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Archive for the ‘CANCER BIOLOGY & Innovations in Cancer Therapy’ Category


AACR and Dr. Margaret Foti Announce Free Virtual Annual Meeting for April 27, 28 2020 and other Free Resources

Reporter: Stephen J. Williams, PhD

Please see the following email from Dr. Foti and the AACR on VIRTUAL MEETING to be conducted April 27 and 28, 2020.

This is truly a wonderful job by AACR.  In a previous posting I had considered the need for moving international scientific meetings to an online format which would make the information available to a wider audience as well as to those who don’t have the opportunity to travel to a meeting site.  At @pharma_BI we will curate and live tweet the talks in order to enhance meeting engagement, as part of the usual eConference Proceedings we do.

Again Great Job by the AACR!

Dear Colleagues,

We hope you are staying safe and well and are adjusting to the challenges of the COVID-19 global pandemic. During this crisis, we remain steadfast in supporting our members and our mission.

I am pleased to announce a number of actions that we are taking to disseminate innovative cancer science and medicine to the global cancer research community:

  • AACR Virtual Annual Meeting 2020: Selected Presentations. We were excited to receive more than 225 clinical trials for presentation at the Annual Meeting. Due to the time-sensitive nature of these trials—many of which are practice-changing—we are making them available to the community at the time of the original April meeting. Therefore, as per our recent announcement, the AACR will host a slate of selected sessions online featuring these cutting-edge data.
This Virtual Annual Meeting will be held on April 27 and 28, 2020, and will include more than 30 oral presentations in several clinical trial plenary sessions along with commentaries from expert discussants, as well as clinical trial poster sessions consisting of short videos providing the authors’ perspectives. The Virtual Meeting will feature a New Drugs on the Horizon session as well as nine minisymposia that will showcase a broad sample of basic and translational science. Topics will include genomics, tumor microenvironment, novel targets, drug discovery, therapeutics, immunotherapy, biomarkers, and cancer prevention. A special minisymposium titled “Advancing Cancer Research Through an International Cancer Registry” will feature use cases of data available through AACR Project GENIE.

This Virtual Meeting will be available free to everyone, although attendees will be asked to register to participate. The session and presentation titles for the Virtual Meeting, as well as a link to the registration site, will be posted to the AACR website by Monday, April 13.

  • Release of Abstracts. All of the abstracts scheduled for presentation in the Virtual Meeting—and any other clinical trial abstracts that are scheduled for presentation at the rescheduled meeting—will be posted online on Monday, April 27. All other abstracts that have been accepted for presentation at the rescheduled meeting will be posted online on Friday, May 15.
  • AACR Annual Meeting 2019: Free Webcast Presentations. The complete webcasts of the AACR Annual Meeting are typically made freely available 15 months after the conclusion of the meeting. However, we have made these webcast presentations available free effective immediately, so that you can review the most compelling science from the Annual Meeting 2019 which was held in Atlanta.
  • Free Access to AACR Journals. To ensure that all members of the cancer research community have access to the information they need during this challenging time, we have opened access to our nine highly esteemed journals effective today through the end of the virtual meeting. Please be sure to visit the AACR journals webpage for journal highlights, and to sign-up for eTOC alerts.
  • Rescheduled AACR Annual Meeting. We are planning to reschedule the Annual Meeting for late August while at the same time closely monitoring the developments surrounding COVID-19. An official announcement of the rescheduled meeting will be made in the near future.

We hope that these plans will enable you to continue your important work during this global health crisis. Thank you for all you do to accelerate progress against cancer, and thank you for your loyalty to the AACR.

Sincerely,
Margaret Foti, PhD, MD (hc)
Chief Executive Officer
American Association for Cancer Research

 

For more information on Virtual Meetings please see

Is It Time for the Virtual Scientific Conference?: Coronavirus, Travel Restrictions, Conferences Cancelled

and  REAL TIME conference coverage at https://pharmaceuticalintelligence.com/press-coverage/

and other article and e-conference proceedings on this Online Open Access Journal

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Live Notes from Town Hall for Patients with Leading Oncologists on Lung Cancer and COVID19 3_28_20

Reporter: Stephen J. Williams, PhD

UPDATED 3/31/2020

Leading Thoracic Oncologists from the United States and Milan, Italy shared their opinions and views on treating lung cancer patients during this COVID-19 pandemic.  Included in the panel is a thoracic oncologist from Milan Italy who gave special insights into the difficulties and the procedures they are using to help control the spread of infection within this high at-risk patient population and changes to current treatment strategy in light of this current virus outbreak.  Please see live notes and can follow on Twitter at #LungCancerandCOVID19.  Included below is the recording of the Zoom session.

