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Mimicking vaginal cells and microbiome interactions on chip microfluidic culture
Reporter and Curator: Dr. Sudipta Saha, Ph.D.
Scientists at Harvard University’s Wyss Institute for Biologically Inspired Engineering have developed the world’s first “vagina-on-a-chip,” which uses living cells and bacteria to mimic the microbial environment of the human vagina. It could help to test drugs against bacterial vaginosis, a common microbial imbalance that makes millions of people more susceptible to sexually transmitted diseases and puts them at risk of preterm delivery when pregnant. Vaginal health is difficult to study in a laboratory setting partly because laboratory animals have “totally different microbiomes” than humans. To address this, scientists have created an unique chip, which is an inch-long, rectangular polymer case containing live human vaginal tissue from a donor and a flow of estrogen-carrying material to simulate vaginal mucus.
The organs-on-a-chip mimic real bodily function, making it easier to study diseases and test drugs. Previous examples include models of the lungs and the intestines. In this case, the tissue acts like that of a real vagina in some important ways. It even responds to changes in estrogen by adjusting the expression of certain genes. And it can grow a humanlike microbiome dominated by “good” or “bad” bacteria. The researchers have demonstrated that Lactobacilli growing on the chip’s tissue help to maintain a low pH by producing lactic acid. Conversely, if the researchers introduce Gardnerella, the chip develops a higher pH, cell damage and increased inflammation: classic bacterial vaginosis signs. So, the chip can demonstrate how a healthy / unhealthy microbiome affects the vagina.
The next step is personalization or subject specific culture from individuals. The chip is a real leap forward, it has the prospect of testing how typical antibiotic treatments against bacterial vaginosis affect the different bacterial strains. Critics of organ-on-a-chip technology often raise the point that it models organs in isolation from the rest of the body. There are limitations such as many researchers are interested in vaginal microbiome changes that occur during pregnancy because of the link between bacterial vaginosis and labor complications. Although the chip’s tissue responds to estrogen, but it does not fully mimic pregnancy without feedback loops from other organs. The researchers are already working on connecting the vagina chip to a cervix chip, which could better represent the larger reproductive system.
All these information indicate that the human vagina chip offers a new model to study host-vaginal microbiome interactions in both optimal and non-optimal states, as well as providing a human relevant preclinical model for development and testing of reproductive therapeutics, including live bio-therapeutics products for bacterial vaginosis. This microfluidic human vagina chip that enables flow through an open epithelial lumen also offers a unique advantage for studies on the effect of cervicovaginal mucus on vaginal health as clinical mucus samples or commercially available mucins can be flowed through this channel. The role of resident and circulating immune cells in host-microbiome interactions also can be explored by incorporating these cells into the vagina chip in the future, as this has been successfully done in various other organ chip models.
2022 FDA Drug Approval List, 2022 Biological Approvals and Approved Cellular and Gene Therapy Products
Reporter: Aviva Lev-Ari, PhD, RN
SOURCE
Tal Bahar’s post on LinkedIn on 1/17/2023
Novel Drug Approvals for 2022
FDA’s Center for Drug Evaluation and Research (CDER)
New Molecular Entities (“NMEs”)
Some of these products have never been used in clinical practice. Below is a listing of new molecular entities and new therapeutic biological products that CDER approved in 2022. This listing does not contain vaccines, allergenic products, blood and blood products, plasma derivatives, cellular and gene therapy products, or other products that the Center for Biologics Evaluation and Research approved in 2022.
Others are the same as, or related to, previously approved products, and they will compete with those products in the marketplace. See Drugs@FDA for information about all of CDER’s approved drugs and biological products.
Certain drugs are classified as new molecular entities (“NMEs”) for purposes of FDA review. Many of these products contain active moieties that FDA had not previously approved, either as a single ingredient drug or as part of a combination product. These products frequently provide important new therapies for patients. Some drugs are characterized as NMEs for administrative purposes, but nonetheless contain active moieties that are closely related to active moieties in products that FDA has previously approved. FDA’s classification of a drug as an “NME” for review purposes is distinct from FDA’s determination of whether a drug product is a “new chemical entity” or “NCE” within the meaning of the Federal Food, Drug, and Cosmetic Act.
To treat adults with HIV whose HIV infections cannot be successfully treated with other available treatments due to resistance, intolerance, or safety considerations Press Release
To decrease the incidence of infection in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with clinically significant incidence of febrile neutropenia
The Center for Biologics Evaluation and Research (CBER) regulates products under a variety of regulatory authorities. See the Development & Approval Process page for a description of what products are approved as Biologics License Applications (BLAs), Premarket Approvals (PMAs), New Drug Applications (NDAs) or 510Ks.
Biologics License Applications and Supplements
New BLAs (except those for blood banking), and BLA supplements that are expected to significantly enhance the public health (e.g., for new/expanded indications, new routes of administration, new dosage formulations and improved safety).
Other Applications Approved or Cleared by the Center for Biologics Evaluation and Research (CBER)
Medical devices involved in the collection, processing, testing, manufacture and administration of licensed blood, blood components and cellular products.
There are five FDA-approved CAR-T treatments for blood cancers and two gene therapies to treat rare diseases now on the market in the U.S. The late-stage pipeline could produce several more cancer CAR-Ts and gene therapies to treat a range of diseases.
One of the biggest races to watch in the cell therapy space will be that between Gilead Sciences’ Yescarta and Bristol Myers Squibb’s Breyanzi, both of which are gunning to move their CAR-Ts into earlier lines of treatment in large B-cell lymphoma (LBCL). At ASH, both companies rolled out impressive data from their trials in the second-line setting, but Gilead could have the upper hand by virtue of its three-year head start in the market, analysts said. Gilead expects to hear from the FDA on a label expansion in the second-line setting in April.
New avenues for research in membrane biology reveals the mobility of protein at work
Curator and Reporter: Dr. Premalata Pati, Ph.D., Postdoc
Membrane proteins(MPs) are proteins that exist in the plasma membrane and conduct a variety of biological functions such as ion transport, substrate transport, and signal transduction. MPs undergo function-related conformational changes on time intervals spanning from nanoseconds to seconds. Many MP structures have been solved thanks to recent developments in structural biology, particularly in single-particle cryo-Electron Microscopy (cryo-EM). Obtaining time-resolved dynamic information on MPs in their membrane surroundings, on the other hand, remains a significant difficulty.
