Curation | Leaders in Pharmaceutical Business Intelligence Group, LLC, Doing Business As LPBI Group, Newton, MA

With the J.P. Morgan Healthcare Conference winding down, companies remain busy striking deals and informing investors about pipeline advances. BioSpace snagged some of the interesting news bits to come out of the conference from Wednesday.

SAGE Therapeutics – Following a positive Phase III report that its postpartum depression treatment candidate SAGE-217 hit the mark in its late-stage clinical trial, Sage Therapeutics is eying the potential to have multiple treatment options available for patients. At the start of J.P. Morgan, Sage said that patients treated with SAGE-217 had a statistically significant improvement of 17.8 points in the Hamilton Rating Scale for Depression, compared to 13.6 for placebo. The company plans to seek approval for SAGE-2017, but before that, the FDA is expected to make a decision on Zulresso in March. Zulresso already passed muster from advisory committees in November, and if approved, would be the first drug specifically for postpartum depression. In an interview with the Business Journal, Chief Business Officer Mike Cloonan said the company believes there is room in the market for both medications, particularly since the medications address different patient populations.

Mersana Therapeutics – After a breakup with Takeda Pharmaceutical and the shelving of its lead product, Cambridge, Mass.-based Mersana is making a new path. Even though a partial clinical hold was lifted following the death of a patient the company opted to shelve development of XMT-1522. During a presentation at JPM, CEO Anna Protopapas noted that many other companies are developing therapies that target the HER2 protein, which led to the decision, according to the Boston Business Journal. Protopapas said the HER2 space is highly competitive and now the company will focus on its other asset, XMT-1536, an ADC targeting NaPi2b, an antigen highly expressed in the majority of non-squamous NSCLC and epithelial ovarian cancer. XMT-1536 is currently in Phase 1 clinical trials for NaPi2b-expressing cancers, including ovarian cancer, non-small cell lung cancer and other cancers. Data on XMT-1536 is expected in the first half of 2019.

Novavax – During a JPM presentation, Stan Erck, CEO of Novavax, pointed to the company’s RSV vaccine, which is in late-stage development. The vaccine is being developed for the mother, in order to protect an infant. The mother transfers the antibodies to the infant, which will provide the baby with protection from RSV in its first six months. Erck called the program historic. He said the Phase III program is in its fourth year and the company has vaccinated 4,636 women. He said they are tracking the women and the babies. Researchers call the mothers every week through the first six months of the baby’s life to acquire data. Erck said the company anticipates announcing trial data this quarter. If approved, Erck said the market for the vaccine could be a significant revenue driver.

“You have 3.9 million birth cohorts and we expect 80 percent to 90 percent of those mothers to be vaccinated as a pediatric vaccine and in the U.S. the market rate is somewhere between $750 million and a $1 billion and then double that for worldwide market. So it’s a large market and we will be first to market in this,” Erck said, according to a transcript of the presentation.

Denali Therapeutics – Denali forged a collaboration with Germany-based SIRION Biotech to develop gene therapies for central nervous disorders. The two companies plan to develop adeno-associated virus (AAV) vectors to enable therapeutics to cross the blood-brain barrier for clinical applications in neurodegenerative diseases including Parkinson’s, Alzheimer’s disease, ALS and certain other diseases of the CNS.

AstraZeneca – Pharma giant AstraZeneca reported that in 2019 net prices on average across the portfolio will decrease versus 2018. With a backdrop of intense public and government scrutiny over pricing, Market Access head Rick Suarez said the company is increasing its pricing transparency. Additionally, he said the company is looking at new ways to price drugs, such as value-based reimbursement agreements with payers, Pink Sheet reported.

Amarin Corporation – As the company eyes a potential label expansion approval for its cardiovascular disease treatment Vascepa, Amarin Corporation has been proactively hiring hundreds of sales reps. In the fourth quarter, the company hired 265 new sales reps, giving the company a sales team of more than 400, CEO John Thero said. Thero noted that is a label expansion is granted by the FDA, “revenues will increase at least 50 percent over what we did in the prior year, which would give us revenues of approximate $350 million in 2019.”

Government Woes – As the partial government shutdown in the United States continues into its third week, biotech leaders at JPM raised concern as the FDA’s carryover funds are dwindling. With no new funding coming in, reviews of New Drug Applications won’t be able to continue past February, Pink Sheet said. While reviews are currently ongoing, no New Drug Applications are being accepted by the FDA at this time. With the halt of NDA applications, that has also caused some companies to delay plans for an initial public offering. It’s hard to raise potential investor excitement without the regulatory support of a potential drug approval. During a panel discussion, Jonathan Leff, a partner at Deerfield Management, noted that the ongoing government shutdown is a reminder of how “overwhelmingly dependent the whole industry of biotech and drug development is on government,” Pink Sheet said.

Curation of selected topics and articles on Role of G-Protein Coupled Receptors in Chronic Disease as supplemental information for #TUBiol3373

Posted in Alzheimer's Disease, Autoimmune Inflammatory DIseases, Biological Networks, Biological Networks, Gene Regulation and Evolution, Bone Disease and Musculoskeletal Disease, Ca2+ triggered activation, Cancer - General, Cancer and Current Therapeutics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Cell Biology, Signaling & Cell Circuits, Chronic Thromboembolic Pulmonary Hypertension (CTEPH) and Pulmonary Arterial Hypertension (PAH), Crohn's disease, Curation, Etiology, Frontiers in Cardiology and Cardiovascular Disorders, interventional oncology, Obesity, Pharmacotherapy and Cell Activity, tagged #TUBiol3373, Alzheimer Disease, Amyloid aggregates, cardiovascular and lung disease, Cardiovascular and Metabolic Diseases, chronic diseases, Chronic Obstructive Lung Disease (COPD), G Protein coupling, G-protein coupled receptors (GPCR), ovarian cancer on May 2, 2018| Leave a Comment »

Curation of selected topics and articles on Role of G-Protein Coupled Receptors in Chronic Disease as supplemental information for #TUBiol3373

Curator: Stephen J. Williams, PhD

Below is a series of posts and articles related to the role of G protein coupled receptors (GPCR) in various chronic diseases. This is only a cursory collection and by no means represents the complete extensive literature on pathogenesis related to G protein function or alteration thereof. However it is important to note that, although we think of G protein signaling as rather short lived, quick, their chronic activation may lead to progression of various disease. As to whether disease onset, via GPCR, is a result of sustained signal, loss of desensitization mechanisms, or alterations of transduction systems is an area to be investigated.

From:

Molecular Pathogenesis of Progressive Lung Diseases

Author: Larry H. Bernstein, MD, FCAP

Chronic Obstructive Lung Disease (COPD)

Inflammatory and infectious factors are present in diseased airways that interact with G-protein coupled receptors (GPCRs), such as purinergic receptors and bradykinin (BK) receptors, to stimulate phospholipase C [PLC]. This is followed by the activation of inositol 1,4,5-trisphosphate (IP3)-dependent activation of IP3 channel receptors in the ER, which results in channel opening and release of stored Ca²⁺ into the cytoplasm. When ER Ca2+ stores are depleted a pathway for Ca²⁺ influx across the plasma membrane is activated. This has been referred to as “capacitative Ca²⁺ entry”, and “store-operated calcium entry” (3). In the next step PLC mediated Ca²⁺ i is mobilized as a result of GPCR activation by inflammatory mediators, which triggers cytokine production by Ca²⁺ i-dependent activation of the transcription factor nuclear factor kB (NF-kB) in airway epithelia.

In Alzheimer’s Disease

Important Lead in Alzheimer’s Disease Model

Larry H. Bernstein, MD, FCAP, Curator discusses findings from a research team at University of California at San Diego (UCSD) which the neuropeptide hormone corticotropin-releasing factor (CRF) as having an important role in the etiology of Alzheimer’s Disease (AD). CRF activates the CRF receptor (a G stimulatory receptor). It was found inhibition of the CRF receptor prevented cognitive impairment in a mouse model of AD. Furthermore researchers at the Flanders Interuniversity Institute for Biotechnology found the loss of a protein called G protein-coupled receptor 3 (GPR3) may lower the amyloid plaque aggregation, resulting in improved cognitive function. Additionally inhibition of several G-protein coupled receptors alter amyloid precursor processing, providing a further mechanism of the role of GPCR in AD (see references in The role of G protein-coupled receptors in the pathology of Alzheimer’s disease by Amantha Thathiah and Bart De Strooper Nature Reviews Feb 2011; 12: 73-87 and read post).

In Cardiovascular and Thrombotic Disease

Adenosine Receptor Agonist Increases Plasma Homocysteine

and read related articles in curation on effects of hormones on the cardiovascular system at

Action of Hormones on the Circulation

In Cancer

A Curated History of the Science Behind the Ovarian Cancer β-Blocker Trial

Further curations and references of G proteins and chronic disease can be found at the Open Access journal https://pharmaceuticalintelligence.com using the search terms “GCPR” and “disease” in the Search box in the upper right of the home page.

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Lesson 9 Cell Signaling: Curations and Articles of reference as supplemental information for lecture section on WNTs: #TUBioll3373

Posted in Anticancer Resistance, Apoptosis, Biochemical pathways, Biological Networks, Biological Networks, Gene Regulation and Evolution, Breast Cancer - impalpable breast lesions, Ca2+ triggered activation, Calcium, Calcium Signaling, Calmodulin, Calmodulin Kinase and Contraction, Cancer - General, Cancer and Current Therapeutics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cancer Genomics, Cell Biology, Cell Biology, Signaling & Cell Circuits, Competition in regenerative stem cell science, Curation, Loss of function gene, Phosphorylation, Scientific Publishing, Signaling, Ubiquitinylation, Uncategorized, tagged #TUBiol3373, actin, APC, breast cancer, Cancer, Cell Motility, colon cancer, epithelial ovarian cancer, Extracellular matrix, Hepatocellular carcinoma, HNPCC, noncanonical, tumor associated fibroblasts, Ubiquitin, Wnt signaling, Wnt signaling pathway, wnt-beta/catenin signaling on May 1, 2018| Leave a Comment »

Lesson 9 Cell Signaling: Curations and Articles of reference as supplemental information for lecture section on WNTs: #TUBiol3373

Stephen J. Wiilliams, Ph.D: Curator

UPDATED 4/23/2019

This has an updated lesson on WNT signaling. Please click on the following and look at the slides labeled under lesson 10

cell motility 9b lesson_2018_sjw

Remember our lessons on the importance of signal termination. The CANONICAL WNT signaling (that is the β-catenin dependent signaling)

is terminated by the APC-driven degradation complex. This leads to the signal messenger β-catenin being degraded by the proteosome. Other examples of growth factor signaling that is terminated by a proteosome-directed include the Hedgehog signaling system, which is involved in growth and differentiation as well as WNTs and is implicated in various cancers.

A good article on the Hedgehog signaling pathway is found here:

The Voice of a Pathologist, Cancer Expert: Scientific Interpretation of Images: Cancer Signaling Pathways and Tumor Progression

All images in use for this article are under copyrights with Shutterstock.com

Cancer is expressed through a series of transformations equally involving metabolic enzymes and glucose, fat, and protein metabolism, and gene transcription, as a result of altered gene regulatory and transcription pathways, and also as a result of changes in cell-cell interactions. These are embodied in the following series of graphics.