 

UPDATED 3/29/2020

Leading Lung Cancer Oncologists from around the world are meeting and discussing concerns for lung cancer patients and oncologist during the novel coronavirus (SARS-COV2; COVID19) pandemic.  The town hall “COVID-19 and the Impact on Thoracic Oncology” will be held on Zoom on Saturday March 28, 2020 at 10:00 – 11:30 AM EST. sponsored by Axiom Healthcare Strategies . You can register at

Please join this virtual Town Hall

Zoom link: https://us04web.zoom.us/j/846752048

Zoom Webinar ID: 846-752-048

eSpeakers

Anne Chiang, MD, PhD, Associate Professor; Chief Network Officer and Deputy Chief Medical Officer, Smilow Cancer Network

Roy S. Herbst, MD, PhD, Ensign Professor of Medicine (Medical Oncology) and Professor of Pharmacology; Chief of Medical Oncology, Yale Cancer Center and Smilow Cancer Hospital; Associate Cancer Center Director for Translational Research, Yale Cancer Center

 Kurt Schalper, MD, PhD Assistant Professor of Pathology; Director, Translational Immuno-oncology Laboratory

Martin J. Edelman, MD, Chair, Department of Hematology/Oncology, Fox Chase Cancer Center

Corey J. Langer, MD , Professor of Medicine, University of Pennsylvania

Hossain Borghaei, DO, MS , Chief of Thoracic Medical Oncology and Director of Lung Cancer Risk Assessment, Fox Chase Cancer Center

Marina Garassino, MD, Fondazione IRCCS Instituto Nazionale del Tumori

Kristen Ashley Marrone, MD, Thoracic Medical Oncologist. Johns Hopkins Bayview Medical Center

Taofeek Owonikoko, MD, PhD, MSCR, Medical Oncologist, Emory University School of Medicine

Jeffrey D. BradleyMD, FACR, FASTRO , Emory University School of Medicine

Brendon Stiles, M.D, Weil Cornell

@pharma_BI will be Live Tweeting in Real Time this Town Hall

Please follow at the following # (hashtags)

#LungCancerandCOVID19

#Livingwithcancer

#LungCancer

#NoOneAlone

and

UPDATED 3/29/2020

Below is a collection of live Tweets from this meeting as well as some notes and comments from each of the speakers and panelists.  The recording of this Town Hall will be posted on this site when available.  The Town Hall was well attended with over 250 participants

Town Hall Notes

The following represent some notes taken at this Town Hall.

Dr. Owonkiko: 1-2% lethality in China; for patients newly diagnosed with lung cancer 1) limit contact between patient, physician and healthcare facility = telemedicine and oral chemo suggested 2) for immunotherapy if i.v. must monitor health carefully

Dr. Kurt Schalper: on COVID19 testing: Three types of tests each having pros and cons.

  •     viral culture: not always practical as you need lots of specimen
  • ELISA: looking for circulating antibodies but not always specific for type of coronavirus
  • RT-PCR: most sensitive but right now not much clarity on best primers to use; he noted that there is a 15% variance in test results using different primers to different targeted COVID19 genes

Dr. Marina Garassino: The Lombardi outbreak was 1st in Italy and took them by surprise.  She admits they were about one month behind in preparation where they did not have enough masks as late as January 31.  It was impractical to socially distance given Italian customs in greeting each other.  In addition, they had to determine which facilities would be COVID negative and COVID positive an this required access to testing.  Right now they are only testing symptomatic patients and healthcare workers have to test negative multiple times.  As concerning therapy with lung cancer patients, they have been delaying as much as possible the initiation of therapy.  Patients that are on immunotherapy and immunosuppresive drugs are being monitored by CT scan more often during this pandemic so as instances of pneumotitis began increasing they were unsure if these patients are at increased risk of infection to COVID19 or just a bias in that they are screening more often so their risk to COVID 19 is unclear.  Dr. Garissino also felt we need to move from hospital based to community based measures of prevention against COVID infection (social distancing, citizens more vigilant).  She noted that usually the cancer patients are more careful with respect to preventative measures than the general populace.  Healthcare workers have to test negative twice in three days if they had been in close contact with a COVID postitive patient.  However her hospital is still running at 80% capacity so patients are getting treated. However there are ethical issues as to who gets treated, who gets respirators, and other ethical issues related to unfortunate rationing of care.

Dr. Anne Chiang: Scheduled visits have notably decreased.  They have seen patients visits decrease from 4500 down to 2300 in two weeks but telemedicine visits or virtual visits have increased to 1000 so are replacing the on site visits.  She also said they are trying to reduce or eliminate the extremely immuno-suppressive drugs from chemotherapy regimens.  For example they are removing pemetrexemed from standard regimens and also considering neoadjuvant chemotherapy.  As far as biopsies, liquid biopsies can be obtained in the home so more preferred as patients do not have to come in for biopsy.

Dr. Edelman: Fox Chase is somewhat unique in being an NCI center which only does oncology so they rely on neighboring Jeanes Hospital of the Temple University Health System for a lot of their outpatient and surgical and general medicine needs.  Patients who will be transferred back to Fox Chase are screened for COVID19.

