Category Archives: Molecular Medicine

It is the National Party leaders job to oppose the government. But as a second case of Covid-19 in New Zealand is confirmed, he should tone down the anecdotal criticisms, and rein in MPs explicitly urging people to panic-buy, writes Siouxsie Wiles, an associate professor in molecular medicine and pathology.

Dear Simon

I do understand that you lead the Opposition. I get that its your job to hold the government to account, and that this is an election year. Of course you and your caucus are keen to score points against the government wherever you can. But the reality is, you dont actually have to oppose everything it does. Sometimes, such as in the case of a public health emergency, it might be worth putting the kneejerk response on hold.

I was really disappointed to hear you get stuck into the official response to the coronavirus outbreak and the testing regime in comments relying on anecdotal feedback.

And when I heard your colleague David Bennett, MP for Hamilton East, telling the listeners of Hamiltons local radio station FreeFM that the government had dropped the ball, big-time and put New Zealanders safety at risk, and that people should be out there panic-buying, well, then I started to see red.

I cant quite believe I need to tell you this, but during a serious outbreak of a new infectious disease, the last thing we need is for our elected representatives to be undermining the important messages coming from the government, scientists, and public health officials.

For example, themessageI have been sharing with the public is that we shouldnt be panic buying and hoarding. That leads to shortages. And shortages mean instead of everyone having what they need, some of the most vulnerable people in our communities will be left with nothing. Is that what the National Party wants? Surely not. Likewise, does Mr Bennett know more about this than I do? Im going to take a wild stab in the dark here and say that, with a degree in Commerce and Law, and previous portfolios in Veterans Affairs and Racing, he does not.

Now I know all our favourite disaster books, movies, and shows might tell us that the way to deal with a situation like this is to grab some weapons, batten down the hatches, and protect our resources from everyone around us. But, in fact, as most people recognise, in the real world the opposite is true. The communities that survive disasters the best are those that work together to share their resources and make sure no one is left out in the cold.

This is one of those times. Without the surest of evidence, it is downright irresponsible during an outbreak such as this to undermine public confidence in the official response. Because when people are scared and panic, they dont respond well to difficult situations. And this could get very difficult. Rest assured, the government is being advised by a team of infectious diseases and public health experts who know their shit, are monitoring whats happening around the around, and adjusting their advice as needed.

It was encouraging to hear signs that youre toning down your response this morning on RNZ in advising people, for example, not to panic. But as we all work to ensure calm, to avoid stoking fear, and to communicate clear scientific information, I would urge you and your colleagues to bite your tongues until we are through this global emergency.

Yours sincerely

Siouxsie

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Some advice for Simon Bridges on being responsible in a health emergency - The Spinoff

Ever since the earliest reports of a pneumonia-like illness spreading within Hubei province in China, the resemblance to the SARS outbreak of 2002-2003 has been uncanny: probable origins in the wild-animal markets of China; an illness that in some people resembles the common cold or a flu, but in others leads to pneumonia-like symptoms that can cause respiratory failure; community transmission that often occurs undetected; super-spreader events; and reported vertical transmission in high-rises or other living spaces where the waste systems are improperly engineered or drain catch-basins are dry, allowing aerosolized particles to pass from one floor of a building to another (see The SARS Scare for an in-depth description of the epidemiology and virology of the SARS outbreak of 2002-2003 and the four independent zoonotic transmissions of 2003-2004).

UPDATED 3-04-2020 at 12:57p.m. See below.

At first, this latest outbreak was referred to as a novel coronavirus, then in the media as COVID-19 (formally, the name for the disease in an infected person who has become sick, a distinction analogous to that between a person who is HIV positive and one who has developed AIDS). Now that the virus has been characterized and its relationship to SARS firmly established, its designation is SARS-CoV-2severe acute respiratory syndrome coronavirus 2.

Will public-health measures be sufficient to contain its spread? How infectious is it? What is the incubation period? Is this a pandemic? What role does the immune-system response play in the progression of the disease? Which populations are most at risk? Can scientists develop a vaccine, and how quickly? These are some of the questions that scientists worldwide are asking, and that a collaboration among Harvard University and Chinese researchers will address as part of a $115-million research initiative funded by China Evergrande Group, which has previously supported Universitygreen-buildings research at the Graduate School of Design, research onimmunologic diseases, and work inmathematics. (See below for the University press release describing the initiative.)

Harvard Magazinespoke with some of the researchers involved in fighting the first SARS outbreak, and those who will be collaborating with Chinese colleagues, in what is already a worldwide effort to control SARS-CoV-2.

Michael Farzan 82, Ph.D. 97, who in 2002 was an assistant professor of microbiology and molecular genetics at Harvard Medical School (HMS) studying the mechanism that viruses use to enter cells, was the first person to identify the receptor that SARS used to bind and infect human cells. SARS-CoV-2 is a close cousin to SARS, and uses the same human receptor, ACE2, reports Farzan, who is now co-chair of the department of immunology and microbiology at Scripps Research. The ACE2 receptor is expressed almost exclusively in the lungs, gastrointestinal tract, and the kidneys, which explains why the disease is so effectively transmitted via both the respiratory and fecal-oral routes.

But there are subtle differences in the new virus behind the current outbreak, he explained in an interview. The viruss receptor binding domainthe part that attaches to the human receptorhas undergone a lot of what we call positive selection, meaning there has been a good deal of evolutionary pressure on that region from natural antibodies, probably in bats or some other animal host that is a reservoir for this disease. So while the virus retains its ability to bind ACE2, Farzan explains, it no longer binds the same antibodies. That is unfortunate, because as the first SARS epidemic wound down, HMS professor of medicine Wayne Marasco had identified a single antibodyfrom what was then a 27-billion antibody librarythat blocked the virus from entering human cells. (Marasco is actively testing new antibodies, hoping to find one that will have the same effect on SARS-CoV-2. For more on Marascos work, see below.) Still, we are not starting from square one, says Farzan.

In animal studies,Remdesivir [a new and experimental antiviral drug] has seemed to work against SARS-like viruses, he says. Its effectiveness will probably hinge on getting it early enough, in the same way that the antiviral drug Tamifluis most effective against the seasonal flu when given to patients early in the course of infection.

And there is a reasonable hope that a vaccine canbe developed, Farzan adds, because the part of the virus that binds the human receptor is exposed and accessible, making it vulnerable to the immune systems antibodies. In addition, the viral genome is relatively stable. That means SARS CoV-2 wont evolve much over the course of an epidemic, so a vaccine that is relatively protective at the beginning of an epidemic will remain effective until its end.

Another reason for optimismdespite the long road to deploying any vaccine in humansis that the science that allows researchers to understand the viruss structure, life cycle, and vulnerabilities is progressing far more rapidly today than during the first SARS outbreak 17 years ago. So, too, is the understanding of the human immune response to the virus, and of the most effective public-health strategies based on the epidemiology of the disease.

When epidemiologists assess the severity of an epidemic, they want to know how effectively the disease can propagate in a population. The first measure they attempt to calculate is the reproductive number (R0)the number of people that an infected individual will in turn infect in an unexposed population, in the absence of interventions. When the reproductive number is greater than 1 (meaning each infected person in turn infects more than one other person), more and more people become infected, and an epidemic begins. Public-health interventions are therefore designed to lower the rate of transmission below 1, which eventually causes the epidemic to wind down. The second number epidemiologists focus on is the serial intervalhow long it takes one infected person at a particular stage of the disease to infect another person to the point of the same stage of the disease. The serial interval thus suggests how rapidly the disease can spread, which in turn determines whether public-health officials can identify and quarantine all known contacts of an infected individual to prevent their retransmitting the disease to others.

Epidemiologist Marc Lipsitch will be one of several Harvard scientists collaborating with Chinese colleagues to fight SARS-CoV-2Photograph by Kent Dayton

Marc Lipsitch, a professor of epidemiology at the Harvard Chan School of Public Health (HSPH), and director of the schoolsCenter for Communicable Disease Dynamics, helped lead one of the two teams that first calculated the reproductive number of SARS in the 2002-2003 outbreak. SARS had an R0 of 3, he recalls: each case led to three others. In that outbreak, about 10 percent of those who became sick died. The good news is that SARS CoV-2 appears to have a much lower R0 than SARS, ranging from the high ones to low twos, and only 1 percent to 2 percent of those who become sick have died. On the other hand, the serial intervalstill being worked outappears to be shorter, meaning the new virus has the potential to spread faster.

