site 0 0% Do you find using an open access, curated information platform like this site more useful than using multiple sources to find useful extra study/presentation materials? (6 votes)  Answer Votes Percent Yes 5 83% No 1 17% Did you use the search engine on the site (located on the top right of the home page) to find extra information on topics for your presentations/study material? (5 votes)  Answer Votes Percent Yes 4 67% No 1 17% Did not use web site 1 17% Were you able to easily find the supplemental information for each lecture on search engines like Google/Yahoo/Bing/Twitter using the hashtag #TUBiol3373? (6 votes)  Answer Votes Percent Yes I was able to find the site easily 4 67% No 1 17% Did not use a search engine to find site, went directly to site 1 17% Encountered some difficulty 0 0% Did not use the site for supplemental or class information 0 0% How did you find the supplemental material included on this site above the Powerpoint presented material for each of the lectures? (7 votes)  Answer Votes Percent Very Useful 4 57% Did not use supplemental information 2 29% Somewhat Useful 1 14% Not Useful 0 0% How many times did you use the information on this site (https://www.pharmaceuticalintelligence.com) for class/test/project preparation? (7 votes)  Answer Votes Percent Frequently 3 43% Sparingly 2 29% Occasionally 1 14% Never 1 14% Views of #TUBiol3373 lessons/posts on www.pharmaceuticalintelligence.com  Lesson/Title Total # views # views 1st day # views 2nd day % views day 1 and 2 % views after 1st 2 days Lesson 1 AND 2 Cell Signaling & Motility: Lessons, Curations and Articles of reference as supplemental information: #TUBiol3373 60 27 15 93% 45% Lesson 3 Cell Signaling And Motility: G Proteins, Signal Transduction: Curations and Articles of reference as supplemental information: #TUBiol3373 56 12 11 51% 93% Lesson 4 Cell Signaling And Motility: G Proteins, Signal Transduction: Curations and Articles of reference as supplemental information: #TUBiol3373 37 17 6 48% 31% Lesson 5 Cell Signaling And Motility: Cytoskeleton & Actin: Curations and Articles of reference as supplemental information: #TUBiol3373 13 6 2 17% 15% Lesson 8 Cell Signaling and Motility: Lesson and Supplemental Information on Cell Junctions and ECM: #TUBiol3373 16 8 2 22% 13% Lesson 9 Cell Signaling: Curations and Articles of reference as supplemental information for lecture section on WNTs: #TUBioll3373 20 10 3 28% 15% Curation of selected topics and articles on Role of G-Protein Coupled Receptors in Chronic Disease as supplemental information for #TUBiol3373 19 11 2 28% 13% Lesson 10 on Cancer, Oncogenes, and Aberrant Cell Signal Termination in Disease for #TUBiol3373 21 10 2 26% 20% Totals 247 69 46 31% 62% Note: for calculation of %views on days 1 and 2 of posting lesson and supplemental material on the journal; %views day1 and 2 = (#views day 1 + #views day 2)*100/45 {45 students in class} For calculation of %views past day 1 and 2 = (total # views – day1 views – day2 views) * 100/45 For calculation in total column last two columns were divided by # of students (45) and # of posts (8) Overall class engagement was positive with 31% of students interacting with the site during the course on the first two days after posting lessons while 61% of students interacted with the site during the rest of the duration of the course. The higher number of students interacting with the site after the first two days after lecture and posting may be due to a higher number of students using the posted material for study for the test and using material for presentation purposes. Engagement with the site for the first two days post lecture ranged from 93% engagement to 22% engagement. As the class neared the first exam engagement with the site was high however engagement was lower near the end of the class period potentially due to the last exam was a group project and not a written exam. Students appeared to engage highly with the site to get material for study for the written exam however there still was significant engagement by students for purposes of preparation for oral group projects. Possibly engagement with the site post 2 days for the later lectures could be higher if a written exam was also given towards the end of the class as well. This type of analysis allows the professor to understand the level of class engagement week by week. The results of post-class polling confirm some of the conclusions on engagement. After the final grades were given out all 45 students received an email with a link to the poll. Of the 45 students emailed, there were 20 views of the poll with 5-7 answers per question. Interestingly, most answers were positive on the site and the use of curated material for learning and a source of research project material. It was very easy finding the posts using the #classname and most students used Google to find the material, which was at the top of Google search results. Not many students used Twitter or other search engines. Some went directly to the site. A majority (71%) found the material useful or somewhat useful for their class presentations and researching topics. Read Full Post » ## eScientific Publishing a Case in Point: Evolution of Platform Architecture Methodologies and of Intellectual Property Development (Content Creation by Curation) Business Model ### eScientific Publishing a Case in Point: Evolution of Platform Architecture Methodologies and of Intellectual Property Development (Content Creation by Curation) Business Model Author: Aviva Lev- Ari, PhD, RN Six demonstrations that justify the claims made in our 2019 VISION: ### https://pharmaceuticalintelligence.com/vision/ • Point #1: Top Author, Chief Scientific Officer, MD, FCAP – share in the Journal’s archive computed • Point #2: Top authors by e-Readers per article – A Team at work • Point #3: Team members Led by Key Opinion Leader [https://lnkd.in/eEyn69r] generated Intellectual Property (IP) of Three Asset Classes • Point #4: Functions and Forms by Asset Class • Point #5: SYNERGY among the Three Asset Classes stimulates Value Creation • Point #6: Plan for Team membership augmentation and Training under existing Leadership and New Ownership ### POINT #1: Top Author, Chief Scientific Officer, a retired Chief of Pathology, LHB, MD, FCAP – share in the Journal’s archive computed Journal archive has 5,486 articles published LHB has published 1,390 articles = 25.33% – he joined our team with a publication list of +200 articles in referred academic journals. LHB is co-curator of many articles with many of the team members • The Young Surgeon and The Retired Pathologist: On Science, Medicine and HealthCare Policy– The Best Writers Among the WRITERS ### POINT #2: Top authors by e-Readers per article – A Team at work Click on this link to review the contributions of Team members who’s articles achieved >1,000 Views. • Article Title, Author/Curator’s Name and Article Views >1,000, 4/2012 – 1/2019 @pharmaceuticalintelligence.com ### POINT #3: Team members led by Key Opinion Leader (KOL) [https://lnkd.in/eEyn69r] generated Intellectual Property (IP) of Three Asset Classes ### List of LPBI IP Assets by Asset Class representing a Team Effort • IP Asset Class I: Launched Open Access Online Scientific Journal @com, 4/2012 https://lnkd.in/erfbayJ • IP Asset Class II: Launched BioMed eSeries, 16-Volumes in Life Sciences and Medicine, 10/2012 BioMed e-Series: 16 Volumes – electronic Table of Contents (eTOCs) of each Volume https://pharmaceuticalintelligence.com/2017/12/12/biomed-e-series-16-volumes-electronic-table-of-contents-of-each-volume/ Launched 6 Volumes Cardiovascular Diseases e-Series, Bundled on Amazon for$515

https://lnkd.in/e6WkMgF

Launched 10 Volumes in Medicine: Genomics 1,2  Cancer 1,2 Immunology 1,2,3  Precision Medicine 1,2,3,4

https://lnkd.in/ekWGNqA

• IP Asset Class III: Launched Real Time Press Coverage of Biotech Conferences, 3/2013

https://pharmaceuticalintelligence.com/press-coverage/

Part One: The Process of Real Time Coverage using Social Media

Part Two: List of BioTech Conferences 2013 to Present

Part Three: Conference eProceedings DELIVERABLES & Social Media Analytics

### POINT #4: FUNCTIONS and FORMS by ASSET CLASS

###### BioMed E-Series– 16 Volumes- 5 Specialties in Medicine- 6 Volumes Cardiovascular Diseases e-Series, Bundled on Amazon for $515https://lnkd.in/e6WkMgF ###### Real Time Coverage BioTech/Medicine Conferences– eProceedings- Real Time Tweets on- Two Twitter Handles- Conference Hash Tags@pharma_BI@AVIVA1950- Part Two: List of BioTech Conferences 2013 to Present ###### Editor-in-Chief’sLeadership:- Senior Editors- Our Team ###### Our Team’s Product ###### https://pharmaceuticalintelligence.com/contributors-biographies/ ###### Senior Editors’ Product with Our Team ###### https://pharmaceuticalintelligence.com/contributors-biographies/senior-editors/https://pharmaceuticalintelligence.com/contributors-biographies/ ###### Editor-in-Chief’s Initiative ###### https://lnkd.in/eEyn69r ###### Architecture Methodologies for ourPlatforms ###### · Multi-Authoring Platform – wordpress.com· Authoring Privilege levels· Categories of research forming the Journal’s Ontology, a Dynamic Relational and Hierarchical database Multi-Authoring architecture· Generation of new categories by authors developing the categories they are Owners of· Article update policy ###### · eTOCs design by Editors· e-Book Style uniformity across all eSeries· Structure of eBook Parts· Structure of Chapters· Structure of Articles· Commission of Articles Specifically for given e-Books by Editor-in-Chief· Overarching guidance for e-Books within each eSeries and across eSeries ###### · Part One: The Process of Real Time Coverage using Social Media· Methodology for Conference Coverage using Social Media: 2014 MassBio Annual Meeting 4/3 – 4/4 2014, Royal Sonesta Hotel, Cambridge, MA· Template Development Process· Channels of Social Media Development ###### Business ModelDevelopment: Content Creation by Curation of Scientific Findings ###### · Author/Curator initiated article· Article Commissions by Editor-in-Chief· Co-Curations· Research Category Ownership· e-Books Editors role defined (Job description) ###### · e-Books in Kindle Store· 30,000 Oncologists in the US· 40,000 Cardiologists in the US· All Primary Care Physicians· All Medical Schools for Curriculum development· Global market for Medical EducationALL BioMed 16 Volumes [$515+$190+$175+$190+$274 = $1,344]@Amazon BUNDLED 6 Volumes Cardiovascular Diseases for$515https://lnkd.in/e6WkMgF@Amazon UNBUNDLED 10 Volumeshttps://lnkd.in/ekWGNqA·       Genomics 1,2 ($190)· Cancer 1,2 ($175)·       Metabolomics, Immunology, Infectious Diseases 1,2,3 (#190)·       Precision Medicine 1,2,3,4 ($274) ###### · The market is defined as “All Biotech Conferences Organizers around the Globe” in need to own eProceedings for their Conferences for electronic dissemination to conference attendees.· Digital Archive of Conferences eProceedingsPart Three: Conference eProceedings DELIVERABLES & Social Media Analytics ###### IP Asset Class III ###### https://pharmaceuticalintelligence.com/press-coverage/ ###### Real Time Coverage BioTech/Medicine Conferences ###### – eProceedings ###### – Real Time Tweets on ###### – Two Twitter Handles ###### – Conference Hash Tags ###### @pharma_BI ###### @AVIVA1950 ###### – Part Two: List of BioTech Conferences 2013 to Present ###### Editor-in-Chief’s Initiative ###### https://lnkd.in/eEyn69r ###### · Part One: The Process of Real Time Coverage using Social Media ###### · Methodology for Conference Coverage using Social Media: 2014 MassBio Annual Meeting 4/3 – 4/4 2014, Royal Sonesta Hotel, Cambridge, MA ###### · Template Development Process ###### · Channels of Social Media Development ###### · The market is defined as “All Biotech Conferences Organizers around the Globe” in need to own eProceedings for their Conferences for electronic dissemination to conference attendees. ###### · Digital Archive of Conferences eProceedings ###### Part Three: Conference eProceedings DELIVERABLES & Social Media Analytics ### POINT #4 (IN DETAIL): Functions and Forms by Asset Class ### IP Asset Class I: The Journal The Methodology of Curation for Scientific Research Findings https://pharmaceuticalintelligence.com/2014/07/30/the-methodology-of-curation-for-scientific-research-findings/ >> Evolution of Platform Architecture Methodologies: • Multi-Authoring Platform – wordpress.com • Authoring Privilege levels • Categories of research forming the Journal’s Ontology, a Dynamic Relational and Hierarchical database Multi-Authoring architecture • Generation of new categories by authors developing the categories they are Owners of • Article update policy >> Intellectual Property Development (Content Creation by Curation) Business Model • Author/Curator initiated article • Article Commissions by Editor-in-Chief • Co-Curations • Research Category Ownership • e-Books Editors role defined (Job description) ### IP Asset Class II: BioMed e-Series > Evolution of Platform Architecture Methodologies Cardiovascular Original Research: Cases in Methodology Design for Content Curation and Co-Curation https://pharmaceuticalintelligence.com/2013/07/29/cardiovascular-original-research-cases-in-methodology-design-for-content-curation-and-co-curation/ • eTOCs design by Editors • e-Book Style uniformity across all eSeries • Structure of eBook Parts • Structure of Chapters • Structure of Articles • Commission of Articles Specifically for given e-Books by Editor-in-Chief • Overarching guidance for e-Books within each eSeries and across eSeries > Intellectual Property Development (Content Creation by Curation) Business Model • e-Books in Kindle Store • 30,000 Oncologists in the US • 40,000 Cardiologists in the US • US & Global markets for Cardiology, Genomics, Cancer, Immunology, Infectious Diseases, Precision Medicine • All Primary Care Physicians • All Medical Schools for Curriculum development • Global market for Medical Education ALL BioMed 16 Volumes [$515+$190+$175+$190+$274 = $1,344] @Amazon BUNDLED 6 Volumes Cardiovascular Diseases for$515 https://lnkd.in/e6WkMgF

@Amazon UNBUNDLED 10 Volumes in #Medicine https://lnkd.in/ekWGNqA

• Genomics 1,2 ($190) • Cancer 1,2 ($175)
• Metabolomics, Immunology, Infectious Diseases 1,2,3 (#190)
• Precision Medicine 1,2,3,4 ($274) Series A – Cardiovascular Diseases – 6 volumes$515

Series B – Genomics 1,2  – 2 volumes $190 • VOLUME 1: Genomics Orientations for Personalized Medicine. On comsince 11/23/2015 http://www.amazon.com/dp/B018DHBUO6 • VOLUME 2: Latest in Genomics Methodologies for Therapeutics: Gene Editing, NGS & BioInformatics, Simulations and the Genome Ontology https://pharmaceuticalintelligence.com/biomed-e-books/genomics-orientations-for-personalized-medicine/volume-two-genomics-methodologies-ngs-bioinformatics-simulations-and-the-genome-ontology/ Volume 2 is Work-in-Progress To Be Published in 6/2019 at$115

Series C – Cancer & Oncology $175 • VOLUME 1 Cancer Biology Genomics http://www.amazon.com/dp/B013RVYR2K • VOLUME 2 Therapies Genomics Interventional Immunotherapy Nanotechnology in Drug Delivery http://www.amazon.com/dp/B071VQ6YYK Series D – Metabolomics, Immunology, Infectious Diseases$190