Figure 1: Sonic_hedgehog_pathway

The Voice of Dr. Larry

The figure shows a modification of nuclear translocation by Sonic hedgehog pathway. The hedgehog proteins have since been implicated in the development of internal organs, midline neurological structures, and the hematopoietic system in humans. The Hh signaling pathway consists of three main components: the receptor patched 1 (PTCH1), the seven transmembrane G-protein coupled receptor smoothened (SMO), and the intracellular glioma-associated oncogene homolog (GLI) family of transcription factors.⁵The GLI family is composed of three members, including GLI1 (gene activating), GLI2 (gene activating and repressive), and GLI3 (gene repressive).⁶ In the absence of an activating signal from either Shh, Ihh or Dhh, PTCH1 exerts an inhibitory effect on the signal transducer SMO, preventing any downstream signaling from occurring.⁷ When Hh ligands bind and activate PTCH1, the inhibition on SMO is released, allowing the translocation of SMO into the cytoplasm and its subsequent activation of the GLI family of transcription factors.

And from the review of Elaine Y. C. Hsia, Yirui Gui, and Xiaoyan Zheng Regulation of Hedgehog Signaling by Ubiquitination Front Biol (Beijing). 2015 Jun; 10(3): 203–220.

the authors state:

Finally, termination of Hh signaling is also important for controlling the duration of pathway activity. Hh induced ubiquitination and degradation of Ci/Gli is the most well-established mechanism for limiting signal duration, and inhibiting this process can lead to cell patterning disruption and excessive cell proliferation (Di Marcotullio et al. 2006; Huntzicker et al. 2006; Kent et al. 2006; Zhang et al. 2006a; Di Marcotullio et al. 2007; Ou et al. 2007). In addition to Ci/Gli, a growing body of evidence suggests that ubiquitination also plays critical roles in regulating other Hh signaling components including Ptc, Smo, and Sufu. Thus, ubiquitination serves as a general mechanism in the dynamic regulation of the Hh pathway.

Overview of Hedgehog signaling showing the signal termination by ubiquitnation and subsequent degradation of the Gli transcriptional factors. obtained from Oncotarget 5(10):2881-911 · May 2014. GSK-3B as a Therapeutic Intervention in Cancer

Note that in absence of Hedgehog ligands Ptch inhibits Smo accumulation and activation but upon binding of Hedgehog ligands (by an autocrine or paracrine fashion) Ptch is now unable to inhibit Smo (evidence exists that Ptch is now targeted for degradation) and Smo can now inhibit Sufu-dependent and GSK-3B dependent induced degradation of Gli factors Gli1 and Gli2. Also note the Gli1 and Gli2 are transcriptional activators while Gli3 is a transcriptional repressor.

UPDATED 4/16/2019

Please click on the following links for the Powerpoint presentation for lesson 9. In addition click on the mp4 links to download the movies so you can view them in Powerpoint slide 22:

cell motility 9 lesson_SJW 2019

movie file 1:

Tumorigenic but noninvasive MCF-7 cells motility on an extracellular matrix derived from normal (3DCntrol) or tumor associated (TA) fibroblasts. Note that TA ECM is “soft” and not organized and tumor cells appear to move randomly if much at all.

Movie 2:

Note that these tumorigenic and invasive MDA-MB-231 breast cancer cells move in organized patterns on organized ECM derived from Tumor Associated (TA) fibroblasts than from the ‘soft’ or unorganized ECM derived from normal (3DCntrl) fibroblasts

The following contain curations of scientific articles from the site https://pharmaceuticalintelligence.com intended as additional reference material to supplement material presented in the lecture.

Wnts are a family of lipid-modified secreted glycoproteins which are involved in:

Normal physiological processes including

A. Development:

– Osteogenesis and adipogenesis (Loss of wnt/β‐catenin signaling causes cell fate shift of preosteoblasts from osteoblasts to adipocytes)

– embryogenesis including body axis patterning, cell fate specification, cell proliferation and cell migration

B. tissue regeneration in adult tissue

read: Wnt signaling in the intestinal epithelium: from endoderm to cancer

And in pathologic processes such as oncogenesis (refer to Wnt/β-catenin Signaling [7.10]) and to your Powerpoint presentation

The curation Wnt/β-catenin Signaling is a comprehensive review of canonical and noncanonical Wnt signaling pathways

To review:

Activating the canonical Wnt pathway frees B-catenin from the degradation complex, resulting in B-catenin translocating to the nucleus and resultant transcription of B-catenin/TCF/LEF target genes.

Fig. 1 Canonical Wnt/FZD signaling pathway. (A) In the absence of Wnt signaling, soluble β-catenin is phosphorylated by a degradation complex consisting of the kinases GSK3β and CK1α and the scaffolding proteins APC and Axin1. Phosphorylated β-catenin is targeted for proteasomal degradation after ubiquitination by the SCF protein complex. In the nucleus and in the absence of β-catenin, TCF/LEF transcription factor activity is repressed by TLE-1; (B) activation of the canonical Wnt/FZD signaling leads to phosphorylation of Dvl/Dsh, which in turn recruits Axin1 and GSK3β adjacent to the plasma membrane, thus preventing the formation of the degradation complex. As a result, β-catenin accumulates in the cytoplasm and translocates into the nucleus, where it promotes the expression of target genes via interaction with TCF/LEF transcription factors and other proteins such as CBP, Bcl9, and Pygo.

NOTE: In the canonical signaling, the Wnt signal is transmitted via the Frizzled/LRP5/6 activated receptor to INACTIVATE the degradation complex thus allowing free B-catenin to act as the ultimate transducer of the signal.

Remember, as we discussed, the most frequent cancer-related mutations of WNT pathway constituents is in APC.

This shows how important the degradation complex is in controlling canonical WNT signaling.

Other cell signaling systems are controlled by protein degradation:

A. The Forkhead family of transcription factors

Read: Regulation of FoxO protein stability via ubiquitination and proteasome degradation

B. Tumor necrosis factor α/NF κB signaling

Read: NF-κB, the first quarter-century: remarkable progress and outstanding questions

1. Question: In cell involving G-proteins, the signal can be terminated by desensitization mechanisms. How is both the canonical and noncanonical Wnt signal eventually terminated/desensitized?

We also discussed the noncanonical Wnt signaling pathway (independent of B-catenin induced transcriptional activity). Note that the canonical and noncanonical involve different transducers of the signal.

Noncanonical WNT Signaling

Note: In noncanonical signaling the transducer is a G-protein and second messenger system is IP₃/DAG/Ca++ and/or kinases such as MAPK, JNK.

Depending on the different combinations of WNT ligands and the receptors, WNT signaling activates several different intracellular pathways (i.e. canonical versus noncanonical)

In addition different Wnt ligands are expressed at different times (temporally) and different cell types in development and in the process of oncogenesis.

The following paper on Wnt signaling in ovarian oncogenesis shows how certain Wnt ligands are expressed in normal epithelial cells but the Wnt expression pattern changes upon transformation and ovarian oncogenesis. In addition, differential expression of canonical versus noncanonical WNT ligands occur during the process of oncogenesis (for example below the authors describe the noncanonical WNT5a is expressed in normal ovarian epithelia yet WNT5a expression in ovarian cancer is lower than the underlying normal epithelium. However the canonical WNT10a, overexpressed in ovarian cancer cells, serves as an oncogene, promoting oncogenesis and tumor growth.

Wnt5a Suppresses Epithelial Ovarian Cancer by Promoting Cellular Senescence

Benjamin G. Bitler,¹ Jasmine P. Nicodemus,¹ Hua Li,¹ Qi Cai,² Hong Wu,³ Xiang Hua,⁴ Tianyu Li,⁵ Michael J. Birrer,⁶Andrew K. Godwin,⁷ Paul Cairns,⁸ and Rugang Zhang^1,*

A. Abstract

Epithelial ovarian cancer (EOC) remains the most lethal gynecological malignancy in the US. Thus, there is an urgent need to develop novel therapeutics for this disease. Cellular senescence is an important tumor suppression mechanism that has recently been suggested as a novel mechanism to target for developing cancer therapeutics. Wnt5a is a non-canonical Wnt ligand that plays a context-dependent role in human cancers. Here, we investigate the role of Wnt5a in regulating senescence of EOC cells. We demonstrate that Wnt5a is expressed at significantly lower levels in human EOC cell lines and in primary human EOCs (n = 130) compared with either normal ovarian surface epithelium (n = 31; p = 0.039) or fallopian tube epithelium (n = 28; p < 0.001). Notably, a lower level of Wnt5a expression correlates with tumor stage (p = 0.003) and predicts shorter overall survival in EOC patients (p = 0.003). Significantly, restoration of Wnt5a expression inhibits the proliferation of human EOC cells both in vitro and in vivo in an orthotopic EOC mouse model. Mechanistically, Wnt5a antagonizes canonical Wnt/β-catenin signaling and induces cellular senescence by activating the histone repressor A (HIRA)/promyelocytic leukemia (PML) senescence pathway. In summary, we show that loss of Wnt5a predicts poor outcome in EOC patients and Wnt5a suppresses the growth of EOC cells by triggering cellular senescence. We suggest that strategies to drive senescence in EOC cells by reconstituting Wnt5a signaling may offer an effective new strategy for EOC therapy.

Oncol Lett. 2017 Dec;14(6):6611-6617. doi: 10.3892/ol.2017.7062. Epub 2017 Sep 26.

Clinical significance and biological role of Wnt10a in ovarian cancer.

Li P¹, Liu W¹, Xu Q¹, Wang C¹.

Ovarian cancer is one of the five most malignant types of cancer in females, and the only currently effective therapy is surgical resection combined with chemotherapy. Wnt family member 10A (Wnt10a) has previously been identified to serve an oncogenic function in several tumor types, and was revealed to have clinical significance in renal cell carcinoma; however, there is still only limited information regarding the function of Wnt10a in the carcinogenesis of ovarian cancer. The present study identified increased expression levels of Wnt10a in two cell lines, SKOV3 and A2780, using reverse transcription-polymerase chain reaction. Functional analysis indicated that the viability rate and migratory ability of SKOV3 cells was significantly inhibited following Wnt10a knockdown using short interfering RNA (siRNA) technology. The viability rate of SKOV3 cells decreased by ~60% compared with the control and the migratory ability was only ~30% of that in the control. Furthermore, the expression levels of β-catenin, transcription factor 4, lymphoid enhancer binding factor 1 and cyclin D1 were significantly downregulated in SKOV3 cells treated with Wnt10a-siRNA3 or LGK-974, a specific inhibitor of the canonical Wnt signaling pathway. However, there were no synergistic effects observed between Wnt10a siRNA3 and LGK-974, which indicated that Wnt10a activated the Wnt/β-catenin signaling pathway in SKOV3 cells. In addition, using quantitative PCR, Wnt10a was overexpressed in the tumor tissue samples obtained from 86 patients with ovarian cancer when compared with matching paratumoral tissues. Clinicopathological association analysis revealed that Wnt10a was significantly associated with high-grade (grade III, P=0.031) and late-stage (T4, P=0.008) ovarian cancer. Furthermore, the estimated 5-year survival rate was 18.4% for patients with low Wnt10a expression levels (n=38), whereas for patients with high Wnt10a expression (n=48) the rate was 6.3%. The results of the present study suggested that Wnt10a serves an oncogenic role during the carcinogenesis and progression of ovarian cancer via the Wnt/β-catenin signaling pathway.

Targeting the Wnt Pathway includes curations of articles related to the clinical development of Wnt signaling inhibitors as a therapeutic target in various cancers including hepatocellular carcinoma, colon, breast and potentially ovarian cancer.