In the current epidemic, Lipsitch notes a further concern: the fact that the incubation-period distribution and the serial-interval distribution are almost identical. Thats a mathematical way of saying that people can start transmitting the virus even when they are pre-symptomatic, or just beginning to exhibit symptoms. That makes tracing and quarantining contacts of infected individualsa classic, frontline public-health measurenearly impossible.

Tracing, quarantining, and other public-health interventions, such as distancing measures (closing workplaces or asking employees to work from home, for example) proved sufficient to defeat SARS in the early 2000s. But with SARS-CoV-2, public-health measures alone may prove inadequate. Controlling this version of SARS may require antivirals, stopgap antibody therapies, and ultimately, vaccines, deployedtogetherwith robust public-health containment strategies.

Unfortunately, SARS-CoV-2 is almost certainly already a pandemic, Lipsitch continues: demonstrating sustained transmission in multiple locations that will eventually reach most, if not all places on the globe. The disease appears to be transmitting pretty effectively, probably in Korea, probably in Japan, and probably in Iran. He now estimates that 20 to 60 percent [figures updated 03-04-2020 at 12:57 p.m.]of the adult global population will eventually become infected.

That said, Infected is different from sick, he is careful to point out. Only some of those people who become infected will become sick. As noted above, only about 1 percent to 2 percent of those who have becomesickthus far have died, he says. But the number of people who areinfectedmay be far greater than the number of those who are sick. In a way, he says, thats really good news. Because if every person who had the disease was also sick, then that would imply gigantic numbers of deaths from the disease.

I'm very gratified, Lipsitch continues, to see that both China and Harvard recognize the complementarity between public health and epidemiology on the one hand, and countermeasure-development on the other hand. We can help target the use of scarce countermeasures [such as antivirals or experimental vaccines] better if we understand the epidemiology; and we will understand the epidemiology better if we have good diagnostics, which is one of the things being developed in this proposal. These approaches are truly complementary.

In the short term, Lipsitchwho has sought to expand the modeling activities of the Center for Communicable Disease Dynamics to better understand the current outbreaks epidemiologysays, It would be great toexpand collaborations with Chinese experts. Longer term, I see a really good opportunity for developing new methods for analyzing data better, as we have in previous epidemics. After the first SARS outbreak, for example, epidemiologists developed software for calculating the reproductive number of novel diseases; that software now runs on the desktop computers of epidemiologists around the world. And in 2009, during an outbreak of swine flu in Mexico, Lipsitch and others developed a method for using the incidence of the disease among awell-documented cohort of travelerswho had left Mexico, to estimate the extent of the disease among amuch larger and less well surveyedpopulation of Mexican residents.

What they found then was that the estimated number of cases in Mexican residents likely exceeded the number of confirmed cases by two to three orders of magnitude. The same method is being used to assess the extent of SARS-CoV-2 in China right nowso far without any hiccups. In the Mexican case, Lipsitchreports, the estimates suggested that severe cases of the disease were uncommon, since thetotal numberof cases was likely much larger than the number ofconfirmedcases. So I think we have learned from each epidemic how to do more things. And in between them, you solidify that less visible, less high-profile research that builds the foundation for doing better the next time. His group, for example, has been developing ways to make vaccine trials faster and better once a vaccine candidate exists.

A vaccine is the best long-term hope for controlling a disease like SARS-CoV-2. Higgins professor of microbiology and molecular genetics David Knipe, who like Lipsitch will participate in the newly announced collaboration, works on vaccine delivery from a molecular perspective. Knipe has developed methods to use the herpes simplex virus (HSV) as a vaccine vector and has even made HSV recombinants that express the SARS spike proteinthe part of the virus that binds the human ACE2 receptor. He now seeks to make HSV recombinants that express the new coronavirus spike protein as a potential vaccine vector.

But Knipe also studies the initial host-cell response to virus infection, which is sometimes called the innate immune response. And he has used HSV vectors that expressed the first SARS spike protein to study how it activates innate immune signaling. That is important because inSARS 1, initial symptoms lasted about a week, but it was the second phasecharacterized by a massive immune-system response that began to damage lung tissuethat led to low levels of oxygen saturation in the blood, and even death.The inflammation in the lungs is basically a cytokine storm, an overwhelming and destructive immune response thats the result of innate signaling, Knipe explains. So were going to look at that with the new coronavirus spike protein, as well. This could help to determine the actual mechanism of inflammation, and then we can screen for inhibitors of that that might be able to alleviate the disease symptoms.

The idea, he says, is to stop theinflammatoryresponse now killing people in the respiratory phase of the disease by targeting the specific molecular interaction between the virus and the host cell. This, he explains, aligns with one of the principal initial goals of the collaboration, which is to support research both in China and at Harvard to address the acute medical needs of infected individuals during the current crisis.

Another form of frontline defense against the virus is antibody therapy. In an epidemic, this type of therapy is usually administered as a prophylaxis to first responders at high risk of infection, or as treatment to patients who are already sick or to people who might be harmed by a vaccine, such as pregnant women, the elderly, or those with co-morbidities. Wayne Marasco, an HMS professor with a lab at the Dana Farber Cancer Institute, was the first to develop antibody therapies against SARS and MERS, a related coronavirus, in 2014. What he learned in those outbreaks was that using only a single antibody to bind the viruss receptor binding domainthe part of the virus that attaches to the human receptoris not enough to prevent escape through mutations that neutralize the therapy. You have to use combinations of antibodies to block the escape pathways, he explains. But the combinations have to be carefully designed to avoid the risk that the virus will evolve a gain of functionor the virus coming out of the patient is more pathogenic than the virus you started to treat.

During the MERS outbreak, Marasco led the Defense Advanced Research Projects Agencys 7-Day Biodefense program.DARPA would drop an unknown pathogen off at our doorstep, Marasco says, and we had seven days to develop a therapeutic that could be manufactured at scale. A second DARPA-funded project focused on reducing the cost of therapies to less than $10 a dose. The government has made efforts to streamline that process to get the production sped up and the cost decreased, he notes, although the efforts are independent of regulatory approval, which has a life of its own.

Marasco currently collaborates with an international team that can perform studiesincluding some that cant be done at Harvardthanks to ready access to a Biosafety Level 4 laboratory and to non-human primates for testing. The team is working to develop antibody therapies effective against SARS-CoV-2, but Marasco cautions that the situation is pretty worrisome with a disease that has a long latency period when people show no symptoms, and when public-health officials cannot identify source cases (as in Italy and in the single case of apparent community transmission in California reported February 26).

The problem in getting ahead of this now, he continues, is funding. Government resources are generally a redistribution of funds that have previously been granted to projects such as the Ebola outbreak in West Africa, or come as administrative supplements to preexisting grants. But with the pace of this epidemic, a lack of resources is limiting what can get done and how quickly it can be accomplished. Beyond the creation of therapeutics, there are all kinds of epidemiologic considerations that require rapid funding, from investigating modes of transmission to field testing for infection.

In the near term, the way to treat masses of patients, he says, is to take blood plasma from someone who has recovered and administer it to an infected person. The convalescents antibodies then fight the infection. The FDA would never approve it, he notes, but it does work. Ultimately, the treatment of choiceand the most cost-effective approach, he says, will be a vaccine.

In the last days of 2019 and the first days after the New Year, we started hearing about a pneumonia-like illness in China, says Dan Barouch, an HMS professor of medicine and of immunology known for his anti-HIV work, whose lab has developed a platform for rapid vaccine development. (During the Zika virus outbreak of 2016, for example, his group was the first to report, within a month, a vaccine protective in animal models.) When the genome of the virus was released on Friday, January 10, we started reviewing the sequence that same evening, working through the weekend. By Monday morning, we were ready to grow it.