• VOLUME 1 Metabolomics

http://www.amazon.com/dp/B012BB0ZF0

• VOLUME 2 Infectious Diseases & VOLUME 3 Immunology

https://www.amazon.com/dp/B075CXHY1B

Series E Precision Medicine – Four Volumes, Volumes 1,2,3,4 at 274 • Patients Voices https://www.amazon.com/dp/B076HGB6MZ • Physiology and Therapeutics https://www.amazon.com/dp/B078313281 • Medical Discoveries: Genomics Therapeutics http://www.amazon.com/dp/B019VH97LU • 3D #BioPrinting in Medicine for Precision Medicine https://www.amazon.com/dp/B078QVDV2W ### IP Asset Class III: Real Time Coverage of BioTech Conferences >> Evolution of Platform Architecture Methodologies https://pharmaceuticalintelligence.com/2014/04/07/methodology-for-conference-coverage-using-social-media-2014-massbio-annual-meeting-43-44-2014-royal-sonesta-hotel-cambridge-ma/ • Template Development Process • Channels of Social Media Development >> Intellectual Property Development (Content Creation by Curation) Business Model • The market is defined as “All Biotech Conferences Organizers around the Globe” in need to own eProceedings for their Conferences for electronic dissemination to conference attendees. • Digital Archive of Conferences eProceedings ### POINT #5: SYNERGY among the Three Asset Classes stimulates Value Creation • Concepts from +60 Conferences I covered yielded ~300 new articles, five new per conference, at least • Electronic Table of Contents [eTOCs] for each e-Book of the [1,2,3..,16] is derived from the Research categories of the Journal • Journal Ontology has 700 Research Categories – knowledge architecture designed by experts • Every article in the Journal is connected with Social Media Icons on wordpress.com as an engine for 1. Pingbacks 2. New eReaders 3. Scientists applying to author for the Journal 4. +7,300 Scientific comments on 5,486 articles published – AGORA Electronic Scientific AGORA: Comment Exchanges by Global Scientists on Articles published in the Open Access Journal @pharmaceuticalintelligence.com – Four Case Studies ### POINT #6: Plan for Team membership augmentation and Training under existing Leadership and New Ownership Work-in-Progress ### Other related articles published in this Open Access Online Scientific Journal include the following: Innovations in electronic Scientific Publishing (eSP): Case Studies in Marketing eContent, Curation Methodology, Categories of Research Functions, Interdisciplinary conceptual innovations by Cross Section of Categories, Exposure to Frontiers of Science by Real Time Press coverage of Scientific Conferences https://pharmaceuticalintelligence.com/2017/05/06/case-studies-of-innovations-in-electronic-scientific-publishing-esp-marketing-econtent-curation-methodology-categories-of-research-functions-interdisciplinary-conceptual-innovations-by-cross-sec/ e-Scientific Publishing: The Competitive Advantage of a Powerhouse for Curation of Scientific Findings and Methodology Development for e-Scientific Publishing – LPBI Group, A Case in Point https://pharmaceuticalintelligence.com/2017/06/20/e-scientific-publishing-the-competitive-advantage-of-a-powerhouse-for-curation-of-scientific-findings-and-methodology-development-for-e-scientific-publishing-lpbi-group-a-case-in-point/ The Methodology of Curation for Scientific Research Findings https://pharmaceuticalintelligence.com/2014/07/30/the-methodology-of-curation-for-scientific-research-findings/ @PharmaceuticalIntelligence.com – A Case Study on the LEADER in Curation of Scientific Findings https://pharmaceuticalintelligence.com/2017/06/29/pharmaceuticalintelligence-com-a-case-study-on-the-leader-in-curation-of-scientific-findings/ Curation of Scientific Content @Leaders in Pharmaceutical Business Intelligence (LPBI) Group, Boston https://pharmaceuticalintelligence.com/2016/08/15/curation-of-scientific-content-leaders-in-pharmaceutical-business-intelligence-lpbi-group-boston/ Scientific Curation Fostering Expert Networks and Open Innovation: Lessons from Clive Thompson https://pharmaceuticalintelligence.com/2014/07/17/scientific-curation-fostering-expert-networks-and-open-innovation-lessons-from-clive-thompson-and-others/ Cardiovascular Diseases and Pharmacological Therapy: Curations by Aviva Lev-Ari, PhD, RN, 2006 – 4/2018 https://pharmaceuticalintelligence.com/2014/04/17/cardiovascular-diseases-and-pharmacological-therapy-curations-by-aviva-lev-ari-phd-rn/ Methodology for Conference Coverage using Social Media: 2014 MassBio Annual Meeting 4/3 – 4/4 2014, Royal Sonesta Hotel, Cambridge, MA https://pharmaceuticalintelligence.com/2014/04/07/methodology-for-conference-coverage-using-social-media-2014-massbio-annual-meeting-43-44-2014-royal-sonesta-hotel-cambridge-ma/ Cardiovascular Original Research: Cases in Methodology Design for Content Curation and Co-Curation https://pharmaceuticalintelligence.com/2013/07/29/cardiovascular-original-research-cases-in-methodology-design-for-content-curation-and-co-curation/ Read Full Post » ## Article Title, Author/Curator’s Name and Article Views >1,000, 4/2012 – 1/2019 @pharmaceuticalintelligence.com ### Article Title, Author/Curator’s Name and Article Views >1,000, 4/2012 – 1/2019 @pharmaceuticalintelligence.com Reporter: Aviva Lev-Ari, PhD, RN  Expert, Author, Writer’s Initials Name & Bio Roles @LPBI Group LHB Larry Bernstein, MD, FACP, Member of the Board Expert, Author, Writer – All Specialties of Medicine & Pathology Content Consultant to Series B,C,D,E Editor, Series D, Vol. 1, Series E, Vols 2,3, Co-Editor – BioMed E-Series 13 of the 16 Vols JDP Justin D. Pearlman, AB, MD, ME, PhD, MA, FACC, Expert, Author, Writer, All Specialties of Medicine, Cardiology and Cardiac Imaging Content Consultant for SERIES A, Cardiovascular Diseases Co-Editor: Vols 2,3,4,5,6 ALA Aviva Lev-Ari, PhD, RN, -Ex – SRI, Int’l -Ex – MITRE -Ex – McGraw-Hill Director and Founder Editor-in-Chief, @pharmaceuticalintelligence.com Methodologies Developer: Journal Platform Architect, CURATION of Scientific Findings Modules, REALTIME eProceedings Digital 1-Click Publishing Expert, Author, Writer: Analytics Molecular Cardiology Vascular Biology TB Tilda Barliya, PhD, @BIU Expert, Author, Writer: Nanotechnology for Drug Delivery Co-Editor, Series C, Vols. 1,2 DN Dror Nir, PhD, Expert, Author, Writer: Cancer & Medical Imaging Algorithms ZR Ziv Raviv, PhD,@Technion Expert, Author, Writer: Biological Sciences, Cancer ZS Zohi Sternberg, PhD, Expert, GUEST Author, Writer Expert, GUEST Author, Writer Neurological Sciences SJW Stephen J. Williams, PhD Pharmacology, BSc Toxicology Ex-Fox Chase EAW – Cancer Biology Co-Editor, Series A, Vol.1 Co-Editor, Series B, Genomics: Vols. 1,2 Co-Editor, Series C, Cancer, Vols. 1,2 DS Demet Sag, PhD, CRA, GCP, Expert, Author, Writer: Genome Biology, Immunology, Biological Sciences: Cancer SS Sudipta Saha, PhD, Expert, Author, Writer: Reproductive Biology, Endocrinology, Bio-Instrumentation Co-Editor, Series D, Volume 2, Infectious Diseases AV Aviral Vatsa, PhD, MBBS Expert, Author, Writer: Medical Sciences, Bone Disease, Human Sensation and Cellular Transduction: Physiology and Therapeutics RS Ritu Saxena, PhD, Expert, Author, Writer: Biological Sciences, Bone Disease, Cancer (Lung, Liver) GST Gail S. 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Kaul, R.Ph., Pharm.D, M.Sc., M.B.A., FCCP, Expert, Author, Writer Ex-Director BWH Pharmacy Expert, Author, Writer: Pharmacology – all aspects of Drug development and dispensation, Policy analyst AS Anamika Sarkar, PhD, Expert, Author, Writer: Computation Biology & Bioinformatics MWF Marcus Feldman, PhD, Stanford University, Biological Sciences, Center for Genomics 751 Research items 51,402 Reads 39,126 Citations Member of the Board, Scientific Counsel: Life Sciences, Ecology Genetics Evolution Genetic Engineering Genotyping Epigenetics Population Genetics Genetic Diversity Human Evolution Cultural Evolution Human Behavioral Ecology Cultural Communication Content Consultant Series B, Genomics, Vols. 1,2 Co-Editor, Vol. 2, NGS ### Other related articles published in this Open Access Online Scientific Journal include the following: FIVE years of e-Scientific Publishing @pharmaceuticalintellicence.com, Top Articles by Author and by e-Views >1,000, 4/27/2012 to 1/29/2018 https://pharmaceuticalintelligence.com/2017/04/28/five-years-of-e-scientific-publishing-pharmaceuticalintellicence-com-top-articles-by-author-and-by-e-views-1000-4272012-to-4272017/ Read Full Post » ## Electronic Scientific AGORA: Comment Exchanges by Global Scientists on Articles published in the Open Access Journal @pharmaceuticalintelligence.com – Four Case Studies ### Electronic Scientific AGORA: Comment Exchanges by Global Scientists on Articles published in the Open Access Journal @pharmaceuticalintelligence.com – Four Case Studies Curator and Editor-in-Chief: Journal and BioMed e-Series, Aviva Lev-Ari, PhD, RN ### Introduction ### Case Study #1: 40 Responses • Is the Warburg Effect the Cause or the Effect of Cancer: A 21st Century View? Author: Larry H. Bernstein, MD, FCAP https://pharmaceuticalintelligence.com/2012/10/17/is-the-warburg-effect-the-cause-or-the-effect-of-cancer-a-21st-century-view/ ### Case Study #2: 26 Responses · Knowing the tumor’s size and location, could we target treatment to THE ROI by applying….. Author: Dror Nir, PhD https://pharmaceuticalintelligence.com/2012/10/16/knowing-the-tumors-size-and-location-could-we-target-treatment-to-the-roi-by-applying-imaging-guided-intervention/ ### Case Study #3: 24 Responses • Personalized Medicine: Cancer Cell Biology and Minimally Invasive Surgery (MIS) Curator: Aviva Lev-Ari, PhD, RN https://pharmaceuticalintelligence.com/2012/12/01/personalized-medicine-cancer-cell-biology-and-minimally-invasive-surgery-mis/ ### Case Study #4: 13 Responses • Judging the ‘Tumor response’-there is more food for thought https://pharmaceuticalintelligence.com/2012/12/04/judging-the-tumor-response-there-is-more-food-for-thought/ ### Conclusions ### Introduction Members of our Team published 5,295 articles, in the period between 4/2012 to 4/10/2018, and engaged in Comment Exchanges with Global Scientists Online. 1,412,106 eReaders had viewed our articles and 7,283 scientific comments are included in the Journal Archive. ### Team Members’ Profile Team Profile: DrugDiscovery @LPBI Group – A BioTech Start Up submitted for Funding Competition to MassChallenge Boston 2016 Accelerator In our Scientific Agora: Multi Scientific Comment exchanges between Global e-Readers Scientists and LPBI’s Scientists/Experts/Authors/Writers take place. In this curation I am presenting four articles that generated dozens of scientific comments and multifaceted exchanges. The Voice of Aviva Lev-Ari, PhD, RN: It is my strongest conviction on the merit of the following features of Global SHARING the Scientific product, aka “An Article written by a Scientist” in the Digital Scientific Publishing Age: • Every new article published in Open Access Journals contributes to mitigate the most acute challenge of the e-Scientific Publishing industry today: Information Obsolescence – the newness of findings • Every new article published in Open Access Journals contributes AND in the Subscription-based Journals contributes to the second most acute challenge of of the e-Scientific Publishing industry today: Information Explosion – the volume of findings • The Scientific Agora as presented, below, in four Case Studies is an optimal means for Global SHARING in Real Time scientific knowledge deriving from clinical expertise and lab experience of all the participants in the Agora. REAL TIME means minimization of the negative impact of the most acute challenge of of the e-Scientific Publishing industry today: Information Obsolescence • Knowledge SHARING of our Scientists articles occurs among two FORUMS: Forum One, is the Scientists that joined the comment exchanges between the Article Author and other members of our Team on a given Scientific product, aka “An Article written by a Scientist” Forum Two, is the Global Universe of Scientists that (a) are e-mail Followers opting to our Open Access Journal free subscription and (b) eReaders of our Journal that did not yet opt to follow the Journal by e-mail, a robust crowd of +1.4 Million Scientists • We mitigate the negative impact of the second most acute challenge of the e-Scientific Publishing industry today: Information Explosion by our own developed and advanced achievements reached in the practice of 1. Development of the Methodology for Curation of Scientific Findings, Curation of Scientific Content @Leaders in Pharmaceutical Business Intelligence (LPBI) Group, Boston 2. Application of the Methodology for Curation of Scientific Findings in a BioMed e-Series of 16-Volumes in Medicine and Life Sciences on Amazon.com electronic Table of Contents (eTOCs) of each Volume in the SIXTEEN Volume BioMed e-Series WE ARE ON AMAZON.COM https://www.amazon.com/s/ref=nb_sb_noss?url=search-alias%3Ddigital-text&field-keywords=Aviva+Lev-Ari&rh=n%3A133140011%2Ck%3AAviva+Lev-Ari Commentaries on each Volume’s Contribution to Medical Education by L.H. Bernstein, MD, FCAP and by Aviva Lev-Ari, PhD, RN – BioMedical e-Books e-Series: Multiple Volumes in Five e-Series https://pharmaceuticalintelligence.com/biomed-e-books/commentaries-on-each-volumes-contribution-to-medical-education-by-l-h-bernstein-md-fcap-and-aviva-lev-ari-phd-rn-biomedical-e-books-e-series-multiple-volumes-in-five-e-series/ In 2016, LPBI’s BioMed e-Series was Submitted for Nomination for 2016 COMMUNICATION AWARD FOR EXCELLENCE IN REPORTING SCIENCE, MEDICINE AND ENGINEERING – Reference #: 9076095, on 1/27/2016 https://pharmaceuticalintelligence.com/biomed-e-books/ • Lastly, It is my strong belief that the Methodology of Curation will become a major tool used in Content creation for Curriculum Development in Medical Schools, in the Life Sciences and Healthcare Allied professions. • We have pioneered and showed the way BY EXAMPLE, +5,200 Scientific products, aka “An Article written by a Scientist” constitute our Journal Archive created by content curation • More New e-Book Titles are coming in 2018-2019 in LPBI’s BioMed e-Series. • More e-Scientific Publishers will use the Methodology of Creation of electronic Table of Contents of e-Books by combing Archives by very experienced subject matter Editors. • Global SHARING of Information became best practice for Academic Course Contents in the last ten years • On-Line Degrees are spreading in many disciplines and are offered by very many colleges, including the Ivy League • Open Access Scientific Journals is the FUTURE of the e-Scientific Publishing Industry. ### Case Study #1: • ### Is the Warburg Effect the Cause or the Effect of Cancer: A 21st Century View? Author: Larry H. Bernstein, MD, FCAP https://pharmaceuticalintelligence.com/2012/10/17/is-the-warburg-effect-the-cause-or-the-effect-of-cancer-a-21st-century-view/ ### 40 Responses 1. This is OUTSTANDING. Now we need a “shortcliff” post to follow one chart that traces the dynamic process, no reader shall get lost inside any of the process boxes. 2. Really nice overview and very interesting metabolic changes. However, related to the title, the cancerous changes- event always comes first before lactate preferred metabolism comes into place. Right? 3. This is what has been inferred. So if that is the premise, then the mutation would be the first event. That position has been successfully challenged and also poses a challenge to the proper view of genomic discovery. The real event may very well be the ongoing oxidative stress with aging, and decreased physiochemical reserve. I haven’t developed the whole picture. Nitric oxide and nitrosylation contribute to both vascular relaxation and vasoconstriction, which is also different in major organs. The major carriers of H+ are NADH and FADH2. Electron transport is in the ETC in mitochondria. I called attention to the “escape” of energy in aerobic glycolysis. As disease ensues, it appears that lactate generation is preferential as the mitochondrion takes up substrate from gluconeogenesis. Whether it is an endotoxic shock or a highly malignant fast growing tumor, the body becomes trapped in “autocatabolism”. So the tumor progresses, apoptosis is suppressed, and there is a loss of lean body mass. All of this is tied to genetic instability. We see the genetic instability as first because of the model DNA–RNA–protein. We don’t have a map. 4. It is a very nice report. I did work for a short time to develop compounds to block the glucose uptake especially using glucose-mimics. I wonder is there any research on this area going on now? 5. Thanks. I have been researching this exhaustively. There are even many patents trying to damp this down. You were on the right track. The biggest problem has been multidrug resistance and tumor progression. 6. […] Is the Warburg Effect the cause or the effect of cancer: A 21st Century View? (pharmaceuticalintelligence.com) […] 7. […] Is the Warburg Effect the cause or the effect of cancer: A 21st Century View? (pharmaceuticalintelligence.com) […] 8. Martin Canizales • Warburg effect (http://www.cellsignal.com/reference/pathway/warburg_effect.html), is responsible of overactivation of the PI3K… the produced peroxide via free radicals over activate the cyclooxigenase and consequently the PI3K pathway activating there, the most important protein-kinase ever described in the last mmmh, 60-70 years? maybe… to broke the Warburg effect, will stop the PI3K activation (http://www.cellsignal.com/reference/pathway/Akt_PKB.html) then all the cancer protein related with the generation of tumor (pAKT,pP70S6K, Cyclin D1, HIF1, VEGF, EGFrc, GSK, Myc, etc, etc, etc), will get down regulation. That is what happen, when I knock down the new protein-kinase in pancreatic cancer cell lines… stable KD of pancreatic cancer cell lines divide very-very-veeeery slow (by Western blotting, cyclin D1 disapear, VEGF, HIF1a, MyC, pAKT, pP70S6K, GSK, and more and more also has, very-very few consume of glucose [diabetes and cancer]. Stable cells can be without change the media for 3 weeks and the color doesn’t change, cells divide but VERY slow and are alive [longevity]) are not able to generate xenograft tumors related, to scramble shRNA stable cell lines. When, we broke the warburg effect, the protein kinase get’s down as well all the others. Is the same, with bacteria infections…. bacteria infections, has many things to teach us about cancer and cell proliferation (http://www.ncbi.nlm.nih.gov/pubmed/22750098) 9. edit this on November 12, 2012 at 5:41 PM | Replyhijoprodigoendistancia research paper, should be ready (writing) very soon and must be submmited before end this year. Hee hee! you know… end of the world is in December 21 2012 • The emphasis on p13 and the work on pancreatic cancer is very interesting. I’ll check the references you give. The Warburg effect is still metabolic, and it looks like you are able to suppress the growth of either cancer cells or bacteria. The outstanding question is whether you can get a head start on the SIR transition to sepsis to severe sepsis to MODS, to shock. It looks like an article will be necessary after your work is accepted for publication. Thanks a lot for the response. 