OmpG (Open state) in a fully hydrated dimyristoylphosphatidylcholine (DMPC) bilayer. The protein is shown in light green cartoon. Lipids units are depicted in yellow, while their phosphate and choline groups are illustrated as orange and green van der Waals spheres, respectively. Potassium and chloride counterions are shown in green and purple, respectively. A continuous and semi-transparent cyan representation is used for water. https://static-content.springer.com/esm/art%3A10.1038%2Fs41467-021-24660-1/MediaObjects/41467_2021_24660_MOESM1_ESM.pdf
Weill Cornell Medicine (WCM) researchers have found that they can record high-speed protein movements while linking them to function. The accomplishment should allow scientists to examine proteins in more depth than ever before, and in theory, it should allow for the development of drugs that work better by hitting their protein targets much more effectively.
The researchers utilized High-Speed Atomic Force Microscopy (HS-AFM) to record the rapid motions of a channel protein and published in a report in Nature Communications on July 16. Such proteins generally create channel or tube-like structures in cell membranes, which open to allow molecules to flow under particular conditions. The researchers were able to record the channel protein’s rapid openings and closings with the same temporal resolution as single channel recordings, a typical technique for recording the intermittent passage of charged molecules through the channel.
Senior author Simon Scheuring, professor of physiology and biophysics in anesthesiology at WCM, said,
There has been a significant need for a tool like this that achieves such a high bandwidth that it can ‘see’ the structural variations of molecules as they work.
Researchers can now produce incredibly detailed photographs of molecules using techniques like X-ray crystallography and electron microscopy, showing their structures down to the atomic scale. The average or dominant structural positionings, or conformations, of the molecules, are depicted in these “images,” which are often calculated from thousands of individual photos. In that way, they’re similar to the long-exposure still photos from the dawn of photography.
Many molecules, on the other hand, are flexible and always-moving machinery rather than fixed structures. Scientists need to generate videos, not still photos, to reveal how such molecules move as they work, to see how their motion translates to function to catch their critical functional conformations, which may only exist for a brief moment. Current techniques for dynamic structural imaging, on the other hand, have several drawbacks, one of which being the requirement for fluorescent tags to be inserted on the molecules being photographed in many cases.
Scheuring and his lab were early adopters of the tag-free HS-AFM approach for studying molecular dynamics. The technology, which can photograph molecules in a liquid solution similar to a genuine cellular environment, employs an extremely sensitive probe, similar to a record player’s stylus, to feel its way over a molecule and therefore build up a picture of its structure. Standard HS-AFM isn’t quick enough to capture the high-speed dynamics of many proteins, but Scheuring and colleagues have developed a modified version, HS-AFM height spectroscopy(HS-AFM-HS), that works much faster by collecting dynamic changes in only one dimension: height.
The researchers used HS-AFM-HS to record the opening and closing of a relatively simple channel protein, OmpG, found in bacteria and widely studied as a model channel protein in the new study, led by the first author Raghavendar Reddy Sanganna Gari, a postdoctoral research associate in Scheuring’s laboratory. They were able to monitor OmpG gating at an effective rate of roughly 20,000 data points per second, seeing how it transitioned from open to closed states or vice versa as the acidity of the surrounding fluid varied.
More significantly, they were able to correlate structural dynamics with functional dynamics in a membrane protein of this size for the first time in a partnership with Crina Nimigean, professor of physiology and biophysics in anesthesiology, and her group at WCM.
The demonstration opens the door for a wider application of this method in basic biology and drug development.
Sanganna Gari stated,
We’re now in an exciting period of HS-AFM technology, for example using this technique to study how some drugs modulate the structural dynamics of the channel proteins they target.
Main Source
Technique reveals proteins moving as they work. By Jim Schnabel in Cornell Chronicle, August 16, 2021.
Despite heated discussion over whether it works, the FDA has approved Aduhelm, bringing a new ray of hope to the Alzheimer’s patients.
Curator and Reporter: Dr. Premalata Pati, Ph.D., Postdoc
Despite heated discussion over whether it works, the FDA has approved Aduhelm, bringing a new ray of hope to the Alzheimer’s patients.
On Monday, 7th June 2021, a controversial new Alzheimer’sDisease treatment was licensed in the United States for the first time in nearly 20 years, sparking calls for it to be made available worldwide despite conflicting evidence about its usefulness. The drug was designed for people with mild cognitive impairment, not severe dementia, and it was designed to delay the progression of Alzheimer’s disease rather than only alleviate symptoms.
The route to FDA clearance for Aducanumab has been bumpy – and contentious.
Though doctors, patients, and the organizations that assist them are in desperate need of therapies that can delay mental decline, scientists question the efficacy of the new medicine, Aducanumab or Aduhelm. In March 2019, two trials were halted because the medications looked to be ineffective. “The futility analysis revealed that the studies were most likely to fail,” said Isaacson of Weill Cornell Medicine and NewYork-Presbyterian. Biogen, the drug’s manufacturer revealed several months later that a fresh analysis with more participants found that individuals who got high doses of Aducanumab exhibited a reduction in clinical decline in one experiment. Patients treated with high-dose Aducanumab had 22% reduced clinical impairment in their cognitive health at 18 months, indicating that the advancement of their early Alzheimer’s disease was halted, according to FDA briefing documents from last year.
When the FDA’s members were split on the merits of the application in November, it was rejected. Three of its advisers went public, claiming that there was insufficient evidence that it worked in a scientific journal. They were concerned that if the medicine was approved, it might reduce the threshold for future approvals, owing to the scarcity of Alzheimer’s treatments.
Dr. Caleb Alexander, a drug safety and effectiveness expert at the Johns Hopkins Bloomberg School of Public Health, was one of the FDA advisers who was concerned that the data presented to the agency was a reanalysis after the experiment was stopped. It was “like the Texas sharpshooter fallacy,” he told the New York Times, “where the sharpshooter blows up a barn and then goes and paints a bullseye around the cluster of holes he loves.”
Some organizations, such as the non-profit Public Citizen’s Health Research Group, claimed that the FDA should not approve Aducanumab for the treatment of Alzheimer’s disease because there is insufficient proof of its efficacy.