His concern about this latest outbreak was that the rate of spread seemed to be very rapid. In addition, the outbreak had the clinical features of an epidemic. We reasoned that this might make it difficult to control solely by public-health measures, he says, particularly because the virus can be transmitted by asymptomatic individuals. Thus, if the epidemic is still spreading toward the end of this year or early 2021, by which point a vaccine might be available, Barouch explains, such a remedy could prove essential. Historically, when viral epidemics don't self-attenuate, the best method of control is a vaccine.

Although Barouchs Beth Israel Deaconess Medical Center lab is working on DNA and RNA vaccines, a new technology that has the potential to cut vaccine development times in half, large-scale manufacturing using so-called nucleotide vaccines is unproven. That's why I think there needs to be multiple parallel vaccine efforts, he emphasizes. Ultimately, we don't know which one will be the fastest and most protective. At the moment, he reports, there are at least a half dozen scientifically distinct vaccine platforms that are being developed and he believes that vaccine development for this pathogen will probably go faster than for any other vaccine target in human history.

Ever since I graduated from medical school, he points out, there have been new emerging or re-emerging infectious disease outbreaks of global significance with a surprising and disturbing sense of regularity. There is Ebola. There was Zika. There were SARS, MERS; the list keeps growing. With climate change, increasing globalization, increasing travel, and population shifts, the expectation is that epidemics will not go away, and might even become more frequent.

In this global context, Barouch emphasizes the importance of a collaborative response that involves governments, physicians, scientists in academiaandin industry, and public-health officials. It has to be a coordinated approach, he says. No one group can do everything. But I do think that the world has a greater sense of readiness this time to develop knowledge, drugs, and therapeutics very rapidly. The scientific knowledge that will be gained from the vaccine efforts [will] be hugely valuable in the biomedical research field, against future outbreaks, and in the development of a vaccine to terminate this epidemic.

University provost Alan Garber, a physician himself, adds that Global crises of such magnitude demand scientific and humanitarian collaborations across borders. Harvard and other institutions in the Boston area conduct research on diagnostics, virology, vaccine and therapeutics development, immunology, epidemiology, and many other areas.With its tremendous range of expertise and experience, our community can be an important resource for any effort to address a major global infectious disease outbreak. Our scientists and clinicians feel an obligation to be part of a promising collaboration to overcome the worldwide humanitarian crisis posed by this novel virus.

UPDATED 3-03-2020 AT 12:10 p.m.TO INCLUDE A REPORT FROM THE MEETING WITH CHINESE COLLEAGUES

In a closed-door meeting that took place Monday, March 2, 2020, at Harvard Medical School, nearly 80 Boston-area scientists gathered to discuss with colleagues from China participating via video link how to respond to COVID-19 disease and the SARS-CoV-2 virus that causes it. This was the first meeting to take place as a result of the collaboration with scientists at theGuangzhou Institute of Respiratory Health announced on Monday, February 24.In attendance locally were experts from Harvard Medical School (HMS), the Harvard T.H. Chan School of Public Health, the HMS-affiliated hospitals, the Ragon Institute, Boston University, the Broad Institute, MIT, the Wyss Institute, as well as representatives from industry. The workshop, convened by HMS dean George Q. Daley, was a planning session to map out the process for coordinating on collaborative projects, designed to allow the participants to meet, form working groups by research area, and determine next steps.

The collaboration harnesses the strengths of the Boston scientific and biomedical ecosystem, the events organizers said in a statement, with the critical experience of Chinese scientists, who are providing on-the-ground insight into diagnostics and care for patients on the frontlines.

This public health crisis, they continued, is an opportunity to catalyze an unprecedented level of collaboration among various scientific efforts across Boston and Cambridge to address both the acute, most pressing challenges of this particular epidemic but also to establish a framework for future collaborations and create a more nimble rapid-response system for other epidemics.

The meeting was organized according to areas of research interest, need, and opportunity including:

The meeting demonstrated the need to establish a collaborative regional response capacity, not only for this outbreak, but for other future emerging infectious diseases, said the organizers. They are now working to create an organizational structure that will formalize the working groups in each of the above areas, and allow for the optimal deployment of resources including disciplinary and clinical expertise, shared core facilities, and funding.

The official Harvard press release follows:

Harvard University Scientists to Collaborate with Chinese Researcherson Development of Novel Coronavirus Therapies, Improved Diagnostics

At a glance:

Since its identification in December, the novel coronavirus has quickly evolved into a global threat, taking a toll on human health, overwhelming vulnerable health care systems and destabilizing economies worldwide.

To address these challenges, Harvard University scientists will join forces with colleagues from China on a quest to develop therapies that would prevent new infections and design treatments that would alleviate existing ones.

The U.S. efforts will be spearheaded by scientists at Harvard Medical School, led by DeanGeorge Q. Daley, working alongside colleagues from the Harvard T.H. Chan School of Public Health. Harvard Medical School will serve as the hub that brings together the expertise of basic scientists, translational investigators and clinical researchers working throughout the medical school and its affiliated hospitals and institutes, along with other regional institutions and biotech companies.

The Chinese efforts will be led by Guangzhou Institute of Respiratory Health and Zhong Nanshan, a renowned pulmonologist and epidemiologist. Zhong is also head of the Chinese 2019n-CoV Expert Taskforce and a member of the Chinese Academy of Engineering.

Through a five-year collaborative research initiative, Harvard University and Guangzhou Institute for Respiratory Health will share $115 million in research funding provided by China Evergrande Group, aFortuneGlobal 500 company in China.

We are confident that the collaboration of Harvard and Guangzhou Institute of Respiratory Health will contribute valuable discoveries to this worldwide effort, said Harvard University President Lawrence Bacow. We are grateful for Evergrandes leadership and generosity in facilitating this collaboration and for all the scientists and clinicians rising to the call of action in combating this emerging threat to global well-being.

Evergrande is honored to have the opportunity to contribute to the fight against this global public health threat, said Hui Ka Yan, chair of the China Evergrande Group. We thank all the scientists who responded so swiftly and enthusiastically from the Harvard community and are deeply moved by Harvard and Dr. Zhongs teams dedication and commitment to this humanitarian cause. We have the utmost confidence in this global collaborative team to reach impactful discoveries against the outbreak soon.

While formal details of the collaboration are being finalized, the overarching goal of the effort is to elucidate the basic biology of the virus and its behavior and to inform disease detection and therapeutic design. The main areas of investigation will include:

With the extraordinary scale and depth of relevant clinical and scientific capabilities in our community, Harvard Medical School is uniquely positioned to convene experts in virology, infectious disease, structural biology, pathology, vaccine development, epidemiology and public health to confront this rapidly evolving crisis, Daley said. Harnessing our science to tackle global health challenges is at the very heart of our mission as an institution dedicated to improving human health and well-being worldwide.

We are extremely encouraged by the generous gesture from Evergrande to coordinate and supportthe collaboration and by the overwhelmingly positive response from our Harvard colleagues, said Zhong, who in 2003 identified another novel pathogen, the severe acute respiratory syndrome (SARS) coronavirus and described the clinical course of the infection.

We look forward to leveraging each of our respective strengths to address the immediate and longer-term challenges and a fruitful collaboration to advance the global well-being of all people, Zhong added.

Harvard University ProvostAlan M. Garbersaid outbreaks of novel infections can move quickly, with a deadly effect.

This means the response needs to be global, rapid and driven by the best science. We believe that the partnershipwhich includes Harvard and its affiliated institutions, other regional and U.S.-based organizations and Chinese researchers and clinicians at the front linesoffers the hope that we will soon be able to contain the threat of this novel virus, Garber said. The lessons we learn from this outbreak should enable us to respond to infectious disease emergencies more quickly and effectively in the future.