10. edit this on November 12, 2012 at 8:52 PM | Replyhijoprodigoendistancia Also, when this protein-kinase is over expressed… UCP1 get down..then, less mitochondria, consequently less aerobic cell functions…in adipose tissue, less mitochondria promote the differentiation of BAT (Brown Adipose Tissue) to, WAT (White Agipose Tissue). Has relation with AS160 phosphorylation, Glut4 membrane translocation, promote the GABA phosphorylation (schizophrenia-autism), neuronal differentiation (NPCs:Neural Progenitor Cells), dopaminergic cell differentiation…. 11. edit this on November 12, 2012 at 8:55 PM | Replyhijoprodigoendistancia Larry, all comments are part of the second paper. 12. […] Is the Warburg Effect the cause or the effect of cancer: A 21st Century View? […] 13. […] Is the Warburg Effect the cause or the effect of cancer: A 21st Century View? […] 14. […] Is the Warburg Effect the cause or the effect of cancer: A 21st Century View? […] 15. Larry please take a look at Gonzalez et al. The Bioenergetic theory of Carcinogenesis. Med Hypotheses 2012; 79: 433-439 and let me know your thoughts. 16. […] Is the Warburg Effect the cause or the effect of cancer: A 21st Century View? Lhb https://pharmaceuticalintelligence.com/2012/10/17/is-the-warburg-effect-the-cause-or-the-effect-of-ca… […] 17. […] The Initiation and Growth of Molecular Biology and Genomics, Part I […] 18. […] https://pharmaceuticalintelligence.com/2012/10/17/is-the-warburg-effect-the-cause-or-the-effect-of-ca… Promising New Approach To Preventing Progression Of Breast Cancer (medicalnewstoday.com) […] 19. […] Is the Warburg Effect the cause or the effect of cancer: A 21st Century View? […] 20. […] Is the Warburg Effect the cause or the effect of cancer: A 21st Century View? […] 21. […] Is the Warburg Effect the cause or the effect of cancer: A 21st Century View? […] 22. Thank you! 23. […] Is the Warburg Effect the cause or the effect of cancer: A 21st Century View? […] 24. edit this on May 22, 2013 at 11:36 PM | ReplyAashir Awan, Phd Informative article especially concerning activation of HIF under normoxic conditions. Recently, a paper has come out showing patients showing symptoms of mood disorder having increased expression of Hif1a. Also, there are reports that Hif1a is important in development of certain tissue types. 25. COLOURS AND LIFE. The basic idea of this theory is that the oxidation of hydrogen and carbon atoms, arising from the degradation of carbohydrates, is by two distinct processes based on oxidation-reduction electron transfer and photochemical process of energy release on the basis of color complementary, predominance of one or another depending on intracellular acid-base balance. I can not understand why nobody wants to do this experiment. I’m sure this assumption hides a truth. Before considering it a fiction to be checked experimentally. I would like to present a research project that concerns me for a long time that I can not experience myself. Involuntarily, after many years of searching, I have concluded that in the final biological oxidation, in addition to the oxidation-reduction electron transfer occurs photo-chemical process, accordance to the principle of color complementary energy transfer. I imagine an experiment that might be relevant (sure it can be improved). In my opinion, if this hypothesis proves true, one can control the energy metabolism of the cell by chromotherapy, as the structures involved are photosensitive and colorful. I would be very happy if this experiment were done under your leadership. Sincerely yours Dr. Viorel Bungau INNER LIGHT – LIGHT OF LIFE. CHROMOTHERAPY AND THE IMPLICATIONS IN THE METABOLISM OF THE NORMAL AND NEOPLASTIC CELL. “Chlorophyll and hemoglobin pigments of life porphyrin structure differs only in that chlorophyll is green because of magnesium atoms in the structure, and hemoglobin in red because of iron atoms in the structure. This is evidence of the common origin of life.” (Heilmeyer) We propose an experiment to prove that the final biological oxidation, in addition to its oxidation-reduction, with formation of H2O and CO2, there is a photochemical effect, by which energy is transferred from the H atom, or C, process is done selct, the colors, complementary colors on the basis of the structures involved are colored (red hemoglobin Fe, Mg chlorophyll green, blue ceruloplasmin Cu, Fe cytochrome oxidase red, green cytochrome oxidase with Cu etc.). The basic idea is that if life pigments (chlorophyll, hemoglobin, cytochromes), which provides energy metabolism of the cell, are colored, we can control their activities through chromotherapy, on the basis of complementary color and energy rebalance the body, with a figured X- body-colored-ray. In my opinion, at the basis of malign transformation is a disturbance of energetical metabolism, which reached a level that cell can not correct (after having succeeded before, many times), disturbance that affects the whole body in different degrees and requires corection from outside starting from the ideea that the final biological oxidizing takes place through photochemical process with releasing and receieving energy. “Duality of cytochrome oxidase. Proliferation (growth) and Differentiation (maturation) cell.” Cytochrome oxidase is present in two forms, depending on the context of acid-base internal environment : 1.- Form acidic (acidosis), which contains two Iron atoms, will be red, will absorb the additional green energy of the hydrogen atom, derived from carbohydrates, with formation of H2O, metabolic context that will promote cell proliferation. 2.-Form alkaline (alkalosis), containing two copper atoms, will be green, will absorb the additional red energy of the carbon atom, derived from carbohydrates, with formation of CO2, metabolic context that will promote cell differentiation. Cytochrome oxidase structure has two atoms of copper. It is known that in conditions of acidosis (oxidative potential), the principle electronegativity metals, copper is removed from combinations of the Iron. So cytochrome oxidase will contain two atoms of iron instead of copper atoms, which changes its oxidation-reduction potential, but (most important), and color. If the copper was green, the iron is red, which radically change its absorption spectrum, based on the principle of complementary colors. “Inner Light- Light of Life. Endogenous monochromatic irradiation. Red ferment of Warburg – Green ferment of Warburg.” In my opinion, at the basis of malign transformation is a disturbance of energetical metabolism, which reached a level that cell can not correct (after having succeeded before, many times), disturbance that affects the whole body in different degrees and requires corection from outside starting from the ideea that the final biological oxidizing takes place through photochemical process with releasing and receieving energy. If the structures involved in biological oxidation finals are colored, then their energy absorption is made based on the principle of complementary colors. If we can determine the absorption spectrum at different levels, we can control energy metabolism by chromotherapy – EXOGENOUS MONOCHROMATIC IRRADIATION . Energy absorption in biological oxidation process itself, based on complementary colors, the structures involved (cytochromes), is the nature of porphyrins, in combination with a metal becomes colored, will absorb the complementary color, corresponding to a specific absorption spectrum, it will be in – ENDOGENOUS MONOCHROMATIC IRRADIATION. This entitles us to believe that: In photosynthesis, light absorption and its storage form of carbohydrates, are selected, the colors, as in cellular energy metabolism, absorption of energy by the degradation of carbohydrates, is also done selectively, based on complementary colors. In the final biological oxidation, in addition to an oxidation-reduction process takes place and a photo-chemical process,based on complementary colors, the first in the electron transfer, the second in the energy transfer. So, in the mitochondria is a process of oxidation of atoms C and H, derived from carbohydrates, with energy release and absorption of its selection (the color), by the structures involved, which is the nature of porphyrins, are photosensitive and colorful, if we accept as coenzymes involved, containing a metal atom gives them a certain color, depending on the state of oxidation or reduction (red ferment of Warburg with iron, all copper cerloplasmin blue, green chlorophyll magnesium, red iron hemoglobin, green cytochrome oxidase with copper, etc.) According to the principle electronegativity metals, under certain conditions the acid-base imbalance (acidosis), iron will replace copper in combination , cytocromoxidase became inactive, leading to changing oxidation-reduction potential, BUT THE COLOR FROM GREEN, TO REED, to block the final biological oxidation and the appearance of aerobic glycolysis. In connection with my research proposal, to prove that the final biological oxidation, in addition to an oxidation-reduction process takes place and a photo-chemical process, the first in the electron transfer, the second in the energy transfer. I SUGGEST TO YOU AN EXPERIMENT: TWO PLANTS, A RED (CORAILLE) LIGHT ONLY, IN BASIC MEDIUM, WITH ADDED COPPER, WILL GROW, FLOWER AND FRUIT WILL SHORT TIME, AND THE OTHER ONLY GREEN LIGHT (TOURQUOISE), IN AN ACID MEDIUM, WITH ADDED COPPER CHELATOR , WHICH GROWS THROUGHOUT WILL NOT GROW FLOWERS AND FRUIT WILL DO. CULTURE OF NEOPLASTIC TISSUE, IRRADIATED WITH MONOCHROMATIC GREEN ( TOURQUOISE) LIGHT, IN AN ALKALINE MEDIUM, WITH ADDED COPPER, WILL IN REGRESSION OF THE TISSUE CULTURE. CULTURE OF NEOPLASTIC TISSUE, IRRADIATED WITH RED ( CORAILLE) LIGHT, IN AN ACID MEDIUM, WITH ADDED COPPER CHELATOR, WILL LEAD TO EXAGERATED AND ANARCHICAL MULTIPLICATION. If in photosynthesis is the direct effect of monochromatic irradiation, in the final biological oxidation effect is reversed. Exogenous irradiation with green, induces endogenous irradiation with red, and vice versa. A body with cancer disease will become chemically color “red”- Acid -(pH, Rh, pCO2, alkaline reserve), and in terms of energy, green (X-body-colored-ray). A healthy body will become chemically color “green”-Alkaline – (as evidenced by laboratory), and in terms of energy, red (visible by X-body-colored-ray). Sincerely, Dr. Viorel Bungau -In addition- “Life balance: Darkness and Light – Water and Fire – Inn and Yang.” Cytochrome oxidase structure has two atoms of copper. It is known that in conditions of acidosis (oxidative potential), the principle electronegativity metals, copper is removed from combinations of the Iron. So cytochrome oxidase will contain two atoms of iron instead of copper atoms, which changes its oxidation-reduction potential, but (most important), and color. If the copper was green, the iron is red, which radically change its absorption spectrum, based on the principle of complementary colors. If neoplastic cells, because acidosis is overactive acid form of cytochrome oxidase (red with iron atoms), which will absorb the additional green energy hydrogen atom (exclusively), the production of H20 , so water will prevail, in Schizophrenia , neuronal intracellular alkaline environment, will promote the basic form of cytochrome oxidase (green with copper atoms), which will oxidize only carbon atoms, the energy absorption of red (complementary) and production of CO2, so the fire will prevail. Drawn from this theory interdependent relationship between water and fire, of hydrogen(H2O) and carbon(CO2) ,in a controlled relationship with oxygen (O2). If photosynthesis is a process of reducing carbon oxide(CO2) and hydrogen oxide(H2O), by increasing electronegativity of C and H atoms, with the electrons back to oxygen, which will be released in the mitochondria is a process of oxidation of atoms C and H, derived from carbohydrates, with energy release and absorption of its selection (the color), by the structures involved, which is the nature of porphyrins, are photosensitive and colorful. It means that matter and energy in the universe are found in a relationship based on complementary colors, each color of energy, corresponding with a certain chemical structure. In my opinion, at the basis of malign transformation is a disturbance of energetical metabolism, which reached a level that cell can not correct (after having succeeded before, many times), disturbance that affects the whole body in different degrees and requires corection from outside starting from the ideea that the final biological oxidizing takes place through photochemical process with releasing and receieving energy. The final biological oxidation is achieved through a process of oxidation-reduction, while a photochemical process, based on the principle of complementary colors, if we accept as coenzymes involved, containing a metal atom gives them a certain color, depending on the state of oxidation or reduction (red ferment of Warburg with copper, all copper cerloplasmin blue, green chlorophyll magnesium, red iron hemoglobin,etc. If satisfied, the final biological oxidation is achieved by a photochemical mechanism (besides the oxidation-reduction), that energy is released based on complementary colors, means that we can control the final biological oxidation mechanism, irreversibly disrupted in cancer, by chromotherapy and correction of acid-base imbalance that underlies this disorder.We reached this conclusions studying the final biological oxidation, for understanding the biochemical mechanism of aerobic glycolysis in cancer. We found that cancer cell, energy metabolism is almost exclusively on hydrogen by oxidative dehydrogenation, due to excessive acidosis , coenzymes which makes carbon oxidation, as dormant (these coenzymes have become inactive). If we accept the nature of these coenzymes chloride (see Warburg ferment red), could be rectivate, by correcting acidosis (because that became leucoderivat), and by chromoterapie, on the basis of complementary colors. According to the principle electronegativity metals, under certain conditions the acid-base imbalance (acidosis), iron will replace copper in combination , cytocromoxidase became inactive (it contains two copper atoms) leading to changing oxidation-reduction potential, BUT THE COLOR FROM GREEN, TO REED, to block the final biological oxidation and the appearance of aerobic glycolysis. Malignant transformation occurs by energy metabolism imbalance in power generation purposes in the predominantly (exclusively) of the hydrogen atom of carbon oxidation is impossible. Thus at the cellular level will produce a multiplication (growth) exaggerated (exclusive), energy from hydrogen favoring growth, multiplication, at the expense of differentiation (maturation). Differentiation is achieved by energy obtained by oxidation of the carbon atom can not take, leading to carcinogenesis . The energy metabolism of the cell, an energy source is carbohydrate degradation, which is done by OXIDATIVE DEHYDROGENATION AND OXIDATIVE DECARBOXYLATION , to obtain energy and CO2 and H2O. In normal cells there is a balance between the two energy sources. If cancer cells, oxidation of the carbon atom is not possible, the cell being forced to summarize the only energy source available, of hydrogen. This disorder underlying malignant transformation of cells and affect the whole body, in various degrees, often managing to rebalance process, until at some point it becomes irreversible. The exclusive production of hydrogen energy will cause excessive multiplication, of immature cells, without functional differentiation. Exclusive carbon energy production will lead to hyperdifferentiation, hyperfunctional, multiplication is impossible. Normal cell is between two extremes, between some limits depending on the adjustment factors of homeostasis. Energy from energy metabolism is vital for cell (body). If the energy comes predominantly (or exclusively) by oxidation of the hydrogen atom, green energy, will occur at the structural level (biochemical), acidification of the cellular structures that will turn red, so WE HAVE MORPHOLOGICAL AND CHEMICAL STRUCTURES “RED”, WITH “GREEN” ENERGY. This background predisposes to accelerated growth, without differentiation, reaching up uncontrolled, anarchical. ENERGY STRUCTURE OF THE CELL BODY WOULD BE INN. If necessary energy cell derived mainly by oxidation of the carbon atom, red energy,cell structures will be colored green, will be alkaline(basic), so WE HAVE MORPHOLOGICAL AND CHEMICAL STRUCTURES “GREEN”, WITH “RED” ENERGY, on the same principle of complementarity. This context will lead hyperdifferentiation, hyperfunctional ,maturation, and grouth stops. ENERGY STRUCTURE OF THE CELL BODY WOULD BE YANG. If in photosynthesis, porphyrins chemicals group, whic be photosensitivity (their first feature), shows and a great affinity for metals with chelate forming and becoming colored (pigments of life), can absorb monochromatic light complementary, so if these pigments, which constitutes the group of chromoprotheine, in photosynthesis will achieve CO2 and H2O reduction the recovery of C, H respectively, and the issuance of and release of O, atoms as H and C that reduced the energy load, representing carbohydrates, is in the form of solar energy storage, in cellular energy metabolism, processes necessary life, energy will come from the degradation of substances produced in photosynthesis, the carbohydrates, by oxidative dehydrogenation and oxidative decarboxylation, through like substances, which form chelates with the metals, are colored, metals contained in the form of oxides of various colors(green Mg, red Fe, blue Cu,etc.),suffering from complementary color absorption process of reduction with H in case,if the oxidative dehydrogenation, when chelated metal pigment is red, becoming leucoderivat (colorless) by absorbing complementary color (green) of hydrogen, formation of H2O, or C, if the oxidative decarboxylation when chelated metallic pigment is green, energy absorbing additional, red energy of atom C, CO2 production, the process is identical. The process that lies at base cellular energy metabolism, takes place in the final biological oxidation, reducing the O atom in the form of metal oxide, in combination with photosensitive substance, porohyrin, colorful,absorbing complementary color, will reduce the O atom, with H and C, with the production of H2O and CO2. Green energy release of H atom in the oxidative dehydrogenation process, it is a process of”IRRADIATION MONOCHROMATIC ENDOGENOUS WITH GREEN”, and red energy release of C atom in the oxidative decarboxylation process, consists in an “IRRADIATION