Category Archives: Molecular Medicine

As more people are tested for COVID-19, experts are warning the results might not be 100 percent accurate.

Preliminary research from China that is yet to be peer reviewed suggests the most common form of COVID-19 test produces false negatives up to 30 percent of the time.

The issue with the tests for the SARS-CoV-2 virus is that there has not been time to test them rigorously before deploying them in the field, Dr. Gary L. LeRoy, FAAFP, president of the American Academy of Family Physicians, told Healthline.

Most polymerase chain reaction (PCR) and antibody tests have years of laboratory testing before they are used. We just dont have that kind of time, LeRoy said. The major concern for false negatives is someone who tests negative, thinking they are not infected, could unknowingly spread the virus into the community.

In the United States, the most common form of test used for COVID-19 is a molecular test known as a reverse transcriptase polymerase chain reaction (RT-PCR) test.

For these tests, specimens are taken from the back of the nose and mouth.

The notion is that this is a virus that likes to implant itself on the mucous membranes high up in the back of the throat behind the nose, Dr. William Schaffner, an infectious disease specialist at Vanderbilt University Medical Center in Tennessee, told Healthline. So you have to put a swab, not at the front of the nose, but rather far back. Then you have the small mucus on the end of that specimen, it gets sent to the laboratory, its extracted from the specimen, then using molecular technology you determine whether the virus is there.

You can have a false negative if you have very little virus up there or perhaps the specimen was taken inappropriately. It didnt get up high enough to actually get to the place where the virus was located. Thats another possibility, Schaffner added.

Dr. Lee Harold Hilborne is a professor of pathology and laboratory medicine at the University of California Los Angeles.

He says no test is faultless and the high rate of false negatives is likely due to collection rather than testing in a laboratory.

Tests have different sensitivity and specificity. Its important to recognize that none are perfect. The 30 percent rate is based on collection, not the analytic performance of the test, Hilborne told Healthline.

The majority of issues contributing to error in diagnostic testing are pre-analytic, he added. These occur during specimen order, collection, and transport, before the specimen ever reaches the lab. We know that collection methods do not always pick up the virus. Studies suggest current swab collection may have sensitivity in the range of 60 to 75 percent. That means the specimen submitted to the laboratory from a patient with the infection will not contain the virus roughly 25 to 40 percent of the time.

Hilborne describes a hypothetical scenario in which a drive-thru collection center sees 100 patients who are unwell enough to warrant a test.

Specimens are collected using a technique that has a 65 percent chance of picking up the virus. Of the 100 people tested at the drive through, 20 percent test positive. Thats 20 patients.

But what about the remainder who tested negative?

If the collection success rate is 65 percent, then there will be an additional roughly 10 to 11 patients who are infected but who have a negative test. That is, one-third of infected patients in this scenario who have the infection will test negative even though the test itself is analytically extremely good, Hilborne explained.

The World Health Organization (WHO) estimates that one person with COVID-19 will pass the virus on to at least two people.

Given this, experts say that if a person with symptoms receives a negative test result, they should still self-isolate.

If a patient presents with symptoms of COVID-19 cough, fever, shortness of breath but they test negative, they should self-isolate out of an abundance of caution to stop the potential spread of the disease, LeRoy said. The tests used are not 100 percent accurate and a negative test does not always equate to not having the disease.

The Centers for Disease Control and Prevention (CDC) notes that even if a person tests negative, that doesnt guarantee they wont become ill.

If you test negative for COVID-19, you probably were not infected at the time your specimen was collected. However, that does not mean you will not get sick. It is possible that you were very early in your infection at the time of your specimen collection and that you could test positive later, or you could be exposed later and then develop illness. In other words, a negative test result does not rule out getting sick later, the CDC website states.

Early indications suggest that people may be most infectious before they become ill and experts say it is important people do their part to contain the spread of the virus.

The current physical distancing measures are in place to help slow the spread of the disease, especially from those who are currently not showing symptoms, LeRoy said.

Many who are later diagnosed with COVID-19 had actually been infected and spreading the virus for several days, he said. Staying home and wearing cloth masks in public, especially when physical distancing is more difficult, will help slow the spread from those who might currently be asymptomatic but who are actually infected.

The rest is here:
'False Negatives' in COVID-19 Tests: Have Symptoms, Assume Illness - Healthline

In the age of the coronavirus, when nothing is certain and we must plot our every move with the utmost caution, some people are wondering if they need not worry quite as much. What if, they ask, I already had COVID-19 weeks ago but didn't realize or couldn't confirm it?

The search terms "did I have coronavirus" spiked in Google Trends early last month, when it became clear the United States was on the cusp of major outbreaks. People also Googled "did I have coronavirus in January" and "did I have coronavirus in February."

Soccer star Carli Lloyd wondered as much on Twitter in late March, detailing symptoms similar to those caused by COVID-19, including a fever, cough, and shortness of breath.

"Beginning to think my husband and I had the Coronavirus back in mid February," she wrote. "A sickness we have never felt before."

Her replies were full of people wondering about the same scenario in their lives.

It's a simultaneously compelling, legitimate thing to ask and a kind of fantasy that we might indulge in because the alternative constantly worrying about contracting a highly infectious, potentially fatal disease is exhausting. The anxiety of extreme social distancing and panic buying might be more tolerable if people knew they'd already survived asymptomatic, mild, or moderate cases of COVID-19.

Unfortunately, the answer to this question is elusive, which means, as far as we know, the risk of contracting COVID-19 remains high. This is particularly true because people who are asymptomatic can infect others, undermining a key assumption about how viruses are transmitted.

There are now more than 370,000 known cases and 12,000 fatalities in the U.S., and public health authorities stress that the only way to stem infections and prevent more deaths is to continue practicing social distancing, hand washing, and other preventive measures.

In order to know how many people in the U.S. have been infected with COVID-19, we'd need widespread availability of highly accurate tests that detect the presence of antibodies against the disease. We also need more scientific information about how long immunity to the disease lasts once someone acquires it. Immunity to common colds, which are caused by coronaviruses, is temporary. Even if someone accurately suspected they'd come down with COVID-19 earlier this year, it doesn't necessarily mean they'd continue to be immune to the virus in the coming months or years.

Then there's the question of whether the timeline makes sense. Prior to the known outbreaks, could people have developed mild or moderate cases of COVID-19 without a simultaneous uptick in severe cases that would've required hospitalization?

Nicholas Reich, an associate professor of biostatistics at the University of Massachusetts in Amherst whose lab focuses on understanding and modeling infectious disease, has been looking for evidence of this happening, and so far sees little data to support that possibility.

He and his lab members noticed influenza-like illnesses increase in December and January and thought perhaps coronavirus had been silently circulating for months. They decided to look at the rate of influenza-like illnesses alongside the rate of negative flu tests as a potential signal of community spread of COVID-19; if illnesses rose but more flu tests came back negative, it could suggest another pathogen playing an unexpected role. By late February, the lab's analysis showed trends that were consistent with historical norms.

Since then, when the lab looked at patterns in March, they saw deviations from the historical norms but it was difficult to draw strong conclusions from that data.

More people went to the doctor with respiratory illnesses and also tested negative for the flu, but Reich said that could be the result of people changing their behavior as media coverage of coronavirus ramped up. In other words, more people sought medical attention for various symptoms because of alarming headlines about COVID-19 but may not have had the disease. The researchers couldn't rule out COVID-19 spreading earlier than thought, but the data also suggested that if the coronavirus had been present, it would've been relatively limited.

Reich believes it's plausible that someone in the vicinity of a hot spot like Seattle or New York could've developed COVID-19 in mid-February, as the disease began to spread throughout communities. (In fact, after this story was published, new research emerged suggesting that the coronavirus began spreading in New York in mid-February.)

"Outbreaks like this take time to build up steam and really start to burn," Reich said.

Still, given the severity of COVID-19, Reich believes it's unlikely that coronavirus was widespread prior to late February and early March. That would've been accompanied by what we're seeing now, and saw in Italy: a fraction of patients streaming into emergency rooms with respiratory distress.

"Outbreaks like this take time to build up steam and really start to burn."

"Based on everything thats been coming out, Ive been increasingly feeling as though it wouldve been really hard to miss a large outbreak," said Reich. "Data points like [what's happening in Italy] make it clearer to me just how this is really different from seasonal flu."

Reich also points to genomic analyses of the coronavirus conducted by Trevor Bedford, a computational biologist at the Fred Hutchinson Cancer Research Center in Seattle, which suggest that the first known COVID-19 case in the U.S. occurred in mid-January, in Washington state. That research looked at minor mutations in the virus' genome to analyze when it might have emerged in the U.S. If that analysis is accurate, it would make it far less likely that the disease caused mysterious respiratory illnesses in late 2019 or early 2020.

Ruth Collins, an associate professor of molecular medicine at Cornell University, said it's very likely that a different, nasty virus could've been circulating this winter. Since the symptoms caused by coronaviruses overlap significantly, it would make sense that some people experienced an awful illness that wasn't actually caused by COVID-19 but still produced similar symptoms like coughing, fever, and aches and pains.

Collins said that wondering about whether an illness experienced prior to the coronavirus outbreak was in fact COVID-19 is a form of highly relatable wishful thinking.

"It's part of human psychology," she said. "We always want to think were better than we are, that we got lucky, that we escaped it somehow."

It doesn't help, either, that tests to diagnose COVID-19 have been difficult to get.