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Harvard and Guangzhou Institute of Respiratory Health Team to Fight SARS-CoV-2 - Harvard Magazine

Verena Gudernatsch, Sylwia Anna Stefaczyk, Valbona Mirakaj

Molecular Intensive Care Medicine, Department of Anesthesiology and Intensive Care Medicine, University Hospital Tbingen, Eberhard Karls University Tbingen, Tbingen, Germany

Correspondence: Valbona MirakajMolecular Intensive Care Medicine, Department of Anesthesiology and Intensive Care Medicine, University Hospital Tbingen, Eberhard Karls University Tbingen, Hoppe-Seyler-Strae 3, Tbingen 72076, GermanyTel +49 7071 29-86622Fax +49 7071 29-5533Email valbona.mirakaj@uni-tuebingen.de

Abstract: Nonresolving inflammation, a hallmark of underlying severe inflammatory processes such as sepsis, acute respiratory distress syndrome and multiple organ failure is a major cause of admission to the intensive care unit and high mortality rates. Many survivors develop new functional limitations and health problems, and in cases of sepsis, approximately 40% of patients are rehospitalized within three months. Over the last few decades, better treatment approaches have been adopted. Nevertheless, the lack of knowledge underlying the complex pathophysiology of the inflammatory response organized by numerous mediators and the induction of complex networks impede curative therapy. Thus, increasing evidence indicates that resolution of an acute inflammatory response, considered an active process, is the ideal outcome that leads to tissue restoration and organ function. Many mediators have been identified as immunoresolvents, but only a few have been shown to contribute to both the initial and resolution phases of severe systemic inflammation, and these agents might finally substantially impact the therapeutic approach to severe inflammatory processes. In this review, we depict different resolution mediators/immunoresolvents contributing to resolution programmes specifically related to life-threatening severe inflammatory processes.

Keywords: inflammation, resolution, specialized lipid mediators, neuronal guidance protein, sepsis, immunoresolvents

This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License.By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.

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Novel Resolution Mediators of Severe Systemic Inflammation | ITT - Dove Medical Press

( NewMediaWire ) - February 14, 2020 - DALLAS - A Newark, N.J., researcher studying a new way to prevent heart injury and eventual heart failure and a Houston physician-scientist working to better understand and prevent stroke risk transmission from mother to child are the most recent American Heart Association Merit Award recipients. Each researcher will receive $1 million in funding from the Association, the worlds leading voluntary organization focused on heart and brain health and research.

Junichi Sadoshima, M.D., Ph.D., professor and chair of cell biology and molecular medicine at Rutgers New Jersey Medical School, and Louise D. McCullough, M.D., Ph.D., professor and chair of neurology at McGovern Medical School at the University of Texas Health Science Center at Houston will receive $200,000 a year for five years.

The American Heart Associations annual Merit Award aims to fuel highly promising, novel research that has the potential to move cardiovascular science forward.

With the Merit Award, we are searching for researchers with fresh ideas and the potential to make a huge impact, which is in line with the American Heart Associations mission to be a relentless force for a world of longer, healthier lives, said American Heart Association President Robert Harrington, M.D., FAHA, an interventional cardiologist and chair of the department of medicine at Stanford University in California. These exceptional scientists are asking the questions that havent been asked and are looking for answers in what we may consider to be nontraditional places. In the end, their work could transform cardiovascular and stroke science.

Sadoshimas research addresses the major public health problem that many people who have a heart attack or stroke die from heart failure or other complications within a few years after their first event. He and his colleagues are studying how inhibiting a previously uncharacterized type of cell death in the heart might prevent weakening of the heart and brain after a heart attack or stroke.

Just like we replace broken or worn-out parts in our cars to make them run better, our cells discard old or broken materials every day through a process called autophagy. While autophagy is a fundamentally important mechanism to maintain the function in the heart, the process can sometimes go awry and actually promote cellular suicide. This cell death triggered by excessive autophagy is termed autosis, Sadoshima said. Our goal with this award is to develop treatment to make the heart stronger when patients have a heart attack or stroke by understanding how autosis is stimulated and how it kills heart and brain cells.

Sadoshima said focusing on this previously uncharacterized form of cell death in the heart may have a significant impact on the future treatment of patients with reduced blood supply to the heart and brain.

McCulloughs research also looks at a big public health issue, stroke, in a new way.

It has been known for some time that health problems that occur during pregnancy, such a mothers high blood pressure, obesity or diabetes, can cause changes leading to obesity and hypertension in the child shes carrying. Initially, it was thought that a lot of this was genetic but there also are epigenetic factors outside factors that can change the genes to increase risk, McCullough said.

Prior research led McCullough and her colleagues to believe the mothers microbiome, the collection of microorganisms that reside in the gastrointestinal tract and are passed during childbirth to the child, might modify genes and increase later stroke risk in offspring. The health of the microbiome tends to change with age, becoming more likely to cause inflammation.

Were studying whether a mothers unhealthy microbiome can be manipulated and improved with diet or supplements, perhaps, to reduce stroke risk in her offspring, she said. If successful, these findings could have huge health ramifications for many generations to come.

Funding research such as the annual merit awards is a cornerstone of the American Heart Associations lifesaving mission. The Association has funded more than $4.6 billion in cardiovascular research since 1949, making it the single largest non-government supporter of heart and brain health research in the U.S.

Additional Resources:

Follow AHA/ASA news on Twitter @HeartNews

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The American Heart Association receives funding primarily from individuals; foundations and corporations (including pharmaceutical, device manufacturers and other companies) also make donations and fund specific association programs and events. The Association has strict policies to prevent these relationships from influencing the science content. Revenues from pharmaceutical and device corporations and health insurance providers are available at https://www.heart.org/en/about-us/aha-financial-information.

About the American Heart Association

The American Heart Association is a leading force for a world of longer, healthier lives. With nearly a century of lifesaving work, the Dallas-based association is dedicated to ensuring equitable health for all. We are a trustworthy source empowering people to improve their heart health, brain health and well-being. We collaborate with numerous organizations and millions of volunteers to fund innovative research, advocate for stronger public health policies, and share lifesaving resources and information. Connect with us on heart.org, Facebook, Twitter or by calling 1-800-AHA-USA1.

For Media Inquiries and AHA/ASA Expert Perspective: 214-706-1173

Cathy Lewis: 214-706-1324; cathy.lewis@heart.org

For Public Inquiries: 1-800-AHA-USA1 (242-8721)

heart.org and strokeassociation.org

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Researchers from Houston and Newark awarded $1 million each to tackle major challenges in heart disease treatment and stroke prevention - Associated...

Feb. 13, 2020 06:00 UTC

CAMBRIDGE, Mass. & TOKYO--(BUSINESS WIRE)-- Foundation Medicine, Inc. and Chugai Pharmaceutical, Ltd. (TOKYO: 4519) have entered into an agreement with the National Cancer Center (NCC) for the use of FoundationOneLiquid, Foundation Medicines laboratory-developed liquid biopsy test, in the third stage of SCRUM-Japan, the largest cancer genomic screening consortium in Japan. The multinational program provides genomic screening in collaboration with hospitals on a regional scale in Japan and other countries in Asia, and aims to accelerate the development of innovative biomarker-driven precision medicine cancer therapies.

This press release features multimedia. View the full release here: https://www.businesswire.com/news/home/20200212005980/en/

The third stage of SCRUM-Japan is structured in two programs LC-SCRUM-Asia and MONSTAR-SCREEN. LC-SCRUM-Asia is investigating genomic changes with the aim of delivering precision medicine to lung cancer patients. MONSTAR-SCREEN is investigating genomic changes across all types of advanced solid tumors, expanding beyond gastrointestinal cancer which was the focus of the second stage.

The SCRUM-Japan program is a model of how collaboration between industry and academia is making precision medicine a reality for people in need of new treatment approaches, said Brian Alexander, chief medical officer of Foundation Medicine. Utilization of FoundationOne Liquid in this program underscores its value in informing potential therapy selection for advanced-stage cancer patients. We look forward to continuing to expand access to comprehensive genomic profiling through this collaboration.

SCRUM-Japan is a groundbreaking program to find therapies for patients with advanced cancer. There is an increasing need for blood-based genomic testing in patients who cannot give tissue samples, including those who are unable to undergo invasive tumor biopsy, said Dr. Minoru Watanabe, vice president, head of Chugais Foundation Medicine Unit. We believe that this collaboration with the NCC, which has led genomic screening in Japan, will pave the way to realize true precision medicine across the country.