MONOCHROMATIC ENDOGENOUS WITH RED”. Porphyrin-metal combination in photosynthesis, the chelated form, by absorbing light in the visible spectrum, will be able to reduce to low and turn, C and H respectively, the state of oxide (CO2 and H2O),release of O. The final biological oxidation, the combination of metal-porphyrins in aerobically in the absence of light, will find in the oxidized state, so in the form of porphyrins and metal-oxide, will oxidize to C and H atom of hydrocarbonates, with formation of CO2 and H2O, or rather, will be reduced by C and H atom of hydrocarbonates,formation of CO2 and H2O, by absorbing energy produced by photosynthesis. If we can control the final biological oxidation, we can control cellular growth, thus multiplying, and on the other hand, maturation, so differentiation. Green energy will prevail if the cell (body) which multiplies (during growth), will in case of adult cell (functional) will prevail red energy . The two types of energy, that obtained by oxidative dehydrogenation , which will cause cell multiplication without differentiation , and that obtained by oxidative decarboxylation , which will be to stop proliferation, and will determine the differentiation (maturity, functionality). This process is carried out based on complementary colors, which are coenzymes oxidative dehydrogenation and oxidative decarboxylation is colored . It reveals the importance of acid-base balance, the predominance of the acidic or basic, as an acid structure (red), not only can gain energy from the carbon atom red (the principle of complementarity), but can not assimilate ( under the same principle). It must therefore acid-base balance of internal environment, and alkalinization his intake of organic substances by the electron donor. By alkalinization (addition of electrons) will occur neutralize acid structures, the red, they become leucoderivat, colorless, and inactive, while the basic, which because of acidosis became neutral, colorless and inactive, will be alkaline in electron contribution, will be in green, and will absorb red energy from the carbon atom. So, on two kinds of vital energy, it is clear correlation between the chemical structure of the cell(body),and type of energy that can produce and use. Thus a cell with acidic chemical structure, can produce only energy by oxidative dehydrogenation (green energy), because the acid can only be active coenzymes with acid chemical structure, red, will absorb the complementarity only green energy of hydrogen. Basic structures which should absorb red energy from carbon , are inactive due to acid environment, which in turn chemically in leucoderivat, so colorless structures, inactive. Conversion of these structures to normal, operation by alkalinization could be a long lasting process, therefore, we use parallel chromotherapy, based on the fact that these COENZYMES INVOLVED IN BIOLOGICAL OXIDATION FINALS ARE COLORED AND PHOTOSENSITIVE. Thus, exogenous irradiation with monochromatic green will neutralize, by complementarity, coenzymes red, acidic. In will reactivate alkaline coenzymes, which have become due acidosis leucoderivat, so colorless and inactive. Without producing CO2, carbonic anhydrase can not form H2CO3, severable and thus transferred through mitochondrial membrane. Will accumulate in the respiratory Flavin, OH groups, leading to excessive hydroxylation, followed by consecutive inclusion of amino (NH2). It is thus an imbalance between the hydrogenation-carboxylation and hydroxylation-amination, in favor of the latter. This will predominate AMINATION and HYDROXYLATION at the expense CARBOXYLATION and HYDROGENATION, leading to CONVERSION OF STRUCTURAL PROTEINS IN NUCLEIC ACIDS. Meanwhile, after chemical criteria not genetic, it synthesizes the remaining unoxidized carbon atoms, nucleic bases “de novo” by the same process of hydroxylation-amination, leading to THE SYNTHESIS OF NUCLEIC ACIDS “DE NOVO”. Sincerely yours, Dr. Viorel Bungau viorelbungau20@yahoo.com • Dr. Viorel Bungau, Your comment is beautiful, clorful, insightful, magestic. This article has drawn 3007 views Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec Total 2012 242 362 247 851 2013 283 330 465 390 288 208 187 164 255 274 163 3,007 26. Dear Mr. Professor, Please join me in this research proposal, as leader, because I can not go alone. The basic idea of this theory is that the oxidation of hydrogen and carbon atoms, arising from the degradation of carbohydrates, is by two distinct processes based on oxidation-reduction electron transfer and photochemical process of energy release on the basis of color complementary, predominance of one or another depending on intracellular acid-base balance. I can not understand why nobody wants to do this experiment. I’m sure this assumption hides a truth. Before considering it a fiction to be checked experimentally. I would like to present a research project that concerns me for a long time that I can not experience myself. Involuntarily, after many years of searching, I have concluded that in the final biological oxidation, in addition to the oxidation-reduction electron transfer occurs photo-chemical process, accordance to the principle of color complementary energy transfer. I imagine an experiment that might be relevant (sure it can be improved). In my opinion, if this hypothesis proves true, one can control the energy metabolism of the cell by chromotherapy, as the structures involved are photosensitive and colorful. I would be very happy if this experiment were done under your leadership. Sincerely yours, Dr. Viorel Bungau INNER LIGHT – LIGHT OF LIFE. CHROMOTHERAPY AND THE IMPLICATIONS IN THE METABOLISM OF THE NORMAL AND NEOPLASTIC CELL. “Chlorophyll and hemoglobin pigments of life porphyrin structure differs only in that chlorophyll is green because of magnesium atoms in the structure, and hemoglobin in red because of iron atoms in the structure. This is evidence of the common origin of life.” (Heilmeyer) We propose an experiment to prove that the final biological oxidation, in addition to its oxidation-reduction, with formation of H2O and CO2, there is a photochemical effect, by which energy is transferred from the H atom, or C, process is done selct, the colors, complementary colors on the basis of the structures involved are colored (red hemoglobin Fe, Mg chlorophyll green, blue ceruloplasmin Cu, Fe cytochrome oxidase red, green cytochrome oxidase with Cu etc.). The basic idea is that if life pigments (chlorophyll, hemoglobin, cytochromes), which provides energy metabolism of the cell, are colored, we can control their activities through chromotherapy, on the basis of complementary color and energy rebalance the body, with a figured X- body-colored-ray. In my opinion, at the basis of malign transformation is a disturbance of energetical metabolism, which reached a level that cell can not correct (after having succeeded before, many times), disturbance that affects the whole body in different degrees and requires corection from outside starting from the ideea that the final biological oxidizing takes place through photochemical process with releasing and receieving energy. “Duality of cytochrome oxidase. Proliferation (growth) and Differentiation (maturation) cell.” Cytochrome oxidase is present in two forms, depending on the context of acid-base internal environment : 1.- Form acidic (acidosis), which contains two Iron atoms, will be red, will absorb the additional green energy of the hydrogen atom, derived from carbohydrates, with formation of H2O, metabolic context that will promote cell proliferation. 2.-Form alkaline (alkalosis), containing two copper atoms, will be green, will absorb the additional red energy of the carbon atom, derived from carbohydrates, with formation of CO2, metabolic context that will promote cell differentiation. Cytochrome oxidase structure has two atoms of copper. It is known that in conditions of acidosis (oxidative potential), the principle electronegativity metals, copper is removed from combinations of the Iron. So cytochrome oxidase will contain two atoms of iron instead of copper atoms, which changes its oxidation-reduction potential, but (most important), and color. If the copper was green, the iron is red, which radically change its absorption spectrum, based on the principle of complementary colors. “Inner Light- Light of Life. Endogenous monochromatic irradiation. Red ferment of Warburg – Green ferment of Warburg.” In my opinion, at the basis of malign transformation is a disturbance of energetical metabolism, which reached a level that cell can not correct (after having succeeded before, many times), disturbance that affects the whole body in different degrees and requires corection from outside starting from the ideea that the final biological oxidizing takes place through photochemical process with releasing and receieving energy. If the structures involved in biological oxidation finals are colored, then their energy absorption is made based on the principle of complementary colors. If we can determine the absorption spectrum at different levels, we can control energy metabolism by chromotherapy – EXOGENOUS MONOCHROMATIC IRRADIATION . Energy absorption in biological oxidation process itself, based on complementary colors, the structures involved (cytochromes), is the nature of porphyrins, in combination with a metal becomes colored, will absorb the complementary color, corresponding to a specific absorption spectrum, it will be in – ENDOGENOUS MONOCHROMATIC IRRADIATION. This entitles us to believe that: In photosynthesis, light absorption and its storage form of carbohydrates, are selected, the colors, as in cellular energy metabolism, absorption of energy by the degradation of carbohydrates, is also done selectively, based on complementary colors. In the final biological oxidation, in addition to an oxidation-reduction process takes place and a photo-chemical process,based on complementary colors, the first in the electron transfer, the second in the energy transfer. So, in the mitochondria is a process of oxidation of atoms C and H, derived from carbohydrates, with energy release and absorption of its selection (the color), by the structures involved, which is the nature of porphyrins, are photosensitive and colorful, if we accept as coenzymes involved, containing a metal atom gives them a certain color, depending on the state of oxidation or reduction (red ferment of Warburg with iron, all copper cerloplasmin blue, green chlorophyll magnesium, red iron hemoglobin, green cytochrome oxidase with copper, etc.) According to the principle electronegativity metals, under certain conditions the acid-base imbalance (acidosis), iron will replace copper in combination , cytocromoxidase became inactive, leading to changing oxidation-reduction potential, BUT THE COLOR FROM GREEN, TO REED, to block the final biological oxidation and the appearance of aerobic glycolysis. In connection with my research proposal, to prove that the final biological oxidation, in addition to an oxidation-reduction process takes place and a photo-chemical process, the first in the electron transfer, the second in the energy transfer. I SUGGEST TO YOU AN EXPERIMENT: TWO PLANTS, A RED (CORAILLE) LIGHT ONLY, IN BASIC MEDIUM, WITH ADDED COPPER, WILL GROW, FLOWER AND FRUIT WILL SHORT TIME, AND THE OTHER ONLY GREEN LIGHT (TOURQUOISE), IN AN ACID MEDIUM, WITH ADDED COPPER CHELATOR , WHICH GROWS THROUGHOUT WILL NOT GROW FLOWERS AND FRUIT WILL DO. CULTURE OF NEOPLASTIC TISSUE, IRRADIATED WITH MONOCHROMATIC GREEN ( TOURQUOISE) LIGHT, IN AN ALKALINE MEDIUM, WITH ADDED COPPER, WILL IN REGRESSION OF THE TISSUE CULTURE. CULTURE OF NEOPLASTIC TISSUE, IRRADIATED WITH RED ( CORAILLE) LIGHT, IN AN ACID MEDIUM, WITH ADDED COPPER CHELATOR, WILL LEAD TO EXAGERATED AND ANARCHICAL MULTIPLICATION. If in photosynthesis is the direct effect of monochromatic irradiation, in the final biological oxidation effect is reversed. Exogenous irradiation with green, induces endogenous irradiation with red, and vice versa. A body with cancer disease will become chemically color “red”- Acid -(pH, Rh, pCO2, alkaline reserve), and in terms of energy, green (X-body-colored-ray). A healthy body will become chemically color “green”-Alkaline – (as evidenced by laboratory), and in terms of energy, red (visible by X-body-colored-ray). Sincerely yours, Dr. Viorel Bungau -In addition- Life balance: Darkness and Light – Water and Fire – Inn and Yang. Cytochrome oxidase structure has two atoms of copper. It is known that in conditions of acidosis (oxidative potential), the principle electronegativity metals, copper is removed from combinations of the Iron. So cytochrome oxidase will contain two atoms of iron instead of copper atoms, which changes its oxidation-reduction potential, but (most important), and color. If the copper was green, the iron is red, which radically change its absorption spectrum, based on the principle of complementary colors. If neoplastic cells, because acidosis is overactive acid form of cytochrome oxidase (red with iron atoms), which will absorb the additional green energy hydrogen atom (exclusively), the production of H20 , so water will prevail, in Schizophrenia , neuronal intracellular alkaline environment, will promote the basic form of cytochrome oxidase (green with copper atoms), which will oxidize only carbon atoms, the energy absorption of red (complementary) and production of CO2, so the fire will prevail. Drawn from this theory interdependent relationship between water and fire, of hydrogen(H2O) and carbon(CO2) ,in a controlled relationship with oxygen (O2). If photosynthesis is a process of reducing carbon oxide(CO2) and hydrogen oxide(H2O), by increasing electronegativity of C and H atoms, with the electrons back to oxygen, which will be released in the mitochondria is a process of oxidation of atoms C and H, derived from carbohydrates, with energy release and absorption of its selection (the color), by the structures involved, which is the nature of porphyrins, are photosensitive and colorful. It means that matter and energy in the universe are found in a relationship based on complementary colors, each color of energy, corresponding with a certain chemical structure. In my opinion, at the basis of malign transformation is a disturbance of energetical metabolism, which reached a level that cell can not correct (after having succeeded before, many times), disturbance that affects the whole body in different degrees and requires corection from outside starting from the ideea that the final biological oxidizing takes place through photochemical process with releasing and receieving energy. The final biological oxidation is achieved through a process of oxidation-reduction, while a photochemical process, based on the principle of complementary colors, if we accept as coenzymes involved, containing a metal atom gives them a certain color, depending on the state of oxidation or reduction (red ferment of Warburg with copper, all copper cerloplasmin blue, green chlorophyll magnesium, red iron hemoglobin,etc. If satisfied, the final biological oxidation is achieved by a photochemical mechanism (besides the oxidation-reduction), that energy is released based on complementary colors, means that we can control the final biological oxidation mechanism, irreversibly disrupted in cancer, by chromotherapy and correction of acid-base imbalance that underlies this disorder.We reached this conclusions studying the final biological oxidation, for understanding the biochemical mechanism of aerobic glycolysis in cancer. We found that cancer cell, energy metabolism is almost exclusively on hydrogen by oxidative dehydrogenation, due to excessive acidosis , coenzymes which makes carbon oxidation, as dormant (these coenzymes have become inactive). If we accept the nature of these coenzymes chloride (see Warburg ferment red), could be rectivate, by correcting acidosis (because that became leucoderivat), and by chromoterapie, on the basis of complementary colors. According to the principle electronegativity metals, under certain conditions the acid-base imbalance (acidosis), iron will replace copper in combination , cytocromoxidase became inactive (it contains two copper atoms) leading to changing oxidation-reduction potential, BUT THE COLOR FROM GREEN, TO REED, to block the final biological oxidation and the appearance of aerobic glycolysis. Malignant transformation occurs by energy metabolism imbalance in power generation purposes in the predominantly (exclusively) of the hydrogen atom of carbon oxidation is impossible. Thus at the cellular level will produce a multiplication (growth) exaggerated (exclusive), energy from hydrogen favoring growth, multiplication, at the expense of differentiation (maturation). Differentiation is achieved by energy obtained by oxidation of the carbon atom can not take, leading to carcinogenesis . The energy metabolism of the cell, an energy source is carbohydrate degradation, which is done by OXIDATIVE DEHYDROGENATION AND OXIDATIVE DECARBOXYLATION , to obtain energy and CO2 and H2O. In normal cells there is a balance between the two energy sources. If cancer cells, oxidation of the carbon atom is not possible, the cell being forced to summarize the only energy source available, of hydrogen. This disorder underlying malignant transformation of cells and affect the whole body, in various degrees, often managing to rebalance process, until at some point it becomes irreversible. The exclusive production of hydrogen energy will cause excessive multiplication, of immature cells, without functional differentiation. Exclusive carbon energy production will lead to hyperdifferentiation, hyperfunctional, multiplication is impossible. Normal cell is between two extremes, between some limits depending on the adjustment factors of homeostasis. Energy from energy metabolism is vital for cell (body). If the energy comes predominantly (or exclusively) by oxidation of the hydrogen atom, green energy, will occur at the structural level (biochemical), acidification of the cellular structures that will turn red, so WE HAVE MORPHOLOGICAL AND CHEMICAL STRUCTURES “RED”, WITH “GREEN” ENERGY. This background predisposes to accelerated growth, without differentiation, reaching up uncontrolled, anarchical. ENERGY STRUCTURE OF THE CELL BODY WOULD BE INN. If necessary energy cell derived mainly by oxidation of the carbon atom, red energy,cell structures will be colored green, will be alkaline(basic), so WE HAVE MORPHOLOGICAL AND CHEMICAL STRUCTURES “GREEN”, WITH “RED” ENERGY, on the same principle of complementarity. This context will lead hyperdifferentiation, hyperfunctional ,maturation, and grouth stops. ENERGY STRUCTURE OF THE CELL BODY WOULD BE YANG. If in photosynthesis, porphyrins chemicals group, whic be photosensitivity (their first feature), shows and a great affinity for metals with chelate forming and