2. Question: Given that different Wnt ligands and receptors activate different signaling pathways, AND WNT ligands can be deferentially and temporally expressed in various tumor types and the process of oncogenesis, how would you approach a personalized therapy targeting the WNT signaling pathway?

3. Question: What are the potential mechanisms of either intrinsic or acquired resistance to Wnt ligand antagonists being developed?

Targeting the Wnt Pathway [7.11]

Wnt/β-catenin Signaling [7.10]

Cancer Signaling Pathways and Tumor Progression: Images of Biological Processes in the Voice of a Pathologist Cancer Expert

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

Electronic Scientific AGORA: Comment Exchanges by Global Scientists on Articles published in the Open Access Journal @pharmaceuticalintelligence.com – Four Case Studies

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Electronic Scientific AGORA: Comment Exchanges by Global Scientists on Articles published in the Open Access Journal @pharmaceuticalintelligence.com – Four Case Studies

Posted in Curation, Curation methodology, De novo synthesis, Explanatory, LPBI Group, e-Scientific Media, DFP, R&D-M3DP, R&D-Drug Discovery, US Patents: SOPs and Team Management, Open Access Journals, Scientific Publishing, Scientist: Career considerations, tagged Electronic Scientific AGORA on April 10, 2018| Leave a Comment »

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

Development of the Methodology for Curation of Scientific Findings, Curation of Scientific Content @Leaders in Pharmaceutical Business Intelligence (LPBI) Group, Boston

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

edit this on October 17, 2012 at 2:18 PM | Reply2012pharmaceutical

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.
edit this on October 18, 2012 at 12:57 PM | ReplyFred Brouns

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?
edit this on October 18, 2012 at 3:35 PM | Replylarryhbern

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.
edit this on October 18, 2012 at 8:25 PM | ReplyKarthikeyan

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?
- edit this on January 9, 2013 at 1:56 PM | Replymjg5
  
  High dose IV vitamin C may be an excellent choice since its structure is similar to glucose and utilizes the same transport system.
edit this on October 19, 2012 at 8:42 AM | Replylarryhbern

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.
edit this on October 23, 2012 at 10:10 PM | ReplyDr. Otto Warburg, Nobel Prize Winner, on Cancer « THE SCARECROW

[…] Is the Warburg Effect the cause or the effect of cancer: A 21st Century View? (pharmaceuticalintelligence.com) […]
edit this on November 2, 2012 at 9:05 AM | ReplyOtto Warburg, A Giant of Modern Cellular Biology « Pharmaceutical Intelligence

[…] Is the Warburg Effect the cause or the effect of cancer: A 21st Century View? (pharmaceuticalintelligence.com) […]
edit this on November 12, 2012 at 5:39 PM | ReplyMart Caniza

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)
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
- edit this on November 12, 2012 at 6:52 PM | Replylarryhbern
  
  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.
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….
edit this on November 12, 2012 at 8:55 PM | Replyhijoprodigoendistancia

Larry, all comments are part of the second paper.
- edit this on January 9, 2013 at 2:00 PM | Replymjg5
  
  When you publish the paper can yuo be so kind to send me a copy of the series? My email is michael.gonzalez5@upr.edu
edit this on November 30, 2012 at 6:04 PM | ReplyHistone Deacetylase Inhibitors Induce Epithelial-to-Mesenchymal Transition in Prostate Cancer Cells « Pharmaceutical Intelligence

[…] Is the Warburg Effect the cause or the effect of cancer: A 21st Century View? […]
edit this on December 6, 2012 at 10:19 PM | ReplyWhat can we expect of tumor therapeutic response? « Pharmaceutical Intelligence

[…] Is the Warburg Effect the cause or the effect of cancer: A 21st Century View? […]
edit this on January 3, 2013 at 11:11 AM | ReplyDifferentiation Therapy – Epigenetics Tackles Solid Tumors « Pharmaceutical Intelligence

[…] Is the Warburg Effect the cause or the effect of cancer: A 21st Century View? […]
edit this on January 9, 2013 at 2:34 PM | Replymjg5

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.
edit this on January 29, 2013 at 8:56 PM | ReplyDirections for genomics in personalized medicine « Pharmaceutical Intelligence

[…] 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… […]
edit this on February 8, 2013 at 5:24 PM | ReplyThe Initiation and Growth of Molecular Biology and Genomics « Pharmaceutical Intelligence

[…] The Initiation and Growth of Molecular Biology and Genomics, Part I […]
edit this on March 4, 2013 at 4:16 PM | ReplyBreast Cancer and Mitochondrial Mutations | Pharmaceutical Intelligence

[…] 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) […]
edit this on March 12, 2013 at 1:33 PM | ReplyAMPK Is a Negative Regulator of the Warburg Effect and Suppresses Tumor Growth In Vivo | Pharmaceutical Intelligence

[…] Is the Warburg Effect the cause or the effect of cancer: A 21st Century View? […]
edit this on March 17, 2013 at 1:17 AM | Replye-Recognition via Friction-free Collaboration over the Internet: “Open Access to Curation of Scientific Research” | Pharmaceutical Intelligence

[…] Is the Warburg Effect the cause or the effect of cancer: A 21st Century View? […]
edit this on April 6, 2013 at 11:13 AM | ReplyTargeting Mitochondrial-bound Hexokinase for Cancer Therapy | Pharmaceutical Intelligence

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edit this on April 15, 2013 at 4:11 PM | ReplyWe celebrate 800 articles, 4040 tags, 158,147 views, first article 4/30/2012 – Open Access Online Scientific Journal | Pharmaceutical Intelligence

[…] Is the Warburg Effect the cause or the effect of cancer: A 21st Century View? […]
edit this on April 29, 2013 at 6:09 PM | Replymjg5Michael

Thank you!
edit this on April 30, 2013 at 5:37 PM | ReplyCelebrating the First Anniversary of PharmaceuticalIntelligence.com, 4/30/2012 – 4/30/2013 | Pharmaceutical Intelligence

[…] Is the Warburg Effect the cause or the effect of cancer: A 21st Century View? […]
edit this on May 13, 2013 at 10:23 AM | ReplyLate Onset of Alzheimer’s Disease and One-carbon Metabolism | Pharmaceutical Intelligence

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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.
edit this on July 13, 2013 at 7:51 AM | ReplyMetabolomics based biomarker discoveries | Pharmaceutical Intelligence

[…] https://pharmaceuticalintelligence.com/2012/10/17/is-the-warburg-effect-the-cause-or-the-effect-of-ca… […]
edit this on November 16, 2013 at 12:31 PM | ReplyViorel Bungau

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
- edit this on November 16, 2013 at 2:10 PM | Reply2012pharmaceutical
  
  Dr. Viorel Bungau,
  
  Your comment is beautiful, clorful, insightful, magestic.
  
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edit this on November 16, 2013 at 1:31 PM | Replyviorelbungau20

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
edit this on November 28, 2013 at 1:01 PM | ReplyWarburg Effect Revisited | Pharmaceutical Intelligence

[…] 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… […]

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

edit this on October 16, 2012 at 10:30 AM | Reply2012pharmaceutical

GREAT work.

I’ll read and comment later on
edit this on October 17, 2012 at 1:49 PM | Reply2012pharmaceutical

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.
edit this on December 1, 2012 at 6:29 AM | ReplyBB

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 !
edit this on December 1, 2012 at 6:48 AM | Reply2012pharmaceutical

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.
edit this on December 2, 2012 at 5:01 PM | Replylarryhbern

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.
- edit this on December 6, 2012 at 4:29 AM | ReplyDror Nir
  
  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.
edit this on December 5, 2012 at 2:05 PM | Replylarryhbern

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).
- edit this on December 5, 2012 at 2:16 PM | Reply2012pharmaceutical
  
  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
- edit this on December 6, 2012 at 4:41 AM | ReplyDror Nir
  
  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.
edit this on December 5, 2012 at 2:11 PM | Replylarryhbern

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?
- edit this on December 6, 2012 at 4:50 AM | ReplyDror Nir
  
  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.
edit this on December 5, 2012 at 2:19 PM | Reply2012pharmaceutical

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
edit this on December 5, 2012 at 2:34 PM | Replysjwilliamspa

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.
- edit this on December 6, 2012 at 4:11 AM | ReplyDror Nir
  
  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
  
  web: http://www.radbee.com/
  blogs: http://radbee.wordpress.com/ ; http://www.MedDevOnIce.com
edit this on December 5, 2012 at 2:39 PM | ReplyBB

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 !
- edit this on December 5, 2012 at 3:23 PM | Reply2012pharmaceutical
  
  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.”
- edit this on December 6, 2012 at 5:05 AM | ReplyDror Nir
  
  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….
edit this on December 11, 2012 at 2:34 AM | Replyritusaxena

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
- edit this on December 11, 2012 at 6:10 AM | Reply2012pharmaceutical
  
  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.
- edit this on December 12, 2012 at 7:11 AM | ReplyDror Nir
  
  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!
edit this on December 13, 2012 at 9:20 PM | ReplyImaging and targeting the tumor & predicting tumor response: Where we stand? « Pharmaceutical Intelligence

[…] 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 […]
edit this on February 15, 2013 at 12:20 PM | ReplyOn the road to improve prostate biopsy « RadBee’s Resonance

[…] 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 […]
edit this on February 15, 2013 at 3:20 PM | ReplyOn the road to improve prostate biopsy « Pharmaceutical Intelligence

[…] 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 […]
edit this on March 17, 2013 at 1:17 AM | Replye-Recognition via Friction-free Collaboration over the Internet: “Open Access to Curation of Scientific Research” | Pharmaceutical Intelligence

[…] Knowing the tumor’s size and location, could we target treatment to THE ROI by applying imaging-gu… […]
edit this on October 20, 2013 at 3:33 PM | ReplyWhat can we expect of tumor therapeutic response? | Pharmaceutical Intelligence

[…] https://pharmaceuticalintelligence.com/2012/10/16/knowing-the-tumors-size-and-location-could-we-targe… […]
edit this on October 20, 2013 at 3:43 PM | ReplyPersonalized Medicine: Cancer Cell Biology and Minimally Invasive Surgery (MIS) | Pharmaceutical Intelligence

[…] https://pharmaceuticalintelligence.com/2012/10/16/knowing-the-tumors-size-and-location-could-we-targe… […]

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

edit this on October 16, 2012 at 10:30 AM | Reply2012pharmaceutical

GREAT work.