The drug is a monoclonal antibody that inhibits the formation of amyloid protein plaques in the brain, which are thought to be the cause of Alzheimer’s disease. The majority of Alzheimer’s medications have attempted to erase these plaques.
Aducanumab appears to do this in some patients, but only when the disease is in its early stages. This means that people must be checked to see if they have the disease. Many persons with memory loss are hesitant to undergo testing because there is now no treatment available.
The few Alzheimer’s medications available appear to have limited effectiveness. When Aricept, also known as Donepezil, was approved more than 20 years ago, there was a major battle to get it. It was heralded as a breakthrough at the time – partly due to the lack of anything else. It has become obvious that it slows mental decline for a few months but makes little effect in the long run.
The findings of another trial for some patients backed up those conclusions.
Biogen submitted a Biologics License Application to the FDA in July 2020, requesting approval of the medicine.
The FDA’s decision has been awaited by Alzheimer’s disease researchers, clinicians, and patients since then.
Support for approval of the drug
Other groups, such as the Alzheimer’s Association, have supported the drug’s approval.
The Alzheimer’s Association‘s website stated on Friday, “This is a critical time, regardless of the FDA’s final judgment. We’ve never been this close to approving an Alzheimer’s drug that could affect the disease’s development rather than just the symptoms. We can keep working together to achieve our goal of a world free of Alzheimer’s disease and other dementias.”
The drug has gotten so much attention that the Knight Alzheimer Disease Research Center at Washington University in St. Louis issued a statement on Friday stating that even if it is approved, “it will still likely take several months for the medication to pass other regulatory steps and become available to patients.”
Biogen officials told KGO-TV on Monday that the medicine will be ready to ship in about two weeks and that they have identified more than 900 facilities across the United States that they feel will be medically and commercially suitable.
Officials stated the corporation will also provide financial support to qualifying patients so that their out-of-pocket payments are as low as possible. Biogen has also pledged not to raise the price for at least the next four years.
Most Medicare customers with supplemental plans, according to the firm, will have a limited or capped co-pay.
Case studies connected to the Drug Approval
Case 1
Ann Lange, one of several Chicago-area clinical trial volunteers who received the breakthrough Alzheimer’s treatment, said,
It really offers us so much hope for a long, healthy life.
Lange, 60, has Alzheimer’s disease, which she was diagnosed with five years ago. Her memory has improved as a result of the monthly infusions, she claims.
She said,
I’d forget what I’d done in the shower, so I’d scribble ‘shampoo, conditioner, face, body’ on the door. Otherwise, I’d lose track of what I’m doing “Lange remarked. “I’m not required to do that any longer.
Case 2
Jenny Knap, 69, has been receiving infusions of the Aducanumab medication for about a year as part of two six-month research trials. She told CNN that she had been receiving treatment for roughly six months before the trial was halted in 2019, and that she had recently resumed treatment.
Knap said,
I can’t say I noticed it on a daily basis, but I do think I’m doing a lot better in terms of checking for where my glasses are and stuff like that.
When Knap was diagnosed with mild cognitive impairment, a clinical precursor to Alzheimer’s disease, in 2015, the symptoms were slight but there.
Her glasses were frequently misplaced, and she would repeat herself, forgetting previous talks, according to her husband, Joe Knap.
Joe added,
We were aware that things were starting to fall between the cracks as these instances got more often
Jenny went to the Lou Ruvo Center for Brain Health at the Cleveland Clinic in Ohio for testing and obtained her diagnosis. Jenny found she was qualified to join in clinical trials for the Biogen medicine Aducanumab at the Cleveland Clinic a few years later, in early 2017. She volunteered and has been a part of the trial ever since.
It turns out that Jenny was in the placebo category for the first year and a half, Joe explained, meaning she didn’t get the treatment.
They didn’t realize she was in the placebo group until lately because the trial was blind. Joe stated she was given the medicine around August 2018 and continued until February 2019 as the trial progressed. The trial was halted by Biogen in March 2019, but it was restarted last October, when Jenny resumed getting infusions.
Jenny now receives Aducanumab infusions every four weeks at the Cleveland Clinic, which is roughly a half-hour drive from their house, with Joe by her side. Jenny added that, despite the fact that she has only recently begun therapy, she believes it is benefiting her, combined with a balanced diet and regular exercise (she runs four miles).
The hope of Aducanumab is to halt the progression of the disease rather than to improve cognition. We didn’t appreciate any significant reduction in her condition, Jenny’s doctor, Dr. Babak Tousi, who headed Aducanumab clinical studies at the Cleveland Clinic, wrote to CNN in an email.
This treatment is unlike anything we’ve ever received before. There has never been a drug that has slowed the growth of Alzheimer’s disease, he stated, Right now, existing medications like donepezil and memantine aid with symptoms but do not slow the disease’s progression.
Jenny claims that the medicine has had no significant negative effects on her.
There was signs of some very minor bleeding in the brain at one point, which was quite some time ago. It was at very low levels, in fact, Joe expressed concern about Jenny, but added that the physicians were unconcerned.
According to Tousi, with repeated therapy, “blood vessels may become leaky, allowing fluid and red blood cells to flow out to the surrounding area,” and “micro hemorrhages have been documented in 19.1% of trial participants who got” the maximal dose of therapy”.
Jenny and Joe’s attitude on the future has improved as a result of the infusions and keeping a healthy lifestyle, according to Joe. They were also delighted to take part in the trial, which they saw as an opportunity to make a positive influence in other people’s lives.
There was this apprehension of what was ahead before we went into the clinical trial, Joe recalled. “The medical aspect of the infusion gives us reason to be optimistic. However, doing the activity on a daily basis provides us with immediate benefits.”
The drug’s final commercialization announcement
Aducanumab, which will be marketed as Aduhelm, is a monthly intravenous infusion that is designed to halt cognitive decline in patients with mild memory and thinking issues. It is the first FDA-approved medication for Alzheimer’s disease that targets the disease process rather than just the symptoms.
The manufacturer, Biogen, stated Monday afternoon that the annual list price will be $56,000. In addition, diagnostic tests and brain imaging will very certainly cost tens of thousands of dollars.
The FDA approved approval for the medicine to be used but ordered Biogen to conduct a new clinical trial, recognizing that prior trials of the medicine had offered insufficient evidence to indicate effectiveness.