Brenden Stiles: Lung cancer surgeries have ground to a halt.  He did only one last week.  The hospital wants to conserve resources and considers lung cancer surgery to great a COVID risk.  They have shut down elective surgeries and there are no clinical trials being conducted.  He said that lung cancer research will be negatively impacted by the pandemic as resources are shuttled to COVID research efforts.

 Live Tweets

 

Other article of note on Coronavirus (COVID19) please see our Coronavirus Portal at

https://pharmaceuticalintelligence.com/coronavirus-portal/

 

 

 

 

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Reporter: Gail S. Thornton, M.A.

LPBI Update

Leaders in Pharmaceutical Business Intelligence (LPBI) Group, Newsletter #1 – February 2020

Welcome to the premier issue of LPBI Group News, where readers can find relevant news and updates about science, business and medical innovation. This newsletter is distributed as a service for our readers.

The Conference Forum Highlights Immuno-Oncology 360° in New York

The Conference Forum is hosting Immuno-Oncology 360°, which reports on current data and developments of immuno-oncology in the science and business communities. The summit takes place on February 26-28 at the Crowne Plaza Times Square in New York.

Please visit www.io360summit.com to register and use code LPBI20 for a 20% discount. 

Ahead of the conference, Immuno-Oncology 360° has created a series celebrating their women speakers in the work they are doing to fight cancer. To read the series, visit: https://theconferenceforum.org/conferences/immuno-oncology-360/io360%cb%9a-leadership-interviews/

This information is published in conjunction with the Immuno-Oncology 360° Summit.

  •  

Venture Summit Attracts Top Innovators in Silicon Valley

Leaders in Pharmaceutical Business Intelligence (LPBI) Group is one of the sponsors of Venture Summit | West, “Where Innovation Meets Capital.”

The meeting will be held on March 23-24 at the Santa Clara Convention Center, Silicon Valley.

 

Special offer:  Register Now & Save $450 off (Use discount code “LPBI-VIP”)

For more information, please visit: https://pharmaceuticalintelligence.com/2019/12/17/venture-summit-west-where-innovation-meets-capital-march-23rd-24th-2020-santa-clara-convention-center-silicon-valley/

  •  

e-Proceedings of 15th Annual Personalized Medicine Conference at Harvard Medical School

The 15th Annual Personalized Medicine Conference at Harvard Medical School, Boston last year [November 13-14, 2019], entitled  The Paradigm Evolves, explored the science, business and policy issues facing personalized medicine. In today’s world, scientists need to understand how molecular diagnostics augmented by artificial intelligence, data analytics and digital health empowers physicians and patients in their health care decisions.

Please visit for LPBI Group coverage of the meeting, including social media activities at the conference:

https://pharmaceuticalintelligence.com/2019/07/19/15th-annual-personalized-medicine-conference-at-harvard-medical-school-the-paradigm-evolves-november-13-14-2019-%e2%80%a2-harvard-medical-school-boston-ma/

https://pharmaceuticalintelligence.com/2019/11/15/tweets-and-retweets-by-aviva1950-and-by-pharma_bi-for-15th-annual-personalized-medicine-conference-at-harvard-medical-school-the-paradigm-evolves-november-13-14-2019-%e2%80%a2/

  •   3D Medical BioPrinting Technology Featured in Podcast

LPBI Group leaders, Aviva Lev-Ari, Ph.D., R.N., Stephen Williams, Ph.D., and Irina Robu, Ph.D., spoke with Partners in Health and Biz, a half-hour audio podcast that reaches 40,000 listeners, about the topic of 3D Medical BioPrinting Technology: A Revolution in Medicine.

Please click on this link to hear the podcast. https://www.youtube.com/watch?v=laozyrfi29c.

The topic is also the title of a recently offered e-book by the LPBI Group on 3D BioPrinting, available on Amazon/Kindle Direct [https://www.amazon.com/Medical-BioPrinting-Technologies-Patient-centered-Patient-Centered-ebook/dp/B078QVDV2W]. 

The 3D BioPrinting technology is being used to develop advanced medical practices that will help with previously difficult processes, such as delivering drugs via micro-robots, targeting specific cancer cells and even assisting in difficult eye operations.

The table of contents in this book includes: Chapter 1: 3D Bioprinting: Latest Innovations in a Forty year-old Technology. Chapter 2: LPBI Initiative on 3D BioPrinting, Chapter 3: Cardiovascular BioPrinting, Chapter 4: Medical and Surgical Repairs – Advances in R&D Research, Chapter 5: Organ on a Chip, Chapter 6: FDA Regulatory Technology Issues, Chapter 7: DNA Origami, Chapter 8: Aptamers and 3D Scaffold Binding, Chapter 9: Advances and Future Prospects, Chapter 10: BioInks and MEMS, Chapter 11: BioMedical MEMS, Chapter 12: 3D Solid Organ Printing and Chapter 13: Medical 3D Printing: Sources and Trade Groups – List of Secondary Material. 