becoming colored (pigments of life), can absorb monochromatic light complementary, so if these pigments, which constitutes the group of chromoprotheine, in photosynthesis will achieve CO2 and H2O reduction the recovery of C, H respectively, and the issuance of and release of O, atoms as H and C that reduced the energy load, representing carbohydrates, is in the form of solar energy storage, in cellular energy metabolism, processes necessary life, energy will come from the degradation of substances produced in photosynthesis, the carbohydrates, by oxidative dehydrogenation and oxidative decarboxylation, through like substances, which form chelates with the metals, are colored, metals contained in the form of oxides of various colors(green Mg, red Fe, blue Cu,etc.),suffering from complementary color absorption process of reduction with H in case,if the oxidative dehydrogenation, when chelated metal pigment is red, becoming leucoderivat (colorless) by absorbing complementary color (green) of hydrogen, formation of H2O, or C, if the oxidative decarboxylation when chelated metallic pigment is green, energy absorbing additional, red energy of atom C, CO2 production, the process is identical. The process that lies at base cellular energy metabolism, takes place in the final biological oxidation, reducing the O atom in the form of metal oxide, in combination with photosensitive substance, porohyrin, colorful,absorbing complementary color, will reduce the O atom, with H and C, with the production of H2O and CO2. Green energy release of H atom in the oxidative dehydrogenation process, it is a process of”IRRADIATION MONOCHROMATIC ENDOGENOUS WITH GREEN”, and red energy release of C atom in the oxidative decarboxylation process, consists in an “IRRADIATION MONOCHROMATIC ENDOGENOUS WITH RED”. Porphyrin-metal combination in photosynthesis, the chelated form, by absorbing light in the visible spectrum, will be able to reduce to low and turn, C and H respectively, the state of oxide (CO2 and H2O),release of O. The final biological oxidation, the combination of metal-porphyrins in aerobically in the absence of light, will find in the oxidized state, so in the form of porphyrins and metal-oxide, will oxidize to C and H atom of hydrocarbonates, with formation of CO2 and H2O, or rather, will be reduced by C and H atom of hydrocarbonates,formation of CO2 and H2O, by absorbing energy produced by photosynthesis. If we can control the final biological oxidation, we can control cellular growth, thus multiplying, and on the other hand, maturation, so differentiation. Green energy will prevail if the cell (body) which multiplies (during growth), will in case of adult cell (functional) will prevail red energy . The two types of energy, that obtained by oxidative dehydrogenation , which will cause cell multiplication without differentiation , and that obtained by oxidative decarboxylation , which will be to stop proliferation, and will determine the differentiation (maturity, functionality). This process is carried out based on complementary colors, which are coenzymes oxidative dehydrogenation and oxidative decarboxylation is colored . It reveals the importance of acid-base balance, the predominance of the acidic or basic, as an acid structure (red), not only can gain energy from the carbon atom red (the principle of complementarity), but can not assimilate ( under the same principle). It must therefore acid-base balance of internal environment, and alkalinization his intake of organic substances by the electron donor. By alkalinization (addition of electrons) will occur neutralize acid structures, the red, they become leucoderivat, colorless, and inactive, while the basic, which because of acidosis became neutral, colorless and inactive, will be alkaline in electron contribution, will be in green, and will absorb red energy from the carbon atom. So, on two kinds of vital energy, it is clear correlation between the chemical structure of the cell(body),and type of energy that can produce and use. Thus a cell with acidic chemical structure, can produce only energy by oxidative dehydrogenation (green energy), because the acid can only be active coenzymes with acid chemical structure, red, will absorb the complementarity only green energy of hydrogen. Basic structures which should absorb red energy from carbon , are inactive due to acid environment, which in turn chemically in leucoderivat, so colorless structures, inactive. Conversion of these structures to normal, operation by alkalinization could be a long lasting process, therefore, we use parallel chromotherapy, based on the fact that these COENZYMES INVOLVED IN BIOLOGICAL OXIDATION FINALS ARE COLORED AND PHOTOSENSITIVE. Thus, exogenous irradiation with monochromatic green will neutralize, by complementarity, coenzymes red, acidic. In will reactivate alkaline coenzymes, which have become due acidosis leucoderivat, so colorless and inactive. Without producing CO2, carbonic anhydrase can not form H2CO3, severable and thus transferred through mitochondrial membrane. Will accumulate in the respiratory Flavin, OH groups, leading to excessive hydroxylation, followed by consecutive inclusion of amino (NH2). It is thus an imbalance between the hydrogenation-carboxylation and hydroxylation-amination, in favor of the latter. This will predominate AMINATION and HYDROXYLATION at the expense CARBOXYLATION and HYDROGENATION, leading to CONVERSION OF STRUCTURAL PROTEINS IN NUCLEIC ACIDS. Meanwhile, after chemical criteria not genetic, it synthesizes the remaining unoxidized carbon atoms, nucleic bases “de novo” by the same process of hydroxylation-amination, leading to THE SYNTHESIS OF NUCLEIC ACIDS “DE NOVO”. Sincerely yours, Dr. Viorel Bungau viorelbungau20@yahoo.com 27. […] Is the Warburg Effect the Cause or the Effect of Cancer: A 21st Century View? Author: Larry H. Bernstein, MD, FCAP https://pharmaceuticalintelligence.com/2012/10/17/is-the-warburg-effect-the-cause-or-the-effect-of-ca&#8230; […] ### Case Study #2: ### · Knowing the tumor’s size and location, could we target treatment to THE ROI by applying….. Author: Dror Nir, PhD https://pharmaceuticalintelligence.com/2012/10/16/knowing-the-tumors-size-and-location-could-we-target-treatment-to-the-roi-by-applying-imaging-guided-intervention/ ### 26 Responses 1. GREAT work. I’ll read and comment later on 2. Highlights of The 2012 Johns Hopkins Prostate Disorders White Paper include: A promising new treatment for men with frequent nighttime urination. Answers to 8 common questions about sacral nerve stimulation for lower urinary tract symptoms. Surprising research on the link between smoking and prostate cancer recurrence. How men who drink 6 cups of coffee a day or more may reduce their risk of aggressive prostate cancer. Should you have a PSA screening test? Answers to important questions on the controversial USPSTF recommendation. Watchful waiting or radical prostatectomy for men with early-stage prostate cancer? What the research suggests. A look at state-of-the-art surveillance strategies for men on active surveillance for prostate cancer. Locally advanced prostate cancer: Will you benefit from radiation and hormones? New drug offers hope for men with metastatic castrate-resistant prostate cancer. Behavioral therapy for incontinence: Why it might be worth a try. You’ll also get the latest news on benign prostatic enlargement (BPE), also known as benign prostatic hyperplasia (BPH) and prostatitis: What’s your Prostate Symptom Score? Here’s a quick quiz you can take right now to determine if you should seek treatment for your enlarged prostate. Your surgical choices: a close look at simple prostatectomy, transurethral prostatectomy and open prostatectomy. New warnings about 5-alpha-reductase inhibitors and aggressive prostate cancer. 3. Promising technique. INCORE pointed out in detail about the general problem judging response and the stil missing quality in standardization: http://www.futuremedicine.com/doi/abs/10.2217/fon.12.78?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dwww.ncbi.nlm.nih.gov I did research in response evaluation and prediction for about 15y now and being honest: neither the clinical, nor the molecular biological data proved significant benefit in changing a strategy in patient diagnosis and / or treatment. I would state: this brings us back on the ground and not upon the sky. Additionally it means: we have to ´work harder on that and the WHO has to take responsibility: clinicians use a reponse classification without knowing, that this is just related to “ONE” experiment from the 70’s and that this experiment never had been rescrutinized (please read the Editorial I provided – we use a clinical response classification since more than 30 years worldwide (Miller et al. Cancer 1981) but it is useless ! 4. Dr. BB Thank you for your comment. Dr. Nir will reply to your comment. Regarding the Response Classification in use, it seems that the College of Oncology should champion a task force to revisit the Best Practice in use in this domain and issue a revised version or a new effort for a a new classification system for Clinical Response to treatment in Cancer. 5. I’m sorry that I was looking for this paper again earlier and didn’t find it. I answered my view on your article earlier. This is a method demonstration, but not a proof of concept by any means. It adds to the cacophany of approaches, and in a much larger study would prove to be beneficial in treatment, but not a cure for serious prostate cancer because it is unlikely that it can get beyond the margin, and also because there is overtreatment at the cutoff of PSA at 4.0. There is now a proved prediction model that went to press some 4 months ago. I think that the pathologist has to see the tissue, and the standard in pathology now is for any result that is cancer, two pathologist or a group sitting together should see it. It’s not an easy diagnosis. Björn LDM Brücher, Anton Bilchik, Aviram Nissan, Itzhak Avital, & Alexander Stojadinovic. Tumor response criteria: are they appropriate? Future Oncol. (2012) 8(8), 903–906. 10.2217/FON.12.78. ISSN 1479-6694. ..Tumor heterogeneity is a ubiquitous phemomenon. In particular, there are important differences among the various types of gastrointestinal (GI) cancers in terms of tumor biology, treatment response and prognosis. ..This forms the principal basis for targeted therapy directed by tumor-specific testing at either the gene or protein level. Despite rapid advances in our understanding of targeted therapy for GI cancers, the impact on cancer survival has been marginal. ..Can tumor response to therapy be predicted, thereby improving the selection of patients for cancer treatment? ..In 2000 theNCI with the European Association for Research and Treatment of Cancer, proposed a replacement of 2D measurement with a decrease in the largest tumor diameter by 30% in one dimension. Tumor response as defined would translate into a 50% decrease for a spherical lesion ..We must rethink how we may better determine treatment response in a reliable, reproducible way that is aimed at individualizing the therapy of cancer patients. ..we must change the tools we use to assess tumor response. The new modality should be based on empirical evidence that translates into relevant and meaningful clinical outcome data. ..This becomes a conundrum of sorts in an era of ‘minimally invasive treatment’. ..integrated multidisciplinary panel of international experts – not sure that that will do it Several years ago i heard Stamey present the totality of his work at Stanford, with great disappointment over hsPSA that they pioneered in. The outcomes were disappointing. I had published a review of all of our cases reviewed for 1 year with Marguerite Pinto. There’s a reason that the physicians line up outside of her office for her opinion. The review showed that a PSA over 24 ng/ml is predictive of bone metastasis. Any result over 10 was as likely to be prostatitis, BPH or cancer. I did an ordinal regression in the next study with Gustave Davis using a bivariate ordinal regression to predict lymph node metastasis using the PSA and the Gleason score. It was better than any univariate model, but there was no followup. I reviewed a paper for Clin Biochemistry (Elsevier) on a new method for PSA, very different than what we are familiar with. It was the most elegant paper I have seen in the treatment of the data. The model could predict post procedural time to recurrence to 8 years. • I hope we are in agreement on the fact that imaging guided interventions are needed for better treatment outcome. The point I’m trying to make in this post is that people are investing in developing imaging guided intervention and it is making progress. Over diagnosis and over treatment is another issue altogether. I think that many of my other posts are dealing with that. 6. Tumor response criteria: are they appropriate? Future Oncology 2012; 8(8): 903-906 , DOI 10.2217/fon.12.78 (doi:10.2217/fon.12.78) Björn LDM Brücher, Anton Bilchik, Aviram Nissan, Itzhak Avital & Alexander Stojadinovic Tumor heterogeneity is a problematic because of differences among the metabolic variety among types of gastrointestinal (GI) cancers, confounding treatment response and prognosis. This is in response to … a group of investigators from Sunnybrook Health Sciences Centre, University of Toronto, Ontario, Canada who evaluate the feasibility and safety of magnetic resonance (MR) imaging–controlled transurethral ultrasound therapy for prostate cancer in humans. Their study’s objective was to prove that using real-time MRI guidance of HIFU treatment is possible and it guarantees that the location of ablated tissue indeed corresponds to the locations planned for treatment. 1. There is a difference between expected response to esophageal or gastric neoplasms both biologically and in expected response, even given variability within a class. The expected time to recurrence is usually longer in the latter case, but the confounders are – age at time of discovery, biological time of detection, presence of lymph node and/or distant metastasis, microscopic vascular invasion. 2. There is a long latent period in abdominal cancers before discovery, unless a lesion is found incidentally in surgery for another reason. 3. The undeniable reality is that it is not difficult to identify the main lesion, but it is difficult to identify adjacent epithelium that is at risk (transitional or pretransitional). Pathologists have a very good idea about precancerous cervical neoplasia. The heterogeneity rests within each tumor and between the primary and metastatic sites, which is expected to be improved by targeted therapy directed by tumor-specific testing. Despite rapid advances in our understanding of targeted therapy for GI cancers, the impact on cancer survival has been marginal. The heterogeneity is a problem that will take at least another decade to unravel because of the number of signaling pathways and the crosstalk that is specifically at issue. I must refer back to the work of Frank Dixon, Herschel Sidransky, and others, who did much to develop a concept of neoplasia occurring in several stages – minimal deviation and fast growing. These have differences in growth rates, anaplasia, and biochemical. This resembles the multiple “hit” theory that is described in “systemic inflammatory” disease leading to a final stage, as in sepsis and septic shock. In 1920, Otto Warburg received the Nobel Prize for his work on respiration. He postulated that cancer cells become anaerobic compared with their normal counterpart that uses aerobic respiration to meet most energy needs. He attributed this to “mitochondrial dysfunction. In fact, we now think that in response to oxidative stress, the mitochondrion relies on the Lynen Cycle to make more cells and the major source of energy becomes glycolytic, which is at the expense of the lean body mass (muscle), which produces gluconeogenic precursors from muscle proteolysis (cancer cachexia). There is a loss of about 26 ATP ~Ps in the transition. The mitochondrial gene expression system includes the mitochondrial genome, mitochondrial ribosomes, and the transcription and translation machinery needed to regulate and conduct gene expression as well as mtDNA replication and repair. Machinery involved in energetics includes the enzymes of the Kreb’s citric acid or TCA (tricarboxylic acid) cycle, some of the enzymes involved in fatty acid catabolism (β-oxidation), and the proteins needed to help regulate these systems. The inner membrane is central to mitochondrial physiology and, as such, contains multiple protein systems of interest. These include the protein complexes involved in the electron transport component of oxidative phosphorylation and proteins involved in substrate and ion transport. Mitochondrial roles in, and effects on, cellular homeostasis extend far beyond the production of ATP, but the transformation of energy is central to most mitochondrial functions. Reducing equivalents are also used for anabolic reactions. The energy produced by mitochondria is most commonly thought of to come from the pyruvate that results from glycolysis, but it is important to keep in mind that the chemical energy contained in both fats and amino acids can also be converted into NADH and FADH2 through mitochondrial pathways. The major mechanism for harvesting energy from fats is β-oxidation; the major mechanism for harvesting energy from amino acids and pyruvate is the TCA cycle. Once the chemical energy has been transformed into NADH and FADH2 (also discovered by Warburg and the basis for a second Nobel nomination in 1934), these compounds are fed into the mitochondrial respiratory chain. The hydroxyl free radical is extremely reactive. It will react with most, if not all, compounds found in the living cell (including DNA, proteins, lipids and a host of small molecules). The hydroxyl free radical is so aggressive that it will react within 5 (or so) molecular diameters from its site of production. The damage caused by it, therefore, is very site specific. The reactions of the hydroxyl free radical can be classified as hydrogen abstraction, electron transfer, and addition. The formation of the hydroxyl free radical can be disastrous for living organisms. Unlike superoxide and hydrogen peroxide, which are mainly controlled enzymatically, the hydroxyl free radical is far too reactive to be restricted in such a way – it will even attack antioxidant enzymes. Instead, biological defenses have evolved that reduce the chance that the hydroxyl free radical will be produced and, as nothing is perfect, to repair damage. Currently, some endogenous markers are being proposed as useful measures of total “oxidative stress” e.g., 8-hydroxy-2’deoxyguanosine in urine. The ideal scavenger must be non-toxic, have limited or no biological activity, readily reach the site of hydroxyl free radical