I’ll read and comment later on
edit this on October 17, 2012 at 1:49 PM | Reply2012pharmaceutical

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.
edit this on December 1, 2012 at 6:29 AM | ReplyBB

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 !
edit this on December 1, 2012 at 6:48 AM | Reply2012pharmaceutical

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.
edit this on December 2, 2012 at 5:01 PM | Replylarryhbern

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.
- edit this on December 6, 2012 at 4:29 AM | ReplyDror Nir
  
  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.
edit this on December 5, 2012 at 2:05 PM | Replylarryhbern

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).
- edit this on December 5, 2012 at 2:16 PM | Reply2012pharmaceutical
  
  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
- edit this on December 6, 2012 at 4:41 AM | ReplyDror Nir
  
  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.
edit this on December 5, 2012 at 2:11 PM | Replylarryhbern

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?
- edit this on December 6, 2012 at 4:50 AM | ReplyDror Nir
  
  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.
edit this on December 5, 2012 at 2:19 PM | Reply2012pharmaceutical

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
edit this on December 5, 2012 at 2:34 PM | Replysjwilliamspa

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.
- edit this on December 6, 2012 at 4:11 AM | ReplyDror Nir
  
  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
  
  web: http://www.radbee.com/
  blogs: http://radbee.wordpress.com/ ; http://www.MedDevOnIce.com
edit this on December 5, 2012 at 2:39 PM | ReplyBB

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 !
- edit this on December 5, 2012 at 3:23 PM | Reply2012pharmaceutical
  
  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.”
- edit this on December 6, 2012 at 5:05 AM | ReplyDror Nir
  
  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….
edit this on December 11, 2012 at 2:34 AM | Replyritusaxena

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
- edit this on December 11, 2012 at 6:10 AM | Reply2012pharmaceutical
  
  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.
- edit this on December 12, 2012 at 7:11 AM | ReplyDror Nir
  
  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

edit this on December 4, 2012 at 2:25 PM | Replysjwilliamspa

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.
edit this on December 4, 2012 at 4:48 PM | Replyritusaxena

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
edit this on December 5, 2012 at 4:40 AM | ReplyBB

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.”
edit this on December 5, 2012 at 5:34 AM | Replyritusaxena

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
edit this on December 5, 2012 at 6:34 AM | Reply2012pharmaceutical

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.
edit this on December 5, 2012 at 6:43 AM | Replyritusaxena

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
- edit this on December 5, 2012 at 6:58 AM | Reply2012pharmaceutical
  
  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.
- edit this on December 5, 2012 at 8:37 AM | Replylbretes
  
  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.

.

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@PharmaceuticalIntelligence.com – A Case Study on the LEADER in Curation of Scientific Findings

Posted in Curation, Open Access Journals, Scientific Publishing, Scientist: Career considerations, tagged Curation of Scientific Findings, Open access journal on June 29, 2017| Leave a Comment »

@PharmaceuticalIntelligence.com – A Case Study on the LEADER in Curation of Scientific Findings

Author: Aviva Lev-Ari, PhD, RN

Multi-facets of the LPBI Group Intellectual Property (IP) ASSETS

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

FIVE years of e-Scientific Publishing @pharmaceuticalintellicence.com, Top Articles by Author and by e-Views >1,000, 4/27/2012 to 4/27/2017

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

Editorial & Publication of Articles in e-Books by Leaders in Pharmaceutical Business Intelligence: Contributions of Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/10/16/editorial-publication-of-articles-in-e-books-by-leaders-in-pharmaceutical-business-intelligence-contributions-of-larry-h-bernstein-md-fcap/

Editorial & Publication of Articles in e-Books by Leaders in Pharmaceutical Business Intelligence: Contributions of Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/10/16/editorial-publication-of-articles-in-e-books-by-leaders-in-pharmaceutical-business-intelligence-contributions-of-aviva-lev-ari-phd-rn/

Innovations in e-Scientific Publishing Methodology Development accomplished by LPBI Group:

A. Methodology for Curation of Scientific Findings – implementations for

Multi-Auhtors Authoring Cloud-based Platform

Journal Statistics – Interdisciplinary Journal covers interfaces of six domains (Life sciences, Pharmaceuticals, Medicine, Healthcare Policy, Biotech Intelligence and Medical Devices)

Curations of Scientific Findings of peer reviewed articles in top three journals in each of the Six domain

Curations written on a multi-Authoring platform by MDs, MD/PhDs, PharmD and PhDs, all 15 years after graduation of the advanced degree program, and each has a publication list before joined my team – they write clinical and medical interpretations of the scientific frontier as evidenced in the Scientific Finding section of published articles in Cell, Nature, Science, NEJM, other top journals in these six domains.

Volume: 1.3 Million eReaders, ~5,150 Scientific articles, +500 categories of Research defining the Journal Ontology, 9,500 tags, 7,300, scientific comment on the articles submitted and exchange recorded between the Scientific community and our Team members

Top two articles >25,000 eReaders

Clicks on two Top Authors: >551,000

from NIH +3,700 hits

2250 Journal subscribers by e-mail

+6,200 Biotech Executive following up on LinkedIn

BioMed e-Series of e-Books in Medicine – 16 Volumes in Five e-Series: Cardiovascular, Genomics, Cancer, Immunology, Patient-centered Medicine

https://www.amazon.com/s/ref=dp_byline_sr_ebooks_9?ie=UTF8&text=Aviva+Lev-Ari&search-alias=digital-text&field-author=Aviva+Lev-Ari&sort=relevancerank

Team expertise

B. Methodology for REAL TIME Coverage of Scientific Conferences using Social Media and Real Time e-Proceedings Generation: Conferences in Biotech, Life Sciences and Medicine

In House Developed Methodology for Real Time Press Coverage of Biotech Top International conferences – selective topics covered at conferences lead to NEW Curations in the Journal

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

9 results for Kindle Store : “Aviva Lev-Ari”

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Cancer Therapies: Metabolic, Genomics, Interventional, Immunotherapy and Nanotechnology in Therapy Delivery (Series C Book 2)

May 13, 2017 | Kindle eBook

by Larry H. Bernstein and Demet Sag

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Etiologies of Cardiovascular Diseases: Epigenetics, Genetics and Genomics

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by Justin D. Pearlman MD ME PhD MA FACC and Stephen J. Williams PhD

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Perspectives on Nitric Oxide in Disease Mechanisms (Biomed e-Books Book 1)

Jun 20, 2013 | Kindle eBook

by Margaret Baker PhD and Tilda Barliya PhD

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Genomics Orientations for Personalized Medicine (Frontiers in Genomics Research Book 1)

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by Sudipta Saha PhD and Marcus W Feldman PhD

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Metabolic Genomics & Pharmaceutics (BioMedicine – Metabolomics, Immunology, Infectious Diseases Book 1)

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by Larry H. Bernstein MD FCAP and Prabodah Kandala PhD

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Milestones in Physiology: Discoveries in Medicine, Genomics and Therapeutics (Series E: Patient-Centered Medicine Book 3)

Dec 26, 2015 | Kindle eBook

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

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Cancer Biology and Genomics for Disease Diagnosis (Series C: e-Books on Cancer & Oncology Book 1)

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by Larry H Bernstein MD FCAP and Prabodh Kumar Kandala PhD

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Regenerative and Translational Medicine: The Therapeutic Promise for Cardiovascular Diseases

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by Justin D. Pearlman MD ME PhD MA FACC and Ritu Saxena PhD

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

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

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Three Genres in e-Scientific Publishing AND Three Scientists’ Dilemmas

Posted in Curation, Curation methodology, Discovery process, Open Access Journals, Scientific Publishing, Scientist: Career considerations on June 28, 2017| Leave a Comment »

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 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 Free content to e-Readers Expert, Authors, Writers -Volunteers 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?

Stephen Buranyi – 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 of $2m – 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.) Stephen Buranyi – June 27, 2017. Elsevier published 420,000 papers last year, after receiving 1.5m submissions Stephen Buranyi – June 28, 2017 [numbers correction to 6/27/2017.]

(B) Open Access Journals and the Phenomenon

Biochemistry
Biophysics and Structural Biology
Cancer Biology
Cell Biology
Computational and Systems Biology
Developmental Biology and Stem Cells
Epidemiology and Global Health
Genomics and Evolutionary Biology
Microbiology and Infectious Disease
Neuroscience

(C) Curation of Scientific Findings

Science and Curation: The New Practice of Web 2.0
Scoop.it
PharmaceuticalIntelligence.com – The LEADER in that Genre

Scientists’ Dilemmas

(1) Confirming or disproving past studies

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

(3) Trendy Topics with Editors

@ 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/

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

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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

Posted in Curation, LPBI Group, e-Scientific Media, DFP, R&D-M3DP, R&D-Drug Discovery, US Patents: SOPs and Team Management on June 20, 2017| Leave a Comment »

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

Author and Editor-in-Chief: Aviva Lev-Ari, PhD, RN,

Nominee for 2018 Yidan Foundation Prize for Medical Education Content Development

Aviva Lev-Ari on 9/2009

Recollections: My days at Berkeley, 9/1978 – 12/1983 – About my doctoral advisor, Allan Pred, other Professors and other Peers

Reflections on a Four-phase Career: Aviva Lev-Ari, PhD, RN, March 2018

Updated on 4/2/2018

Question: WHAT MAKES us so unique

The JOURNAL pharmaceuticlintelligence.com
The BioMed e-Series – 16-Volume five e-Series in Medicine and Life Sciences

Answers: 1,2,3,4

1. Sustainability

The books are online topics in medical science, diagnostics and therapy that are maintained by updating the chapter material in the Biomed e-series directly pertaining to the chapter content that is directly available from the e-series online. The Chapters are compiled from detailed review of the available literature, and the content of each book is related to current concepts researched and coordinated for the published work. One of the Research Categories: Interviews with Scientific Leaders includes in its growth plan the option of Podcasts which is an Audio Media component to supplement the video media component which is used extensively in the BioMed e-Series

How we accomplish the Sustainability goal:

Online continuing updates are made to articles in the Journal
Each e-Book has an abbreviated electronic Table of Contents which consists of LIVE LINKS for each article in an e-Book to the article in the Journal. eReaders of the e-Books clicks on the link and get the most updated State of Science for each topic in the e-books.
Journal Ontology is a relational and hierarchical knowledge base allowing for expansion of the content creation process on these two dimensions and is not limited to these two. For example: One of the Research Categories: Interviews with Scientific Leaders includes in its growth plan the option of Podcasts which is an Audio Media component to supplement the video media component which is used extensively in the BioMed e-Series.

2. A Future-Oriented Vision

Cutting edge research is the content of a research reservoir that allows for the creation of up-to-date content, and which supports new developments as they arise. The cutting edge concepts are reviewed in concordance with timely conferences on topical material. These conferences are also recorded and conveyed in the related documents. Since 2013, International leading Breakthroughs in BioTechnology Conferences are covered in Real Time by Dr. Aviva Lev-Ari on PRESS Pass.

How we accomplish the Future-Oriented Vision goal:

The Intellectual Property Vault (N= +5,200) has the potential of being used for creation of New Titles for New e-Books. It is a reservoir of Ideas in the form of Research Categories populated by Scientific Curations
Online reach is growing and is driven by cutting edge subject matters added on a continuous basis to the Intellectual Property Vault
Innovations in Drug Discovery and Drug Delivery are covered in Real Time, on average up to 12 per year
See Section
In 2018, the list of International leading Breakthroughs in BioTechnology Conferences that will be covered in Real Time by Aviva Lev-Ari, PhD, RN includes the following, as confirmed on 1/2018, more will be confirmed in during 2018:

AI & Machine Learning in Clinical Trials, APRIL 12, 2018 PFIZER INNOVATION RESEARCH LAB – CAMBRIDGE, MA

https://pharmaceuticalintelligence.com/2018/04/02/ai-machine-learning-in-clinical-trials-april-12-2018-pfizer-innovation-research-lab-cambridge-ma/

2018 Annual World Medical Innovation Forum Artificial Intelligence April 23–25, 2018 Boston, Massachusetts, Westin Copley Place

https://pharmaceuticalintelligence.com/2018/01/18/2018-annual-world-medical-innovation-forum-artificial-intelligence-april-23-25-2018-boston-massachusetts-westin-copley-place/

12th Annual US-India BioPharma & Healthcare Summit, May 8, 2018, Marriott Cambridge

https://pharmaceuticalintelligence.com/2018/01/18/12th-annual-us-india-biopharma-healthcare-summit-may-8-2018-marriott-cambridge/

The 14th Annual Personalized Medicine Conference, November 13 – 15, 2018, Joseph B. Martin Conference Center, HARVARD MEDICAL SCHOOL, Boston

http://www.personalizedmedicinecoalition.org/Events

3. Transformation

We Focus on Transformative subject matters:
Examples: We published e-Books on

Regenerative and Translation Medicine
Next Generation Sequencing in Genomics (work-in-progress)
Epigenetics, Genetics and Genomics
Precision Medicine & Voices of Patients

These contents are timely and among other material are subject to periodic updating. The reports are subject to a rigorous process of investigation, up-to-date reporting, analysis, and interpretation. The curation is done by experts with a perspective on the field allowing for the creation of the scientific CONTEXT that unifies the concept evolution with the breakthrough presented at hand and the future implications to be anticipated.