Biogen Inc said on Tuesday that it expects to start shipping Aduhelm, a newly licensed Alzheimer’s medicine, in approximately two weeks and that it has prepared over 900 healthcare facilities for the intravenous infusion treatment.
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Thriving Vaccines and Research: Weizmann Institute Coronavirus Research Development
Reporter:Amandeep Kaur, B.Sc., M.Sc.
In early February, Prof. Eran Segal updated in one of his tweets and mentioned that “We say with caution, the magic has started.”
The article reported that this statement by Prof. Segal was due to decreasing cases of COVID-19, severe infection cases and hospitalization of patients by rapid vaccination process throughout Israel. Prof. Segal emphasizes in another tweet to remain cautious over the country and informed that there is a long way to cover and searching for scientific solutions.
A daylong webinar entitled “COVID-19: The epidemic that rattles the world” was a great initiative by Weizmann Institute to share their scientific knowledge about the infection among the Israeli institutions and scientists. Prof. Gideon Schreiber and Dr. Ron Diskin organized the event with the support of the Weizmann Coronavirus Response Fund and Israel Society for Biochemistry and Molecular Biology. The speakers were invited from the Hebrew University of Jerusalem, Tel-Aviv University, the Israel Institute for Biological Research (IIBR), and Kaplan Medical Center who addressed the molecular structure and infection biology of the virus, treatments and medications for COVID-19, and the positive and negative effect of the pandemic.
The article reported that with the emergence of pandemic, the scientists at Weizmann started more than 60 projects to explore the virus from different range of perspectives. With the help of funds raised by communities worldwide for the Weizmann Coronavirus Response Fund supported scientists and investigators to elucidate the chemistry, physics and biology behind SARS-CoV-2 infection.
Prof. Avi Levy, the coordinator of the Weizmann Institute’s coronavirus research efforts, mentioned “The vaccines are here, and they will drastically reduce infection rates. But the coronavirus can mutate, and there are many similar infectious diseases out there to be dealt with. All of this research is critical to understanding all sorts of viruses and to preempting any future pandemics.”
The following are few important projects with recent updates reported in the article.
Mapping a hijacker’s methods
Dr. Noam Stern-Ginossar studied the virus invading strategies into the healthy cells and hijack the cell’s systems to divide and reproduce. The article reported that viruses take over the genetic translation system and mainly the ribosomes to produce viral proteins. Dr. Noam used a novel approach known as ‘ribosome profiling’ as her research objective and create a map to locate the translational events taking place inside the viral genome, which further maps the full repertoire of viral proteins produced inside the host.
She and her team members grouped together with the Weizmann’s de Botton Institute and researchers at IIBR for Protein Profiling and understanding the hijacking instructions of coronavirus and developing tools for treatment and therapies. Scientists generated a high-resolution map of the coding regions in the SARS-CoV-2 genome using ribosome-profiling techniques, which allowed researchers to quantify the expression of vital zones along the virus genome that regulates the translation of viral proteins. The study published in Nature in January, explains the hijacking process and reported that virus produces more instruction in the form of viral mRNA than the host and thus dominates the translation process of the host cell. Researchers also clarified that it is the misconception that virus forced the host cell to translate its viral mRNA more efficiently than the host’s own translation, rather high level of viral translation instructions causes hijacking. This study provides valuable insights for the development of effective vaccines and drugs against the COVID-19 infection.
Like chutzpah, some things don’t translate
Prof. Igor Ulitsky and his team worked on untranslated region of viral genome. The article reported that “Not all the parts of viral transcript is translated into protein- rather play some important role in protein production and infection which is unknown.” This region may affect the molecular environment of the translated zones. The Ulitsky group researched to characterize that how the genetic sequence of regions that do not translate into proteins directly or indirectly affect the stability and efficiency of the translating sequences.
Initially, scientists created the library of about 6,000 regions of untranslated sequences to further study their functions. In collaboration with Dr. Noam Stern-Ginossar’s lab, the researchers of Ulitsky’s team worked on Nsp1 protein and focused on the mechanism that how such regions affect the Nsp1 protein production which in turn enhances the virulence. The researchers generated a new alternative and more authentic protocol after solving some technical difficulties which included infecting cells with variants from initial library. Within few months, the researchers are expecting to obtain a more detailed map of how the stability of Nsp1 protein production is getting affected by specific sequences of the untranslated regions.
The landscape of elimination
The article reported that the body’s immune system consists of two main factors- HLA (Human Leukocyte antigen) molecules and T cells for identifying and fighting infections. HLA molecules are protein molecules present on the cell surface and bring fragments of peptide to the surface from inside the infected cell. These peptide fragments are recognized and destroyed by the T cells of the immune system. Samuels’ group tried to find out the answer to the question that how does the body’s surveillance system recognizes the appropriate peptide derived from virus and destroy it. They isolated and analyzed the ‘HLA peptidome’- the complete set of peptides bound to the HLA proteins from inside the SARS-CoV-2 infected cells.
After the analysis of infected cells, they found 26 class-I and 36 class-II HLA peptides, which are present in 99% of the population around the world. Two peptides from HLA class-I were commonly present on the cell surface and two other peptides were derived from coronavirus rare proteins- which mean that these specific coronavirus peptides were marked for easy detection. Among the identified peptides, two peptides were novel discoveries and seven others were shown to induce an immune response earlier. These results from the study will help to develop new vaccines against new coronavirus mutation variants.
Gearing up ‘chain terminators’ to battle the coronavirus
Prof. Rotem Sorek and his lab discovered a family of enzymes within bacteria that produce novel antiviral molecules. These small molecules manufactured by bacteria act as ‘chain terminators’ to fight against the virus invading the bacteria. The study published in Nature in January which reported that these molecules cause a chemical reaction that halts the virus’s replication ability. These new molecules are modified derivates of nucleotide which integrates at the molecular level in the virus and obstruct the works.
Prof. Sorek and his group hypothesize that these new particles could serve as a potential antiviral drug based on the mechanism of chain termination utilized in antiviral drugs used recently in the clinical treatments. Yeda Research and Development has certified these small novel molecules to a company for testing its antiviral mechanism against SARS-CoV-2 infection. Such novel discoveries provide evidences that bacterial immune system is a potential repository of many natural antiviral particles.