In the absence of diagnostic testing, we need widespread individual and epidemiological testing to determine who contracted COVID-19 and developed antibodies to the disease. That requires highly accurate serology tests, or blood-based tests, that detect the presence of antibodies against COVID-19. Such testing is being rolled out by the Centers for Disease Control and Prevention, but the government agency is focusing on areas that became hot spots. Antibody tests are not widely available, and though there are efforts to make them accessible to the public, it's not clear when they will be.

Collins also said that antibody tests, like any other test, can be unreliable, producing both false negatives and false positives. Tests, for example, might not pick up antibodies present in small amounts because immunity declined, even if the person was infected.

What we need is more conclusive medical and scientific research on how COVID-19 is transmitted, particularly through asymptomatic people, and a more precise tally of how many people have been infected. Individual access to accurate antibody tests will be important to answering the lingering question about potential infection, but it's still unclear how long immunity lasts.

In the meantime, suspicion of a COVID-19 infection without confirmation is no reason to relax social distancing or hygiene practices.

"This thing is not going to go away fast," said Collins. "Weve got to know more about how the disease spreads. The idea of testing will give some level of confidence, but it wont be enough until we know more about how the disease is transmitted."

UPDATE: April 9, 2020, 8:48 a.m. PDT This story was updated to include information about new genomic research suggesting that COVID-19 was beginning to spread in New York in mid-February.

Link:
'Did I already have coronavirus?': People wonder if they previously had COVID-19, but the answer isn't easy - Mashable

There was a time when waking up with a scratchy throat or a dry cough didnt elicit such a sense of dread, but Covid-19 has made us all hyper-aware of its symptoms. Many people have been left wondering if they are asymptomatic carriers of the disease, or if a slight cold they may have recently experienced was actually something more menacing.

These fears are not unfounded: More than a million patients around the world have confirmed cases of coronavirus, but the real number of infections is far higherthough nobody yet knows by how much.

Thats why medical professionals are rushing to develop tests for antibodies that might reveal if a patient ever contracted Covid-19, regardless of whether they experienced symptoms. These tests may even be able to determine individual immunities to the virus, which has led to speculation that some people could reenter the workforce or resume normal activities if they have the right antibodies.

While this proposed solution may provide a sense of hope, it is far from a certain outcome at this point in time. Theres no clear consensus about the immunological response to Covid-19, and murky ethical problems undergird the idea of lifting restrictions on some populations, while isolating others, especially based on unsettled science.

Heres what you need to know about these tests, their development, and their potential to influence the global Covid-19 response.

Antibody tests, also known as serological tests, differ from the diagnostic swab tests that have been in high demand since the pandemic gained momentum.

Swab tests, or PCR tests, are designed to directly detect the virus by searching for its RNA, which is a genetic signature of its presence. These tests require collection of mucus samples from patients, typically sourced from deep within the nasal cavity, which are then sent to a laboratory to be examined. If the results come back positive, the patient is considered an active carrier of Covid-19 who could potentially infect other people.

Antibody tests, in contrast, dont look for the virus itself, but rather our immunological response to it. When our bodies are invaded by antigens such as the coronavirus, our immune systems react by creating a type of blood protein called an antibody. Antibodies flow through the blood, attacking the alien antigens by binding to them, which can neutralize the spread of infection. Many known antibodies can be detected with a quick blood test.

The idea is that you have volunteers who have recovered from infection, and you look to see what antibodies theyre expressing and test that against samples of the virus, basically, to see what are the circulating antibodies that recognize your virus, said Ruth Collins, professor of molecular medicine at Cornell University College of Veterinary Medicine, in a call.

It can take several weeks for the immune system to develop antibodies to fight a virus, which means positive serological tests may not indicate an active infection. Instead, the presence of coronavirus antibodies demonstrates if a patient ever had Covid-19, whether or not they experienced symptoms.

While it is common for an exposed person to develop immunity to other known viruses, it is important to emphasize that nobody knows yet whether the presence of Covid-19 antibodies indicates that a patient has either temporary or permanent immunity to the infection.

We dont know yet exactly how peoples immune systems respond to the infection, so wed have to find something that would mark everybodys response to the virusthe universal human response to the virusand to make sure that it was specific to this virus, Collins said.

These things are doable, she added, they just take a long time to work out.

Short answer: We have no idea.

Countless teams of scientists around the world are developing serological tests to detect antibodies related to Covid-19, including researchers at the Centers for Disease Control (CDC). Last Thursday, the US Food and Drug Administration approved the first test for antibodies test for Covid-19, though it is intended as a diagnostic test for active infections.

Last week, a team of scientists at Stanford University conducted finger-prick blood tests on 3,200 volunteers to help refine their antibody test. Likewise, in Italy, an entire town of 3,000 people that already received swab tests is now in the process of providing blood samples to follow-up on the diagnostic data with antibody studies.

Regardless, there have also been setbacks with the roughly 100 test kits for these antibodies that are already in development. None of these tests are close to reaching the high bar required for public distribution.

"Theres so much we really dont know"

Youd have to have a very high specificity and sensitivity, so you would be able to pick up even small amounts of those antibodies or the evidence of infection in people's blood, Collins said. Without that, you could well have people that have been infected without knowing about it, she continued, or people who might think they were still naive, immunologically, when in fact they werent.

In other words, antibody tests not only need to be good enough to yield reliable positive results, they also need to clearly show who does not have Covid-19 antibodies. Finding the right balance requires making sure that antibodies linked to viruses that arent Covid-19 do not produce false positives, and ensuring that the antibodies that are specifically linked to this particular coronavirus cannot evade detection.

Its hard to predict how long this process will take, given that so many teams are actively working on it, but its probably optimistic to expect they will take weeks or even months to be widely available to the public.

This timeline might be further delayed by new revelations about Covid-19. For instance, its possible that some carriers may never develop symptoms, but could still remain infectious to others for months.

Theres not even a consensus that everybody will completely clear the virus from their system, Collins noted. Some people may be asymptomatic shedders for a while. Theres so much we really dont know.

The phrase immunity passport has been floated by the government of the United Kingdom, and others, as a potential way to allow people with immunity to Covid-19 to return to regular work and travel routines.

Assuming that widespread serological testing is achievable, the idea is that people with antibodies linked to Covid-19 would be cleared of social distancing measures because they are theoretically immune to the virus and cannot actively spread it. This would bring back some normalcy for some of the population, and it would also enable scientists to better estimate the total number of Covid-19 cases, as opposed to confirmed cases involving patients who were sick enough to receive a swab test.

On the flip side, antibody tests for this purpose raise concerns about privacy rights and employment inequities, given that authorities would be using medical information to judge whether patients can return to work and normal life.

In the United States, the Americans with Disabilities Act (ADA) and the Genetic Information Act (GINA) prevent employers from discriminating on the basis of disability or genetic information. But discrimination for health reasons remains legal in many contexts in the United States, according to Jessica Roberts, director of the Health Law and Policy Institute at the University of Houston Law Center.

"We can go some way towards knowing who has been infected, but the idea of it being used as employment criteria is somewhat dystopian

Both laws would likely permit employers to screen employees for antibodies, Roberts said in an email. She noted that GINA only applies to genetic test results and family medical history, which are not likely to apply to antibody tests, which do not look for individual genetic information.

Moreover, the ADA actually allows employers to discriminate if employing a person with a disability could threaten the safety of the workplace, Roberts added. Assuming that ADA protection applies to people with Covid-19 (which a court would have to ask whether having Covid-19 constitutes a legally recognized disability), the employer could still prohibit an employee from coming to work if the employer could show that the employee would pose a significant risk.

The notion of planning a staggered reopening of society, in which restrictions are lifted on people judged immune to Covid-19, is inherently risky on both an epidemiological and ethical level.

While it may be soothing to daydream about receiving an immunity passport that allows you to return to your "normal" life, it is probably better to invest your energy in adapting to the restrictions, following health guidelines until more information is available, and working towards a better "normal" in whatever way you can.

It sounds good because it gives us what we want, which is definitive answers, Collins said.

But we dont know enough to be able to provide those definitive answers. We can go some way towards knowing who has been infected, but the idea of it being used as employment criteria is somewhat dystopian.

This article originally appeared on VICE US.

This article originally appeared on VICE US.

Original post:
What Are Antibody Tests, and Can They Prove Coronavirus Immunity? - VICE

Lung injury and acute respiratory distress syndrome have taken center stage as the most dreaded complications of COVID-19, the disease caused by the new coronavirus, SARS-CoV-2. But heart damage has recently emerged as yet another grim outcome in the virus'srepertoire of possible complications.

Get more HM news

COVID-19 is a spectrum disease, spanning the gamut from barely symptomatic infection to critical illness. Reassuringly, for the large majority of individuals infected with the new coronavirus, the ailment remains in the mild-to-moderate range.

Yet, a number of those infected develop heart-related problems either out of the blue or as a complication of preexisting cardiac disease. A report from the early days of the epidemic described the extent of cardiac injury among 41 patients hospitalized with COVID-19 in Wuhan, China: Five, or 12 percent, had signs of cardiovascular damage. These patients had both elevated levels of cardiac troponina protein released in the blood by the injured heart muscleand abnormalities on electrocardiograms and heart ultrasounds. Since then, other reports have affirmed that cardiac injury can be part of coronavirus-induced harm. Moreover, some reports detail clinical scenarios in which patients initial symptoms were cardiovascular rather than respiratory in nature.

How does the new coronavirus stoke cardiac damage?