How we accomplish the Transformation goal:

Methodology of Curation is Transformative as a Medium for written scientific communication: Synthesis, Analysis and Interpretation

Experts, Authors, Writers add their depth in thinking on subjects to the breath of materials selected by their expertise to be forming new curations or updating existing ones
It is transformative in its capacity to accelerated diffusion of scientific innovations process, the curation is done by experts with a perspective on the field allowing for the creation of the scientific CONTEXT that unifies the concept evolution with the breathrough presented at hand and the future implications to be anticipated. In an analogy, it is an expressive medium for creative exposition of multiple combinations of Past, Present, Future tenses in grammar, when the presentation is on the continuous process of discovery.

4. Innovation & Creativity

The content available provides commentaries on each Volume’s Contribution to Medical Education by L.H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN. In addition, it provides a knowledge architecture that features Innovative ideas that tackle pressing challenges in the field of Medical Education. Content includes methodology development for: Curation of Scientific Findings by Experts; Actual Curations, “Mapping” the Medicine Disciplines; Exposition of the Scientific Frontier in Five Specialties in Medicine, and then also pressing challenges in the field of Medical Education such as the Digital Information Explosion in the fields of Life Sciences and Medicine; and finally the Pursuit of Excellence in Content Creation by Curation Methodology for Medical subject matters in multiple areas of the Health Care field.

How we accomplish the Innovation & Creativity goal:

Seven factors are presented, below

F1 What was accomplished by Development of the Curation Methodology

F2 Method Selection of the Open Access Journal Publishing Medium

F3 Selection of electronic Books vs Hardcover or Softcover type of product

F4 Examples of Creative Article Titles

F5 Examples of Creative eTOCs

F6 Examples of Hierarchical Ontologies created by Experts/Authors/Writers for selected Categories of Research with +500 Articles

F7. Articles of Note on selective Research Topic @PharmaceuticalIntelligence

The Body of Work

A. Publication of the BioMedical e-Books e-Series, 2013 – Present

This is the link to Amazon.com, Kindle Store’s Page for the 13 volumes published till 12/30/2017

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

These are the links to Amazon.com, Kindle Store’s Page for each volume

http://www.amazon.com/dp/B00DINFFYC

http://www.amazon.com/dp/B018Q5MCN8

http://www.amazon.com/dp/B018PNHJ84

http://www.amazon.com/dp/B018DHBUO6

http://www.amazon.com/dp/B013RVYR2K

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

http://www.amazon.com/dp/B019UM909A

http://www.amazon.com/dp/B019VH97LU

http://www.amazon.com/dp/B071VQ6YYK

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

https://www.amazon.com/dp/B076HGB6MZ

https://www.amazon.com/dp/B078313281

https://www.amazon.com/dp/B078QVDV2W

B. BioMedical e-Books e-Series: Multiple Volumes in Five e-Series with Commentaries on each Volume’s Contribution to Medical Education by L.H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

Commentaries on each Volume’s 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

C. electronic Table of Contents (eTOCs) of each Volume in the SIXTEEN-Volume BioMed e-Series

https://pharmaceuticalintelligence.com/2017/12/12/biomed-e-series-16-volumes-electronic-table-of-contents-of-each-volume/

Analytics for the BioMed e-Series based on:

Number of Articles per Volume
E-Readers per Article
Volume e-Impression since DATE of Publication [Summation of 2, above for all articles inside each Volume, before it was inside an e-Book and after the DATE of publication [Product details per Volume in attachment – Five e-Series – several Volumes per e-Series] PENDING

D. Innovative ideas that tackle pressing challenges in the field of Medical Education: Knowledge Architecture

D1 Methodology Development for Content Creation targeted at Medical and Life Sciences Education (Curation of Scientific Findings by Experts)

D2 Methodology Development for Scientific Inquiry in Medicine: Case Studies in a Medical Specialty – Application of the Methodology of Curation to Case Studies – Published as a Book, 2015

D3 Methodology Development for Mapping the Medicine Discipline for Education

D4 Methodology Development for Exposition of the Scientific Frontier in Five Specialties in Medicine (D4.1, D4.2, D4.3, D4.4, D4.5).

E. Innovative ideas that tackle pressing challenges in the field of Medical Education: Digital Information Explosion in the fields of Life Sciences and Medicine

E1 Open Access Scientific Journal Launch in Biomedicine and Site Statistics:

+1.3 Million eReaders and eSubscribers

E2 Journal Ontology for Knowledge Architecture – +600 Categories of Research

E3 Intellectual Property Vault: Knowledge Base of +5,200 Scientific articles applying the Curation of Scientific Findings Methodology

E4 Scientific Agora: Multi Scientific Comment exchanges between e-Readers Scientists and LPBI’s Scientists/Experts/Authors/Writers

E5 Real Time (RT) Press Coverage of Leading Conferences in BioMedicine: RT Methodology and the Archive

E6 Impact of E5 on E3

F. Innovation & Creativity Demonstrated in the Pursuit of Content Creation by Curation Methodology for Medical Education. For us perfection of the application process of curation methodologies in Medicine is a pursuit of excellence in the creation of content in Life Sciences and in Medicine.

F1 What was accomplished in five years by Development of the Curation Methodology

F2 Method Selection of the Open Access Journal Publishing Medium

F3 Selection of electronic Books vs Hardcover or Softcover type of product

F4 Examples of Creative Article Titles

F5 Examples of Creative eTOCs

F6 Examples of Hierarchical Ontologies created by Experts/Authors/Writers for selected Categories of Research with +500 Articles

F7 Articles of Note in selective Research Topic @PharmaceuticalIntelligence

G. Editor-in-Chief’s Roles and Accomplishments

G1 Curation Methodology Development

G2 Content Creation and Key Opinion Leader (KOL) Recognition

Editorial & Publication of Articles in e-Books by Leaders in Pharmaceutical Business Intelligence: Contributions of Aviva Lev-Ari, PhD, RN

G2.1         Volume of Articles in the Journal and in the 16 Volume-BioMed e-Series

G2.2         Digital Presence

G2.3         Digital KOL Parameters

G3 Team building: Editors and Expert, Authors, Writers

G4 Book Title Generation and Cover Page Design

G5 Style Setting: Instruction manual for Journal, Articles, Books

G6 Annual Workflow Management of Multiple eTOCs – Multi-year Book Publishing Scheduling Plan, 2013 – Present

In this article I cover the Business Synopsis and the following Four Parts of the Business:

Part 1: The Vision

Part 2: Scientific Journal – Site Statistics on 6/20/2017

Part 3: BioMed e-Series

Part 4: Real Time (RT) Press Coverage of 50 Biotech Top Conferences

Synopsis

Dr. Aviva Lev-Ari, PhD, RN has launched in 4/2012 the PharmaceuticalIntelligence.com an Internet-based website as an educational Open Access Online Scientific Journal. On 10/2012 Dr. Lev-Ari, launched a BioMed e-Series of electronic Book in Medicine and Life Sciences which use the Kindle Direct Publishing platform for book publishing by Amazon.com.

The books having evolved for six years from specifically identified topics in Medicine and Biomedical Sciences, including molecular biology, genomics, pharmaceutics and pathophysiology. There have been a number of contributors with the necessary professional competences. The books have been organized into five series that include cardiovascular, genomics, proteomics, pharmacotherapy, cancer and carcinogenesis, infectious disease and immune mechanisms. In addition to these basic disciplines for study there are also important deliberations on the history of medicine and physiology and a focus on the impact of disease on human experience in three books of Series E: Patient-centered Medicine.

The work involved in the writing took many hundreds of hours of study and preparation. These sources have considerable electronic readership (+1.3Million) and have a potential for growing use in teaching of medical students, advanced undergraduate and graduate students in Medical Sciences. Currently, two e-Books are used in curriculum development in Medical Schools in the US. An outreach plan for Deans of Medical Schools and Oncologists and Cardiologists in the Community Hospitals and Clinics is in the making.

The XXXXXXX Prize is awarded for outstanding contributions to education. In this respect the contributions of PharmaceuticalIntelligence.com current and authentic documents is deserving of consideration. Nomination is submitted for recognition as a means in tackling challenges in the field of MEDICAL education, and especially the “Sixteen Volumes in Medicine and Life Sciences” which are LPBI Group’s BioMed e-Series, an initiative of innovative ideas and development of curation methodologies for scientific contents. The BioMedical e-Books e-Series, 2013 – present, includes Commentaries on each Volume’s Contribution to Medical Education by L.H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN. In addition, there is supporting material for an understanding of the role played by electronic Scientific Publishing in mastering the continued progress in Medical Sciences for the electronic exposition of the process used in new scientific content creations. These topics are fully covered in the BioMed e-series. Volume Two in Series A is dedicated to the Curation methodology of scientific findings.

Highlights

Interdisciplinary Journal covers interfaces of six domains

(Life sciences, Pharmaceuticals, Medicine, Healthcare Policy, Biotech Intelligence and Medical Devices)

Curations of Scientific Findings of peer reviewed articles in top three journals in each of the Six domain
Curations written on a multi-Authoring platform by MDs, MD/PhDs, PharmD and PhDs, all 15 years after graduation of the advanced degree program, and each has a publication list before joined my team – they write clinical and medical interpretations of the scientific frontier as evidenced in the Scientific Finding section of published articles in Cell, Nature, Science, NEJM, other top journals in these six domains.
Volume, ~5,150 Scientific articles, +500 categories of Research defining the Journal Ontology, 9,500 tags, 7,300, scientific comment on the articles submitted and exchange recorded between the Scientific community and our Team members
Top two articles >25,000 eReaders
Clicks on two Top Authors: >551,000
from NIH +3,700 hits
2250 Journal subscribers by e-mail
+6,200 Biotech Executive following up on LinkedIn
BioMed e-Series: 16 volumes, 13 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

In House Developed Methodology for Real Time Press Coverage of Biotech Top International conferences – selective topics covered at conferences lead to NEW Curations in the Journal

Part 1: The Vision

https://pharmaceuticalintelligence.com/vision/

Part 2: Scientific Journal – Site Statistics on 4/2/2018

https://pharmaceuticalintelligence.com/

1,407,787 Million eReaders on WordPress.com in 4/2018

Best ever daily views

2,508 views

Our DOMAINS in Scientific Media

I. Pharmaceutical: Biologics, Small Molecules, Diagnostics

II. Life Sciences: Genomics and Cancer Biology

III. Patient-centered Medicine: Focus on #1: Cardiovascular, #2: Cancer, #3: Physiology: Metabolomics, Immunology

IV. Biomedicine, BioTech, and MedTech (Medical Devices)

V. HealthCare: Patient-centered Medicine and Personalized/Precision Medicine

All time

1,239,246 eReaders on 6/25/2017

on 4/2/2018

1,407,787 eReaders &
2,295 Subscribers by e-mail
7,283 Scientific comments
5,291 Scientific Articles
634 Categories of Research – Journal Ontology
9,782 Tags