production (i.e., pass through barriers such as the blood-brain barrier), react rapidly with the free radical, be specific for this radical, and neither the scavenger nor its product(s) should undergo further metabolism. Nitric oxide has a single unpaired electron in its π*2p antibonding orbital and is therefore paramagnetic. This unpaired electron also weakens the overall bonding seen in diatomic nitrogen molecules so that the nitrogen and oxygen atoms are joined by only 2.5 bonds. The structure of nitric oxide is a resonance hybrid of two forms. In living organisms nitric oxide is produced enzymatically. Microbes can generate nitric oxide by the reduction of nitrite or oxidation of ammonia. In mammals nitric oxide is produced by stepwise oxidation of L-arginine catalyzed by nitric oxide synthase (NOS). Nitric oxide is formed from the guanidino nitrogen of the L-arginine in a reaction that consumes five electrons and requires flavin adenine dinucleotide (FAD), flavin mononucleotide (FMN) tetrahydrobiopterin (BH4), and iron protoporphyrin IX as cofactors. The primary product of NOS activity may be the nitroxyl anion that is then converted to nitric oxide by electron acceptors. The thiol-disulfide redox couple is very important to oxidative metabolism. GSH is a reducing cofactor for glutathione peroxidase, an antioxidant enzyme responsible for the destruction of hydrogen peroxide. Thiols and disulfides can readily undergo exchange reactions, forming mixed disulfides. Thiol-disulfide exchange is biologically very important. For example, GSH can react with protein cystine groups and influence the correct folding of proteins, and it GSH may play a direct role in cellular signaling through thiol-disulfide exchange reactions with membrane bound receptor proteins (e.g., the insulin receptor complex), transcription factors (e.g., nuclear factor κB), and regulatory proteins in cells. Conditions that alter the redox status of the cell can have important consequences on cellular function. So the complexity of life is not yet unraveled. Can tumor response to therapy be predicted, thereby improving the selection of patients for cancer treatment? The goal is not just complete response. Histopathological response seems to be related post-treatment histopathological assessment but it is not free from the challenge of accurately determining treatment response, as this method cannot delineate whether or not there are residual cancer cells. Functional imaging to assess metabolic response by 18-fluorodeoxyglucose PET also has its limits, as the results are impacted significantly by several variables: • tumor type • sizing • doubling time • anaplasia? • extent of tumor necrosis • type of antitumor therapy and the time when response was determined. The new modality should be based on individualized histopathology as well as tumor molecular, genetic and functional characteristics, and individual patients’ characteristics, a greater challenge in an era of ‘minimally invasive treatment’. This listing suggests that for every cancer the following data has to be collected (except doubling time). If there are five variables, the classification based on these alone would calculate to be very sizable based on Eugene Rypka’s feature extraction and classification. But looking forward, time to remission and disease free survival are additionally important. Treatment for cure is not the endpoint, but the best that can be done is to extend the time of survival to a realistic long term goal and retain a quality of life. Brücher BLDM, Piso P, Verwaal V et al. Peritoneal carcinomatosis: overview and basics. Cancer Invest.30(3),209–224 (2012). Brücher BLDM, Swisher S, Königsrainer A et al. Response to preoperative therapy in upper gastrointestinal cancers. Ann. Surg. Oncol.16(4),878–886 (2009). Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer47(1),207–214 (1981). Therasse P, Arbuck SG, Eisenhauer EA et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J. Natl Cancer Inst.92(3),205–216 (2000). Brücher BLDM, Becker K, Lordick F et al. The clinical impact of histopathological response assessment by residual tumor cell quantification in esophageal squamous cell carcinomas. Cancer106(10),2119–2127 (2006). • Dr. Larry, Thank you for this comment. Please carry it as a stand alone post, Dr. Ritu will refer to it and reference it in her FORTHCOMING pst on Tumor Response which will integrate multiple sources. Please execute my instruction Thank you • Thank you Larry for this educating comment. It explains very well why the Canadian investigators did not try to measure therapy response! What they have demonstrated is the technological feasibility of coupling a treatment device to an imaging device and use that in order to guide the treatment to the right place. the issue of “choice of treatment” to which you are referring is not in the scope of this publication. The point is: if one treatment modality can be guided, other can as well! This should encourage others, to try and develop imaging-based treatment guidance systems. 7. The crux of the matter in terms of capability is that the cancer tissue, adjacent tissue, and the fibrous matrix are all in transition to the cancerous state. It is taught to resect leaving “free margin”, which is better aesthetically, and has had success in breast surgery. The dilemma is that the patient may return, but how soon? • Correct. The philosophy behind lumpectomy is preserving quality of life. It was Prof. Veronesi (IEO) who introduced this method 30 years ago noticing that in the majority of cases, the patient will die from something else before presenting recurrence of breast cancer.. It is well established that when the resection margins are declared by a pathologist (as good as he/she could be) as “free of cancer”, the probability of recurrence is much lower than otherwise. 8. Dr. Larry, To assist Dr. Ritu, PLEASE carry ALL your comments above into a stand alone post and ADD to it your comment on my post on MIS Thank you 9. Great post! Dr. Nir, can the ultrasound be used in conjunction with PET scanning as well to determine a spatial and functional map of the tumor. With a disease like serous ovarian cancer we typically see an intraperitoneal carcimatosis and it appears that clinicians are wanting to use fluorogenic probes and fiberoptics to visualize the numerous nodules located within the cavity Also is the technique being used mainy for surgery or image guided radiotherapy or can you use this for detecting response to various chemotherapeutics including immunotherapy. • Ultrasound can and is actually used in conjunction with PET scanning in many cases. The choice of using ultrasound is always left to the practitioner! Being a non-invasive, low cost procedure makes the use of ultrasound a non-issue. The down-side is that because it is so easy to access and operate, nobody bothers to develop rigorous guidelines about using it and the benefits remains the property of individuals. In regards to the possibility of screening for ovarian cancer and characterising pelvic masses using ultrasound I can refer you to scientific work in which I was involved: 1. VAES (E.), MANCHANDA (R), AUTIER, NIR (R), NIR (D.), BLEIBERG (H.), ROBERT (A.), MENON (U.). Differential diagnosis of adnexal masses: Sequential use of the Risk of Malignancy Index and a novel computer aided diagnostic tool. Published in Ultrasound in Obstetrics & Gynecology. Issue 1 (January). Vol. 39. Page(s): 91-98. 2. VAES (E.), MANCHANDA (R), NIR (R), NIR (D.), BLEIBERG (H.), AUTIER (P.), MENON (U.), ROBERT (A.). Mathematical models to discriminate between benign and malignant adnexal masses: potential diagnostic improvement using Ovarian HistoScanning. Published in International Journal of Gynecologic Cancer (IJGC). Issue 1. Vol. 21. Page(s): 35-43. 3. LUCIDARME (0.), AKAKPO (J.-P.), GRANBERG (S.), SIDERI (M.), LEVAVI (H.), SCHNEIDER (A.), AUTIER (P.), NIR (D.), BLEIBERG (H.). A new computer aided diagnostic tool for non-invasive characterisation of malignant ovarian masses: Results of a multicentre validation study. Published in European Radiology. Issue 8. Vol. 20. Page(s): 1822-1830. Dror Nir, PhD Managing partner BE: +32 (0) 473 981896 UK: +44 (0) 2032392424 10. totally true and i am very thankfull for these briliant comments. Remember: 10years ago: every cancer researcher stated: “look at the tumor cells only – forget the stroma”. The era of laser-captured tumor-cell dissection started. Now , everyone knows: it is a system we are looking at and viewing and analyzing tumor cells only is really not enough. So if we would be honest, we would have to declare, that all data, which had been produced 13-8years ago, dealing with laser capture microdissection, that al these data would need a re-scrutinization, cause the influence of the stroma was “forgotten”. I ‘d better not try thinking about the waisted millions of dollars. If we keep on being honest: the surgeon looks at the “free margin” in a kind of reductionable model, the pathologist is more the control instance. I personally see the pathologist as “the control instance” of surgical quality. Therefore, not the wish of the surgeon is important, the objective way of looking into problems or challenges. Can a pathologist always state, if a R0-resection had been performed ? The use of the Resectability Classification: There had been many many surrogate marker analysis – nothing new. BUT never a real substantial well tought through structured analysis had been done: mm by mm by mm by mm and afterwards analyzing that by a ROC analysis. BUt against which goldstandard ? If you perform statistically a ROC analysis – you need a golstandard to compare to. Therefore what is the real R0-resectiòn? It had been not proven. It just had been stated in this or that tumor entity that this or that margin with this margin free mm distance or that mm distance is enough and it had been declared as “the real R0-classification”. In some organs it is very very difficult and we all (surgeons, pathologists, clinicians) that we always get to the limit, if we try interpretating the R-classification within the 3rd dimension. Often it is just declared and stated. Otherwise: if lymph nodes are negative it does not mean, lymph nodes are really negative, cause up to 38% for example in upper GI cancers have histological negative lymph nodes, but immunohistochemical positive lymph nodes. And this had been also shown by Stojadinovic at el analyzing the ultrastaging in colorectal cancer. So the 4th dimension of cancer – the lymph nodes / the lymphatic vessel invasion are much more important than just a TNM classification, which unfortunately does often not reflect real tumor biology. AS we see: cancer has multifactorial reasons and it is necessary taking the challenge performing high sophisticated research by a multifactorial and multidisciplinary manner. Again my deep and heartly thanks for that productive and excellent discussion ! • Dr. BB, Thank you for your comment. Multidisciplinary perspectives have illuminated the discussion on the pages of this Journal. Eager to review Dr. Ritu’s forthcoming paper – the topic has a life of its own and is embodied in your statement: “the 4th dimension of cancer – the lymph nodes / the lymphatic vessel invasion are much more important than just a TNM classification, which unfortunately does often not reflect real tumor biology.” • Thank you BB for your comment. You have touched the core limitation of healthcare professionals: how do we know that we know! Do we have a reference to each of the test we perform? Do we have objective and standardise quality measures? Do we see what is out-there or are we imagining? The good news: Everyday we can “think” that we learned something new. We should be happy with that, even if it is means that we learned that yesterday’s truth is not true any-more and even if we are likely to be wrong again…:) But still, in the last decades, lots of progress was made…. 11. Dr. Nir, I thoroughly enjoyed reading your post as well as the comments that your post has attracted. There were different points of view and each one has been supported with relevant examples in the literature. Here are my two cents on the discussion: The paper that you have discussed had the objective of finding out whether real-time MRI guidance of treatment was even possible and if yes, and also if the treatment could be performed in accurate location of the ROI? The data reveals they were pretty successful in accomplishing their objective and of course that gives hope to the imaging-based targeted therapies. Whether the ROI is defined properly and if it accounts for the real tumor cure, is a different question. Role of pathologists and the histological analysis they bring about to the table cannot be ruled out, and the absence of a defined line between the tumor and the stromal region in the vicinity is well documented. However, that cannot rule out the value and scope of imaging-based detection and targeted therapy. After all, it is seminal in guiding minimally invasive surgery. As another arm of personalized medicine-based cure for cancer, molecular biologists at MD Anderson have suggested molecular and genetic profiling of the tumor to determine genetic aberrations on the basis of which matched-therapy could be recommended to patients. When phase I trial was conducted, the results were obtained were encouraging and the survival rate was better in matched-therapy patients compared to unmatched patients. Therefore, everytime there is more to consider when treating a cancer patient and who knows a combination of views of oncologists, pathologists, molecular biologists, geneticists, surgeons would device improvised protocols for diagnosis and treatment. It is always going to be complicated and generalizations would never give an answer. Smart interpretations of therapies – imaging-based or others would always be required! Ritu • Dr. Nir, One of your earlier comments, mentioned the non invasiveness of ultrasound, thus, it’s prevalence in use for diagnosis. This may be true for other or all areas with the exception of Mammography screening. In this field, an ultrasound is performed only if a suspected area of calcification or a lump has been detected in the routine or patient-initiated request for ad hoc mammography secondery to patient complain of pain or patient report of suspected lump. Ultrasound in this field repserents ascalation and two radiologists review. It in routine use for Breast biopsy. • Thanks Ritu for this supporting comment. The worst enemy of finding solutions is doing nothing while using the excuse of looking for the “ultimate solution” . Personally, I believe in combining methods and improving clinical assessment based on information fusion. Being able to predict, and then timely track the response to treatment is a major issue that affects survival and costs! 12. […] Dror Nir authored a post on October 16th titled “Knowing the tumor’s size and location, could we target treatment to THE ROI by applying imaging-gu…” The article attracted a lot of comments from readers including researchers and oncologists and […] 13. […] ted in this area; New clinical results supports Imaging-guidance for targeted prostate biopsy and Knowing the tumor’s size and location, could we target treatment to THE ROI by applying imagin… Today I report on recent publication presenting the advantage of using targeted trans-perineal […] 14. […] ted in this area; New clinical results supports Imaging-guidance for targeted prostate biopsy and Knowing the tumor’s size and location, could we target treatment to THE ROI by applying imaging-gu… Today I report on recent publication presenting the advantage of using targeted trans-perineal […] 15. […] Knowing the tumor’s size and location, could we target treatment to THE ROI by applying imaging-gu… […] ### Case Study #3: • ### Personalized Medicine: Cancer Cell Biology and Minimally Invasive Surgery (MIS) Curator: Aviva Lev-Ari, PhD, RN https://pharmaceuticalintelligence.com/2012/12/01/personalized-medicine-cancer-cell-biology-and-minimally-invasive-surgery-mis This article generated a Scientific Exchange of 24 Comments, some scholarly comments are quite lengthy ### 24 Responses 1. GREAT work. I’ll read and comment later on 2. Highlights of The 2012 Johns Hopkins Prostate Disorders White Paper include: A promising new treatment for men with frequent nighttime urination. Answers to 8 common questions about sacral nerve stimulation for lower urinary tract symptoms. Surprising research on the link between smoking and prostate cancer recurrence. How men who drink 6 cups of coffee a day or more may reduce their risk of aggressive prostate cancer. Should you have a PSA screening test? Answers to important questions on the controversial USPSTF recommendation. Watchful waiting or radical prostatectomy for men with early-stage prostate cancer? What the research suggests. A look at state-of-the-art surveillance strategies for men on active surveillance for prostate cancer. Locally advanced prostate cancer: Will you benefit from radiation and hormones? New drug offers hope for men with metastatic castrate-resistant prostate cancer. Behavioral therapy for incontinence: Why it might be worth a try. You’ll also get the latest news on benign prostatic enlargement (BPE), also known as benign prostatic hyperplasia (BPH) and prostatitis: What’s your Prostate Symptom Score? Here’s a quick quiz you can take right now to determine if you should seek treatment for your enlarged prostate. Your surgical choices: a close look at simple prostatectomy, transurethral prostatectomy and open prostatectomy. New warnings about 5-alpha-reductase inhibitors and aggressive prostate cancer. 3. Promising technique. INCORE pointed out in detail about the general problem judging response and the stil missing quality in standardization: http://www.futuremedicine.com/doi/abs/10.2217/fon.12.78?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dwww.ncbi.nlm.nih.gov I did research in response evaluation and prediction for about 15y now and being honest: neither the clinical, nor the molecular biological data proved significant benefit in changing a strategy in patient diagnosis and / or treatment. I would state: this brings us back on the ground and not upon the sky. Additionally it means: we have to ´work harder on that and the WHO has to take responsibility: clinicians use a reponse classification without knowing, that this is just related to “ONE” experiment from the 70′s and that this experiment never had been rescrutinized (please read the Editorial I provided – we use a clinical response classification since more than 30 years worldwide (Miller et al. Cancer 1981) but it is useless ! 4. Dr. BB Thank you for your comment. Dr. Nir will reply to your comment. Regarding the Response Classification in use, it seems that the College of Oncology should champion a task force to revisit the Best Practice in use in this domain and issue a revised version or a new effort for a a new classification system for Clinical Response to treatment in Cancer. 