The ways in which the new coronavirus provokes cardiac injury are neither that new nor surprising, according to Harvard Medical School physician-scientists Peter Libby and Paul Ridker. The part that remains unclear is whether SARS-CoV-2 is somehow more virulent toward the heart than other viruses.

Libby and Ridker, who are practicing cardiologists at Brigham and Womens, say COVID-19-related heart injury could occur in any several ways.

First, people with preexisting heart disease are at a greater risk for severe cardiovascular and respiratory complications from COVID-19. This is hardly a surprise. Research has shown that infection with the influenza virus poses a more severe threat for people with heart disease than those without cardiac problems. Research also shows that heart attacks can actually be brought on by respiratory infections such as the flu.

Second, people with previously undiagnosed heart disease may be presenting with previously silent cardiac symptoms unmasked by the viral infection. In people with existing heart-vessel blockages, infection, fever and inflammation can destabilize previously asymptomatic fatty plaques inside the heart vessels. Fever and inflammation also render the blood more prone to clotting, while also interfering with the bodys ability to dissolve clotsa one-two punch akin to throwing gasoline on smoldering embers.

Its like one big stress test for the heart, said Ridker, who is the Eugene Braunwald Professor of Medicine at Brigham and Womens Hospital.

Third, some people may experience heart damage that mimics heart attack injury even if their arteries lack the fatty, calcified flow-limiting blockages known to cause classic heart attacks. This scenario, called myocardial infarction type 2, can occur when the heart muscle is starved for oxygen, which in the case of COVID-19 may be triggered by a mismatch between oxygen supply and oxygen demand. Fever and inflammation accelerate heart rate and increase metabolic demands on many organs, including the heart. That stress is compounded if the lungs are infected and incapable of exchanging oxygen and carbon dioxide optimally. This impaired gas exchange can further diminish oxygen supply to the heart muscle.

Finally, there is a subset of people with COVID-19some of them previously healthy and with no underlying cardiac problemswho develop fulminant inflammation of the heart muscle as a result of the virus directly infecting the heart. This type of inflammation could lead to heart rhythm disturbances and cardiac muscle damage as well as interfere with the hearts ability to pump blood optimally.

The propensity of certain viruses to attack the heart muscle and cause viral myocarditis is well known, Libby said, adding that the most notorious viral offender has been the Coxsackie B virus. Nonetheless, a recent case report from Italy underscores the notion that the new coronavirus could also infect the heart and affect heart muscle function in healthy adults even after the acute phase of the infection has resolved and even in the absence of lung damage.

There are definitely some people who develop acute fulminant myocarditisin which the virus infects the heart muscle itself or the cells within the heartand causes a horrible inflammatory reaction, said Libby, who is also the Mallinckrodt Professor of Medicine at Brigham and Womens Hospital. This can be life threatening, and it can happen in people who don't have any preexisting risk factors.

Libby and Ridker, however, say this out-of-the-blue scenario in otherwise healthy individuals is likely rare relative to the overall number of people with COVID-19 who experience heart problems.

The frenemy within

For Ridker and Libby, who have studied the immune pathways of cardiovascular disease for decades, the cardiac involvement in COVID-19 is yet another striking example of the widespread effects of inflammation on multiple organs and systems.

Inflammation is a critical defense response during infection, but it has a dark side. Infections can set off a cascade of immune signals that affect various organs.

Libby and Ridker hypothesize that any infection in the bodya festering boil, an injured joint, a viruscan become a source of inflammation that activates the release of inflammatory proteins known as cytokines and calls up armies of white blood cells and other messenger molecules that, in an effort to fight the infection, disrupt normal processes. When these inflammatory molecules reach the welcoming soil of a fatty deposit in the blood vessel wallone that is already studded with resident inflammatory white blood cellsthe cytokines can boost the local inflammatory response and trigger a heart attack.

Our work has shown that cytokines can impinge on these cells in the plaque and push it through a round of further activation, Libby said.

The inflammatory chemicals released during infection can also induce the liver to ramp up the production of important proteins that defend the body from infection. These proteins, however, make the blood more prone to clotting, while also reducing the secretion of natural clot-dissolving substances. The tiny clots that may form can clog the small blood vessels in the heart and other organs, such as the kidneys, depriving them of oxygen and nutrients and setting the stage for the multisystem failure that can occur in acute infection.

Thus, immune-mediated injury to the heart and other organs could be collateral damage because of the bodys overwhelming systemic immune responsea condition known as cytokine storm, which is marked by the widespread release of cytokines that can cause cellular demise, tissue injury and organ damage.

COVID-19 and blood pressure medications

SARS-CoV-2 invades human cells by latching its spike protein onto the ACE2 receptor found on the surface of cells in the airways, lungs, heart, kidneys and blood vessels. The ACE2 protein is an important player in the renin-angiotensin-aldosterone system, which regulates blood vessel dilation and blood pressure. Two classes of drugs widely used to treat high blood pressure and heart diseaseACE inhibitors and angiotensin receptor blockersinteract with the ACE2 receptor. A possible concern related to COVID-19 stems from the notion that these blood pressure medications could increase the number of ACE2 receptors expressed on cells, possibly creating more molecular gates for the virus to enter. Some experts have wondered whether the use of such drugs could render people who take them more susceptible to infection. Conversely, others have postulated that the abundance of ACE2 receptors may enhance cardiovascular function, exercising a protective effect during infection.

The answer is far from clear, but a recent review suggests these medicines may play a dual role in COVID-19on the one hand, enhancing susceptibility to infection and, on the other, protecting the heart and ameliorating lung damage from the disease.

Libby and Ridker cautioned that patients who take such life-saving medications should stay on them or at least have a careful discussion with their cardiologists. This is because these drugs have clear and well-established benefits in hypertension and certain forms of heart disease, while their propensity to make humans more susceptible to SARS-CoV-2 remains speculative for the time being.

But what remains speculative today will crystalize in the weeks and months to come, Ridker and Libby said, because the science is moving forward rapidly, with new papers coming out daily and a growing pool of patients to draw observations from.

In 12 to 18 months we're going to have a great deal of information, but right now our job is to, number one, keep people from getting COVID-19 by strict adherence to now-familiar containment measures, Libby said. Then, we need to get people who get the disease through this acute phase.

The need for rigorous randomized trials done quickly and effectively is acute, they said. Until the evidence from these trials begins to coalesce, clinicians will have to navigate the uncharted territory of delivering cardiac care in the time of pandemic with caution but also with resolve.

We don't have the comfort of our usual databases, so we have to rely on our clinical skills and judgment. But we have to do so in all humility because often data dont bear out our logical preconceptions, Libby said. Yet, we must act.

RelatedEnding the Pandemic

See the article here:
Coronavirus and the Heart - Harvard Medical School

Twenty-four University of Miami research teams have received rapid response grants to undertake innovative projects that will provide critical information about the novel coronavirus.

Imagine this: developing an oral rinse test to detect COVID-19 earlier, creating a behavior therapy program for parents so that they do not pass on the stress they are feeling to their children during the pandemic, and gauging the effects of COVID-19 on pregnant women and trying to determine the impacts on their new babies.

These are just a few of the 24 projects recently awarded rapid response grants from the University of Miamis Office of the Vice Provost for Research. The grants, which range from $5,000 to $40,000, require faculty members and students to develop and execute research that will somehow broaden our understanding of COVID-19 and begin to mitigate its impacts within the next four months.

Our idea was to take advantage of researchers creativity and commitment in tackling some of the most pressing problems around the COVID-19 epidemic, said John Bixby, vice provost for research and professor of molecular and cellular pharmacology and neurological surgery. We challenged them to examine the effects of the pandemic on multiple aspects of peoples livesnot just the physical ones, but the social aspects, the economic ones, and the environmental.

With just 10 days to submit proposals, faculty members across the university flooded the office with applications and more than 70 ideas were submitted. Each award was reviewed by three individuals, and the awardees were selected based on novelty, potential impact on the effort to combat COVID-19, and whether the study could be completed in short turnaround time.

The faculty response was inspiring, said Erin Kobetz, co-vice provost for research. There was a level of innovation across multiple disciplines that demonstrates an institutional commitment to addressing the COVID-19 pandemic. We look forward to the outcomes of those applications that were funded and imagine that they will lead to positive, measurable impact now and in the future.

After the four months are over, teams will be asked to report their progress, Bixby said. Below is a list of all the projects awarded grants:

This team will evaluate the potential benefits of nitric oxide in treating COVID-19 utilizing the iNOpulse technology, which may potentially allow future patients to be treated outside of the hospital.

Principal investigator: Roger Alvarez, assistant professor of clinical medicine,

This team will develop a novel vaccine to protect against the current coronavirus pandemic caused by SARS-CoV-2. Its strategy involves replacing the envelope glycoprotein (G) of vesicular stomatitis virus (VSV) with the spike of COVID-19. The resulting virus will form the basis of a vaccine to generate neutralizing antibody to the SARS-CoV-2 spike that could prevent disease if exposed to the real virus.

Principal investigator: Glen Barber, professor and chair of cell biology

This study will exploit the enzyme TMPRSS2 as a potential link between androgen receptors and COVID-19 by providing preliminary data on whether certain drugscalled androgen receptor antagoniststhat are effective and safe for treating prostate cancer, might also be effective in treating COVID-19.