Resolving borderline diagnoses
Currently, Real-time Polymerase chain reaction (RT-PCR) is the only choice and extensively used for diagnosis of COVID-19 patients around the globe. Beside its benefits, there are problems associated with RT-PCR, false negative and false positive results and its limitation in detecting new mutations in the virus and emerging variants in the population worldwide. Prof. Eran Elinavs’ lab and Prof. Ido Amits’ lab are working collaboratively to develop a massively parallel, next-generation sequencing technique that tests more effectively and precisely as compared to RT-PCR. This technique can characterize the emerging mutations in SARS-CoV-2, co-occurring viral, bacterial and fungal infections and response patterns in human.
The scientists identified viral variants and distinctive host signatures that help to differentiate infected individuals from non-infected individuals and patients with mild symptoms and severe symptoms.
In Hadassah-Hebrew University Medical Center, Profs. Elinav and Amit are performing trails of the pipeline to test the accuracy in borderline cases, where RT-PCR shows ambiguous or incorrect results. For proper diagnosis and patient stratification, researchers calibrated their severity-prediction matrix. Collectively, scientists are putting efforts to develop a reliable system that resolves borderline cases of RT-PCR and identify new virus variants with known and new mutations, and uses data from human host to classify patients who are needed of close observation and extensive treatment from those who have mild complications and can be managed conservatively.
Moon shot consortium refining drug options
The ‘Moon shot’ consortium was launched almost a year ago with an initiative to develop a novel antiviral drug against SARS-CoV-2 and was led by Dr. Nir London of the Department of Chemical and Structural Biology at Weizmann, Prof. Frank von Delft of Oxford University and the UK’s Diamond Light Source synchroton facility.
To advance the series of novel molecules from conception to evidence of antiviral activity, the scientists have gathered support, guidance, expertise and resources from researchers around the world within a year. The article reported that researchers have built an alternative template for drug-discovery, full transparency process, which avoids the hindrance of intellectual property and red tape.
The new molecules discovered by scientists inhibit a protease, a SARS-CoV-2 protein playing important role in virus replication. The team collaborated with the Israel Institute of Biological Research and other several labs across the globe to demonstrate the efficacy of molecules not only in-vitro as well as in analysis against live virus.
Further research is performed including assaying of safety and efficacy of these potential drugs in living models. The first trial on mice has been started in March. Beside this, additional drugs are optimized and nominated for preclinical testing as candidate drug.
This update is the video from the COVID-19 Series 4.
UPDATED 4/08/2020 see below
The Second in a Series of Virtual Town Halls with Leading Oncologist on Cancer Patient Care during COVID-19 Pandemic: What you need to know
The second virtual Town Hall with Leading International Oncologist, discussing the impact that the worldwide COVID-19 outbreak has on cancer care and patient care issues will be held this Saturday April 4, 2020. This Town Hall Series is led by Dr. Roy Herbst and Dr. Hossain Borghaei who will present a panel of experts to discuss issues pertaining to oncology practice as well as addressing physicians and patients concerns surrounding the risk COVID-19 presents to cancer care. Some speakers on the panel represent oncologist from France and Italy, and will give their views of the situation in these countries.
Speakers include:
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
Hossain Borghaei, DO, MS , Chief of Thoracic Medical Oncology and Director of Lung Cancer Risk Assessment, Fox Chase Cancer Center
Giuseppe Curigliano, MD, PhD, University of Milan and Head of Phase I Division at IEO, European Institute of Oncology
Paolo Ascierto, MD National Tumor Institute Fondazione G. Pascale, Medical oncologist from National Cancer Institute of Naples, Italy
Dr. Jack West from City of Hope talked about telemedicine: Coordination of the patient experience, which used to be face to face now moved to a telemedicine alternative. For example a patient doing well on personalized therapy, many patients are well suited for a telemedicine experience. A benefit for both patient and physician.
Dr. Rohit Kumar: In small cancer hospitals, can be a bit difficult to determine which patient needs to come in and which do not. For outpatients testing for COVID is becoming very pertinent as these tests need to come back faster than it is currently. For inpatients the issue is personal protection equipment. They are starting to reuse masks after sterilization with dry heat. Best to restructure the system of seeing patients and scheduling procedures.
Dr. Christopher Manley: hypoxia was an issue for COVID19 patients but seeing GI symptoms in 5% of patients. Nebulizers have potential to aerosolize. For patients in surgery prep room surgical masks are fine. Ventilating these patients are a challenge as hypoxia a problem. Myocarditis is a problem in some patients. Diffuse encephalopathy and kidney problems are being seen. So Interleukin 6 (IL6) inhibitors are being used to reduce the cytokine storm presented in patients suffering from COVID19.
Dr. Hope Rugo from UCSF: Breast cancer treatment during this pandemic has been challenging, even though they don’t use too much immuno-suppressive drugs. How we decide on timing of therapy and future visits is crucial. For early stage breast cancer, neoadjuvant therapy is being used to delay surgeries. Endocrine therapy is more often being used. In patients that need chemotherapy, they are using growth factor therapy according to current guidelines. Although that growth factor therapy might antagonize some lung problems, there is less need for multiple visits.
For metastatic breast cancer, high risk ER positive are receiving endocrine therapy and using telemedicine for followups. For chemotherapy they are trying to reduce the schedules or frequency it is given. Clinical trials have been put on hold, mostly pharmokinetic studies are hard to carry out unless patients can come in, so as they are limiting patient visits they are putting these type of clinical studies on hold.
Dr. Harriet Kluger: Melanoma community of oncologists gathered together two weeks ago to discuss guidelines and best practices during this pandemic. The discussed that there is a lack of data on immunotherapy long term benefit and don’t know the effectiveness of neoadjuvant therapy. She noted that many patients on BRAF inhibitors like Taflinar (dabrafenib) or Zelboraf (vemurafenib) might get fevers as a side effect from these inhibitors and telling them to just monitor themselves and get tested if they want. Yale has also instituted a practice that, if a patient tests positive for COVID19, Yale wants 24 hours between the next patient visit to limit spread and decontaminate.
Marianne Davies: Blood work is now being done at satellite sites to limit number of in person visits to Yale. Usually they did biopsies to determine resistance to therapy but now relying on liquid biopsies (if insurance isn’t covering it they are working with patient to assist). For mesothelioma they are dropping chemotherapy that is very immunosuppressive and going with maintenance pembrolizumab (Keytruda). It is challenging in that COPD mimics the symptoms of COVID and patients are finding it difficult to get nebulizers at the pharmacy because of shortages; these patients that develop COPD are also worried they will not get the respirators they need because of rationing.