5. I’m sorry that I was looking for this paper again earlier and didn’t find it. I answered my view on your article earlier. This is a method demonstration, but not a proof of concept by any means. It adds to the cacophany of approaches, and in a much larger study would prove to be beneficial in treatment, but not a cure for serious prostate cancer because it is unlikely that it can get beyond the margin, and also because there is overtreatment at the cutoff of PSA at 4.0. There is now a proved prediction model that went to press some 4 months ago. I think that the pathologist has to see the tissue, and the standard in pathology now is for any result that is cancer, two pathologist or a group sitting together should see it. It’s not an easy diagnosis. Björn LDM Brücher, Anton Bilchik, Aviram Nissan, Itzhak Avital, & Alexander Stojadinovic. Tumor response criteria: are they appropriate? Future Oncol. (2012) 8(8), 903–906. 10.2217/FON.12.78. ISSN 1479-6694. ..Tumor heterogeneity is a ubiquitous phemomenon. In particular, there are important differences among the various types of gastrointestinal (GI) cancers in terms of tumor biology, treatment response and prognosis. ..This forms the principal basis for targeted therapy directed by tumor-specific testing at either the gene or protein level. Despite rapid advances in our understanding of targeted therapy for GI cancers, the impact on cancer survival has been marginal. ..Can tumor response to therapy be predicted, thereby improving the selection of patients for cancer treatment? ..In 2000 theNCI with the European Association for Research and Treatment of Cancer, proposed a replacement of 2D measurement with a decrease in the largest tumor diameter by 30% in one dimension. Tumor response as defined would translate into a 50% decrease for a spherical lesion ..We must rethink how we may better determine treatment response in a reliable, reproducible way that is aimed at individualizing the therapy of cancer patients. ..we must change the tools we use to assess tumor response. The new modality should be based on empirical evidence that translates into relevant and meaningful clinical outcome data. ..This becomes a conundrum of sorts in an era of ‘minimally invasive treatment’. ..integrated multidisciplinary panel of international experts – not sure that that will do it Several years ago i heard Stamey present the totality of his work at Stanford, with great disappointment over hsPSA that they pioneered in. The outcomes were disappointing. I had published a review of all of our cases reviewed for 1 year with Marguerite Pinto. There’s a reason that the physicians line up outside of her office for her opinion. The review showed that a PSA over 24 ng/ml is predictive of bone metastasis. Any result over 10 was as likely to be prostatitis, BPH or cancer. I did an ordinal regression in the next study with Gustave Davis using a bivariate ordinal regression to predict lymph node metastasis using the PSA and the Gleason score. It was better than any univariate model, but there was no followup. I reviewed a paper for Clin Biochemistry (Elsevier) on a new method for PSA, very different than what we are familiar with. It was the most elegant paper I have seen in the treatment of the data. The model could predict post procedural time to recurrence to 8 years. • I hope we are in agreement on the fact that imaging guided interventions are needed for better treatment outcome. The point I’m trying to make in this post is that people are investing in developing imaging guided intervention and it is making progress. Over diagnosis and over treatment is another issue altogether. I think that many of my other posts are dealing with that. 6. Tumor response criteria: are they appropriate? Future Oncology 2012; 8(8): 903-906 , DOI 10.2217/fon.12.78 (doi:10.2217/fon.12.78) Björn LDM Brücher, Anton Bilchik, Aviram Nissan, Itzhak Avital & Alexander Stojadinovic Tumor heterogeneity is a problematic because of differences among the metabolic variety among types of gastrointestinal (GI) cancers, confounding treatment response and prognosis. This is in response to … a group of investigators from Sunnybrook Health Sciences Centre, University of Toronto, Ontario, Canada who evaluate the feasibility and safety of magnetic resonance (MR) imaging–controlled transurethral ultrasound therapy for prostate cancer in humans. Their study’s objective was to prove that using real-time MRI guidance of HIFU treatment is possible and it guarantees that the location of ablated tissue indeed corresponds to the locations planned for treatment. 1. There is a difference between expected response to esophageal or gastric neoplasms both biologically and in expected response, even given variability within a class. The expected time to recurrence is usually longer in the latter case, but the confounders are – age at time of discovery, biological time of detection, presence of lymph node and/or distant metastasis, microscopic vascular invasion. 2. There is a long latent period in abdominal cancers before discovery, unless a lesion is found incidentally in surgery for another reason. 3. The undeniable reality is that it is not difficult to identify the main lesion, but it is difficult to identify adjacent epithelium that is at risk (transitional or pretransitional). Pathologists have a very good idea about precancerous cervical neoplasia. The heterogeneity rests within each tumor and between the primary and metastatic sites, which is expected to be improved by targeted therapy directed by tumor-specific testing. Despite rapid advances in our understanding of targeted therapy for GI cancers, the impact on cancer survival has been marginal. The heterogeneity is a problem that will take at least another decade to unravel because of the number of signaling pathways and the crosstalk that is specifically at issue. I must refer back to the work of Frank Dixon, Herschel Sidransky, and others, who did much to develop a concept of neoplasia occurring in several stages – minimal deviation and fast growing. These have differences in growth rates, anaplasia, and biochemical. This resembles the multiple “hit” theory that is described in “systemic inflammatory” disease leading to a final stage, as in sepsis and septic shock. In 1920, Otto Warburg received the Nobel Prize for his work on respiration. He postulated that cancer cells become anaerobic compared with their normal counterpart that uses aerobic respiration to meet most energy needs. He attributed this to “mitochondrial dysfunction. In fact, we now think that in response to oxidative stress, the mitochondrion relies on the Lynen Cycle to make more cells and the major source of energy becomes glycolytic, which is at the expense of the lean body mass (muscle), which produces gluconeogenic precursors from muscle proteolysis (cancer cachexia). There is a loss of about 26 ATP ~Ps in the transition. The mitochondrial gene expression system includes the mitochondrial genome, mitochondrial ribosomes, and the transcription and translation machinery needed to regulate and conduct gene expression as well as mtDNA replication and repair. Machinery involved in energetics includes the enzymes of the Kreb’s citric acid or TCA (tricarboxylic acid) cycle, some of the enzymes involved in fatty acid catabolism (β-oxidation), and the proteins needed to help regulate these systems. The inner membrane is central to mitochondrial physiology and, as such, contains multiple protein systems of interest. These include the protein complexes involved in the electron transport component of oxidative phosphorylation and proteins involved in substrate and ion transport. Mitochondrial roles in, and effects on, cellular homeostasis extend far beyond the production of ATP, but the transformation of energy is central to most mitochondrial functions. Reducing equivalents are also used for anabolic reactions. The energy produced by mitochondria is most commonly thought of to come from the pyruvate that results from glycolysis, but it is important to keep in mind that the chemical energy contained in both fats and amino acids can also be converted into NADH and FADH2 through mitochondrial pathways. The major mechanism for harvesting energy from fats is β-oxidation; the major mechanism for harvesting energy from amino acids and pyruvate is the TCA cycle. Once the chemical energy has been transformed into NADH and FADH2 (also discovered by Warburg and the basis for a second Nobel nomination in 1934), these compounds are fed into the mitochondrial respiratory chain. The hydroxyl free radical is extremely reactive. It will react with most, if not all, compounds found in the living cell (including DNA, proteins, lipids and a host of small molecules). The hydroxyl free radical is so aggressive that it will react within 5 (or so) molecular diameters from its site of production. The damage caused by it, therefore, is very site specific. The reactions of the hydroxyl free radical can be classified as hydrogen abstraction, electron transfer, and addition. The formation of the hydroxyl free radical can be disastrous for living organisms. Unlike superoxide and hydrogen peroxide, which are mainly controlled enzymatically, the hydroxyl free radical is far too reactive to be restricted in such a way – it will even attack antioxidant enzymes. Instead, biological defenses have evolved that reduce the chance that the hydroxyl free radical will be produced and, as nothing is perfect, to repair damage. Currently, some endogenous markers are being proposed as useful measures of total “oxidative stress” e.g., 8-hydroxy-2’deoxyguanosine in urine. The ideal scavenger must be non-toxic, have limited or no biological activity, readily reach the site of hydroxyl free radical production (i.e., pass through barriers such as the blood-brain barrier), react rapidly with the free radical, be specific for this radical, and neither the scavenger nor its product(s) should undergo further metabolism. Nitric oxide has a single unpaired electron in its π*2p antibonding orbital and is therefore paramagnetic. This unpaired electron also weakens the overall bonding seen in diatomic nitrogen molecules so that the nitrogen and oxygen atoms are joined by only 2.5 bonds. The structure of nitric oxide is a resonance hybrid of two forms. In living organisms nitric oxide is produced enzymatically. Microbes can generate nitric oxide by the reduction of nitrite or oxidation of ammonia. In mammals nitric oxide is produced by stepwise oxidation of L-arginine catalyzed by nitric oxide synthase (NOS). Nitric oxide is formed from the guanidino nitrogen of the L-arginine in a reaction that consumes five electrons and requires flavin adenine dinucleotide (FAD), flavin mononucleotide (FMN) tetrahydrobiopterin (BH4), and iron protoporphyrin IX as cofactors. The primary product of NOS activity may be the nitroxyl anion that is then converted to nitric oxide by electron acceptors. The thiol-disulfide redox couple is very important to oxidative metabolism. GSH is a reducing cofactor for glutathione peroxidase, an antioxidant enzyme responsible for the destruction of hydrogen peroxide. Thiols and disulfides can readily undergo exchange reactions, forming mixed disulfides. Thiol-disulfide exchange is biologically very important. For example, GSH can react with protein cystine groups and influence the correct folding of proteins, and it GSH may play a direct role in cellular signaling through thiol-disulfide exchange reactions with membrane bound receptor proteins (e.g., the insulin receptor complex), transcription factors (e.g., nuclear factor κB), and regulatory proteins in cells. Conditions that alter the redox status of the cell can have important consequences on cellular function. So the complexity of life is not yet unraveled. Can tumor response to therapy be predicted, thereby improving the selection of patients for cancer treatment? The goal is not just complete response. Histopathological response seems to be related post-treatment histopathological assessment but it is not free from the challenge of accurately determining treatment response, as this method cannot delineate whether or not there are residual cancer cells. Functional imaging to assess metabolic response by 18-fluorodeoxyglucose PET also has its limits, as the results are impacted significantly by several variables: • tumor type • sizing • doubling time • anaplasia? • extent of tumor necrosis • type of antitumor therapy and the time when response was determined. The new modality should be based on individualized histopathology as well as tumor molecular, genetic and functional characteristics, and individual patients’ characteristics, a greater challenge in an era of ‘minimally invasive treatment’. This listing suggests that for every cancer the following data has to be collected (except doubling time). If there are five variables, the classification based on these alone would calculate to be very sizable based on Eugene Rypka’s feature extraction and classification. But looking forward, time to remission and disease free survival are additionally important. Treatment for cure is not the endpoint, but the best that can be done is to extend the time of survival to a realistic long term goal and retain a quality of life. Brücher BLDM, Piso P, Verwaal V et al. Peritoneal carcinomatosis: overview and basics. Cancer Invest.30(3),209–224 (2012). Brücher BLDM, Swisher S, Königsrainer A et al. Response to preoperative therapy in upper gastrointestinal cancers. Ann. Surg. Oncol.16(4),878–886 (2009). Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer47(1),207–214 (1981). Therasse P, Arbuck SG, Eisenhauer EA et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J. Natl Cancer Inst.92(3),205–216 (2000). Brücher BLDM, Becker K, Lordick F et al. The clinical impact of histopathological response assessment by residual tumor cell quantification in esophageal squamous cell carcinomas. Cancer106(10),2119–2127 (2006). • Dr. Larry, Thank you for this comment. Please carry it as a stand alone post, Dr. Ritu will refer to it and reference it in her FORTHCOMING pst on Tumor Response which will integrate multiple sources. Please execute my instruction Thank you • Thank you Larry for this educating comment. It explains very well why the Canadian investigators did not try to measure therapy response! What they have demonstrated is the technological feasibility of coupling a treatment device to an imaging device and use that in order to guide the treatment to the right place. the issue of “choice of treatment” to which you are referring is not in the scope of this publication. The point is: if one treatment modality can be guided, other can as well! This should encourage others, to try and develop imaging-based treatment guidance systems. 7. The crux of the matter in terms of capability is that the cancer tissue, adjacent tissue, and the fibrous matrix are all in transition to the cancerous state. It is taught to resect leaving “free margin”, which is better aesthetically, and has had success in breast surgery. The dilemma is that the patient may return, but how soon? • Correct. The philosophy behind lumpectomy is preserving quality of life. It was Prof. Veronesi (IEO) who introduced this method 30 years ago noticing that in the majority of cases, the patient will die from something else before presenting recurrence of breast cancer.. It is well established that when the resection margins are declared by a pathologist (as good as he/she could be) as “free of cancer”, the probability of recurrence is much lower than otherwise. 8. Dr. Larry, To assist Dr. Ritu, PLEASE carry ALL your comments above into a stand alone post and ADD to it your comment on my post on MIS Thank you 9. Great post! Dr. Nir, can the ultrasound be used in conjunction with PET scanning as well to determine a spatial and functional map of the tumor. With a disease like serous ovarian cancer we typically see an intraperitoneal carcimatosis and it appears that clinicians are wanting to use fluorogenic probes and fiberoptics to visualize the numerous nodules located within the cavity Also is the technique being used mainy for surgery or image guided radiotherapy or can you use this for detecting response to various chemotherapeutics including immunotherapy. • Ultrasound can and is actually used in conjunction with PET scanning in many cases. The choice of using ultrasound is always left to the practitioner! Being a non-invasive, low cost procedure makes the use of ultrasound a non-issue. The down-side is that because it is so easy to access and operate, nobody bothers to develop rigorous guidelines about using it and the benefits remains the property of individuals. In regards to the possibility of screening for ovarian cancer and characterising pelvic masses using ultrasound I can refer you to scientific work in which I was involved: 1. VAES (E.), MANCHANDA (R), AUTIER, NIR (R), NIR (D.), BLEIBERG (H.), ROBERT (A.), MENON (U.). Differential diagnosis of adnexal masses: Sequential use of the Risk of Malignancy Index and a novel computer aided diagnostic tool. Published in Ultrasound in Obstetrics & Gynecology. Issue 1 (January). Vol. 39. Page(s): 91-98. 2. VAES (E.), MANCHANDA (R), NIR (R), NIR (D.), BLEIBERG (H.), AUTIER (P.), MENON (U.), ROBERT (A.). Mathematical models to discriminate between benign and malignant adnexal masses: potential diagnostic improvement using Ovarian HistoScanning. Published in International Journal of Gynecologic Cancer (IJGC). Issue 1. Vol. 21. Page(s): 35-43. 3. LUCIDARME (0.), AKAKPO (J.