Principal investigator: Kerry Burnstein, professor of molecular and cellular pharmacology

Artist Xavier Cortada will develop a socially engaged art platform online to mitigate stress related to COVID-19 infection and/or social distancing. He is also working to develop participatory art projects and an online message mural to capture stories from individuals across South Florida as they are affected by the pandemic. https://cortadaprojects.org/projects/corona/

Principal investigator: Xavier Cortada, professor of practice, art and art history

Public health emergencies pose huge challenges to the behavioral health system, and consequences on the psychosocial well-being of people in at-risk communities largely go overlooked. This project will first identify community psychosocial needs and then create and disseminate a multilingual COVID-19 online toolkit and resource hub to mitigate negative mental health outcomes throughout the pandemic.

Principal investigator: Bridget Davidson, assistant professor of clinical pediatrics

This team will develop a prototype for a socially engaging online experience targeting vulnerable and older adults where future University live cultural offerings could benefit from a secondary virtual platform.

Principal investigator: Joy Doan, head of Marta and Austin Weeks Music Library

Since parental stress during disasters or quarantine may be associated with child traumatic stress and/or subsequent incidents of abuse or neglect, this study will examine how parent-directed telehealth interventions using motivational, opposite action, and mindfulness strategies can be deployed during crisis situations to mitigate risk for parents exhibiting mental health concerns during our current COVID-19 pandemic.

Principal investigator: Jill Ehrenreich-May, professor of psychology

This project will enable the development of an oral rinse test that detects COVID-19 earlier and saves lives by directing resources and quarantine efforts to patients who need them most. Researchers will perform testing with the current prototype on a confirmed COVID-19 patient to determine the best antigen and concentration.

Principal investigator: Elizabeth Franzmann, associate professor of otolaryngology

This team will take blood samples from asymptomatic health care personnel working in any patient care capacity in three high-risk medical specialtiesotolaryngology, anesthesiology, and ophthalmologyand examine them for the presence of immunity. The results could help South Florida hospitals consider strategies for resource and personnel deployment.

Principal investigator: Michael Hoffer, professor of otolaryngology and neurological surgery

This team will gather data and insight on loneliness and other behaviors in the wake of CDC recommendations for social distancing during the COVID-19 pandemic. Results will demonstrate the effects of this public health crisis on loneliness, as well as other psychosocial symptoms. The team will also assist public health professionals in preparation for post-pandemic interventions and future global health emergencies.

Principal investigator: Viviana Horigian, associate professor of public health sciences

More than 20 models of the viral protease (which if targeted, might stop the virus) have been openly shared on Twitter, prompting labs around the world to begin a collective search for protease inhibitors. This project will provide a cheap, accessible screening test for characterizing potential protease inhibitors and use the available crystal structures to develop effective protease inhibitors through computational techniques.

Principal investigator: Daniel Isom, assistant professor, molecular and cellular pharmacology

Researchers will investigate the ability to detect the COVID-19 virus in donor allograft tissue and frozen tissue. They will also attempt to determine whether the COVID-19 virus in the donor tissue is associated with transmission to the recipient and influences short- or long-term survival, as well as the health of the recipient.

Principal investigators: Hugo Kaneku Nagahama, assistant professor, surgery and Phillip Ruiz, professor of surgery and pathology and director of Transplantation Laboratories and immunopathology

Partnering with Breakthrough Miami, a community-based academic enrichment organization for low-income students, this study will contact families involved with this organization to understand the educational and health-related challenges as a result of COVID-19. Researchers will also investigate the role of community-based organizations in the mitigation of stress related to the concerns of infection and social distancing.

Principal Investigator: Laura Kohn Wood, dean and professor in the School of Education and Human Development.

Ear, nose, and throat (ENT) doctors play a key role in the treatment of COVID-19, but they are at high risk of exposure. This team will identify ENT issues in COVID-19 patients at the University of Miami and Jackson Memorial Hospital and evaluate new approaches to case identification and health care worker protection.

Principal investigator: Xue Liu, professor and Marian and Walter Hotchkiss Endowed Chair in otolaryngology

Mindfulness training has emerged as an effective program to enhance cognitive functioning, improve psychological and physical health, and to reduce loneliness in young to mid-aged adults. But little is known about its effects in elderly adults. This proposal aims to offer mindfulness training via online delivery to elderly adults and to assess the trainings potential to protect against cognitive decline and degradation in psychological and physical health during the COVID-19 pandemic.

Principal investigator: Ekaterina Ninova (Denkova), research assistant professor, psychology

Individuals who have hypertension, diabetes, or underlying cardiovascular disease have higher rates of mortality from COVID-19 than the average person. Patients with these diseases have a high likelihood of being prescribed ACE inhibitors or angiotensin receptor blockers (ARBs) in order to treat their underlying ailments. This project will examine whether there is a link between drugs that are given to patients with hypertension, coronary artery disease, diabetes, or cardiovascular disease and the outcomes of COVID-19 patients.

Principal investigator: Savita Pahwa, professor, microbiology and immunology

This project aims to determine the rate of COVID-19 positivity among pregnant women and their newborns delivering at a tertiary care center in Miami with the highest rates of coronavirus in Florida. They also want to identify cases of maternal transmission of COVID-19, which is critical to establish treatment guidelines, while also answering questions about disease progression, perinatal transmission, and effects on the newborn.

Principal investigator: JoNell Potter, professor of clinical, obstetrics, gynecology, and reproductive services

This team will test, evaluate, and create new reusable mask designs for use in the health care setting to limit exposure and protect medical personnel and first responders who treat coronavirus patients. The aim is to provide masks to workers within the University of Miami and Jackson Memorial Hospital first. Finalized mask designs can be shared with other medical facilities.

Principal investigator: Carl Schulman, executive dean for research and professor

This project hopes to develop a deep learning program that could classify X-ray or CT scan imaging characteristics in COVID-19 patients that could help radiologists categorize them into those patients who require hospitalization, those who will need Intensive Care Unit admission, and those at risk for death. In addition, such a deep learning network could be used to predict the patients response to current experimental drugs.

Principal investigator: Radka Stoyanova, research professor in radiation oncology

This project aims to understand the relationship between cardiac injury and COVID-19 severity. The team will conduct an extensive evaluation of 50 patients with a new COVID-19 infection who require hospital admission and will test myocardial injury and inflammatory biomarkers, use cardiac magnetic resonance imaging (CMR), and offer a social determinants of health survey. Blood will be saved for future biomarker discovery and genomic evaluation.

Principal investigator: Leonardo Tamariz, professor of medicine

While respiratory distress dominates acute symptoms of COVID-19, ruptures in the brains capillary cells accompanied by bleeding within the brain have fatal consequences in patients with COVID-19.Moreover, impacts of COVID-19 on the brain depend largely on the ability of the SARS-CoV-2 virus to leak in through brain capillaries, the cells of which express the SARS-CoV-2 receptor (ACE2). This study is based on the hypothesis that interaction of the virus with ACE2 disrupts the normal barrier function of brain capillary cells, and induces inflammatory responses derived from these cells.

Principal Investigator: Michal Toborek, vice-chair for research and professor, biochemistry and molecular biology

Given the surfeit of social media data accompanying the recent outbreak of COVID-19, this group will take a computational and big data-driven approach to uncovering information about viral transmission, social sentiment and response, decision-making, and public health policy recommendations. The group proposes to develop algorithm(s), as well as an online early alert system, to provide early warnings for disease surveillance tied to geographical data.

Principal investigator: Nicholas Tsinoremas, director of the Institute for Data Science and Computing

This team will investigate Florida citizens opinions on COVID-19, including their thoughts about the causes and consequences of the pandemic, their preferred sources of information, and subsequent behavior changes. They will also assess public perceptions of government responses to COVID-19 to determine how Floridians change their perceptions and behaviors over time in response to changing policies, messaging, and conditionsparticularly if they or someone they know becomes ill. This will be one of very few studies to track a statewide populations opinions, lifestyle factors, and health behaviors during an ongoing pandemicwith clear implications for policymakers, health communicators, and disaster specialists.

Principal investigator: Joseph Uscinski, associate professor of political science

Because young adults appear to experience fewer cases of the COVID-19 virus, this population may engage in behaviors that contribute to the spread of COVID-19. Yet, little is known about the impact of COVID-19 on adolescent mental and physical health and their substance-use behaviors. This project hopes to collect epidemiologic data on the patterns of mental and physical health, substance use (frequency and dose), and potential disease transmission behaviors among young adults during the COVID-19 pandemic.

Principal investigator: Denise Vidot, assistant professor in the School of Nursing and Health Studies

Original post:
Fast-tracked research projects aim to respond quickly to mitigate effects of COVID-19 - University of Miami

Immunotherapies have revolutionized treatment for people with a variety of cancers. But when given to those with triple-negative breast cancer (TNBC), a particularly aggressive form of the disease, less than 20% respond.

A big question in the field has been, Why are the rest not responding? says Rumela Chakrabarti, an assistant professor at Penns School of Veterinary Medicine.

In a new paper in Nature Cell Biology, Chakrabarti and colleagues illuminate the molecular details at play. They found a signaling pathway which could be exploited in TNBC patients to better target therapies in the future. Using a mouse model of the disease that mimics key characteristics of human disease, they showed that losing the activity of the protein ELF5 promotes the activity of another protein, interferon-gamma receptor 1. Stabilized Interferon-gamma receptor 1 leads to activated interferon gamma signaling, which in turn leads to increases in tumor aggression and spread, which could be mitigated with therapeutics that block interferon gamma signaling.