Followers (includes Publicize)

788 Twitter

699 Facebook

67 Tumblr

All Time

Title		Views
Home page / Archives		535,337
Is the Warburg Effect the Cause or the Effect of Cancer: A 21st Century View?		16,243
Do Novel Anticoagulants Affect the PT/INR? The Cases of XARELTO (rivaroxaban) and PRADAXA (dabigatran)		11,938
Recent comprehensive review on the role of ultrasound in breast cancer management		9,675
Paclitaxel vs Abraxane (albumin-bound paclitaxel)		9,376
Clinical Indications for Use of Inhaled Nitric Oxide (iNO) in the Adult Patient Market: Clinical Outcomes after Use, Therapy Demand and Cost of Care		6,141
Mesothelin: An early detection biomarker for cancer (By Jack Andraka)		5,992
Our TEAM		5,979
Apixaban (Eliquis): Mechanism of Action, Drug Comparison and Additional Indications		4,833
Akt inhibition for cancer treatment, where do we stand today?		4,447
Newer Treatments for Depression: Monoamine, Neurotrophic Factor & Pharmacokinetic Hypotheses		3,995
Biochemistry of the Coagulation Cascade and Platelet Aggregation – Part I		3,805
AstraZeneca’s WEE1 protein inhibitor AZD1775 Shows Success Against Tumors with a SETD2 mutation		3,587
Confined Indolamine 2, 3 dioxygenase (IDO) Controls the Hemeostasis of Immune Responses for Good and Bad		3,582
Cardiovascular Diseases, Volume One: Perspectives on Nitric Oxide in Disease Mechanisms		3,534
AMPK Is a Negative Regulator of the Warburg Effect and Suppresses Tumor Growth In Vivo		3,329
The Centrality of Ca(2+) Signaling and Cytoskeleton Involving Calmodulin Kinases and Ryanodine Receptors in Cardiac Failure, Arterial Smooth Muscle, Post-ischemic Arrhythmia, Similarities and Differences, and Pharmaceutical Targets		3,252
Founder		3,243
BioMed e-Series		3,170
Introduction to Transdermal Drug Delivery (TDD) system and nanotechnology		3,129
FDA Guidelines For Developmental and Reproductive Toxicology (DART) Studies for Small Molecules		3,037

Title		Views
Home page / Archives		460077
Is the Warburg Effect the Cause or the Effect of Cancer: A 21st Century View?		15,602
Do Novel Anticoagulants Affect the PT/INR? The Cases of XARELTO (rivaroxaban) and PRADAXA (dabigatran)		10,279
Recent comprehensive review on the role of ultrasound in breast cancer management		7,782
Paclitaxel vs Abraxane (albumin-bound paclitaxel)		7,111
Our TEAM		5,786
Mesothelin: An early detection biomarker for cancer (By Jack Andraka)		5,513
Clinical Indications for Use of Inhaled Nitric Oxide (iNO) in the Adult Patient Market: Clinical Outcomes after Use, Therapy Demand and Cost of Care		4,731
Akt inhibition for cancer treatment, where do we stand today?		4,131
Newer Treatments for Depression: Monoamine, Neurotrophic Factor & Pharmacokinetic Hypotheses		3,873
Apixaban (Eliquis): Mechanism of Action, Drug Comparison and Additional Indications		3,730
Volume One: Perspectives on Nitric Oxide in Disease Mechanisms		3,471
Confined Indolamine 2, 3 dioxygenase (IDO) Controls the Hemeostasis of Immune Responses for Good and Bad		3,388
AMPK Is a Negative Regulator of the Warburg Effect and Suppresses Tumor Growth In Vivo		3,227
Founder		3,159
BioMed e-Series		3,040

Clicks for all days ending 2018-04-02 (Summarized) – All Time

URL	Clicks
WordPress.com Media	38,388
commons.wikipedia.org	6,447
http://www.ncbi.nlm.nih.gov	4,036
en.wikipedia.org	3,292
http://www.nature.com	3,139
dx.doi.org	1,818
http://www.scoop.it	1,316
pharmaceuticalintelligence.wordpress.com	749
gravatar.com	703
http://www.sciencedirect.com	645
http://www.fda.gov	613
http://www.fiercepharma.com	552
apps.societyforscience.org/intelisef2012/project.cfm?PID=ME028&CFID=28485&CFTOKEN=10931553	550
http://www.cancer.gov	456
informahealthcare.com	413
ars.els-cdn.com	406
http://www.hindawi.com	367
http://www.youtube.com	361
http://www.medscape.com	353
http://www.nejm.org	310
http://www.linkedin.com	300

Referrers for all days ending 2018-04-02 (Summarized) – All Time

Referrer		Views
Search Engines		742,459
linkedin.com		25,349
Facebook		7,662
lnkd.in		6,289
scholar.google.com		4,440
Twitter		3,363
android-app		1,847
investorshub.advfn.com		1,050
WordPress Dashboard		900
scoop.it		826
mail.yahoo.com		781
scholar.google.co.in		630
scholar.google.co.uk		584
WordPress.com Reader		555
avanza.se		401
correio.portugalmail.pt/imp/		381
scholar.google.co.jp		349

Content

Top Authors for all days ending 2018-04-02 (Summarized) – All Time

Author		Views
2012pharmaceutical		359,700
larryhbern	Following	258,904
tildabarliya		53,989
sjwilliamspa	Following	46,989
Dror Nir	Follow	28,039
Dr. Sudipta Saha	Following	25,298
ritusaxena	Following	16,060
Demet Sag, Ph.D., CRA, GCP	Follow	14,927

aviralvatsa	Following	8,437
zraviv06	Following	8,202
Gail S Thornton	Following	5,904
zs22	Following	3,996
danutdaagmailcom	Following	3,594
anamikasarkar	Following	3,380
Alan F. Kaul, PharmD., MS, MBA, FCCP	Following	2,205
pkandala	Follow	2,179
Aashir Awan, Phd	Following	2,006
Irina Robu	Following	1,880
jdpmd	Following	1,639
megbaker58	Following	1,479
S. Chakrabarti, Ph.D.		745
Ed Kislauskis	Following	651
David Orchard-Webb, PhD	Following	579
howarddonohue	Follow	552
stuartlpbi	Following	490
marzankhan	Following	464
evelinacohn	Follow	392
apreconasia	Follow	365
anayou1	Follow	238
jukkakarjalainen	Follow	230
Dr.Sreedhar Tirunagari	Follow	162
lmulligan13gmailcom	Following	147
gerag2015		125

Graphics for 4/2012 to 3/10/2015

Part 3: BioMed e-Series

The Methodology of Co-Curation

Image Source: Original Graphic Conceptualization of the Co-Curation Concept by Stephen J Williams, 3/10/2015

Titles in the BioMed e-Series: 16 e-Books in Medicine and Life Sciences

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

In each e-Book: Curations and Scientific reports by Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/10/16/editorial-publication-of-articles-in-e-books-by-leaders-in-pharmaceutical-business-intelligence-contributions-of-aviva-lev-ari-phd-rn/

13 results for Kindle Store :

“Aviva Lev-Ari”

The VOICES of Patients, Hospitals CEOs, Health Care Providers, Caregivers and Families: Personal Experience with Critical Care and Invasive Medical Procedures … E: Patient-Centered Medicine Book 1)

Oct 16, 2017 | Kindle eBook

by Larry H. Bernstein and Aviva Lev-Ari

$0.00

Subscribers read for free.

Read for Free

$49.00^$ 49 ⁰⁰ to buy Kindle Edition

Get it TODAY, Apr 2

Sold by: Amazon Digital Services LLC
Amazon’s Aviva Lev-Ari Page

Discover books, read about the author, find related products, and more.More about Aviva Lev-Ari
The Immune System, Stress Signaling, Infectious Diseases and Therapeutic Implications: VOLUME 2: Infectious Diseases and Therapeutics and VOLUME 3: The … (Series D: BioMedicine & Immunology)

Sep 4, 2017 | Kindle eBook

by Larry H. Bernstein and Aviva Lev-Ari

$0.00

Subscribers read for free.

Read for Free

$115.00^$ 115 ⁰⁰ to buy Kindle Edition

Get it TODAY, Apr 2

Sold by: Amazon Digital Services LLC
Cancer Therapies: Metabolic, Genomics, Interventional, Immunotherapy and Nanotechnology in Therapy Delivery (Series C Book 2)

May 13, 2017 | Kindle eBook

by Larry H. Bernstein and Demet Sag

$0.00

Subscribers read for free.

Read for Free

$100.00^$ 100 ⁰⁰ to buy Kindle Edition

Get it TODAY, Apr 2

Sold by: Amazon Digital Services LLC
Perspectives on Nitric Oxide in Disease Mechanisms (Biomed e-Books Book 1)

Jun 20, 2013 | Kindle eBook

by Margaret Baker PhD and Tilda Barliya PhD

$0.00

Subscribers read for free.

Read for Free

$75.00^$ 75 ⁰⁰ to buy Kindle Edition

Get it TODAY, Apr 2

6

Sold by: Amazon Digital Services LLC
Medical Scientific Discoveries for the 21st Century & Interviews with Scientific Leaders (Series E)

Dec 9, 2017 | Kindle eBook

by Larry H. Bernstein and Aviva Lev-Ari

$0.00

Subscribers read for free.

Read for Free

$75.00^$ 75 ⁰⁰ to buy Kindle Edition

Get it TODAY, Apr 2

Sold by: Amazon Digital Services LLC
Etiologies of Cardiovascular Diseases: Epigenetics, Genetics and Genomics

Nov 28, 2015 | Kindle eBook

by Justin D. Pearlman MD ME PhD MA FACC and Stephen J. Williams PhD

$0.00

Subscribers read for free.

Read for Free

$75.00^$ 75 ⁰⁰ to buy Kindle Edition

Get it TODAY, Apr 2

Sold by: Amazon Digital Services LLC
Metabolic Genomics & Pharmaceutics (BioMedicine – Metabolomics, Immunology, Infectious Diseases Book 1)

Jul 21, 2015 | Kindle eBook

by Larry H. Bernstein MD FCAP and Prabodah Kandala PhD

$0.00

Subscribers read for free.

Read for Free

$75.00^$ 75 ⁰⁰ to buy Kindle Edition

Get it TODAY, Apr 2

1

Sold by: Amazon Digital Services LLC
Cancer Biology and Genomics for Disease Diagnosis (Series C: e-Books on Cancer & Oncology Book 1)

Aug 10, 2015 | Kindle eBook

by Larry H Bernstein MD FCAP and Prabodh Kumar Kandala PhD

$0.00

Subscribers read for free.

Read for Free

$75.00^$ 75 ⁰⁰ to buy Kindle Edition

Get it TODAY, Apr 2

Sold by: Amazon Digital Services LLC
Milestones in Physiology: Discoveries in Medicine, Genomics and Therapeutics (Series E: Patient-Centered Medicine Book 3)

Dec 26, 2015 | Kindle eBook

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

$0.00

Subscribers read for free.

Read for Free

$75.00^$ 75 ⁰⁰ to buy Kindle Edition

Get it TODAY, Apr 2

Sold by: Amazon Digital Services LLC
Genomics Orientations for Personalized Medicine (Frontiers in Genomics Research Book 1)

Nov 22, 2015 | Kindle eBook

by Sudipta Saha PhD and Ritu Saxena PhD

$0.00

Subscribers read for free.