Dr. Barbara Burtness: Head and neck cancer. Dr. Burtness stresses to patients that the survival rate now for HPV positive head and neck is much better and leaves patients with extra information on their individual cancers. She also noted a registry or database that is being formed to track data on COVID in patients undergoing surgery and can be found here at https://globalsurg.org/covidsurg/
About CovidSurg
There is an urgent need to understand the outcomes of COVID-19 infected patients who undergo surgery.
Capturing real-world data and sharing international experience will inform the management of this complex group of patients who undergo surgery throughout the COVID-19 pandemic, improving their clinical care.
CovidSurg has been designed by an international collaborating group of surgeons and anesthetists, with representation from Canada, China, Germany, Hong Kong, Italy, Korea, Singapore, Spain, United Kingdom, and the United States.
Dr. Burtness had noted that healthcare care workers are at high risk of COVID exposure during ear nose and throat (ENT) procedures as the coronavirus resides in the upper respiratory tract. As for therapy for head and neck cancers, they are staying away from high dose cisplatin because of the nephrotoxicity seen with high dose cisplatin. An alternative is carboplatin which generally you do not see nephrotoxicity as an adverse event (a weekly carboplatin). Changing or increasing dose schedule (like 6 weeks Keytruda) helps reduce immunologic problems related to immunosupression and patients do not have to come in as often.
Italy and France
Dr. Paolo Ascierto: with braf inhibitors, using in tablet form so patients can take from home. Also they are moving chemo schedules for inpatients so longer dosing schedules. Fever still a side effect from braf inhibitors and they require a swab to be performed to ascertain patient is COVID19 negative. Also seeing pneumonitis as this is an adverse event from checkpoint inhibitors so looking at CT scans and nasal swab to determine if just side effect of I/O drugs or a COVID19 case. He mentioned that their area is now doing okay with resources.
Dr. Guiseppe Curigliano mentioned about the redesign of the Italian health system with spokes and hubs of health care. Spokes are generalized medicine while the hubs represent more specialized centers like CV hubs or cancer hubs. So for instance, if a melanoma patient in a spoke area with COVID cases they will be referred to a hub. He says they are doing better in his area
In the question and answer period, Dr. West mentioned that they are relaxing many HIPAA regulations concerning telemedicine. There is a website on the Centers for Connective Health Policy that shows state by state policy on conducting telemedicine. On immuno oncology therapy, many in the panel had many questions concerning the long term risk to COVID associated with this type of therapy. Fabrice mentioned they try to postpone use of I/O and although Dr. Kluger said there was an idea floating around that PD1/PDL1 inhibitors could be used as a prophylactic agent more data was needed.
Please revisit this page as the recording of this Town Hall will be made available next week.
UPDATED 4/08/2020
Below find theLIVE RECORDING and TAKEAWAYSby the speakers
Town Hall Takeaways
Utilize Telehealth to Its Fullest Benefit
· Patients doing well on targeted therapy or routine surveillance are well suited to telemedicine
· Most patients are amenable to this, as it is more convenient for them and minimizes their exposure
· A patient can speak to multiple specialists with an ease that was not previously possible
· CMS has relaxed some rules to accommodate telehealth, though private insurers have not moved as quickly, and the Center for Connected Health Policy maintains a repository of current state-by-state regulations: https://www.cchpca.org/
Practice Management Strategies
· In the face of PPE shortages, N95 masks can be decontaminated using UV light, hydrogen peroxide, or autoclaving with dry heat; the masks can be returned to the original user until the masks are no longer suitable for use
· For blood work or scans, the use of external satellite facilities should be explored
· Keep pumps outside of the room so nurses can attend to them quickly
· Limit the use of nebulizers, CPAPs, and BiPAPs due to risk of aerosolization
· Caution is urged in the presence of cardiac complications, as ventilated patients may appear to improve, only to suffer severe myocarditis and cardiac arrest following extubation
· When the decision is made to intubate, intubate quickly, as less invasive methods result in aerosolization and increased risks to staff
Study the Lessons of Europe
· The health care system in Italy has been reorganized into “spokes” and “hubs,” with a number of cancer hubs; if there is a cancer patient in a spoke hospital with many COVID patients, this patient may be referred to a hub hospital
· Postpone adjuvant treatments whenever possible
· Oral therapies, which can be managed at home, are preferred over therapies that must be administered in a healthcare setting
· Pneumonitis patients without fevers may be treated with steroids, but nasal swab testing is needed in the presence of concomitant fever
· Any staff who are not needed on site should be working from home, and rotating schedules can be used to keep people healthy
· Devise an annual epidemic control plan now that we have new lessons from COVID
We Must Be Advocates for Our Cancer Patients
· Be proactive with other healthcare providers on behalf of patients with a good prognosis
· Consider writing letters for cancer patients for inclusion into their chart, or addendums on notes, then encourage patients to print these out, or give it to them during their visit
· The potential exists for a patient to be physiologically stable on a ventilator, but intolerant of decannulation; early discussions are necessary to determine reasonable expectations of care
· Be sure to anticipate a second wave of patients, comprised of cancer patients for whom treatments and surgery have been delayed!
Tumor-Specific Learnings
Ø Strategies in Breast Cancer:
· In patients with early-stage disease, promote the use of neoadjuvant therapy where possible to delay the need for surgery
· For patients with metastatic disease in the palliative setting, transition to less frequent chemotherapy dosing if possible
· While growth factors may pose a risk in interstitial lung disease, new guidelines are emerging
· The use of BRAF/MEK inhibitors can cause fevers that are drug-related, and access to an alternate clinic where patients can be assessed is a useful resource
Ø Strategies in Lung Cancer:
· For patients who are stable on an oral, targeted therapy, telehealth check-in is a good option
· For patients who progress on targeted therapies, increased use of liquid biopsies when appropriate can minimize use of bronchoscopy suites and other resources
· For patients on pembrolizumab monotherapy, consider switching to a six-week dosing of 400 mg
· Many lung cancer patients worry about “discrimination” should they develop a COVID infection; it is important to support patients and help manage expectations and concerns
UPDATED 5/11/2020
Townhall on COVID-19 and Cancer Care with Leading Oncologists Series 4
Addressing the Challenges of Cancer Care in the Community
The second virtual Town Hall with Leading International Oncologist, discussing the impact that the worldwide COVID-19 outbreak has on cancer care and patient care issues will be held this Saturday April 4, 2020. This Town Hall Series is led by Dr. Roy Herbst and Dr. Hossein Borghaei who will present a panel of experts to discuss issues pertaining to oncology practice as well as addressing physicians and patients concerns surrounding the risk COVID-19 presents to cancer care. Some speakers on the panel represent oncologist from France and Italy, and will give their views of the situation in these countries.