  •  

New e-Book: Latest in Genomics Methodologies for Therapeutics: Gene Editing, NGS & BioInformatics, Simulations and the Genome Ontology

LPBI Group’s latest e-book entitled, Latest in Genomics Methodologies for Therapeutics: Gene Editing, NGS & BioInformatics, Simulations and the Genome Ontology, offers the reader content curation with embedded videos and audio podcasts, real-time conference e-Proceedings by LPBI’s scientists and professors and archived tweets of quotes from speakers at leading biotechnology conferences.

Please click on this link on Amazon/Kindle Direct: https://www.amazon.com/dp/B08385KF87

 

The book integrates in a single volume four distinct perspectives: basic science, technologies and methodologies, clinical aspects and business and legal aspects of genomics research. “The materials in this book represents the scientific frontier in Biological Sciences and Medicine related to the genomics aspects of disease onset,” said Aviva Lev-Ari, Ph.D., R.N., and founder of LPBI Group.

The book addresses:

  • aspects of life: the Cell, the Organ, the Human Body and Human Populations;
  • methodologies of genomic data analysis: Next Generation Sequencing, Gene Editing, AI, Single Cell Genomics, Evolution Biology Genomics, Simulation Modeling in Genomics, Genotypes and Phenotypes Modeling, measurement of Epigenomics effects on disease, and developments in Pharmaco-Genomics.

Additionally, artificial Intelligence in medicine is covered in Part 3 of the e-Book, which represents the frontier in this emerging field, with topics, such as the science, technologies and methodologies, clinical aspects, business and legal implications as well as the latest machine learning algorithms harnessed for medical diagnosis.

This e-book is significant because it:

  • contains 326 articles on topics, such as gene editing, bioinformatics and genome ontology;
  • incorporates 74 e-Proceedings created in real time by the Book’s authors and editors
  • includes four collections of Tweets representing quotes from speakers at global leading conferences on Genomics
  • has 13 locations of Videos and Audio Podcasts that serve to enrich the e-Reader’s experience.

We welcome your comments and suggestions. Please send them to Aviva Lev-Ari at avivalev-ari@alum.berkeley.edu.

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Google AI improves accuracy of reading mammograms, study finds

Google AI improves accuracy of reading mammograms, study finds

Google CFO Ruth Porat has blogged about twice battling breast cancer.

Artificial intelligence was often more accurate than radiologists in detecting breast cancer from mammograms in a study conducted by researchers using Google AI technology.

The study, published in the journal Nature, used mammograms from approximately 90,000 women in which the outcomes were known to train technology from Alphabet Inc’s DeepMind AI unit, now part of Google Health, Yahoo news reported.

The AI system was then used to analyze images from 28,000 other women and often diagnosed early cancers more accurately than the radiologists who originally interpreted the mammograms.

In another test, AI outperformed six radiologists in reading 500 mammograms. However, while the AI system found cancers the humans missed, it also failed to find cancers flagged by all six radiologists, reports The New York Times.

The researchers said the study “paves the way” for further clinical trials.

Writing in NatureEtta D. Pisano, chief research officer at the American College of Radiology and professor in residence at Harvard Medical School, noted, “The real world is more complicated and potentially more diverse than the type of controlled research environment reported in this study.”

Ruth Porat, senior vice president and chief financial officer Alphabet, Inc., wrote in a company blog titled “Breast cancer and tech…a reason for optimism” in October about twice battling the disease herself, and the importance of her company’s application of AI to healthcare innovations.

She said that focus had already led to the development of a deep learning algorithm to help pathologists assess tissue associated with metastatic breast cancer.

“By pinpointing the location of the cancer more accurately, quickly and at a lower cost, care providers might be able to deliver better treatment for more patients,” she wrote.

Google also has created algorithms that help medical professionals diagnose lung cancer, and eye disease in people with diabetes, per the Times.

Porat acknowledged that Google’s research showed the best results occur when medical professionals and technology work together.

Any insights provided by AI must be “paired with human intelligence and placed in the hands of skilled researchers, surgeons, oncologists, radiologists and others,” she said.

Anne Stych is a staff writer for Bizwomen.
Industries:

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Diversity and Health Disparity Issues Need to be Addressed for GWAS and Precision Medicine Studies

Curator: Stephen J. Williams, PhD

 

 

From the POLICY FORUM ETHICS AND DIVERSITY Section of Science

Ethics of inclusion: Cultivate trust in precision medicine

 See all authors and affiliations

Science  07 Jun 2019:
Vol. 364, Issue 6444, pp. 941-942
DOI: 10.1126/science.aaw8299

Precision medicine is at a crossroads. Progress toward its central goal, to address persistent health inequities, will depend on enrolling populations in research that have been historically underrepresented, thus eliminating longstanding exclusions from such research (1). Yet the history of ethical violations related to protocols for inclusion in biomedical research, as well as the continued misuse of research results (such as white nationalists looking to genetic ancestry to support claims of racial superiority), continue to engender mistrust among these populations (2). For precision medicine research (PMR) to achieve its goal, all people must believe that there is value in providing information about themselves and their families, and that their participation will translate into equitable distribution of benefits. This requires an ethics of inclusion that considers what constitutes inclusive practices in PMR, what goals and values are being furthered through efforts to enhance diversity, and who participates in adjudicating these questions. The early stages of PMR offer a critical window in which to intervene before research practices and their consequences become locked in (3).