This was an eye-opener, says Chakrabarti, because often interferon gamma has a protective effect in cancer and is commonly given as a cancer therapy to some patients. It works well in certain cancer types, but for particular subtypes of triple-negative breast cancer we see that blocking interferon gamma may be the best strategy for patients.

Chakrabarti had a deep familiarity with the biology of the ELF5 protein. She began studying it more than a decade ago as a postdoctoral researcher at the State University of New York at Buffalo, finding that its normal function supported pregnancy and lactation. More recently, in 2012 she and colleagues published a previous report in Nature Cell Biology showing that ELF5 could suppress a key transition that occurs to enable breast cancers to spread.

That earlier work, however, did not focus on TNBC specifically, in part because scientists had lacked an effective mouse model. Over the course of three years, Chakrabartis team developed a preclinical TNBC model that recapitulated two hallmarks of the disease: its propensity to spread and the influx of immune cells that accompanies tumor growth.

In the current study, the researchers found that, when these TNBC mices tumors also lost the function of the ELF5 protein, their disease course resembled that of human patients even more closely. Losing ELF5 made the disease very metastatic and very aggressive, says Chakrabarti.

To elucidate the molecular happenings that resulted in a more dangerous form of TNBC, Chakrabarti and colleagues examined the RNA that was being expressed in tumor cells of the TNBC mice whose tumors lost ELF5 expression. They found increased activity of the interferon-gamma pathway, caused, they believe, by an increase in expression of that proteins receptor. This loss also led to an accumulation of neutrophils, a type of immune cell, which has immune suppressive function. In contrast, normal mammary cells that retained ELF5 had low levels of interferon gamma signaling.

Blocking this signaling using an antibody against the interferon gamma receptor 1, or by genetically manipulating tumor cells to express lower levels of the receptor caused tumors to grow and spread more slowly.

Finally, to determine whether these findings in a mouse model may be relevant to humans, the research team looked at genetic and protein data from patients to determine their level of ELF5 and interferon gamma receptor expression. Patients with lower ELF5 and higher receptor levels, they observed, fared poorer; their cancers tended to spread sooner around their bodies.

The findings, Chakrabarti says, should be considered carefully by clinicians who are using interferon gamma and immunotherapies to treat cancer patients.

This is telling us that we need to target patients more selectively when we treat them, says Chakrabarti. It could be that if someone has low ELF5, they should be given an interferon-gamma signaling blocking therapy in addition to their immunotherapy.

In future work, Chakrabartis group will be diving in deeper into the immunology of TNBC, examining the role that different immune cells are playing in driving cancer metastasis and aggression. They also hope to see whether what they found regarding interferon gamma signaling in TNBC holds true in other tumor types, such as kidney and ovarian cancers.

Rumela Chakrabarti is an assistant professor of biomedical sciences at the University of Pennsylvania School of Veterinary Medicine.

Chakrabartis coauthors on the paper were first author Snahlata Singh, Sushil Kumar, Ratnesh Kumar Srivastava, Ajeya Nandi, Gatha Thacker, Hemma Murali, Sabrina Kim, Mary Baldeon, Mario Andres Blanco, and Serge Fuchs of Penn Vet; John Tobias, Rizwan Saffie, and Luca Busino of Penn s Perelman School of Medicine; Temple Universitys M. Raza Zaidi; and Satrajit Sinha of the State University of New York at Buffalo.

The work was supported by the National Cancer Institute (grants CA193661 and CA237243).

Read this article:
Tailoring treatment for triple-negative breast cancer - Penn: Office of University Communications

HER2-positive breast cancer may be a misnomer, according to a growing body of evidence that one of the most widely recognized oncogenes, HER2, may not be the primary driver of the disease. The research, which comes from several groups including Genentech, makers of the prevailing anti-HER2 treatment, has researchers questioning whether current clinical guidelines for classifying and treating breast cancer may be off the mark. New classification schemes may better identify those patients more likely to benefit from anti-HER2 treatment, or point to therapies that might be more effective.

HER2 is short for human epidermal growth factor receptor 2. Researchers discovered HER2 breast cancer in the 1980s. Too many copies of the HER2 gene or its overexpression appeared to cause an especially aggressive form of the disease. By the late 90s, a drug called Herceptin that targeted the HER2 receptor, sped into the clinic on the US Food and Drug Administrations new fast-track status. As Dana-Farber Cancer Institute oncologist Harold Burstein put it a couple of years ago, HER2 breast cancer, once the most feared type of the disease, had gone from worst to first, largely because of Herceptin.

After analyzing multiple, published genomic data sets, researchers at Genentech, which makes Herceptin, reported in 2018 that there was no evidence that HER2 amplification represents a breast cancer subtype.

About 14 percent of breast cancers are HER2-positive, a diagnosis largely based on immunohistochemical staining to reveal an overabundance of HER2 receptors spanning the cancer cells membranes, with ambiguous cases decided by testing for an abnormally high HER2 gene copy number. The American Society of Clinical Oncology recommends Herceptin as the first-line treatment for HER2-positive breast cancer. In the US, tens of thousands of patients receive Herceptin each year. Recently, however, researchersincluding those from Herceptin maker Genentechhave begun to reconsider the HER2-positive subtype.

In the HER2-centric model of breast cancer, highly dysregulated HER2 signaling drives uncontrolled cell growth. HER2-positive breast cancers carry as many as 50 copies of the HER2 gene, compared with just two in noncancerous cells, and the gene can be highly expressed, leading to HER2 protein levels as much as 40- to 100-fold higher than normal.

But after analyzing multiple, published genomic datasets, researchers at Genentech reported in 2018 that there was no evidence that HER2 amplification (and, by extension, HER2 overabundance) represents a breast cancer subtype at all. HER2 amplification by itself seemed to have a negligible influence on the expression of genes thought to be mediated by the HER2 signaling. Rather, HER2 amplification was associated with upregulation of genes governed by androgen receptor (AR) signaling, which orchestrates the actions of testosterone and related hormones and is often boosted in breast cancer. This link between HER2 amplification and AR signaling suggests the androgen receptor may play a bigger role in the disease than previously recognized.

Other researchers have similarly reevaluated breast cancers using transcriptional profiles that look at gene expression across the genome, rather than focusing on individual genes thought to have large effect. The resulting subtypes require a more nuanced view of HER2 or dont include HER2 at all.

[T]he whole state of subdividing and classifying breast cancers is in a state of flux, says Larry Norton, a medical oncologist at Memorial Sloan Kettering Cancer Center who played a key role in the clinical trials establishing HER2-positive breast cancer as a subtype and Herceptin as the first drug for treating it. Were in a molecular era now, so we think we know more.

The conventional view of HER2 breast cancer that guides current clinical practice has been under pressure for some time. While most researchers remain convinced that HER2 is a clear driver of some breast cancers, Herceptin by itself struggled to knock down HER2-positive tumors in early clinical trials. It was the synergy with [the chemotherapy drug] paclitaxel that really put the drug on the map, says Norton, who was involved in the early trials of the combination therapy. Had we focused in on trastuzumab [Herceptin] as a single agent . . . the drug would have been abandoned.

Norton was the senior author of the published trial that led to FDA approval of Herceptin for advanced breast cancer in 1998. However, that trial did not actually demonstrate that the combination of Herceptin and paclitaxel, a type of chemotherapy drug known as a taxane, was superior to paclitaxel alone in increasing survival. Only when the data were combined with separate trial arms testing non-taxane chemotherapy with and without Herceptin did the researchers see a statistically significant difference in survival.

In addition, the two trials that led to Herceptins 2006 approval for early breast cancer later cast doubt on HER2 as a biomarker for response to the drug. A 2007 reanalysis of one of the trials found no statistical interaction between patients HER2 status and whether they benefitted from Herceptin. A similar reanalysis of the second trial corroborated this result: [Herceptin] benefit seemed independent of HER2 amplification, the researchers wrote in their report.

In 2000, a group at the Stanford University School of Medicine used state-of-the-art microarray technology to propose molecular subtypes of breast cancer based on the expression of more than 8,000 genes in biopsies from 42 patients. While the researchers identified a molecular signature for a HER2-based subtype, it wasnt strictly based on overabundance of the HER2 receptor or high HER2 copy numbers in the genome. Rather, they used the expression patterns from nearly 500 genes as indicators of the activation of the HER2 signaling pathway.

Breast cancer tissue stained for HER2 using antibody clone IHC002

The new subtype, which the team later dubbed HER2-enriched (HER2E), fractured the HER2 classification: a tumor might be HER2-positive based on the classical methods but not show evidence of HER2-mediated signaling activity at the transcriptional level. Only 47 percent of HER2-amplified tumors are HER2E, a concordance the 2018 paper from Genentech calls remarkably weak. Margaret Gatti-Mays of the National Cancer Institute estimates that 30 percent to 40 percent of tumors classified as HER2E tumors are not clinically HER2-positive.

A number of research groups have found no HER2-based subtype at all. In a 2005 paper, Richard Iggo, then at the Swiss Institute for Experimental Cancer Research, and colleagues performed experiments similar to those that had identified the molecular subtypes put forward by the Stanford researchers in 2000. Iggos team found that the previously discovered HER2 group did not appear to be defined by HER2, but by genes that looked like they might be related to androgen signaling, says Iggo, now at INSERM and the University of Bordeaux in France.

Similarly, in their 2018 study from Genentech, Anneleen Daemen and Gerard Manning found that AR activity is a key part of the HER2E subtype. HER2-enriched is not HER2-driven, per se. Its rather the androgen signaling, says Daemen, now head of translational medicine at ORIC Pharmaceuticals. You have androgen signaling that is massively on . . . and that is regardless of whether the HER2-enriched tumor is also HER2-positive or not.