With the aim of delivering optimal treatments to patients, SCRUM-Japan was started with a view to detect cancer genomic alterations. The important achievements we saw from the first two stages include registration of over 10,000 patients clinical and genomic data, and approval of five therapeutic drugs and six in vitro diagnostics products based on clinical studies conducted by utilizing the data, said Atsushi Ohtsu, M.D., Ph.D., director of National Cancer Center Hospital East and Representative of SCRUM-Japan. Cancers remain leading causes of deaths in Japan and lung cancer has been ranked as the first leading cause of death among all cancer types. By incorporating FoundationOne Liquid into LC-SCRUM-Asia and MONSTAR-SCREEN, we believe the third stage of SCRUM-Japan will further prove the benefit of comprehensive genomic profiling tests such as FoundationOne Liquid.

Lung and gastrointestinal cancers are among the leading causes of cancer-related deaths in Japan, accounting for over 72 percent of cancer deaths in 2018, according to the World Health Organization. Through this collaboration, Foundation Medicine and Chugai will provide FoundationOne Liquid to academic centers participating in LC-SCRUM-Asia and MONSTAR-SCREEN.

In April 2018, Foundation Medicine received Breakthrough Device Designation from the U.S. Food and Drug Administration (U.S. FDA) on a forthcoming version of Foundation Medicines liquid biopsy test, which is currently under U.S. FDA review. Chugai and Foundation Medicine are preparing for the regulatory filing of this version of the test in Japan with the intention that the product will be approved for use under the National Health Insurance coverage in Japan. The parties intend that both LC-SCRUM-Asia and MONSTAR-SCREEN will transition from the existing FoundationOne Liquid test to the forthcoming version of Foundation Medicines liquid biopsy test following its anticipated approval by the U.S. FDA and subject to the terms of the agreement.

About SCRUM-Japan SCRUM-Japan is the largest cancer genomic screening consortium in Japan and aims to accelerate the development of innovative biomarker-driven precision medicine cancer therapies. Since its launch in 2015, more than 10,000 patients with advanced cancers have participated in SCRUM-Japan. The third stage of SCRUM-Japan started in June 2019, and includes two programs LC-SCRUM-Asia and MONSTAR-SCREEN. LC-SCRUM-Asia is investigating genomic changes with the aim of delivering precision medicine to lung cancer patients. More than 200 hospitals in Japan and Taiwan have joined the program and its scope area is expanding across Asia. MONSTAR-SCREEN is investigating genomic changes across all types of advanced solid tumors including gastrointestinal cancer. 28 hospitals have registered in Japan, and it aims for patients with various types of cancer to participate in the program.

About Foundation Medicine Foundation Medicine is a molecular information company dedicated to a transformation in cancer care in which treatment is informed by a deep understanding of the genomic changes that contribute to each patient's unique cancer. The company offers a full suite of comprehensive genomic profiling assays to identify the molecular alterations in a patients cancer and match them with relevant targeted therapies, immunotherapies and clinical trials. Foundation Medicines molecular information platform aims to improve day-to-day care for patients by serving the needs of clinicians, academic researchers and drug developers to help advance the science of molecular medicine in cancer. For more information, please visit http://www.FoundationMedicine.com or follow Foundation Medicine on Twitter (@FoundationATCG).

About Chugai Chugai Pharmaceutical is one of Japans leading research-based pharmaceutical companies with strengths in biotechnology products. Chugai, based in Tokyo, specializes in prescription pharmaceuticals and is listed on the 1st section of the Tokyo Stock Exchange. As an important member of the Roche Group, Chugai is actively involved in R&D activities in Japan and abroad. Specifically, Chugai is working to develop innovative products which may satisfy the unmet medical needs.Additional information is available at https://www.chugai-pharm.co.jp/english/.

Foundation Medicineand FoundationOne are registered trademarks of Foundation Medicine, Inc.

Source: Foundation Medicine

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A German research institute is offering scientists a 1,000 (847) bonus if they publish null results or a replication study as part of its bid to reshape academic incentives.

The unusual offer made to the Berlin Institute of Healths 7,000 researchers is part of a programme to boost research transparency and confidence in science amid international concerns that the pressure to produce positive experimental results that are more likely to be published by leading journals drives some scientists to manipulate data.

The institute, which combines the Charit Universittsmedizin Berlin university hospital and the Max Delbrck Center for Molecular Medicine, is also offering the 1,000 bonus if researchers publish a preregistered pre-clinical study or a paper that reuses data previously published by others.

There are also financial incentives available for scholars who publish their experiments raw data. Some might be disappointed to learn, however, that the money goes towards a scientists research funds rather than into their personal bank account.

Ulrich Dirnagl, director of Charits department of experimental neurology, told Times Higher Education that the bonuses which have been awarded over the past two years had sparked useful debate about research integrity.

You cannot do major research with 1,000, but it might help a student travel to a research conference, said Professor Dirnagl, who is the founding director of the Quest (Quality, Ethics, Open Science and Translation) Center for Transforming Biomedical Research.

It is mainly a way to start a conversation about the topic.

While scientists are invited to apply for the bonuses and normally get them, the institute has also recently been seeking out good practice to reward, Professor Dirnagl said.

We have been mining the publication records of our researchers, pulling out papers where open data has been provided and giving them the money, he said.

Such incentives helped to complement Germanys more traditional performance-oriented system, in which journal impact factors and the ability to attract third-party funding were prized by promotion and hiring panels, Professor Dirnagl explained.

Since we are not convinced this is the best way of doing things, we wanted to think how to complement this structure with rewards that are individually based, he said.

Those who accrue several bonuses could find they gain quite a nice supplement to their research funds, Professor Dirnagl added.

The Berlin institute has also applied the same principles to its promotion practices, with those applying for a professorial post having to outline how they have encouraged responsible science.

Applicants must describe their top five research papers without naming the publication in which they appeared, a move that seeks to combat over-reliance on journal reputation and to encourage engagement with the substance of the work.

We are trying to nudge the process to get them to consider different factors and ideas, said Professor Dirnagl. We are perhaps rewarding things that should be normal process, but it needs to be done.

We hope this programme can provide a model for widespread adoption by other research institutions globally.

The initiative is outlined in a paper published in Plos Biology on 11February.

jack.grove@timeshighereducation.com

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Scientists offered 1000 to publish null results - Times Higher Education (THE)

SALT LAKE CITY, Feb. 14, 2020 (GLOBE NEWSWIRE) -- Myriad Genetics, Inc. (MYGN), a leader in molecular diagnostics and precision medicine, announced that it is presenting new data at the American Society of Clinical Oncology Genitouranary Cancer Symposium in San Francisco, California. The key finding is that Prolaris accurately predicts which men with intermediate or high-risk prostate cancer will benefit from multi-modality therapy and which can avoid unnecessary treatment.

While it has been demonstrated that multi-modality therapy can improve overall survival in prostate cancer, it comes at the risk of increased morbidity and increased cost to the healthcare system, said Jonathan Tward M.D., PhD, associate professor in the Department of Radiation Oncology at the University of Utah. Prolaris provides a unique tool that can accurately predict which patients with high-risk prostate cancer will truly benefit from multi-modality therapy and conversely which patients with lower risk can safely avoid such treatments.

The investigators evaluated 718 men with intermediate or high-risk prostate cancer. The Prolaris score predicted metastasis (HR=3.75; p=1.6x10-16) and remained highly predictive after adjusting for the effect of standard clinical and pathological features (HR=4.30; p=4.4x10-8). In the study, patients above the high-risk threshold with a Prolaris score of greater than 2.112, which comprised approximately 44 percent of the men in the study, saw a statistically significant benefit from multi-modality therapy leading to a reduction in risk of metastases. Patients below the high-risk threshold saw no benefit from multi-modality therapy, suggesting that such patients may be able to avoid additional morbidity associated with additional treatment.