Initiatives such as the All of Us program have set out to collect and analyze health information and biological samples from millions of people (1). At the same time, questions of trust in biomedical research persist. For example, although the recent assertions of white nationalists were eventually denounced by the American Society of Human Genetics (4), the misuse of ancestry testing may have already undermined public trust in genetic research.

There are also infamous failures in research that included historically underrepresented groups, including practices of deceit, as in the Tuskegee Syphilis Study, or the misuse of samples, as with the Havasupai tribe (5). Many people who are being asked to give their data and samples for PMR must not only reconcile such past research abuses, but also weigh future risks of potential misuse of their data.

To help assuage these concerns, ongoing PMR studies should open themselves up to research, conducted by social scientists and ethicists, that examines how their approaches enhance diversity and inclusion. Empirical studies are needed to account for how diversity is conceptualized and how goals of inclusion are operationalized throughout the life course of PMR studies. This is not limited to selection and recruitment of populations but extends to efforts to engage participants and communities, through data collection and measurement, and interpretations and applications of study findings. A commitment to transparency is an important step toward cultivating public trust in PMR’s mission and practices.

From Inclusion to Inclusive

The lack of diverse representation in precision medicine and other biomedical research is a well-known problem. For example, rare genetic variants may be overlooked—or their association with common, complex diseases can be misinterpreted—as a result of sampling bias in genetics research (6). Concentrating research efforts on samples with largely European ancestry has limited the ability of scientists to make generalizable inferences about the relationships among genes, lifestyle, environmental exposures, and disease risks, and thereby threatens the equitable translation of PMR for broad public health benefit (7).

However, recruiting for diverse research participation alone is not enough. As with any push for “diversity,” related questions arise about how to describe, define, measure, compare, and explain inferred similarities and differences among individuals and groups (8). In the face of ambivalence about how to represent population variation, there is ample evidence that researchers resort to using definitions of diversity that are heterogeneous, inconsistent, and sometimes competing (9). Varying approaches are not inherently problematic; depending on the scientific question, some measures may be more theoretically justified than others and, in many cases, a combination of measures can be leveraged to offer greater insight (10). For example, studies have shown that American adults who do not self-identify as white report better mental and physical health if they think others perceive them as white (1112).

The benefit of using multiple measures of race and ancestry also extends to genetic studies. In a study of hypertension in Puerto Rico, not only did classifications based on skin color and socioeconomic status better predict blood pressure than genetic ancestry, the inclusion of these sociocultural measures also revealed an association between a genetic polymorphism and hypertension that was otherwise hidden (13). Thus, practices that allow for a diversity of measurement approaches, when accompanied by a commitment to transparency about the rationales for chosen approaches, are likely to benefit PMR research more than striving for a single gold standard that would apply across all studies. These definitional and measurement issues are not merely semantic. They also are socially consequential to broader perceptions of PMR research and the potential to achieve its goals of inclusion.

Study Practices, Improve Outcomes

Given the uncertainty and complexities of the current, early phase of PMR, the time is ripe for empirical studies that enable assessment and modulation of research practices and scientific priorities in light of their social and ethical implications. Studying ongoing scientific practices in real time can help to anticipate unintended consequences that would limit researchers’ ability to meet diversity recruitment goals, address both social and biological causes of health disparities, and distribute the benefits of PMR equitably. We suggest at least two areas for empirical attention and potential intervention.

First, we need to understand how “upstream” decisions about how to characterize study populations and exposures influence “downstream” research findings of what are deemed causal factors. For example, when precision medicine researchers rely on self-identification with U.S. Census categories to characterize race and ethnicity, this tends to circumscribe their investigation of potential gene-environment interactions that may affect health. The convenience and routine nature of Census categories seemed to lead scientists to infer that the reasons for differences among groups were self-evident and required no additional exploration (9). The ripple effects of initial study design decisions go beyond issues of recruitment to shape other facets of research across the life course of a project, from community engagement and the return of results to the interpretation of study findings for human health.

Second, PMR studies are situated within an ecosystem of funding agencies, regulatory bodies, disciplines, and other scholars. This partly explains the use of varied terminology, different conceptual understandings and interpretations of research questions, and heterogeneous goals for inclusion. It also makes it important to explore how expectations related to funding and regulation influence research definitions of diversity and benchmarks for inclusion.