Gerard Tarulli, an endocrinology researcher at the University of Melbourne who was not involved in the study, explains that this may be because the androgen receptor can play a role similar to the estrogen receptor (ER), which, in the most common form of breast cancer, drives tumor growth. In HER2E tumors, AR signaling is thought to replace ER as the driver, with the androgen receptor almost physically substituting for the presence of the estrogen receptor, says Tarulli.

Iggo and his colleagues called for the HER2E subtype to be renamed molecular apocrine to reflect a pathology very different from a HER2-centric model of disease, one that appears to involve signaling by AR and perhaps other pathways as well. The thing thats slightly disappointing for me, says Iggo, [is that] rather than changing the name . . . [the Stanford team] just said HER2-enriched, which perpetuates the idea that [HER2 amplification] defines a biological subtype.

Daemen agrees. When they originally defined these subtypes, they should not have used the word HER2-enriched because thats misleading, she says. [The nomenclature is] so ingrained in the research thats happening for breast cancer that people really hold on to it. . . . The field at large has not questioned those subtypes or deviated from them as much as is happening in other fields or other cancer types. The Stanford team did not respond to The Scientists request for comment.

Which subtypes are real is a very difficult question, says Tarulli. One recently published breast cancer scheme includes seven types, three of which could be considered subsets of the traditional HER2-positive categorization, while yet another research group has proposed 10 molecular subtypes, including one that pertains to HER2-type disease.

According to Daemen, her work was closely followed by the clinicians and the biomarker scientists who were running trials in breast and gastric cancers. I worked closely with the clinical teams at Genentech at that time to see if we could explain why some patients in our trials were not responding as well to anti-HER2 agents because of AR expression, for example. However, Daemen left Genentech last fall and says, to my knowledge, there is no additional research that is being undertaken [at the company] as a result of this. Genentech spokesperson Kayla Bruneau says that the company did not have any researchers available to discuss the [Daemen and Manning] paper at this time.

For now, clinical practice continues in strict adherence to the HER2-positive subtype as classically defined. HER2 receptor overabundance or HER2amplification has been validated as a biomarker of clinical effect for HER2-targeting therapies, Gatti-Mays says in a statement emailed to The Scientist. But the diversity of subtypes churned out by recent molecular analyses has thrown the field for a loop.

We thought that there should be some underlying molecular characteristic that is shared by all the HER2-positive breast tumors, and that turned out not to be the case, says Daemen. This absence of HER2-related biology in HER2-positive tumors seems to clash with how targeted therapies, including anti-HER2 treatments, are thought to work, namely, by interrupting a well-understood, cancer-driving pathway.

If you can demonstrate that adding a HER2 enrichment analysis in terms of clinical decision-making improves patient outcomes, then that classification needs to go in.

Gerard Tarulli, University of Melbourne

HER2E in particular is gaining traction as a possible subtype to consider for eventual clinical use. According to a meta-analysis published earlier this year, HER2E patients show a stronger clinical benefit from anti-HER2 therapies than other molecular subtypes. Tarulli says the inclusion of HER2E in future clinical trials of anti-HER2 therapies makes a lot of sense, because now were understanding more about the mechanisms behind what [HER2] is doing.

Once clinical trial data start rolling in, researchers can make a more informed decision, he says. If you can demonstrate that adding a HER2 enrichment analysis in terms of clinical decision-making improves patient outcomes, then that classification needs to go in. Tarulli also says that for HER2E patients, inhibiting both the androgen receptor and HER2 makes a lot of sense and will probably increase the effect of both. The authors of the meta-analysis did not respond to a request for comment.

Daemen disagrees with using HER2E to decide who gets anti-HER2 therapy, which can have heart-related side effects, in a clinical trial. If you were to base treatment decisions on the HER2-enriched label of a tumor, you would do harm, rather, in patients that lack HER2 amplification.

HER2E is an interesting subgroup, agrees Gatti-Mays, but [m]ore information is needed about the long-term clinical outcomes of these HER2E patients.

Still, earlier conceptions might be falling away, Norton says. The simplistic notionHER2 is a signaling molecule, you blockade, stop the signaling, so you get apoptosis rather than going into cell division[that] all makes sense, but it could be wrong.

Robert Fortner is a freelance journalist based in Portland, Oregon. Email him atrobertwfortner@gmail.comor follow him on Twitter@robertfortner1.

Read more here:
Who Benefits from Herceptin and Other Anti-HER2 Cancer Therapies? - The Scientist

For the millions of people in the job market during this COVID-19 pandemic, the task is daunting: Find work in a historically bad economy.

The class of 2008 understands the problem well. They lived it, trying to join the workforce during the Great Recession.

Weve had to make a lot of sacrifices that a lot of people probably arent used to, said Christopher Brown, a 2008 University of South Florida graduate.

At the height of the recession, in 2010, the unemployment rate for young people hit a record-high 19.5 percent, according to the Bureau of Labor Statistics.

Workers like Brown who found jobs still faced challenges different than prior generations. They were more likely to settle for smaller paychecks and less likely to risk jumping to other, better-paying jobs as the recovery crawled along, according to Brookings Institute economist Gary Burtless.

COVID-19s long-term economic effects wont be known for years. And because the pandemic upended everything, soon-to-be graduates have had to focus more on finding housing and finishing school virtually than securing jobs.

Career education and career services are on the low end of the totem pole for these students, said Christian Garcia, the associate dean and executive director of the University of Miamis Toppel Career Center.

But when employment rises on their priority lists, they can look to Great Recession graduates for perspective. The Tampa Bay Times spoke with 10 of them to reflect on the job-hunting challenges they faced a dozen years ago.

Their advice: Broaden your search. Expand your network. Invest in yourself. Reset your expectations. And, most of all, remember that this, too, shall pass.

Curtiss Gibson, 40, nonprofit fundraising, New York

Gibson was the first college graduate in his family, earning an English degree from USF. He wasnt picky where he landed. Florida. New York. Illinois. Wherever.

I needed any job, Gibson said.

The Clearwater native sent out at least 147 resumes and got three serious looks. A lifestyle magazine publisher in New York hired him as an editorial assistant for $30,000 a year.

That November, the firm cut a quarter of the staff and froze wages. The magazine kept Gibson. Four months later, his son was born.

Everyone had to deal with the fact that theyre stuck with their salary, and that person in the cube next to you is gone now, so you do their job. Its absolutely a wild amount of stress.

Gibson left, landing a job in fundraising at the New York Botanical Garden. But hes feeling the stress again, this time from a different vantage point.

Two weeks after Gibson hired a woman from Philadelphia, the pandemic shut everything down. Now, her future is at risk.

I see the impact on her that a lot of people felt in 2008. I have to remember: I did not create the virus. I did not do this. But I feel, like, horrible, absolutely terrible having to tell her.

Jordan McDonald, 35, information technology, Tampa

The Plant City native started a job with business consultant Accenture soon after graduating from the University of Florida with an industrial engineering degree.

Then the economy collapsed. McDonald outlasted the layoffs and survived the do-more-with-less culture. But there are still emotional scars.

I saw senior partners getting let go. These are men and women who had devoted their whole careers to this company. That was a big lesson learned for me, I think, just in terms of companies arent necessarily going to be loyal to you when things get bad.

To prepare for that, McDonald advises the next wave of jobseekers to focus on expanding their network and gaining new skills until the economy recovers.

Hes also trying to keep a broader perspective. Things could always be worse. He still has his job at Tampa Electric. But its hard not to see this as another hit to millennials, those born from the early 1980s to the late 1990s.

I saw a funny meme, said McDonald, who has a 4-year-old child. For our generation, when we were sort of coming of age in high school, 9/11 happened. When we were graduating college, the Great Recession happened. Then when were all starting families, the pandemic happens.

Lara Goldstein, 33, advertising, Miami

Goldstein was apprehensive after graduating with her mass communications degree from USF, but she found a job quickly at a TV production company in Apopka.

The work was freelance, with no set hours, salary or benefits. And after about a year, the company went on hiatus.

It was tough, because they kept telling you, Dont get another job, well have work.'

Goldstein stayed loyal. She worked as a bartender to get by and took the sporadic production days when they were available.

But she couldnt wait forever. Goldstein left for a six-month production job in Miami, moving back in with her parents while still paying rent at an unused apartment in Apopka.

Everyone expects young people to get a job, pay their dues and move on to bigger and better things. At a certain point, dont you want stability?

A 2013 survey by the Federal Reserve Boards Division of Consumer and Community Affairs found that 67 percent of young workers preferred steady employment to higher pay.

Goldstein did, too. She abandoned her production goals to get into advertising similar work, but with commercials instead of TV shows.

Almost 10 years later, shes still there.

Gregory Gibbs, 30, teacher, Largo

Gibbs entered the workforce straight out of Apopka High School and worked at GameStop until he was laid off in 2010.

By then, he was preparing to study secondary education at USF. But he still needed money, and retailers werent hiring.

His delayed pursuit of teaching shapes the advice he would give soon-to-be graduates.

Explore many different types of certification programs and remember that college is not the only path that encourages a successful life. There are many ways to achieve your goals despite the one-sided view of our educational system.

Jennifer Perez, 44, photography, Jacksonville

Perez entered the job market after graduating from the University of Central Florida.