AboutProlarisProlaris is a genetic test developed by Myriad that directly measures tumor cell growth. The Prolaris test paired with both prostate-specific antigen (PSA) and Gleason provides the level of aggressiveness of a patients individual prostate cancer. PSA and Gleason only have the ability to identify how far the cancer has progressed thus far. However, when these are combined with a Prolaris test score, patients get an accurate assessment of how aggressively that cancer will progress over the next ten years. For more information visit:www.prolaris.com

About Myriad GeneticsMyriad Genetics Inc. is a leading precision medicine company dedicated to being a trusted advisor transforming patient lives worldwide with pioneering molecular diagnostics. Myriad discovers and commercializes molecular diagnostic tests that: determine the risk of developing disease, accurately diagnose disease, assess the risk of disease progression, and guide treatment decisions across six major medical specialties where molecular diagnostics can significantly improve patient care and lower healthcare costs. Myriad is focused on five critical success factors: building upon a solid hereditary cancer foundation, growing new product volume, expanding reimbursement coverage for new products, increasing RNA kit revenue internationally and improving profitability with Elevate 2020. For more information on how Myriad is making a difference, please visit the Company's website: http://www.myriad.com.

Myriad, the Myriad logo, BART, BRACAnalysis, Colaris, Colaris AP, myPath, myRisk, Myriad myRisk, myRisk Hereditary Cancer, myChoice, myPlan, BRACAnalysis CDx, Tumor BRACAnalysis CDx, myChoice CDx, EndoPredict, Vectra, GeneSight, riskScore, Prolaris, Foresight and Prequel are trademarks or registered trademarks of Myriad Genetics, Inc. or its wholly owned subsidiaries in the United States and foreign countries. MYGN-F, MYGN-G.

Lynparza is a registered trademark of AstraZeneca.

Safe Harbor StatementThis press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, including statements relating to the Company presenting new data at the American Society of Clinical Oncology Genitouranary Cancer Symposium in San Francisco, California; patients below the high-risk threshold being able to avoid additional morbidity associated with additional treatment; and the Companys strategic imperatives under the caption About Myriad Genetics. These forward-looking statements are managements present expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those described or implied in the forward-looking statements. These risks include, but are not limited to: the risk that sales and profit margins of the Companys existing molecular diagnostic tests and pharmaceutical and clinical services may decline or will not continue to increase at historical rates; risks related to the Companys ability to successfully transition from its existing product portfolio to its new tests; risks related to changes in the governmental or private insurers reimbursement levels for the Companys tests or the Companys ability to obtain reimbursement for its new tests at comparable levels to its existing tests; risks related to increased competition and the development of new competing tests and services; the risk that the Company may be unable to develop or achieve commercial success for additional molecular diagnostic tests and pharmaceutical and clinical services in a timely manner, or at all; the risk that the Company may not successfully develop new markets for its molecular diagnostic tests and pharmaceutical and clinical services, including the Companys ability to successfully generate revenue outside the United States; the risk that licenses to the technology underlying the Companys molecular diagnostic tests and pharmaceutical and clinical services tests and any future tests are terminated or cannot be maintained on satisfactory terms; risks related to delays or other problems with operating the Companys laboratory testing facilities; risks related to public concern over the Companys genetic testing in general or the Companys tests in particular; risks related to regulatory requirements or enforcement in the United States and foreign countries and changes in the structure of the healthcare system or healthcare payment systems; risks related to the Companys ability to obtain new corporate collaborations or licenses and acquire new technologies or businesses on satisfactory terms, if at all; risks related to the Companys ability to successfully integrate and derive benefits from any technologies or businesses that it licenses or acquires; risks related to the Companys projections about the potential market opportunity for the Companys products; the risk that the Company or its licensors may be unable to protect or that third parties will infringe the proprietary technologies underlying the Companys tests; the risk of patent-infringement claims or challenges to the validity of the Companys patents; risks related to changes in intellectual property laws covering the Companys molecular diagnostic tests and pharmaceutical and clinical services and patents or enforcement in the United States and foreign countries, such as the Supreme Court decisions Mayo Collab. Servs. v. Prometheus Labs., Inc., 566 U.S. 66 (2012), Assn for Molecular Pathology v. Myriad Genetics, Inc., 569 U.S. 576 (2013), and Alice Corp. v. CLS Bank Intl, 573 U.S. 208 (2014); risks of new, changing and competitive technologies and regulations in the United States and internationally; the risk that the Company may be unable to comply with financial operating covenants under the Companys credit or lending agreements; the risk that the Company will be unable to pay, when due, amounts due under the Companys credit or lending agreements; and other factors discussed under the heading Risk Factors contained in Item 1A of the Companys most recent Annual Report on Form 10-K filed with the Securities and Exchange Commission, as well as any updates to those risk factors filed from time to time in the Companys Quarterly Reports on Form 10-Q or Current Reports on Form 8-K.

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New Study Demonstrates the Ability of Prolaris to Predict Which Men With Prostate Cancer Will Benefit from Multi-Modality Therapy - Yahoo Finance

Nanotechnology will transform our lifes, our economy, our future. The book of the Oxford professor of biological physics, Sonia Contera, Nano Comes To Life: How Nanotechnology Is Transforming Medicine and the Future of Biology (Amazon.com, Amazon.co.uk, Amazon.de, Amazon.fr), explains why and how.

Nanotechnologies allow scientists to visualize, interact with, manipulate and create matter at the nanometer scale. Nanotechnology can manipulate the building blocks of life and, therefore, life itself because proteins and DNA are nano-size.

According to Sonia Contera, health and longevity will be affected. Nanoscale machines can target individual cancer cells and deliver drugs more effectively. Nanoantibiotics can fight resistant bacteria and makes it possible to engineer tissues and organs for research, drug discovery and transplantation.

Nanotechnology directly links the macroscopic world of our perceptions with the nanoscopic world of individual biomolecules. To restore humans to perfect health, we would need to know how molecules work in a specific environment, why and how they malfunction in a desease and who to reach them, target them, deactivate or activate them. To cure, we need to go from the macroscopic size of the doctor to the nanometer scale of biomolecules. Sonia Conteras book tries to show how far we have come so far.

Nanotechnology has attracted physical scientists to biology. In the last decades of the 20th century, artificial nanomaterials and the tools of nanotechnology came into existence. Physcial scientists sought to know how and why biology first constructed itself using nano-size building blocks in the medium of (salty) water. The coupling of physics and chemistry give rise to biological function. Scientists focused on using nanotechnologys methods to learn the workings of proteins, DNA and other important nano-size biomolecules. They became biological physicists. Others, more practical, saw opportunities to design nanomaterials that could be used to address disease, improving on current pharmacological treatments; they became nanomedicine scientists.

Cross-disciplinary activity led to the development of tools specifically built for studying biological processes and their nano-actors in physiological conditions. Nano-bioscientists eroded the boundaries between materials sciences, physics, chemistry and biology.

The last decades saw the emergence of quantitative biology. Physicists try to create mathematical models of biological processes. They try to predict the behavior of specific biological processes in the computer (in silico), without experiments. This shall allow to progressively abandon the trial-and-error methods of the traditional biological, medical and pharmacological sciences which are slow, costly and often lead to inefficient new drugs.

Biological physics, the help of algorithms, the analysis of biological big data and AI will lead to increasingly (more) accurate and smart models of life. However, knowing the workings of the building blocks (of life) is not enough to predict the behaviour of the whole: at larger scales, biology exhibits behaviors that the smaller constituents do not exhibit, or that cannot be explained from the relationships between their molecular building blocks. Sonia Contera explains that this is because complexly organized matter presents collective phenomena arising from cooperative interactions between the building blocks (these properties emerge). Examples are cellular movements, mechanical vibrations in the brain, electrical signaling across the membranes of cells, changes in the shape or stiffness, none of which can be predicted from just knowing the molecules that constitute a particular structure. For instance, nanotechnology would allow simultanously targeting the molecular, the cellular and the issue-level biology of a tumor.

Biology, mathematics, physics and engineering sciences used in nanotechnology will radically change, the way we find, interpret and treat disease. Nanotechnology will transform biology and medicine. Sonia Contera explores the complexity of biology, the birth of DNA technology, DNA nanorobotics, nanomedicine, recreating tissues and organs, addresses issues such as fear of technology, technology and equality. These are just a few take-aways from this substantial book written for non-specialists.