For example, who defines a diverse study population, and how might those definitions vary across different institutional actors? Who determines the metrics that constitute successful inclusion, and why? Within a research consortium, how are expectations for data sharing and harmonization reconciled with individual studies’ goals for recruitment and analysis? In complex research fields that include multiple investigators, organizations, and agendas, how are heterogeneous, perhaps even competing, priorities negotiated? To date, no studies have addressed these questions or investigated how decisions facilitate, or compromise, goals of diversity and inclusion.

The life course of individual studies and the ecosystems in which they reside cannot be easily separated and therefore must be studied in parallel to understand how meanings of diversity are shaped and how goals of inclusion are pursued. Empirically “studying the studies” will also be instrumental in creating mechanisms for transparency about how PMR is conducted and how trade-offs among competing goals are resolved. Establishing open lines of inquiry that study upstream practices may allow researchers to anticipate and address downstream decisions about how results can be interpreted and should be communicated, with a particular eye toward the consequences for communities recruited to augment diversity. Understanding how scientists negotiate the challenges and barriers to achieving diversity that go beyond fulfilling recruitment numbers is a critical step toward promoting meaningful inclusion in PMR.

Transparent Reflection, Cultivation of Trust

Emerging research on public perceptions of PMR suggests that although there is general support, questions of trust loom large. What we learn from studies that examine on-the-ground approaches aimed at enhancing diversity and inclusion, and how the research community reflects and responds with improvements in practices as needed, will play a key role in building a culture of openness that is critical for cultivating public trust.

Cultivating long-term, trusting relationships with participants underrepresented in biomedical research has been linked to a broad range of research practices. Some of these include the willingness of researchers to (i) address the effect of history and experience on marginalized groups’ trust in researchers and clinicians; (ii) engage concerns about potential group harms and risks of stigmatization and discrimination; (iii) develop relationships with participants and communities that are characterized by transparency, clear communication, and mutual commitment; and (iv) integrate participants’ values and expectations of responsible oversight beyond initial informed consent (14). These findings underscore the importance of multidisciplinary teams that include social scientists, ethicists, and policy-makers, who can identify and help to implement practices that respect the histories and concerns of diverse publics.

A commitment to an ethics of inclusion begins with a recognition that risks from the misuse of genetic and biomedical research are unevenly distributed. History makes plain that a multitude of research practices ranging from unnecessarily limited study populations and taken-for-granted data collection procedures to analytic and interpretive missteps can unintentionally bolster claims of racial superiority or inferiority and provoke group harm (15). Sustained commitment to transparency about the goals, limits, and potential uses of research is key to further cultivating trust and building long-term research relationships with populations underrepresented in biomedical studies.

As calls for increasing diversity and inclusion in PMR grow, funding and organizational pathways must be developed that integrate empirical studies of scientific practices and their rationales to determine how goals of inclusion and equity are being addressed and to identify where reform is required. In-depth, multidisciplinary empirical investigations of how diversity is defined, operationalized, and implemented can provide important insights and lessons learned for guiding emerging science, and in so doing, meet our ethical obligations to ensure transparency and meaningful inclusion.

References and Notes

  1. C. P. Jones et al Ethn. Dis. 18496 (2008).
  2. C. C. GravleeA. L. NonC. J. Mulligan
  3. S. A. Kraft et al Am. J. Bioeth. 183 (2018).
  4. A. E. Shields et al Am. Psychol. 6077 (2005).

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

 

Effective humoral immune responses to infection and immunization are defined by high-affinity antibodies generated as a result of B cell differentiation and selection that occurs within germinal centers (GC). Within the GC, B cells undergo affinity maturation, an iterative and competitive process wherein B cells mutate their immunoglobulin genes (somatic hypermutation) and undergo clonal selection by competing for T cell help. Balancing the decision to remain within the GC and continue participating in affinity maturation or to exit the GC as a plasma cell (PC) or memory B cell (MBC) is critical for achieving optimal antibody avidity, antibody quantity, and establishing immunological memory in response to immunization or infection. Humoral immune responses during chronic infections are often dysregulated and characterized by hypergammaglobulinemia, decreased affinity maturation, and delayed development of neutralizing antibodies. Previous studies have suggested that poor antibody quality is in part due to deletion of B cells prior to establishment of the GC response.

 

In fact the impact of chronic infections on B cell fate decisions in the GC remains poorly understood. To address this question, researchers used single-cell transcriptional profiling of virus-specific GC B cells to test the hypothesis that chronic viral infection disrupted GC B cell fate decisions leading to suboptimal humoral immunity. These studies revealed a critical GC differentiation checkpoint that is disrupted by chronic infection, specifically at the point of dark zone re-entry. During chronic viral infection, virus-specific GC B cells were shunted towards terminal plasma cell (PC) or memory B cell (MBC) fates at the expense of continued participation in the GC. Early GC exit was associated with decreased B cell mutational burden and antibody quality. Persisting antigen and inflammation independently drove facets of dysregulation, with a key role for inflammation in directing premature terminal GC B cell differentiation and GC exit. Thus, the present research defines GC defects during chronic viral infection and identify a critical GC checkpoint that is short-circuited, preventing optimal maturation of humoral immunity.