-P.), GRANBERG (S.), SIDERI (M.), LEVAVI (H.), SCHNEIDER (A.), AUTIER (P.), NIR (D.), BLEIBERG (H.). A new computer aided diagnostic tool for non-invasive characterisation of malignant ovarian masses: Results of a multicentre validation study. Published in European Radiology. Issue 8. Vol. 20. Page(s): 1822-1830. Dror Nir, PhD Managing partner BE: +32 (0) 473 981896 UK: +44 (0) 2032392424 10. totally true and i am very thankfull for these briliant comments. Remember: 10years ago: every cancer researcher stated: “look at the tumor cells only – forget the stroma”. The era of laser-captured tumor-cell dissection started. Now , everyone knows: it is a system we are looking at and viewing and analyzing tumor cells only is really not enough. So if we would be honest, we would have to declare, that all data, which had been produced 13-8years ago, dealing with laser capture microdissection, that al these data would need a re-scrutinization, cause the influence of the stroma was “forgotten”. I ‘d better not try thinking about the waisted millions of dollars. If we keep on being honest: the surgeon looks at the “free margin” in a kind of reductionable model, the pathologist is more the control instance. I personally see the pathologist as “the control instance” of surgical quality. Therefore, not the wish of the surgeon is important, the objective way of looking into problems or challenges. Can a pathologist always state, if a R0-resection had been performed ? The use of the Resectability Classification: There had been many many surrogate marker analysis – nothing new. BUT never a real substantial well tought through structured analysis had been done: mm by mm by mm by mm and afterwards analyzing that by a ROC analysis. BUt against which goldstandard ? If you perform statistically a ROC analysis – you need a golstandard to compare to. Therefore what is the real R0-resectiòn? It had been not proven. It just had been stated in this or that tumor entity that this or that margin with this margin free mm distance or that mm distance is enough and it had been declared as “the real R0-classification”. In some organs it is very very difficult and we all (surgeons, pathologists, clinicians) that we always get to the limit, if we try interpretating the R-classification within the 3rd dimension. Often it is just declared and stated. Otherwise: if lymph nodes are negative it does not mean, lymph nodes are really negative, cause up to 38% for example in upper GI cancers have histological negative lymph nodes, but immunohistochemical positive lymph nodes. And this had been also shown by Stojadinovic at el analyzing the ultrastaging in colorectal cancer. So the 4th dimension of cancer – the lymph nodes / the lymphatic vessel invasion are much more important than just a TNM classification, which unfortunately does often not reflect real tumor biology. AS we see: cancer has multifactorial reasons and it is necessary taking the challenge performing high sophisticated research by a multifactorial and multidisciplinary manner. Again my deep and heartly thanks for that productive and excellent discussion ! • Dr. BB, Thank you for your comment. Multidisciplinary perspectives have illuminated the discussion on the pages of this Journal. Eager to review Dr. Ritu’s forthcoming paper – the topic has a life of its own and is embodied in your statement: “the 4th dimension of cancer – the lymph nodes / the lymphatic vessel invasion are much more important than just a TNM classification, which unfortunately does often not reflect real tumor biology.” • Thank you BB for your comment. You have touched the core limitation of healthcare professionals: how do we know that we know! Do we have a reference to each of the test we perform? Do we have objective and standardise quality measures? Do we see what is out-there or are we imagining? The good news: Everyday we can “think” that we learned something new. We should be happy with that, even if it is means that we learned that yesterday’s truth is not true any-more and even if we are likely to be wrong again…:) But still, in the last decades, lots of progress was made…. 11. Dr. Nir, I thoroughly enjoyed reading your post as well as the comments that your post has attracted. There were different points of view and each one has been supported with relevant examples in the literature. Here are my two cents on the discussion: The paper that you have discussed had the objective of finding out whether real-time MRI guidance of treatment was even possible and if yes, and also if the treatment could be performed in accurate location of the ROI? The data reveals they were pretty successful in accomplishing their objective and of course that gives hope to the imaging-based targeted therapies. Whether the ROI is defined properly and if it accounts for the real tumor cure, is a different question. Role of pathologists and the histological analysis they bring about to the table cannot be ruled out, and the absence of a defined line between the tumor and the stromal region in the vicinity is well documented. However, that cannot rule out the value and scope of imaging-based detection and targeted therapy. After all, it is seminal in guiding minimally invasive surgery. As another arm of personalized medicine-based cure for cancer, molecular biologists at MD Anderson have suggested molecular and genetic profiling of the tumor to determine genetic aberrations on the basis of which matched-therapy could be recommended to patients. When phase I trial was conducted, the results were obtained were encouraging and the survival rate was better in matched-therapy patients compared to unmatched patients. Therefore, everytime there is more to consider when treating a cancer patient and who knows a combination of views of oncologists, pathologists, molecular biologists, geneticists, surgeons would device improvised protocols for diagnosis and treatment. It is always going to be complicated and generalizations would never give an answer. Smart interpretations of therapies – imaging-based or others would always be required! Ritu • Dr. Nir, One of your earlier comments, mentioned the non invasiveness of ultrasound, thus, it’s prevalence in use for diagnosis. This may be true for other or all areas with the exception of Mammography screening. In this field, an ultrasound is performed only if a suspected area of calcification or a lump has been detected in the routine or patient-initiated request for ad hoc mammography secondery to patient complain of pain or patient report of suspected lump. Ultrasound in this field repserents ascalation and two radiologists review. It in routine use for Breast biopsy. • Thanks Ritu for this supporting comment. The worst enemy of finding solutions is doing nothing while using the excuse of looking for the “ultimate solution” . Personally, I believe in combining methods and improving clinical assessment based on information fusion. Being able to predict, and then timely track the response to treatment is a major issue that affects survival and costs! ### Case Study #4: • ### Judging the ‘Tumor response’-there is more food for thought https://pharmaceuticalintelligence.com/2012/12/04/judging-the-tumor-response-there-is-more-food-for-thought/ ### 13 Responses 1. Dr. Sanexa you have brought up an interesting and very clinically relevant point: what is the best measurement of response and 2) how perspectives among oncologists and other professionals differ on this issues given their expertise in their respective subspecialties (immunologist versus oncologist. The advent of functional measurements of tumors (PET etc.) seems extremely important in the therapeutic use AND in the development of these types of compounds since usually a response presents (in cases of solid tumors) as either a lack of growth of the tumor or tumor shrinkage. Did the authors include an in-depth discussion of the rapidity of onset of resistance with these types of compounds? Thanks for the posting. 2. Dr. Williams, Thanks for your comment on the post. The editorial brings to attention a view that although PET and other imaging methods provide vital information on tumor growth, shrinkage in response to a therapy, however, there are more aspects to consider including genetic and molecular characteristics of tumor. It was an editorial review and the authors did not include any in-depth discussion on the rapidity of onset of resistance with these types of compounds as the focus was primarily on interpreting tumor response. I am glad you found the contents of the write-up informative. Thanks again! Ritu 3. Thank you for your wonderful comment and interpretation. Dr.Sanexa made a brilliant comment. May I allow myself putting my finger deeper into this wound ? Cancer patients deserve it. It had been already pointed out by international experts from Munich, Tokyo, Hong-Kong and Houston, dealing with upper GI cancer, that the actual response criteria are not appropriate and moreover: the clinical response criteria in use seem rather to function as an alibi, than helping to differentiate and / or discriminate tumor biology (Ann Surg Oncol 2009): http://www.ncbi.nlm.nih.gov/pubmed/19194759 The response data in a phase-II-trial (one tumor entity, one histology, one treatment, one group) revealed: clinical response evaluation according to the WHO-criteria is not appropriate to determine response: http://www.ncbi.nlm.nih.gov/pubmed/15498642 Of course, there was a time, when it seemed to be useful and this also has to be respected. There is another challenge: using statistically a ROC and resulting in thresholds. This was, is and always be “a clinical decision only” and not the decision of the statistician. The clinician tells the statistician, what decision, he wants to make – the responsibility is enormous. Getting back to the roots: After the main results of the Munich-group had been published 2001 (Ann Surg) and 2004 (J Clin Oncol): http://www.ncbi.nlm.nih.gov/pubmed/11224616 http://www.ncbi.nlm.nih.gov/pubmed/14990646 the first reaction in the community was: to difficult, can’t be, not re-evaluated, etc.. However, all evaluated cut-offs / thresholds had been later proven to be the real and best ones by the MD Anderson Cancer Center in Houston, Texas. Jaffer Ajani – a great and critical oncologist – pushed that together with Steve Swisher and they found the same results. Than the upper GI stakeholders went an uncommon way in science: they re-scrutinized their findings. Meanwhile the Goldstandard using histopathology as the basis-criterion had been published in Cancer 2006. http://www.ncbi.nlm.nih.gov/pubmed/16607651 Not every author, who was at the authorlist in 2001 and 2004 wanted to be a part of this analysis and publication ! Why ? Everyone should judge that by himself. The data of this analysis had been submitted to the New England Journal of Medicine. In the 2nd review stage process, the manuscript was rejected. The Ann Surg Oncol accepted the publication: the re-scrutinized data resulted in another interesting finding: in the future maybe “one PET-scan” might be appropriate predicting the patient’s response. Where are we now ? The level of evidence using the response criteria is very low: Miller’s (Cancer 1981) publication belonged to ”one single” experiment from Moertel (Cancer 1976). During that time, there was no definition of “experiences” rather than “oncologists”. These terms had not been in use during that time. Additionally they resulted in a (scientifically weak) change of the classification, published by Therasse (J Natl Cancer Inst 2000). Targeted therapy did not result in a change so far. In 2009, the international upper GI experts sent their publication of the Ann Surg Oncol 2009 to the WHO but without any kind of reaction. Using molecular biological predictive markers within the last 10years all seem to have potential. http://www.ncbi.nlm.nih.gov/pubmed/20012971 http://www.ncbi.nlm.nih.gov/pubmed/18704459 http://www.ncbi.nlm.nih.gov/pubmed/17940507 http://www.ncbi.nlm.nih.gov/pubmed/17354029 But, experts are aware: the real step breaking barriers had not been performed so far. Additionally, it is very important in trying to evaluate and / predict response, that not different tumor entities with different survival and tumor biology are mixed together. Those data are from my perspective not helpful, but maybe that is my own Bias (!) of my view. INCORE, the International Consortium of Research Excellence of the Theodor-Billroth-Academy, was invited publishing the Editorial in Future Oncology 2012. The consortium pointed out, that living within an area of ‘prove of principle’ and also trying to work out level of evidence in medicine, it is “the duty and responsibility” of every clinician, but also of the societies and institutions, also of the WHO. Complete remission is not the only goal, as experts dealing with ‘response-research’ are aware. It is so frustrating for patients and clinicians: there is a rate of those patients with complete remission, who develop early recurrence ! This reflects, that complete remission cannot function as the only criterion describing response ! Again, my heartly thanks, that Dr.Sanexa discussed this issue in detail. I hope, I found the way explaining the way of development and evaluating response criteria properly and in a differentiated way of view. From the perspective of INCORE: “an interdisciplinary initiative with all key stake¬holders and disciplines represented is imperative to make predictive and prognostic individualized tumor response assessment a modern-day reality. The integrated multidisciplinary panel of international experts need to define how to leverage existing data, tissue and testing platforms in order to predict individual patient treatment response and prognosis.” 4. Dr. Brucher, First of all thanks for expressing your views on the ‘tumor response’ in a comprehensive way. You are the first author of the editorial review one of the prominent people who has taken part in the process of defining tumor response and I am glad that you decided to write a comment on the writeup. The topic has been explained well in an immaculate manner and that it further clarifies the need for the perfect markers that would be able to evaluate and predict tumor response. There are, as you mentioned, some molecular markers available including VEGF, cyclins, that have been brought to focus in the context of squamous cell carcinoma. It would be great if you could be the guest author for our blog and we could publish your opinion (comment on this blog post) as a separate post. Please let us know if it is OK with you. Thanks again for your comment Ritu 5. Thank you all to the compelling discussions, above. Please review the two sources on the topic I placed at the bottom of the post, above as post on this Scientific Journal, All comments made to both entries are part of thisvdiscussion, I am referring to Dr. Nir’s post on size of tumor, to BB comment to Nir’s post, to Larry’ Pathologist view on Tumors and my post on remission and minimally invasive surgery (MIS). Great comments by Dr. Williams, BB and wonderful topic exposition by Dr. Ritu. 6. Aviva, Thats a great idea. I will combine all sources referred by you, the post on tumor imaging by Dr. Nir and the comments made on the these posts including Dr. Brucher’s comments in a new posts. Thanks Ritu • Great idea, ask Larry, he has written two very long important comments on this topic, one on Nir’s post and another one, ask him where, if it is not on MIS post. GREAT work, Ritu, integration is very important. Dr, Williams is one of our Gems. • Assessing tumour response it is not an easy task!Because tumours don’t change,but happilly our knowlege(about them) does really change,is everchanging(thans god!).In the past we had the Recist Criteria,then the Modified Recist Criteria,becausa of Gist and other tumors.At this very moment,these are clearly insuficient.We do need more new validated facing the reality of nowadays. A great, enormoust post Dr. Ritu! Congratulations! ### Conclusions The Voice of Aviva Lev-Ari, PhD, RN: The relevance of the Scientific Agora to Medical Education is vast. The Open Access Journal allows EVERY Scientist on the internet the GLOBAL reach and access to Open Access published scientific contents NOT only to the subscription payer base of Journals. If you don’t have a HIGH FEE subscription you get NO access to content in the Journal, you can’t participate in Multiple Comment Exchanges. In the Medical Education context – COMMENTS are the medium to debate with peers. Multiple Comment Exchanges on Four articles in the Journal, above, demonstrate the vibrancy of the scientific discussion, the multiplicity of perspectives, the subjectivity of the contribution to the debate and the unique expertise and clinical experience expressed by each Scientist. . Read Full Post » ## Three Genres in e-Scientific Publishing AND Three Scientists’ Dilemmas ### Three Genres in e-Scientific Publishing AND Three Scientists’ Dilemmas Curator: Aviva Lev-Ari, PhD, RN That’s what I tell students. The way to succeed is to get born at the right time and in the right place. If you can do that then you are bound to succeed. You have to be receptive and have some talent as well. Professor Sydney Brenner, a professor of Genetic medicine at the University of Cambridge and Nobel Laureate in Physiology or Medicine in 2002 ### Cell/Nature/Science ### [CNS] Subscription-based Access ### Open Access 1. Online journals, to which scientists pay an upfront free to cover editing costs, which then ensure the work is available free to access for anyone in perpetuity ### Curation of Scientific Findings i.e., Kindle Direct Publishing [KDP] – Royalty-based system 1. Free content to e-Readers 2. Expert, Authors, Writers -Volunteers 3. Editor -Voluneers Confirming or disproving past studies Confirming or disproving past studies Decades-long pursuit of a risky “moonshot” Decades-long pursuit of a risky “moonshot” Trendy topics with Editors Trendy topics with Editors ## Genres in e-Scientific Publishing (A) Cell/Nature/Science • ### Is the staggeringly profitable business of scientific publishing bad for science? – June 27, 2017 • ### How Academia and Publishing are Destroying Scientific Innovation: A Conversation with Sydney Brenner Elizabeth Dzeng — Feb 24th, 2014 • http://www.cell.com/ • http://www.sciencemag.org/ • https://www.nature.com/ • In 1998, Elsevier rolled out its plan for the internet age, which would come to be called “The Big Deal”. It offered electronic access to bundles of hundreds of journals at a time: a university would pay a set fee each year – according to a report based on freedom of information requests, Cornell University’s 2009 tab was just short of2m – and any student or professor could download any journal they wanted through Elsevier’s website. Universities signed up en masse. …. Elsevier owned 24% of the scientific journal market, while Maxwell’s old partners Springer, and his crosstown rivals Wiley-Blackwell, controlled about another 12% each. These three companies accounted for half the market. (An Elsevier representative familiar with the report told me that by their own estimate they publish only 16% of the scientific literature.)  – June 27, 2017.  Elsevier published 420,000 papers last year, after receiving 1.5m submissions  – June 28, 2017 [numbers correction to 6/27/2017.]

(B) Open Access Journals and the Phenomenon

1. Biochemistry
2. Biophysics and Structural Biology
3. Cancer Biology
4. Cell Biology
5. Computational and Systems Biology
6. Developmental Biology and Stem Cells
7. Epidemiology and Global Health
8. Genomics and Evolutionary Biology
9. Microbiology and Infectious Disease
10. Neuroscience

(C) Curation of Scientific Findings

## Scientists’ Dilemmas

(1) Confirming or disproving past studies

(2) Decades-long pursuit of a risky “moonshot”

(3) Trendy Topics with Editors

### Cardiovascular Original Research: Cases in Methodology Design for Content Co-Curation: The Art of Scientific & Medical Curation

Nov 29, 2015 | Kindle eBook

by Larry H. Bernstein MD FCAP and Aviva Lev-Ari PhD RN