Freelance photography wasnt steady, so she cobbled together odd jobs, juggling three at one point to get by. She even snapped photos of tourists at an alligator farm something she never imagined doing.

You have to get creative."

Eventually, it all paid off. She landed a full-time photography job in 2012 and has been doing it ever since.

Hannah Goodwin, 33, fashion, Tampa

Goodwin moved in with her parents in Houston after earning her communications degree from Virginias Washington and Lee University in 2009. An internship at Anthropologie didnt lead to a job, so she expanded her search. Two months later, she had a fashion internship in New York at a company that folded in 2010.

Her connections led to a job at a start-up where she has worked for the past nine years. She moved to Tampa last year.

Goodwin stayed in the industry because she liked it, but also because she remembered how hard it was to get a job in the first place. Starting over would have been tough, just as it would be now.

Unfortunately, now is not really the time to be so picky."

Timothy Van Emden, 30, engineering, Maryland

Without any major marketable skills, Van Emden didnt see a lot of job opportunities when he graduated from George Jenkins High School in Lakeland. Thats why he enlisted in the Army Reserve.

It taught me a tangible skill and added to my resume."

He works as a system integrator/engineer in Maryland and has this advice: Dont get hung up on locations, titles or salaries.

If you want $65,000 and the job offered $60,000, take the job. The $5,000 will come quickly.

Ruan Cox, 34, healthcare, Tampa

After studying biology and biotechnology at the University of Florida, Cox thought he would get scooped up immediately at a lab somewhere.

But employers wanted lower-risk workers they wouldnt need to train, not new graduates. Some jobs he considered paid only $10 an hour.

So Cox decided to delay his career by investing in himself. He fast-tracked his plan for graduate school.

School was just a safer option than entering the job market."

Five years later, he had a Ph.D. in molecular medicine from USF.

I think I was a little bit jaded," said Cox, now a development manager at Moffitt Cancer Center in Tampa. You spend this money or you get loans then you come out and you cant find a job. Its very demoralizing.

It did work out for me, but until it did, it was a very humbling experience.

Corbin deNagy, 33, higher-education finance, Tallahassee

DeNagy studied finance at Florida State University with the goal of becoming an investment banker in Tampa or Jacksonville. He knew the crash made that impossible, but he didnt realize how hard it would be to find any job.

After a few months, he became an accounting associate at Florida State University a job that required only a high school diploma.

When youre thinking about the finance degree Im going to work in banking, Im going to make a lot of money.' Now, youre making $25,100. But it paid the bills.

DeNagy has a familiar story, said Elise Gould, senior economist at the Economic Policy Institute. College graduates in the Great Recession often were underemployed. Only 42 percent of them worked in their field of study, the Federal Reserve Board study said.

Instead of complaining, deNagy got to work. When his supervisor left less than a year later, he took her spot. Now hes the finance director for FSUs College of Human Sciences.

I just went in and tried to prove myself. You have to put your head down and start working, whether you think the job is beneath you or whatever. You just work hard.

Christopher Brown, 33, marketing, Brandon

Browns parents werent sure about the offer he received not long after graduating from USF.

Youre going to move all the way to Miami for a job in sales at a cruise line?

Brown didnt see many options.

If I didnt, it could have been six months, a year of no paycheck, trying to fight for the same handful of jobs everyone else is fighting for."

He made it work.

Brown quickly realized that the cruise lines sales script was too formulaic for him, so he ditched it to focus on building connections what he learned to do as a marketing major. While his colleagues printed thank-you notes, Brown wrote his cards by hand.

You had to put that extra work in, especially in 2009, 2010."

It took three years, but Brown finally got a marketing job in Tampa. Now, in the face of another economic collapse, Brown is vulnerable, again.

He does side work as a travel agent at a time when no one wants to travel. His marketing portfolio in Brandon includes a pair of Chick-fil-A restaurants.

Theyre doing fine but if we shut down, what happens?

GET THE DAYSTARTER MORNING UPDATE: Sign up to receive the most up-to-date information on COVID-19 and Tampa Bay, six days a week

UNEMPLOYMENT Q&A: We answer your questions about Florida unemployment benefits

CONTRIBUTE TO THE SCRAPBOOK: Help us tell the story of life under coronavirus

MEET THE HELPERS: Highlighting Tampa Bays everyday heroes in this crisis

FOLLOW OUR COVERAGE ON SOCIAL MEDIA: Facebook. Instagram. Twitter. Reddit.

LISTEN TO THE CORONAVIRUS PODCAST: New episodes every week, including interviews with experts and reporters

HAVE A TIP? Send us confidential news tips

Were working hard to bring you the latest news on the coronavirus in Florida. This effort takes a lot of resources to gather and update. If you havent already subscribed, please consider buying a print or digital subscription.

Read this article:
Trying to land a job, graduates? Heres advice from Great Recession veterans - Tampa Bay Times

Text Size:A- A+

New Delhi:As the world reels from the impact of the Covid-19 crisis, which has also induced an economic recession, there are many working tirelessly at the forefront to tackle the challenge. In India, several women are working round-the-clock, seven days a week, to ensure the smooth functioning of key departments administration, diagnosis, prevention, research and cure.

ThePrint takes a look at some of those leading these efforts.

Preeti Sudan, secretary at the Ministry of Health and Family Welfare, has been working on aligning all departments to execute the Narendra Modi governments policies to prevent the spread of the disease. Beela Rajesh, health secretary of Tamil Nadu, has been proactive in engaging with citizens through her department and Twitter. The state currently has more than 600 active cases, one of the highest in the country.

Dr Priya Abraham, director of National Institute of Virology, Pune, has made a significant medical breakthrough by isolating the deadly coronavirus. This helps in understanding the disease better and finding treatment regimens.

Dr Nivedita Gupta, senior scientist at Indian Council of Medical Research (ICMR), is busy designing the treatment and testing protocols for the country while Dr Renu Swarup, secretary, Department of Biotechnology, is spending her time trying to find a vaccine.

Also read: Coronavirus has challenged & changed how worlds top scientists work to find a cure

A 1983 batch IAS officer from the Andhra Pradesh cadre, Sudan is usually seen leaving her office at Nirman Bhawan late at night.

An M.Phil. in Economics and postgraduate in Social Policy and Planning from the London School of Economics, Sudan also served the World Bank in Washington as a consultant.

Her ministry is the nodal agency for fighting the present coronavirus challenge. Sudan, along with Union Health Minister Harsh Vardhan, coordinates with sister departments in the central and state government. The two conduct regular reviews of the evolving situation.

She is also involved in the regular review of preparedness with the states and union territories. Also, she is the first point of contact for any query arising from Prime Minister Narendra Modis office or from the office of Union Minister, said a senior official from her ministry who did not wish to be identified.

She played a major role in the evacuation of the 645 students from Wuhan, China, the official added.

Among her cadre, Sudan has a distinguished track record of serving in finance, disaster management, tourism and agriculture.

Also read: How experts are using maths to stay ahead of the coronavirus

Working in the Division of Epidemiology & Communicable Diseases, and in-charge of viral diseases at the countrys apex health research department, Dr Guptas primary responsibility is building testing and treatment protocols in India.

She was also the primary scientist involved in the investigations and containment of the Nipah virus outbreak in Kerala last year.

An MBBS from Lady Hardinge Medical College, Dr Gupta is the key person to augment the Covid-19 diagnostic capacity all across the country. In the short time span of two months, over 130 laboratories in the government sector and 52 laboratories in the private sector were roped in to diagnose coronavirus cases.

She worked day and night, including Sundays, to investigate the Nipah cases last year. It was not even a pandemic like coronavirus. Nowadays, for several days together, several scientists stay in the office to conclude the investigations, including her, said an official in her department, also on the condition of anonymity.

Gupta has a PhD in molecular medicine from Jawaharlal Nehru University and has been instrumental in setting up the virus research and diagnostic laboratory network of ICMR. This network was established subsequent to the 2009 pandemic influenza outbreak. The Virus Research and Diagnostic Laboratory (VRDL) network of 106 laboratories is largely considered as the backbone of the nation, and has ensured the capacity to detect the virus in almost all parts of the country.

Dr Gupta has aggressively investigated the viral outbreaks such as enteroviruses, arboviruses (dengue, chikungunya, Japanese encephalitis & Zika), influenza, measles and rubella among others. She was part of the team that worked extensively on deciphering the aetiology, and developed management guidelines, for the acute encephalitis syndrome in different parts of India.

Also read: Pancreatitis drug trials to a wastewater test for tracking virus top research on Covid-19

Swarup has been working at the Ministry of Science and Technologys Department of Biotechnology (DBT) for the past 30 years. She held the position of Scientist H which denotes an outstanding scientist until April 2018, when she was appointed as secretary.

A key person in the formulation of the Biotechnology Vision in 2001, the National Biotechnology Development Strategy in 2007 and Strategy II in 2015-20, Swarup is now involved in the crucial research to develop a coronavirus vaccine.

In an interview to ThePrint, Swarup had said that she is busy scaling up the manufacturing capacity of start-ups that have made low-cost testing kits and ventilators for Covid-19.

Her ministry has asked all IIT incubators to focus on research and development of portable ventilators, genome sequencing and isolation of the strain of the novel coronavirus from blood samples.

A PhD in Genetics and Plant Breeding, Swarup is known for promoting women in science, and was a member of the Task Force on Women in Science, which was constituted by the Scientific Advisory Committee to the Prime Minister.