 

Together, these studies identify a key GC B cell differentiation checkpoint that is dysregulated during chronic infection. Further, it was found that the chronic inflammatory environment, rather than persistent antigen, is sufficient to drive altered GC B cell differentiation during chronic infection even against unrelated antigens. However, the data also indicate that inflammatory circuits are likely linked to perception of antigen stimulation. Nevertheless, this study reveals a B cell-intrinsic program of transcriptional skewing in chronic viral infection that results in shunting out of the cyclic GC B cell process and early GC exit with consequences for antibody quality and hypergammaglobulinemia. These findings have implications for vaccination in individuals with pre-existing chronic infections where antibody responses are often ineffective and suggest that modulation of inflammatory pathways may be therapeutically useful to overcome impaired humoral immunity and foster affinity maturation during chronic viral infections.

 

References:

 

https://www.biorxiv.org/content/10.1101/849844v1

 

https://www.ncbi.nlm.nih.gov/pubmed/25656706

 

https://www.ncbi.nlm.nih.gov/pubmed/27653600

 

https://www.ncbi.nlm.nih.gov/pubmed/26912368

 

https://www.ncbi.nlm.nih.gov/pubmed/26799208

 

https://www.ncbi.nlm.nih.gov/pubmed/23001146

 

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New Mutant KRAS Inhibitors Are Showing Promise in Cancer Clinical Trials: Hope For the Once ‘Undruggable’ Target

Curator: Stephen J. Williams, Ph.D.

The November 1st issue of Science highlights a series of findings which give cancer researchers some hope in finally winning a thirty year war with the discovery of drugs that target KRAS, one of the most commonly mutated oncogenes  (25% of cancers), and thought to be a major driver of tumorigenesis. Once considered an undruggable target, mainly because of the smooth surface with no obvious pockets to fit a drug in, as well as the plethora of failed attempts to develop such an inhibitor, new findings with recently developed candidates, highlighted in this article and other curated within, are finally giving hope to researchers and oncologists who have been hoping for a clinically successful inhibitor of this once considered elusive target.

 

For a great review on development of G12C KRas inhibitors please see Dr. Hobb’s and Channing Der’s review in Cell Selective Targeting of the KRAS G12C Mutant: Kicking KRAS When It’s Down

Figure 1Mechanism of Action of ARS853 showing that the inhibitors may not need bind to the active conformation of KRAS for efficacy

Abstract: Two recent studies evaluated a small molecule that specifically binds to and inactivates the KRAS G12C mutant. The new findings argue that the perception that mutant KRAS is persistently frozen in its active GTP-bound form may not be accurate.

 

Although the development of the KRASG12C-specific inhibitor, compound 12 (Ostrem et al., 2013), was groundbreaking, subsequent studies found that the potency of compound 12 in cellular assays was limited (Lito et al., 2016, Patricelli et al., 2016). A search for more-effective analogs led to the development of ARS853 (Patricelli et al., 2016), which exhibited a 600-fold increase of its reaction rate in vitro over compound 12 and cellular activities in the low micromolar range.

 

A Summary and more in-depth curation of the Science article is given below:

After decades, progress against an ‘undruggable’ cancer target

Summary

Cancer researchers are making progress toward a goal that has eluded them for more than 30 years: shrinking tumors by shutting off a protein called KRAS that drives growth in many cancer types. A new type of drug aimed at KRAS made tumors disappear in mice and shrank tumors in lung cancer patients, two companies report in papers published this week. It’s not yet clear whether the drugs will extend patients’ lives, but the results are generating a wave of excitement. And one company, Amgen, reports an unexpected bonus: Its drug also appears to stimulate the immune system to attack tumors, suggesting it could be even more powerful if paired with widely available immunotherapy treatments.

Jocelyn Kaiser. After decades, progress against an ‘undruggable’ cancer target. Science  01 Nov 2019: Vol. 366, Issue 6465, pp. 561 DOI: 10.1126/science.366.6465.561

The article highlights the development of three inhibitors: by Wellspring Biosciences, Amgen, and Mirati Therapeutics.

Wellspring BioSciences

 

In 2013, Dr. Kevan Shokat’s lab at UCSF discovered a small molecule that could fit in the groove of the KRAS mutant G12C.  The G12C as well as the G12D is a common mutation found in KRAS in cancers. KRAS p.G12C mutations predominate in NSCLC comprising 11%–16% of lung adenocarcinomas (45%–50% of mutant KRAS is p.G12C) (Campbell et al., 2016; Jordan et al., 2017), as well as 1%–4% of pancreatic and colorectal adenocarcinomas, respectively (Bailey et al., 2016; Giannakis et al., 2016).  This inhibitor was effective in shrinking, in mouse studies conducted by Wellspring Biosciences,  implanted tumors containing this mutant KRAS.