This series is being hosted in partnership with Axiom Healthcare Strategies, Inc..
The Town Hall proceedings and live notes will be made available on this site and Live Notes will be Tweeted in Real Time using the #CancerCareandCOVID19 and @pharma_BI
The goal of these town halls is to improve outcomes of cancer patients across the globe, by sharing insights and lessons learned from oncologists fighting COVID-19. Dr. Roy Herbst and Dr. Hossein Borghaei will be joined by a panel of thought leaders with expertise in a variety of solid tumors to discuss how COVID-19 has impacted patient care in oncology.
Following the session, a video, transcript, and key takeaways will be released on Monday 4/6.
Time
For Live Notes From the Last Town Hall Meeting Specifically on Lung Cancer and COVID19 please go to
As part of the Harvard Medical School Series on Bioethics: author, clinician and professor Jerome Groopman, MD and Pamel Harzband, MD gave an online discussion of their book “Your Medical Mind”, a part of Harvard Medical School Center for Bioethics Program’s Critical Reading of Contemporary Books in Bioethics Series. The Contemporary Authors in Bioethics series brings together authors and the community to discuss books that explore new and developing topics in the field. This was held as an online Zoom meeting on March 26, 2020 at 5 pm EST and could be followed on Twitter using #HarvardBioethics. A recording of the discussion will be made available at the Harvard Med School Center for Bioethics.
Available at Amazon: From the Amazon book description:
An entirely new way to make the best medical decisions.
Making the right medical decisions is harder than ever. We are overwhelmed by information from all sides—whether our doctors’ recommendations, dissenting experts, confusing statistics, or testimonials on the Internet. Now Doctors Groopman and Hartzband reveal that each of us has a “medical mind,” a highly individual approach to weighing the risks and benefits of treatments. Are you a minimalist or a maximalist, a believer or a doubter, do you look for natural healing or the latest technology? The authors weave vivid narratives of real patients with insights from recent research to demonstrate the power of the medical mind. After reading this groundbreaking book, you will know how to arrive at choices that serve you best.
Doctors Groopman and Hartzband began the discussion with a recapping medical research studies and medical panels, which had reported conflicting results or reversal of recommendations, respectively. These included studies on the benefits of statin therapy in cholesterol management, studies on whether or not Vitamin D therapy is beneficial for postmenopausal women, the ongoing controversy on the frequency with which women should get mammograms, as well as the predictive value of Prostate Specific Antigen and prostate cancer screening. The authors singled out the research reports and medical panels reviewing the data on PSA in which the same medical panel first came out in support of using PSA levels to screen for prostate cancer and then later, after reconvening, recommended that PSA was not useful for mass screenings for prostate cancer.
In fact, both authors were
completed surprised of the diametrically opposed views within or between panels given similar data presented to those medical professionals.
The authors then asked a question: Why would the same medical panel come to a reversal of their decision and more, importantly, why are there such disparate conclusions from the same medical data sets, leading to varied clinical decision-making.
In general, Drs. Groopman and Hartzband asked how do physicians and patients make their decisions?
To answer this they looked at studies that Daniel Bernouli had conducted to model the economic behaviors of risk aversion in the marketplace. Bernouli’s theorem correlated market expectation with probability and outcomes
expectation = probability x utility of outcome
However, in medicine, one can measure probability (or risk) but it is very hard to measure utility (which is the value or worth of the outcome).
For example, they gave an example if a person was born blind but offered a risky to regain sight, the individual values their quality of life from their own perspective and might feel that, as their life is worthwhile as it is, they would not undergo a risky procedure. However a person who had suddenly lost their sight might value sight more, and be willing to undergo a risky procedure.
Three methods are used to put a value on utility or outcome worth with regards to medical decisions
linear scale (life or death; from 0 to 1)
time trade off: e.g. how much longer do I have to live
standard gamble: let’s try it
All of these methods however are flawed because one doesn’t know their future medical condition (e.g. new information on the disease) and people values and perceptions change over time.
An example of choice of methods the medical community uses to make decisions include:
In the United Kingdom, their system uses a time trade off method to determine value in order to determine appropriate course of action which may inadvertently, result in rationed care
in the United States, the medical community uses the time trade off to determine cost effectiveness
Therefore Drs. Groopman and Harztband, after conducing multiple interviews with patients and physicians were able to categorize medical decision making based on groups of mindsets
Maximalist: Proactive behavior, wants to stay ahead of the curve
Minimalist: less intervention is more; more hesitant to try any suggested therapy
Naturalist: more prone to choose natural based therapies or home remedies
Tech Oriented: wants to try the latest therapies and more apt to trust in branded and FDA approved therapeutics
Believer: trust in suggestions by physician; physician trusts medical panels suggestions
Doubter: naturally inquisitive and more prone to investigate risk benefits of any suggested therapy
The authors also identified many Cognitive Traps that both physicians and patients may fall into including:
Relative versus Absolute Numbers: for instance putting emphasis on one number or the other without regard to context; like looking at disease numbers without taking into consideration individual risk
Availability: availability or lack of available information; they noticed if you fall in this trap depends on whether you are a Minimalist or Maximalist
Framing: for example when people talk to others about their conditions and hear stories about others treatments, conditions .. mainly anecdotal evidence
Stories can be helpful but they sometimes increase our overestimation of risk or benefit so framing the information is very important for both the patient as well as the physician (even doctors as patients)
Both authors have noticed a big shift in US to minimalism probably because of the rising costs of healthcare.
How do these mindsets affect the patient-physician relationship?
A University of Michigan study revealed that patients who would be characterized as maximalists pushed their physicians to do more therapy and were more prone to seek outside advice.