Read for Free

$75.00^$ 75 ⁰⁰ to buy Kindle Edition

Get it TODAY, Apr 2

Sold by: Amazon Digital Services LLC
Medical 3D BioPrinting – The Revolution in Medicine Technologies for Patient-centered Medicine: From R&D in Biologics to New Medical Devices (Series E: Patient-Centered Medicine Book 4)

Dec 30, 2017 | Kindle eBook

by Larry H. Bernstein and Irina Robu

$0.00

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Read for Free

$75.00^$ 75 ⁰⁰ to buy Kindle Edition

Get it TODAY, Apr 2

Sold by: Amazon Digital Services LLC
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

$0.00

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Read for Free

$75.00^$ 75 ⁰⁰ to buy Kindle Edition

Get it TODAY, Apr 2

Sold by: Amazon Digital Services LLC
Regenerative and Translational Medicine: The Therapeutic Promise for Cardiovascular Diseases

Dec 26, 2015 | Kindle eBook

by Justin D. Pearlman MD ME PhD MA FACC and Ritu Saxena PhD

$0.00

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Read for Free

$75.00^$ 75 ⁰⁰ to buy Kindle Edition

Get it TODAY, Apr 2

Sold by: Amazon Digital Services LLC

Forthcoming e-Books in 2018 & 2019

https://pharmaceuticalintelligence.com/biomed-e-books/

Series C, Volume Two was published in 2017 !!!

Work-in-Progress:

Series A, Volume 5 and Volume 6, and

Series B, Volume 2

Part 4: Real Time Coverage of 50 Biotech Top Conferences

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

Articles in each e-Book in the BioMed e-Series

Editorial & Publication of Articles in e-Books by Leaders in Pharmaceutical Business Intelligence: Contributions of Larry H Bernstein, MD, FCAP

Editorial & Publication of Articles in e-Books by Leaders in Pharmaceutical Business Intelligence: Contributions of Aviva Lev-Ari, PhD, RN

Read Full Post »

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

Posted in Curation, LPBI Group, e-Scientific Media, DFP, R&D-M3DP, R&D-Drug Discovery, US Patents: SOPs and Team Management on May 6, 2017| Leave a Comment »

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

Editor-in-Chief http://pharmaceuticalintelligence.com: Aviva Lev-Ari, PhD, RN

We have identified the following FIVE Innovations and provide Case Studies to demonstrate these statements.

Innovation #1:

Methodology of Expert Curation of Scientific Findings is applied in all the articles that are included in LPBI Group’s 16 e-Books

Innovation #2:

The Journal Archive by Month is sorted by Categories of Research that can serve multiple Goals in eScientific Publishing

Innovation #3:

Marketing of electronic Scientific Contents – eReaders’ Views Analytics: Site Statistics, Top Article Views, Top Author’s Views

Innovation #4:

Cross section of several Categories of Research supports interdisciplinary conceptual innovations – it is evidence that knowledge is in SILOS to a great degree, still.

Innovation #5:

Real Time Press coverage of Scientific Conferences Builds exposure to FRONTIER of Science that guides CONTENT creation in the Journal and in the BioMed e-Series

Case Studies for Innovations #1, #2, #3, #4, #5

Innovation #1:

1.1 Methodology of Expert Curation of Scientific Findings is applied in all the articles that are included in LPBI Group’s 16 e-Books

Editorial & Publication of Articles in e-Books by Leaders in Pharmaceutical Business Intelligence: Contributions of Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/10/16/editorial-publication-of-articles-in-e-books-by-leaders-in-pharmaceutical-business-intelligence-contributions-of-larry-h-bernstein-md-fcap/

Editorial & Publication of Articles in e-Books by Leaders in Pharmaceutical Business Intelligence: Contributions of Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/founder/editorial-publication-of-articles-in-e-books-by-leaders-in-pharmaceutical-business-intelligence/

1.2 The Methodology of Expert Curation of Scientific Findings deserves the status of an eScientific Publishing Class, in its own right – Our 5100 articles demonstrate that capability and virtue

http://pharmaceuticalintelligence.com

Cardiovascular, Volume Two: Cardiovascular Original Research: Cases in Methodology Design for Content Co-Curation, on Amazon since 11/30/2015

http://www.amazon.com/dp/B018Q5MCN8

Innovation #2:

The Journal Archive by Month is sorted by Categories of Research that can serve multiple Goals in eScientific Publishing:

2.1 Repository for generation of electronic Table of Contents (eTOCs) used in creation of electronic Books (eBooks).

Examples include our BioMed e-Series:

Forthcoming SEVEN e-Books in 2017/18 AND Eight e-Books on Amazon.com

https://pharmaceuticalintelligence.com/2016/04/24/new-e-book-titles-forthcoming-on-amazon-com-in-2016-from-lpbi-groups-biomed-e-series-forthcoming-cover-pages/

BioMed e-Series

https://pharmaceuticalintelligence.com/biomed-e-books/

BioMed e-Series

WE ARE ON AMAZON.COM

https://www.amazon.com/s/ref=nb_sb_ss_i_1_15?url=search-alias%3Dstripbooks&field-keywords=aviva+lev-ari+phd+rn&sprefix=%22Aviva+Lev-Ari%2C%2Caps%2C129&crid=3V1F20IV5LHE3

2.2 Categories of Research serves as Ontologies for Journals

Examples. include our Open Access Online Scientific Journal

http://pharmaceuticalintelligence.com

Our DOMAINS in Scientific Media

I. Pharmaceutical: Biologics, Small Molecules, Diagnostics

II. Life Sciences: Genomics and Cancer Biology

III. Patient-centered Medicine: Focus on #1: Cardiovascular, #2: Cancer, #3: Physiology: Metabolomics, Immunology

IV. Biomedicine, BioTech, and MedTech (Medical Devices)

V. HealthCare: Patient-centered Medicine and Personalized/Precision Medicine

Innovation #3:

Marketing of electronic Scientific Contents – eReaders’ Views Analytics: Site Statistics, Top Article Views, Top Author’s Views

3.1 Site Statistics on 5/5/52017

1,208,981 Views – all articles [not only articles with e-Views >1,000 = 445,321]

7,267 Scientific Comments

5,096 articles

9,566 tags

578 Categories of Research

3.2 FIVE years of e-Scientific Publishing @pharmaceuticalintellicence.com, Top Articles by Author and by

e-Views >1,000, 4/27/2012 to 4/27/2017

Article Title

Views All Time

Author

Home page / Archives

445,321

e-Readers

Is the Warburg Effect the Cause or the Effect of Cancer: A 21st Century View?

15,461

Larry H. Bernstein, MD, FCAP

Do Novel Anticoagulants Affect the PT/INR? The Cases of XARELTO (rivaroxaban) and PRADAXA (dabigatran)

10,005

Vivek Lal, MBBS, MD, FCIR, Justin D. Pearlman, MD, PhD, FACC and Aviva Lev-Ari, PhD, RN

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/

3.3 Top Authors, by 5 years of e-Views, 4/25/2017, on pharmaceuticalintelligence.com

4/30/2012 – 4/25/2017 (All Times – Summarized)

Author

Views

Aviva Lev-Ari, PhD, RN

315,262

Larry H Bernnstein, MD, FCAP

220,787

Tilda Barliya, PhD

47,008

Stephen J Williams, PhD

39,704

Dror Nir, PhD

24,484

Sudipta Saha, PhD

22,253

Ritu Saxena, PhD

15,302

Demet Sag, Ph.D., CRA, GCP

12,982

Aviral Vatsa, PhD

8,082

Ziv Raviv, PhD

7,525

Zohi Sternberg, PhD

3,839

Anamika Sarkar, PhD, MBA

3,269

Gail S Thornton, MA, PhD(c)

2,885

Danut Dragoi, PhD

2,607

Prabodh Kandala, PhD

2,115

Alan F. Kaul, PharmD., MS, MBA, FCCP

2,057

Aashir Awan, PhD

1,841

Meg Baker, PhD

1,439

Justin D Pearlman, MD, PhD

1,429

https://pharmaceuticalintelligence.com/2017/04/25/top-authors-by-5-years-of-e-views-4252017-on-pharmaceuticalintelligence-com/

Innovation #4:

Cross section of several Categories of Research supports interdisciplinary conceptual innovations – it is evidence that knowledge is in SILOS to a great degree, still.

Examples for interdisciplinary conceptual innovations include:

Dr. Aviva Lev-Ari‘s early curations represent an intersection of Vascular Biology and Molecular Cardiology – that has yielded a Novel Combination Drug Therapy Concept in cardiovascular diseases.

Cardiovascular Diseases and Pharmacological Therapy: Curations

Dr. Larry H. Bernstein, MD, FCAP curations in Enzymology and Pathophysiology

ATP – the universal energy carrier in the living cell: Reflections on the discoveries and applications in Medicine

Curators: Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

Milestones in Physiology: Discoveries in Medicine, Genomics and Therapeutics

Editor: Larry H. Bernstein, MD, FCAP

http://www.amazon.com/dp/B019VH97LU

Cyclic Dinucleotides and Histone deacetylase inhibitors

Curators: Larry H. Bernsten, MD, FCAP and Aviva Lev-Ari, PhD, RN

Dr. Stephen J. Williams curations in Pharmacology and Oncology

Why Does Cytotoxic Chemotherapy Still Remain a Mainstay in Many Chemotherapy Regimens

New Generation of Platinated Compounds to Circumvent Resistance

New Topoisomerase Inhibitors: Agents From Nature

Are Cyclin D Inhibitors a Good Target?

Dr. Dror Nir’s curations in Medical Imaging and Oncology

Imaging Technology in Cancer Surgery

Metastatic Diseases – Examples of Surgical Procedures in Treatment of Cancer

Ablation Techniques in Interventional Oncology

Dr. Tilda Barliya’s curations in Nanotechnology, Molecular Biology and Drug Delivery

Building a Drug-Delivery System (DDS): choice of polymers and drugs

Factors affecting the PK of the nanocarrier

Detection and Imaging

Single-Molecule Detection by Philip Tinnefeld

Mesothelin: An early detection biomarker for cancer (By Jack Andraka)

Nanotechnology and MRI imaging

Nanotechnology: Detecting and Treating metastatic cancer in the lymph node

Diagnosing lung cancer in exhaled breath using gold nanoparticles

Innovation #5:

Real Time Press coverage of Scientific Conferences Builds exposure to FRONTIER of Science that guides CONTENTS creation in the Journal and in the BioMed e-Series

5.1 Press Coverage of BioTech, Medicine and Life Sciences Conferences, 2013 – 2017

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

List of Conferences in 2017

The 13th Annual Personalized Medicine Conference, NOVEMBER 14 – 16, 2017, Joseph B. Martin Conference Center, HARVARD MEDICAL SCHOOL, Boston

https://pharmaceuticalintelligence.com/2017/03/13/the-13th-annual-personalized-medicine-conference-from-concept-to-the-clinic-november-14-16-2017-joseph-b-martin-conference-center-harvard-medical-school-77-avenue-louis-pasteur-boston/

16th Annual Cancer Research Symposium, Koch Institute, Friday, June 16, 2017, 9AM – 5PM, Kresge Auditorium, MIT

https://pharmaceuticalintelligence.com/2017/03/13/16th-annual-cancer-research-symposium-koch-institute-friday-june-16-9am-5pm-kresge-auditorium-mit/