 

See Wellspring’s news releases below:

March, 2016 – Publication – Selective Inhibition of Oncogenic KRAS Output with Small Molecules Targeting the Inactive State

February, 2016 – Publication – Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism

Amgen

 

Amgen press release on AMG510 Clinical Trial at ASCO 2019

 

THOUSAND OAKS, Calif., June 3, 2019 /PRNewswire/ — Amgen (NASDAQ: AMGN) today announced the first clinical results from a Phase 1 study evaluating investigational AMG 510, the first KRASG12C inhibitor to reach the clinical stage. In the trial, there were no dose-limiting toxicities at tested dose levels. AMG 510 showed anti-tumor activity when administered as a monotherapy in patients with locally-advanced or metastatic KRASG12C mutant solid tumors. These data are being presented during an oral session at the 55th Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago.

“KRAS has been a target of active exploration in cancer research since it was identified as one of the first oncogenes more than 30 years ago, but it remained undruggable due to a lack of traditional small molecule binding pockets on the protein. AMG 510 seeks to crack the KRAS code by exploiting a previously hidden groove on the protein surface,” said David M. Reese, M.D., executive vice president of Research and Development at Amgen. “By irreversibly binding to cysteine 12 on the mutated KRAS protein, AMG 510 is designed to lock it into an inactive state. With high selectivity for KRASG12C, we believe investigational AMG 510 has high potential as both a monotherapy and in combination with other targeted and immune therapies.”

The Phase 1, first-in-human, open-label multicenter study enrolled 35 patients with various tumor types (14 non-small cell lung cancer [NSCLC], 19 colorectal cancer [CRC] and two other). Eligible patients were heavily pretreated with at least two or more prior lines of treatment, consistent with their tumor type and stage of disease. 

Canon, J., Rex, K., Saiki, A.Y. et al. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature 575, 217–223 (2019) doi:10.1038/s41586-019-1694-1

Besides blocking tumor growth, AMG510 appears to stimulate T cells to attack the tumor, thus potentially supplying a two pronged attack to the tumor, inhibiting oncogenic RAS and stimulating anti-tumor immunity.

 

Mirati Therapeutics

 

Mirati’s G12C KRAS inhibitor (MRTX849) is being investigated in a variety of solid malignancies containing the KRAS mutation.

 

For recent publication on results in lung cancer see Patricelli M.P., et al. Cancer Discov. 2016; (Published online January 6, 2016)

For more information on Mirati’s KRAS G12C inhibitor see https://www.mirati.com/pipeline/kras-g12c/

 

KRAS G12C Inhibitor (MRTX849)

Study 849-001 – Phase 1b/2 of single agent MRTX849 for solid tumors with KRAS G12C mutation

Phase 1b/2 clinical trial of single agent MRTX849 in patients with advanced solid tumors that have a KRAS G12C mutation.

See details for this study at clinicaltrials.gov

 

Additional References:

Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism.

Lito P et al. Science. (2016)

Targeting KRAS Mutant Cancers with a Covalent G12C-Specific Inhibitor.

Janes MR et al. Cell. (2018)

Potent and Selective Covalent Quinazoline Inhibitors of KRAS G12C.

Zeng M et al. Cell Chem Biol. (2017)

Campbell, J.D., Alexandrov, A., Kim, J., Wala, J., Berger, A.H., Pedamallu, C.S., Shukla, S.A., Guo, G., Brooks, A.N., Murray, B.A., et al.; Cancer Genome Atlas Research Network (2016). Distinct patterns of somatic genome alterations in lung adenocarcinomas and squamous cell carcinomas. Nat. Genet.48, 607–616

Jordan, E.J., Kim, H.R., Arcila, M.E., Barron, D., Chakravarty, D., Gao, J., Chang, M.T., Ni, A., Kundra, R., Jonsson, P., et al. (2017). Prospective comprehensive molecular characterization of lung adenocarcinomas for efficient patient matching to approved and emerging therapies. Cancer Discov. 7, 596–609.

Bailey, P., Chang, D.K., Nones, K., Johns, A.L., Patch, A.M., Gingras, M.C., Miller, D.K., Christ, A.N., Bruxner, T.J., Quinn, M.C., et al.; Australian Pancreatic Cancer Genome Initiative (2016). Genomic analyses identify molecular subtypes of pancreatic cancer. Nature 531, 47–52.

Giannakis, M., Mu, X.J., Shukla, S.A., Qian, Z.R., Cohen, O., Nishihara, R., Bahl, S., Cao, Y., Amin-Mansour, A., Yamauchi, M., et al. (2016). Genomic correlates of immune-cell infiltrates in colorectal carcinoma. Cell Rep. 15, 857–865.

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