Also read: 5 new projects India will pursue to find treatment for Covid-19 and similar diseases

Abraham leads the backbone of the country right now the National Institute of Virology (NIV), Pune, which is affiliated to the ICMR. The NIV was initially the only testing centre in the country for Covid-19.

As the number of cases spike on a daily basis, the NIV has succeeded in reducing the testing time of Covid-19 samples to just four hours a sample from 12-14 hours.

The NIV had confirmed the first three positive Covid-19 cases in India. The institute had initially done all the testing, but ICMR subsequently increased the number of laboratories, anticipating a jump in cases. Under Abrahams leadership, theNIV helped these labs with troubleshooting, and ensured reagent supplies to the network of labs.

The achievements which NIV has made at this crucial juncture were not possible without a hardworking and well-coordinated team, Abraham told ThePrint.

Abraham holds an MBBS, MD (Medical Microbiology) and PhD from Christian Medical College in Vellore, where she was also the former head of the department of Clinical Virology at CMC Vellore. She is also a fellow of the Royal College of Pathologists and Royal Society of Tropical Medicine and Hygiene. On invitation from the Medical Council of India, Abraham also drafted the syllabus for the Doctor of Medicine (DM) in Virology.

Her achievements also include being a key member of the WHOs Guidelines Development Working Group Meeting for Hepatitis and HIV in 2012, and for Hepatitis B in 2014. In 2017, she served as WHO consultant in Myanmar to formulate the National Hepatitis Testing.

Also read: India Covid-19 death rate lower than Italy, UK, but cant play down virus impact: NIV chief

As the health secretary of Tamil Nadu, Rajesh has been at the forefront of tackling the challenge in her state.

A 1997 batch IAS officer, she is known as a media-friendly bureaucrat and is very active on Twitter.

Virus can affect anyone, lets be gentle and sensitive towards each other and wage a coordinated battle against Covid19, she posted recently.

Apart from sharing her thoughts, she also responds to queries directed at her or her department.

An MBBS graduate from Madras Medical College, Beela earlier served as sub-collector of Chengalpattu, commissioner of Fisheries and commissioner of Town and Country Planning in Tamil Nadu. She was also the commissioner of Indian Medicine and Homeopathy before being transferred as the health secretary in 2019.

Tamil Nadu ranks third among all Indian states in the NITI Aayog Health Index given its vastly improved health outcomes.

Under Rajesh, the Tamil Nadu Health System Reform Program was set up with the state government, Centre and World Bank signing a $287 million loan agreement in June 2019. The program aims to improve the quality of health care, reduce the burden of non-communicable diseases (NCDs), and fill equity gaps in reproductive and child health services in Tamil Nadu.

Also read: These are the 11 Indian women scientists the new STEM chairs are named after

ThePrint is now on Telegram. For the best reports & opinion on politics, governance and more, subscribe to ThePrint on Telegram.

Subscribe to our YouTube channel.

The rest is here:
Doctors, IAS officers & a scientist the 5 women leading Indias fight against Covid-19 - ThePrint

Gosselies, Belgium, 26March 2020, 7am CET BONE THERAPEUTICS(Euronext Brussels and Paris: BOTHE), the bone cell therapy company addressing high unmet medical needs in orthopaedics and bone diseases, today announces that it is further strengthening its management team with the appointment of Stefanos Theoharis, PhD, as Chief Business Officer (CBO).

Stefanos will be responsible for the companys corporate development activities and executing its business strategy. His immediate priorities will be concentrating on partnering Bone Therapeutics products and in-licensing innovations. He will also further develop the commercial strategies for the product portfolio and cell therapy platform.

At this stage of the development of Bone Therapeutics, it is very important to appoint a proven executive with a high level of business experience to achieve our next set of commercial goals,said Miguel Forte, MD, PhD, Chief Executive Officer of Bone Therapeutics. Stefanos has gathered considerable achievements in business development at both rapidly growing biotech and global biopharma companies, coupled with an extensive expertise in cell therapy drug development and manufacturing. His diverse skill set, which includes licensing, M&A transactions and R&D partnerships, will be invaluable to bolster our business initiatives as we continue to advance our mid- to late stage product pipeline through clinical development with a potential commercialization in sight.

Stefanos will contribute more than 15 years of business development experience in the pharma and biotech industry to Bone Therapeutics, specifically in the cell and gene therapy space. This includes his achievements as Senior Vice-President at Cell Medica, a clinical-stage biotech company, where he expanded the companys allogeneic T-cell immunotherapy platform through strategic partnerships with leading research institutions and targeted acquisitions. Prior to Cell Medica, Stefanos was Chief Business Officer at apceth GmbH, a company developing genetically-engineered mesenchymal stromal (MSC) cell products and also acting as a contract manufacturer in the ATMP space. He led all apceths business development activities, including in- and out-licensing and service contracts negotiations. He also held positions as Head of Business Development at the antisense RNA drug specialist Antisense Pharma (now Isarna), and Director Business Development at Roche, focused on partnering activities in emerging science and technologies. Stefanos also worked at Lazard, the global investment bank, advising to a variety of life sciences firms on M&As and financing transactions. Stefanos achieved an MSc. in Molecular Medicine and a PhD in Pathology and Immunology from Imperial College London.

I really wanted to join a cell therapy company where I was able to make a significant difference to the company, the wider field and patients outcomes.With an innovative allogeneic, off the shelf, cell therapy platform and a potentially best-in-class knee osteoarthritic pain treatment, Bone Therapeutics is uniquely positioned to make a meaningful difference in the lives of patients with severe orthopaedic conditions,said Stefanos Theoharis, PhD, Chief Business Officer of Bone Therapeutics. As both products are entering advanced stage clinical trials, Im delighted to join the company at such a critical time and I look forward to working with its talented leadership and scientific teams to take these promising treatments to market.

About Bone Therapeutics

Bone Therapeutics is a leading biotech company focused on the development of innovative products to address high unmet needs in orthopedics and bone diseases. The Company has a broad, diversified portfolio of bone cell therapies and an innovative biological product in later-stage clinical development, which target markets with large unmet medical needs and limited innovation.

Bone Therapeutics is developing an off-the-shelf protein solution, JTA-004, which is entering PhaseIII development for the treatment of pain in knee osteoarthritis. Positive PhaseIIb efficacy results in patients with knee osteoarthritis showed a statistically significant improvement in pain relief compared to a leading viscosupplement. The clinical trial application (CTA) for the pivotal PhaseIII program has been approved by the Danish relevant authorities allowing the start of the study.

Bone Therapeutics other core technology is based on its cutting-edge allogeneic cell therapy platform (ALLOB) which can be stored at the point of use in the hospital, and uses a unique, proprietary approach to bone regeneration, which turns undifferentiated stem cells from healthy donors into bone-forming cells. These cells can be administered via a minimally invasive procedure, avoiding the need for invasive surgery, and are produced via a proprietary, scalable cutting-edge manufacturing process. Following the CTA approval by the Belgian regulatory authority, the Company is ready to start the PhaseIIb clinical trial with ALLOB in patients with difficult tibial fractures, using its optimized production process.

The ALLOB platform technology has multiple applications and will continue to be evaluated in other indications including spinal fusion, osteotomy and maxillofacial and dental applications.

Bone Therapeutics cell therapy products are manufactured to the highest GMP (Good Manufacturing Practices) standards and are protected by a broad IP (Intellectual Property) portfolio covering ten patent families as well as knowhow. The Company is based in the BioPark in Gosselies, Belgium. Further information is available at http://www.bonetherapeutics.com.

Contacts

Bone Therapeutics SAMiguel Forte, MD, PhD, Chief Executive OfficerJean-Luc Vandebroek, Chief Financial OfficerTel: +32 (0) 71 12 10 00investorrelations@bonetherapeutics.com

International Media Enquiries:Image Box CommunicationsNeil Hunter / Michelle BoxallTel: 44 (0)20 8943 4685neil@ibcomms.agency / michelle@ibcomms.agency

For French Media and Investor Enquiries:NewCap Investor Relations & Financial CommunicationsPierre Laurent, Louis-Victor Delouvrier and Arthur RouillTel: + 33 (0)1 44 71 94 94bone@newcap.eu

Certain statements, beliefs and opinions in this press release are forward-looking, which reflect the Company or, as appropriate, the Company directors` current expectations and projections about future events. By their nature, forward-looking statements involve a number of risks, uncertainties and assumptions that could cause actual results or events to differ materially from those expressed or implied by the forward-looking statements. These risks, uncertainties and assumptions could adversely affect the outcome and financial effects of the plans and events described herein. A multitude of factors including, but not limited to, changes in demand, competition and technology, can cause actual events, performance or results to differ significantly from any anticipated development. Forward looking statements contained in this press release regarding past trends or activities should not be taken as a representation that such trends or activities will continue in the future. As a result, the Company expressly disclaims any obligation or undertaking to release any update or revisions to any forward-looking statements in this press release as a result of any change in expectations or any change in events, conditions, assumptions or circumstances on which these forward-looking statements are based. Neither the Company nor its advisers or representatives nor any of its subsidiary undertakings or any such person`s officers or employees guarantees that the assumptions underlying such forward-looking statements are free from errors nor does either accept any responsibility for the future accuracy of the forward-looking statements contained in this press release or the actual occurrence of the forecasted developments. You should not place undue reliance on forward-looking statements, which speak only as of the date of this press release.

See the rest here:
Bone Therapeutics appoints Stefanos Theoharis as Chief Business Officer - OrthoSpineNews