The author writes that we as human beings have no other choice than to mature to become part of the whole in a physical, economic and social sense. We have to advance into the construction of a new relationship with nature that allows our survival.

Sonia Contera: Nano Comes To Life: How Nanotechnology Is Transforming Medicine and the Future of Biology. Hardcover, Princeton University Press, November 2019, 216 pages. Order the book, the source for this article, from Amazon.com, Amazon.co.uk, Amazon.de, Amazon.fr.

For a better reading, quotations and partial quotations in this book review are not put between quotation marks.

Book review added on February 14, 2020 at 16:14 German time.

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How nanotechnology is transforming medicine and the future of biology - Cosmopolis

ROCKVILLE, Md., Feb. 13, 2020 /PRNewswire/ --National Foundation for Cancer Research (NFCR) (NFCR) announced today that Susan Band Horwitz, Ph.D., has been selected to receive the 2020 Szent-Gyrgyi Prize for Progress in Cancer Research. The Prize selection committee awarded Dr. Horwitz for pioneering the understanding, at the molecular level, of the mechanisms of action and resistance of multiple effective and widely utilized anti-tumor drugs, particularly Taxol, of natural product origin.

A Distinguished Professor and Rose C. Falkenstein Chair in Cancer Research at the Albert Einstein College of Medicine in New York, Dr. Horwitz most notably elucidated the mechanism of action of Taxol, a natural product obtained from the yew tree. Specifically, in the late 1970s and early 1980s, she discovered that the compound, whose generic name is paclitaxel, binds to microtubules in cells, stabilizing them, thereby leading to cell cycle arrest and subsequent cell death. This body of work enabled the successful translation of the drug into the clinic, and it is now one of the most frequently prescribed medications in the world for the treatment of ovarian, breast and lung cancers.

Her work with Taxol, which became a blockbuster drug, led to an interest in microtubule stabilizing agents, which has resulted in the U.S. Food and Drug Administration's approval of docetaxel (Taxotere), ixabepilone (Ixempra), carbazitaxal (Jevtana) and new formulations, including, most notably, nabpaclitaxel (Abraxane). Additionally, she has made major contributions to the understanding of many other naturally occurring molecules or their derivatives which serve as cancer treatments. These include camptothecin, bleomycin and the epipdophyllotoxins.

Funded continuously by NFCR for the past two decades, Dr. Horwitz's work now includes research into which isoforms of tubulin may have a role in resistance to Taxol, as well as efforts that may help predict which patients would be more likely to respond well to the drug.

The 2020 Szent-GyrgyiPrize's independent selection committee was unanimous in its decision to recognize Dr. Horwitz's contributions. She will be honored at an award ceremony held Saturday, April 25, at the National Press Club in Washington, D.C. Media are invited and encouraged to attend.

"Dr. Horwitz has made several seminal contributions, including the major finding of the mechanism of action of a drug that has been deployed in the treatment of over a million cancer patients," exclaimed Steven A. Rosenberg, M.D., Ph.D., chair of the 2020 Prize selection committee, surgery branch chief of the U.S. National Cancer Institute and winner of the 2019 Szent-Gyrgyi Prize. "She has profoundly impacted and improved the treatment of cancer patients."

"Matching the key criteria for this prestigious prizeher seminal and extensive scientific achievements and lasting impact in saving patients' livesplaces Dr. Horwitz in the uppermost tier of cancer researchers," said Sujuan Ba, Ph.D., co-chair of the 2020 Prize selection committee and president and CEO of NFCR. "We are so proud that Dr. Horwitz becomes the third National Foundation for Cancer Research supported scientist to be awarded the Szent-Gyrgyi Prize, after Dr. Web Cavenee in 2007 and Dr. Harold Dvorak in 2006."

"I am deeply honored by this award from the National Foundation for Cancer Research and the Szent-Gyrgyi Prize selection committee," stated Dr. Horwitz. "It is a real privilege to be among the winners of this prize, all of whom have greatly advanced cancer research and treatment. And this award is also a testament to all the students, fellows and visiting scientists who contributed to the research conducted in my lab over the years."

About the Szent-Gyrgyi Prize for Progress in Cancer ResearchThe Szent-Gyrgyi Prize for Progress in Cancer Research was established in 2006 by the National Foundation for Cancer Research in honor of its co-founder, Albert Szent-Gyrgyi, M.D., Ph.D., recipient of the 1937 Nobel Prize for Physiology and Medicine. The award recognizes and honors scientists who have made seminal discoveries or produced pioneering bodies of work that have resulted in, or led toward significant contributions to, cancer prevention, diagnosis and treatment with a high impact of saving people's lives. Its past recipients (and their associated institutions at the time of the award) are:

The 2020 Szent-Gyrgyi Prize's selection committee was comprised of the following persons, each an authority in the field of cancer research:

About the National Foundation for Cancer ResearchThe National Foundation for Cancer Research (NFCR) is a 501(c)(3) non-profit organization that provides scientists in the lab the funding they need to make and apply game-changing discoveries in cancer treatments, detection, prevention and, ultimately, a cure. It has distinguished itself in the cancer sector by emphasizing long-term, transformative research often overlooked by other major funding sources. With the help of more than 5.3 million individual donors over the last 47 years, NFCR has delivered more than $380 million in funding to public education and cancer research leading to several important, life-saving discoveries. For more information, visit http://www.nfcr.org.

CONTACT:National Foundation for Cancer ResearchBradley Gillenwater, Senior Director for Global Program DevelopmentE-mail: bgillenwater@nfcr.org / Phone: 301-961-9161

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2020 Szent-Gyrgyi Prize Awarded to a Pioneering Researcher Who Has Unlocked Workings of Cancer Drugs of Natural Product Origin - BioSpace

In August of 2011, Carl June and his team published a landmark paper showing their CART treatment had cleared a patient of cancer. A year-to-the-month later, Jennifer Doudna made an even bigger splash when she published the first major CRISPR paper, setting off a decade of intense research and sometimes even more intense public debate over the ethics of what the gene-editing tool could do.

Last week, June, whose CART work was eventually developed by Novartis into Kymriah, published in Sciencethe first US paper showing how the two could be brought together. It was not only one of the first time scientists have combined the groundbreaking tools, but the first peer-reviewed American paper showing how CRISPR could be used in patients.

June used CRISPR to edit the cells of three patients with advanced blood cancer, deleting the traditional T cell receptor and then erasing the PD1 gene, a move designed to unleash the immune cells. The therapy didnt cure the patients, but the cells remained in the body for a median of 9 months, a major hurdle for the therapy.

Endpoints caught up with June about the long road both he and the field took to get here, if the treatment will ever scale up, and where CRISPR and other advancements can lead it.

The interview has been condensed and edited.

Youve spoken in the past about howyou started working in this field in the mid-90s after your wife passed away from cancer. What were some of those early efforts? How did you start?

Well, I graduated from high school and had a low draft number [for the Vietnam War] and was going to go to study engineering at Stanford, but I was drafted and went into the Naval Academy in 1971, and I did that so I wouldnt have to go to the rice fields.

The war ended in 73, 74, so when I graduated in 1975, I was allowed to go to medical school, and then I had a long term commitment to the Navy because they paid for the Acadamy and Medical school. And I was interested in research and at the time, what the Navy cared about was a small scale nuclear disaster like in a submarine, and like what happened at Chernobyl and Fukushima. So they sent me to the Fred Hutchinson Cancer Center where I got trained in cancer, as a medical oncologist. I was going to open a bone marrow transplant center in Bethesda because the Navy wanted one in the event of a nuclear catastrophe.

And then in 1989, the Berlin Wall came down and there was no more Cold War. I had gone back to the Navy in 86 for the transplant center, which never happened, so then I had to work in the lab full time. But in the Navy, all the research has to be about combat and casualty. They care about HIV, so my first papers were on malaria and infectious disease. And the first CAR-T trials were on HIV in the mid-90s.