Physicians need to understand and listen to their patients during the patients’s first visit and determine what medical mindset that this patient has.
About the authors:
Jerome Groopman, M.D. is the Dina and Raphael Recanati Professor of Medicine at Harvard Medical School, Chief of Experimental Medicine at Beth Israel Deaconess Medical Center, and one of the world’s leading researchers in cancer and AIDS. He is a staff writer for The New Yorker and has written for The New York Times, The Wall Street Journal,The Washington Post and The New Republic. He is author of The Measure of Our Days (1997), Second Opinions (2000), Anatomy of Hope (2004), How Doctors Think (2007), and the recently released, Your Medical Mind.
Dr. Pamela Hartzband is an Assistant Professor at the Harvard Medical School and Attending Physician in the Division of Endocrinology at the Beth Israel Deaconess Medical Center in Boston. She specializes in disorders of the thyroid and pituitary glands. A magna cum laude graduate of Radcliffe College, Harvard University, she received her M.D. from Harvard Medical School. She served her internship and residency in internal medicine at the Massachusetts General Hospital, and her specialty fellowships in endocrinology and metabolism at UCLA.
More articles on BioEthics and Patient experiences in this Online Open Access Journal Include:
The webinar started with a brief introduction of attendees , most who are breast cancer survivors. Survivingbreastcancer.org is an organization committed to supplying women affected with breast cancer up to date information, including podcasts, webinars, and information for treatment, care, and finding support and support groups.
Some of the comments of survivors:
being strong
making sure to not feel overwhelmed on initial diagnosis
get good information
sometimes patients have to know to ask for genetic testing as physicians may not offer it
Laura Carfang discussed her study results presented at a bioethics conference in Clearwater, FL on issues driving breast cancer patient’s as well as at-risk women’s decision making process for genetic testing. The study was a phenomenological study in order to determine, through personal lived experiences, what are pivotal choices to make genetic testing decisions in order to improve clinical practice.
The research involved in depth interviews with 6 breast cancer patients (all women) who had undergone breast cancer genetic testing.
Main themes coming from the interviews
information informing decisions before diagnosis: they did not have an in depth knowledge of cancer or genetics or their inherent risk before the diagnosis.
these are my genes and I should own it: another common theme among women who were just diagnosed and contemplating whether or not to have genetic testing
information contributing to decision making after diagnosis: women wanted the option, and they wanted to know if they carry certain genetic mutations and how it would guide their own personal decision to choose the therapy they are most comfortable with and gives them the best chance to treat their cancer (the decision and choice is very personal)
communicating to family members and children was difficult for the individual affected; women found that there were so many ramifications about talking with family members (how do I tell children, do family members really empathize with what I am going through). Once women were tested they felt a great strain because they now were more concerned with who in their family (daughters) were at risk versus when they first get the diagnosis the bigger concern was obtaining information.
Decision making to undergo genetic testing not always linear but a nonlinear process where women went from wanting to get tested for the information to not wanting to get tested for reasons surrounding negative concerns surrounding knowing results (discrimination based on results, fear of telling family members)
Complex decision making involves a shift or alteration in emotion
The Mayo Clinic has come out with full support of genetic testing and offer to any patient.
Additional resources discussed was a book by Leslie Ferris Yerger “Probably Benign” which discusses misdiagnoses especially when a test comes back as “probably benign” and how she found it was not.
Parkinson’s Disease (PD), characterized by both motor and non-motor system pathology, is a common neurodegenerative disorder affecting about 1% of the population over age 60. Its prevalence presents an increasing social burden as the population ages. Since its introduction in the 1960’s, dopamine (DA)-replacement therapy (e.g., L-DOPA) has remained the gold standard treatment. While improving PD patients’ quality of life, the effects of treatment fade with disease progression and prolonged usage of these medications often (>80%) results in side effects including dyskinesias and motor fluctuations. Since the selective degeneration of A9 mDA neurons (mDANs) in the substantia nigra (SN) is a key pathological feature of the disease and is directly associated with the cardinal motor symptoms, dopaminergic cell transplantation has been proposed as a therapeutic strategy.
Researchers showed that mammalian fibroblasts can be converted into embryonic stem cell (ESC)-like induced pluripotent stem cells (iPSCs) by introducing four transcription factors i.e., Oct4, Sox2, Klf4, and c-Myc. This was then accomplished with human somatic cells, reprogramming them into human iPSCs (hiPSCs), offering the possibility of generating patient-specific stem cells. There are several major barriers to implementation of hiPSC-based cell therapy for PD. First, probably due to the limited understanding of the reprogramming process, wide variability exists between the differentiation potential of individual hiPSC lines. Second, the safety of hiPSC-based cell therapy has yet to be fully established. In particular, since any hiPSCs that remain undifferentiated or bear sub-clonal tumorigenic mutations have neoplastic potential, it is critical to eliminate completely such cells from a therapeutic product.
In the present study the researchers established human induced pluripotent stem cell (hiPSC)-based autologous cell therapy. Researchers reported a platform of core techniques for the production of mDA progenitors as a safe and effective therapeutic product. First, by combining metabolism-regulating microRNAs with reprogramming factors, a method was developed to more efficiently generate clinical grade iPSCs, as evidenced by genomic integrity and unbiased pluripotent potential. Second, a “spotting”-based in vitro differentiation methodology was established to generate functional and healthy mDA cells in a scalable manner. Third, a chemical method was developed that safely eliminates undifferentiated cells from the final product. Dopaminergic cells thus produced can express high levels of characteristic mDA markers, produce and secrete dopamine, and exhibit electrophysiological features typical of mDA cells. Transplantation of these cells into rodent models of PD robustly restored motor dysfunction and reinnervated host brain, while showing no evidence of tumor formation or redistribution of the implanted cells.
Together these results supported the promise of these techniques to provide clinically applicable personalized autologous cell therapy for PD. It was recognized by researchers that this methodology is likely to be more costly in dollars and manpower than techniques using off-the-shelf methods and allogenic cell lines. Nevertheless, the cost for autologous cell therapy may be expected to decrease steadily with technological refinement and automation. Given the significant advantages inherent in a cell source free of ethical concerns and with the potential to obviate the need for immunosuppression, with its attendant costs and dangers, it was proposed that this platform is suitable for the successful implementation of human personalized autologous cell therapy for PD.
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