BioInformatics: Track 6: BioIT World Conference & Expo ’17, May 23-25, 2017, Seaport World Trade Center, Boston, MA

https://pharmaceuticalintelligence.com/2017/01/12/2017-agenda-bioinformatics-track-6-bioit-world-conference-expo-17-may-23-35-2017-seaport-world-trade-center-boston-ma/

2017 World Medical Innovation Forum: Cardiovascular, May 1-3, 2017, Partners HealthCare, Boston, at the Westin Hotel, Boston

https://pharmaceuticalintelligence.com/2016/12/14/2017-world-medical-innovation-forum-cardiovascular-may-1-3-2017-partners-healthcare-boston-at-the-westin-hotel-boston/

2017 MassBio Annual Meeting March 30, 2017 8:00 AM – March 31, 2017 4:00 PM, Royal Sonesta Boston, Cambridge MA

https://pharmaceuticalintelligence.com/2017/02/28/2017-massbio-annual-meeting-march-30-2017-800-am-march-31-2017-400-pm-royal-sonesta-boston-cambridge-ma/

5.2 eProceedings generated in Real Time, Social Media facilitate Global e-Readers Reach and instantaneous reach of conference attendees

World Medical Innovation Forum – CARDIOVASCULAR • MAY 1-3, 2017, BOSTON, MA

(a) Real Time Highlights and Tweets: Day 1,2,3: World Medical Innovation Forum – CARDIOVASCULAR • MAY 1-3, 2017, BOSTON, MA

https://pharmaceuticalintelligence.com/2017/05/03/deliverables-day-123-world-medical-innovation-forum-cardiovascular-%E2%80%A2-may-1-3-2017-boston-ma-httpsworldmedicalinnovation-orgagenda-highlights-of-live-day-1-world-medical/

(b) e-Proceedings for Day 1,2,3: World Medical Innovation Forum – CARDIOVASCULAR • MAY 1-3, 2017, BOSTON, MA

https://pharmaceuticalintelligence.com/2017/05/05/e-proceedings-for-day-123-world-medical-innovation-forum-cardiovascular-%E2%80%A2-may-1-3-2017-boston-ma/

(c) Tweets by @pharma_BI and @AVIVA1950 at World Medical Innovation Forum – CARDIOVASCULAR • MAY 1-3, 2017, BOSTON, MA

https://pharmaceuticalintelligence.com/2017/05/05/tweets-by-pharma_bi-and-aviva1950-at-world-medical-innovation-forum-cardiovascular-%E2%80%A2-may-1-3-2017-boston-ma/

5.3 Opportunities for Import of Innovations from Conferences to the Journal and to the BioMed e-Series

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Artificial womb for survival of premature fetus

Posted in Biological Networks, Biomedical Measurement Science, Cell Biology, Clinical & Translational, Developmental biology, Discovery process, Embryology, Experimental validation, Great Discoveries, Innovations, Reproductive Biology & Bio Instrumentation, tagged amniotic fluid, fetus, gestation, premature fetus, survival, uterus, womb on April 27, 2017| Leave a Comment »

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

Babies born at or before 25 weeks have quite low survival outcomes, and in the US it is the leading cause of infant mortality and morbidity. Just a few weeks of extra ‘growing time’ can be the difference between severe health problems and a relatively healthy baby.

Researchers from The Children’s Hospital of Philadelphia (USA) Research Institute have shown it’s possible to nurture and protect a mammal in late stages of gestation inside an artificial womb; technology which could become a lifesaver for many premature human babies in just a few years.

The researchers took eight lambs between 105 to 120 days gestation (the physiological equivalent of 23 to 24 weeks in humans) and placed them inside the artificial womb. The artificial womb is a sealed and sterile bag filled with an electrolyte solution which acts like amniotic fluid in the uterus. The lamb’s own heart pumps the blood through the umbilical cord into a gas exchange machine outside the bag.

The artificial womb worked in this study and after just four weeks the lambs’ brains and lungs had matured like normal. They had also grown wool and could wiggle, open their eyes, and swallow. Although this study is looking incredibly promising but getting the research up to scratch for human babies still requires a big leap.

Nevertheless, if all goes well, the researchers hope to test the device on premature humans within three to five years. Potential therapeutic applications of this invention may include treatment of fetal growth retardation related to placental insufficiency or the salvage of preterm infants threatening to deliver after fetal intervention or fetal surgery.

The technology may also provide the opportunity to deliver infants affected by congenital malformations of the heart, lung and diaphragm for early correction or therapy before the institution of gas ventilation. Numerous applications related to fetal pharmacologic, stem cell or gene therapy could be facilitated by removing the possibility for maternal exposure and enabling direct delivery of therapeutic agents to the isolated fetus.

References:

https://www.nature.com/articles/ncomms15112

https://www.sciencealert.com/researchers-have-successfully-grown-premature-lambs-in-an-artificial-womb

http://www.npr.org/sections/health-shots/2017/04/25/525044286/scientists-create-artificial-womb-that-could-help-prematurely-born-babies

http://www.telegraph.co.uk/science/2017/04/25/artificial-womb-promises-boost-survival-premature-babies/

https://www.theguardian.com/science/2017/apr/25/artificial-womb-for-premature-babies-successful-in-animal-trials-biobag

http://www.theblaze.com/news/2017/04/25/new-artificial-womb-technology-could-keep-babies-born-prematurely-alive-and-healthy/

http://www.theverge.com/2017/4/25/15421734/artificial-womb-fetus-biobag-uterus-lamb-sheep-birth-premie-preterm-infant

http://www.abc.net.au/news/2017-04-26/artificial-womb-could-one-day-keep-premature-babies-alive/8472960

https://www.theatlantic.com/health/archive/2017/04/preemies-floating-in-fluid-filled-bags/524181/

http://www.independent.co.uk/news/health/artificial-womb-save-premature-babies-lives-scientists-create-childrens-hospital-philadelphia-nature-a7701546.html

https://www.cnet.com/news/artificial-womb-births-premature-lambs-human-infants/

https://science.slashdot.org/story/17/04/25/2035243/an-artificial-womb-successfully-grew-baby-sheep—-and-humans-could-be-next

http://newatlas.com/artificial-womb-premature-babies/49207/

https://www.geneticliteracyproject.org/2015/06/12/artificial-wombs-the-coming-era-of-motherless-births/

http://news.nationalgeographic.com/2017/04/artificial-womb-lambs-premature-babies-health-science/

https://motherboard.vice.com/en_us/article/artificial-womb-free-births-just-got-a-lot-more-real-cambridge-embryo-reproduction

http://www.disclose.tv/news/The_Artificial_Womb_Is_Born_Welcome_To_The_WORLD_Of_The_MATRIX/114199

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Archive for the ‘Curation’ Category

Article Title, Author/Curator’s Name and Article Views >1,000, 4/2012 – 1/2019 @pharmaceuticalintelligence.com

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4/2012 – -1/2018

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37th Annual J.P. Morgan HEALTHCARE CONFERENCE: News at #JPM2019 for Jan. 10, 2019: Deals and Announcements

JP Morgan Healthcare Conference Update: Sage, Mersana, Shutdown Woes and Babies

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Curation of selected topics and articles on Role of G-Protein Coupled Receptors in Chronic Disease as supplemental information for #TUBiol3373

In Alzheimer’s Disease

In Cardiovascular and Thrombotic Disease

In Cancer

Further curations and references of G proteins and chronic disease can be found at the Open Access journal https://pharmaceuticalintelligence.com using the search terms “GCPR” and “disease” in the Search box in the upper right of the home page.

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Lesson 9 Cell Signaling: Curations and Articles of reference as supplemental information for lecture section on WNTs: #TUBiol3373

All images in use for this article are under copyrights with Shutterstock.com

Normal physiological processes including

A. Development:

– Osteogenesis and adipogenesis (Loss of wnt/β‐catenin signaling causes cell fate shift of preosteoblasts from osteoblasts to adipocytes)

– embryogenesis including body axis patterning, cell fate specification, cell proliferation and cell migration

B. tissue regeneration in adult tissue

The curation Wnt/β-catenin Signaling is a comprehensive review of canonical and noncanonical Wnt signaling pathways

A. The Forkhead family of transcription factors

Read: Regulation of FoxO protein stability via ubiquitination and proteasome degradation

B. Tumor necrosis factor α/NF κB signaling

Read: NF-κB, the first quarter-century: remarkable progress and outstanding questions

1. Question: In cell involving G-proteins, the signal can be terminated by desensitization mechanisms. How is both the canonical and noncanonical Wnt signal eventually terminated/desensitized?

Note: In noncanonical signaling the transducer is a G-protein and second messenger system is IP3/DAG/Ca++ and/or kinases such as MAPK, JNK.

Depending on the different combinations of WNT ligands and the receptors, WNT signaling activates several different intracellular pathways (i.e. canonical versus noncanonical)

A. Abstract

Li P1, Liu W1, Xu Q1, Wang C1.

2. Question: Given that different Wnt ligands and receptors activate different signaling pathways, AND WNT ligands can be deferentially and temporally expressed in various tumor types and the process of oncogenesis, how would you approach a personalized therapy targeting the WNT signaling pathway?

3. Question: What are the potential mechanisms of either intrinsic or acquired resistance to Wnt ligand antagonists being developed?

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Electronic Scientific AGORA: Comment Exchanges by Global Scientists on Articles published in the Open Access Journal @pharmaceuticalintelligence.com – Four Case Studies

Introduction

Case Study #1: 40 Responses

Case Study #2: 26 Responses

Case Study #3: 24 Responses

Case Study #4: 13 Responses

Conclusions

Introduction

Team Members’ Profile

Case Study #1:

Is the Warburg Effect the Cause or the Effect of Cancer: A 21st Century View?

40 Responses

Case Study #2:

· Knowing the tumor’s size and location, could we target treatment to THE ROI by applying…..

26 Responses

Case Study #3:

Personalized Medicine: Cancer Cell Biology and Minimally Invasive Surgery (MIS)

24 Responses

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Judging the ‘Tumor response’-there is more food for thought

13 Responses

Conclusions

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@PharmaceuticalIntelligence.com – A Case Study on the LEADER in Curation of Scientific Findings

Multi-facets of the LPBI Group Intellectual Property (IP) ASSETS

Innovations in e-Scientific Publishing Methodology Development accomplished by LPBI Group:

9 results for Kindle Store : “Aviva Lev-Ari”

Cancer Therapies: Metabolic, Genomics, Interventional, Immunotherapy and Nanotechnology in Therapy Delivery (Series C Book 2)

Etiologies of Cardiovascular Diseases: Epigenetics, Genetics and Genomics

Perspectives on Nitric Oxide in Disease Mechanisms (Biomed e-Books Book 1)

Genomics Orientations for Personalized Medicine (Frontiers in Genomics Research Book 1)

Metabolic Genomics & Pharmaceutics (BioMedicine – Metabolomics, Immunology, Infectious Diseases Book 1)

Milestones in Physiology: Discoveries in Medicine, Genomics and Therapeutics (Series E: Patient-Centered Medicine Book 3)

Cancer Biology and Genomics for Disease Diagnosis (Series C: e-Books on Cancer & Oncology Book 1)

Regenerative and Translational Medicine: The Therapeutic Promise for Cardiovascular Diseases

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

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Note: In noncanonical signaling the transducer is a G-protein and second messenger system is IP₃/DAG/Ca++ and/or kinases such as MAPK, JNK.

Li P¹, Liu W¹, Xu Q¹, Wang C¹.