In 96, my wife got diagnosed with ovarian cancer and she was in remission for 3-4 years. I moved to the University of Pennsylvania in 1999 and started working on cancer because I wasnt allowed to do that with the Navy. My wife was obviously a lot of motivation to do that. She passed away in 2001. Then I started working with David Porter on adoptive transfer T cells.

I got my first grant to do CAR-T cells on HIV in 2004, and I learned a whole lot. I was lucky to have worked on HIV because we did the first trials using lentiviruses, which is an engineered HIV virus.

I was trained in oncology, and then because of the Navy forced to work on HIV. It was actually a blessing in disguise.

So if you hadnt been drafted, you wouldve become an engineer?

Yes. Thats what I was fully intending. My dad was a chemical engineer, my brother is an engineer. Thats what I thought I was going to do. No one in my family was ever a physician. Its one of those many quirks of fate.

Back then, we didnt have these aptitude tests. It was just haphazard. I applied to three schools Berkeley, Stanford and Caltech and I got into all three. It was just luck, fate.

And it turned out when I went to the Naval Academy, they had added a pre-med thing onto the curriculum the year before, so thats what I did when I started, I did chemistry.

I wouldve [otherwise] been in nuclear submarines. The most interesting thing in the Navy then was the nuclear sub technology.

You talked about doing the first CAR-T trials on HIV patients because thats where the funding was. Was it always in your head that this was eventually going to be something for cancer?

So I got out of the Navy in 99 and moved to Penn. I started in 98 working on treating leukemia, and then once I got to Penn, I continued working one day a week on HIV.

Its kind of a Back-to-the-Future thing because now cancer has paved out a path to show that CART cells can work and put down the manufacturing and its going to be a lot cheaper making it for HIV. I still think thats going to happen.

Jim Riley, who used to be a postdoc in my lab, has some spectacular results in monkeys with HIV models. They have a large NIH and NIAID research program.

So were going to see more and more of that. The CAR technology is going to move outside of cancer, and into autoimmune and chronic infections.

I want to jump over to cytotoxic release syndrome (CRS)because a big part of the CRISPR study was that it didnt provoke this potentially deadly adverse effect. When did you first become aware that CRS was going to be a problem?

I mean we saw it in the very first patient we treated but in all honesty, we missed it. Im an MD, but I dont see the patient and David Porter tookcare of the first three patients and our first pediatric patient,Emily Whitehead.

In our first patients, 2 out of 3, had complete remission and there were fevers and it was CRS but we thought it was just an infection, and we treated with antibiotics for 3 weeks and[eventually] it went away. And sort of miraculously he was in remission and is still in remission, 9 years later.

And then when we treated Emily. She was at a 106-degree fever over three days, and there was no infection.

Ive told this story before. My daughter has rheumatoid arthritis, and I had been president of the Clinical Immunologists Society from 2009 to 2010, and the first good drug for juvenile rheumatoid arthritisthat came out. I was invited to give the Japanese scientist Tadamitsu Kishimoto the presidential award for inventing the drug.

Then in 2012, Emily Whitehead was literally dying from CRS, she had multiple organ failures. And her labs came back and IL-6 levels were 1000x normal. It turns out the drug I was looking at for my daughter, it blocks IL-6 levels. I called the physician and I said, listen theres something actionable here, since its in your formulary to give it to her off-label.

And she gave her the appropriate dose for rheumatoid arthritis. It was miraculous. She woke up very rapidly.

Now its co-labeled. When the FDA approvedKymriah, it was co-labeled. It kind of saved the field.

How were you feeling during this time? Did you have any idea what was happening to her?

No, not until we got the cytokine levels, and then it was really clear. The cytokine levels go up and it exactly coincided. Then we retroactively checked out adults and they had adverse reactions and it easy to see. We hadnt been on the lookout because it wasnt in our mouse models.

And it appeared with those who got cured. Its one of the first on-target toxicities seen in cancer, a toxicity that happens when you get better. All the toxicities from chemotherapy are off-target: like leukopenia or hair loss.

I had a physician who had a fever of 106, I saw him on a fever when he was starting to get CRS. When the nurse came in and it said 106, they thought the thermometer must be broken. On Monday, I saw him, and said how are you feeling and he said fine. And I looked at the thermometer and histemperature was still 102.

People will willingly tolerate on-target toxicity thats very different from chemotherapy if they know it helps get them better. Thats a new principle in cancer therapy.

You had these early CART results almost at the same time that Doudna publishes the first CRISPR papers, then still in bacteria. When did you first start thinking about combining the two?

Yeah, it was published inSciencein 2012 and thats when Emily Whitehead got treated. Its an amazing thing.

Thats something so orthogonal. You think how in the heck can that ever benefit CART cells? but my lab had done the first edited cells in patients, published in 2012. And we used zinc-fingered nucleases, which were the predecessors to CRISPR. It knocked out one gene at a time, but we showed it was safe.

I was already into gene editing because it could make T cells resistant to HIV. So it was pretty obvious that there were candidates in T cells that you can knock out. And almost every lab started working on some with CRISPR, cause it was much easier.

We were the first to get full approval by the FDA, so we worked on it from 2012, had all the preclinical data by 2016, and then it takes a while to develop a lot of new assays for this as we were very cautious to optimize safety and it took longer than we wanted, but in the end, we learned a tremendous amount.

So what did we learn?

First of all our patients had advanced metastatic cancer and had had a lot of chemotherapy. The first patient had had 3 bone marrow transplants.

One thing is feasibility: could you really do all the complex engineering? So we found out we could. feasibility was passed.

Another was the fact that cas9 came out of bacteria, forms of strep and staph. Everyone has pre-existing immunity to Cas9 and we had experience from the first trial with Sangamo[with zinc-finger nucleases] where some patients had a very high fever. In that case, we had used adenoviruses, and it turned out our patients had very high levels of baseline immune response to adenoviruses, so we were worried that would happen with CRISPR, and it did not happen.

It did not have any toxicity. If it had, it would have really set the field back. If there was animmune response to cas9 and CRISPR, there couldve been a real barrier to the field.

And then, the cells survived in the patients. The furthest on, it was 9 months. The cells had a very high level of survival. In the previous trials, the cells survived less than 7 days. In our case, the half-life was 85 days. We dont know the mechanism yet.

And we found very big precision in the molecular scissors, and that was a good thing for the field. You could cut 3 different genes on 3 different chromosomes and have such high fidelity.

It [CRISPR] is living up to the hype. Its going to fix all these diseases.

Whats the potential in CAR-T, specifically?

Well theres many many genes that you can add. There are many genes that knocking outwill make the cells work better. We started with the cell receptor. There are many, I think, academics and biotechs doing this now and it should make the cells more potent and less toxic.

And more broadly, what else are you looking at for the future of CART? The week before your paper, there were the results from MD Anderson on natural killer cells.

Different cell types, natural killer cells, stem cells putting CAR molecules into stem cells, macrophages. One of my graduate students started a company to do CAR macrophages and macrophages actually eat tumor cells, as opposed to T cells that punch holes in them.

There will be different cell types and there will be many more ways to edit cells. The prime editing and base editing. All different new variations.

Youve talked about how people used to think the immuno-oncology, if it ever worked, would nevertheless be a boutique treatment. Despite all the advancements, Novartis and Gilead still have not met the sales they once hoped to grab from their CART treatments. Are you confident CART will ever be widely accessible?

Oh yeah, Novartis sales are going up. They had a hiccup launching.

Back in 96 or 97, when Genentech launched Herceptin, their commercial antibody, they couldnt meet the demand either and then they scaled up and learned how to do better cultures. So right now Novartis is using tech invented in my lab in the 1990s culture tech thats complex and requires a lot of labor, so the most expensive part is human labor. A lot can be made robotic. The scale problem will be much easier.

Thats an engineering problem that will become a thing of the past. The manufacturing problem will get a lot cheaper. Here in the US, we have a huge problem with how drugs are priced. We have a problem with pricing. Thats a political issue.

But in cell therapy, its just kind of the growth things you see in a new industry. Itll get worked out.

This article has been updated to reflect that Jim Riley conducted work on CAR in HIV.

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Carl June on CRISPR, CART and how the Vietnam War dropped him into medicine - Endpoints News