Posts Tagged ‘health’

Fluorsecence microscopy image of human epithelial cells form the colon and infected with the novel coronovirus shows production of filopodia (white) extending our from the cell surface and containing viral particlea.

Most of us have already absorbed the idea that the coronavirus does some weird and sinister things to the human body that are unlike most other respiratory viruses known to man. But now a new study finds yet another unsettling thing that the virus appears to do to help spread from cell to cell.

A new study by an international team led by UC San Francisco finds that cells infected with SARS-CoV-2 quickly begin to grow new arms or dendrites — referred to clinically as filopodia — which are themselves studded with fresh virus particles. These filopodia then seek to reach into and through the walls of neighboring cells, thereby infecting them. And this appears to be a second mode that the virus has for replicating and spreading itself in the body.

As the LA Times reports via the study, up until now, researchers believed that this virus spread itself like most other viruses, by docking itself onto healthy cells, invading, and then turning those cells into copying machines. A team in UCSF’s Quantitative Biosciences Institute led by systems biologist Nevan Krogan launched a project in February to rapidly identify existing drugs and compounds that might treat or slow the spread of the coronavirus. They published initial findings in late April pointing to 10 existing drugs and experimental compounds that showed promise in lab settings when it came to targeting the human proteins this virus most needs to survive.

The latest study is an extension of that work, and Krogan is one of the lead authors of the paper published today in the journal Nature. The important new finding, Krogan and the team hope, will lead to some rapid study of several existing cancer treatments that themselves inhibit the growth of filopedia — thereby shutting down this second means that the virus is using to invade cells.

“It’s just so sinister that the virus uses other mechanisms to infect other cells before it kills the cell,” Krogan says, speaking to the LA Times.

Krogan says that while other viruses — including HIV and the family of viruses that cause smallpox — also use filopedia as mechanisms of spreading infection, the way this virus so rapidly prompts the growth of these tentacles is highly unusual. And the shape of them, branching off the cell and each other like trees, is also apparently strange. Other infectious diseases like HIV don’t cause these kinds of prolific, mutant growths.

Expanding the earlier list of promising drugs, the latest study points to seven cancer drugs already in use that could prove effective against COVID-19. Those include a drug already being used to treat acute myeloid leukemia called Xospata (generic name: gilteritinib); the experimental drug Silmitasertib, which is being studied as a treatment for bile duct cancer and one form of childhood brain cancer; and ralimetinib, another cancer drug which was developed by Eli Lilly to treat multiple forms of cancer.

“We’ve tested a number of these kinase inhibitors and some are better than remdesivir,” Krogan says, via the Milwaukee Journal-Sentinel.

Another experimental drug called Dinaciclib was found by the research team to stop the virus’s assault on a family of kinases called CDKs, which are responsible for cell growth and dealing with DNA damage.

Other infectious disease researchers are just waking up to the revelations of the paper, but most reactions seem fairly excited. While much research is being done on shutting down virus proteins, Krogan’s field of study, called proteomics, instead focuses on the less-likely-to-mutate human proteins involved in helping the virus do its dirty work.

“This paper shows just how completely the virus is able to rewire all of the signals going on inside the cell,” says University of Wisconsin-Madison medical professor Andrew Mehle to the Journal-Sentinel. “That’s really remarkable and it’s something that occurs very rapidly (as soon as two hours after cells are infected).”

And Lynne Cassimeris, a professor of biological sciences at Lehigh University, calls the latest findings “an amazing leap.” “We know that the virus has to be manipulating these human proteins,” Cassimeris says. “Now we have a list of what is changing over time.”

While Krogan’s lab at UCSF got this research off the ground just as the pandemic was emerging in February, there were 70 authors listed on the latest paper, with Krogan as the lead. The work was also done by scientists at Mt. Sinai Hospital in New York, Rocky Mountain Labs in Montana, the Pasteur Institute in Paris, and the University of Freiburg in Germany

https://sfist.com/2020/06/26/ucsf-researchers-discover-how-coronavirus-makes-zombies-of-human-cells-causes-them-to-sprout/

Thanks to Kebmodee for bringing this to the It’s Interesting community.

By Ryan Prior

Every morning, Dr. David Fajgenbaum takes three life-saving pills. He wakes up his 21-month-old daughter Amelia to help feed her. He usually grabs some Greek yogurt to eat quickly before sitting down in his home office.

Then he spends most of the next 14 hours leading dozens of fellow researchers and volunteers in a systematic review of all the drugs that physicians and researchers have used so far to treat Covid-19. His team has already pored over more than 8,000 papers on how to treat coronavirus patients.

The 35-year-old associate professor at the University of Pennsylvania Perelman School of Medicine leads the school’s Center for Cytokine Storm Treatment & Laboratory. For the last few years, he has dedicated his life to studying Castleman disease, a rare condition that nearly claimed his life.

Against epic odds, he found a drug that saved his own life six years ago, by creating a collaborative method for organizing medical research that could be applicable to thousands of human diseases.

But after seeing how the same types of flares of immune-signaling cells, called cytokine storms, kill both Castleman and Covid-19 patients alike, his lab has devoted nearly all of its resources to aiding doctors fighting the pandemic.

During a cytokine storm, the body’s overactive immune response begins to attack its own cells rather than just the virus. When that inflammatory response occurs in Covid-19 patients, cytokines are often the culprit for the severe lung damage, organ failure, blood clots or pneumonia that kills them.

Having personal experience tamping down his own cytokine responses gives him a unique insight.
“I’m alive because of a repurposed drug,” he said.

Now, repurposing old drugs to fight similar symptoms caused by a novel virus has become a global imperative.


Researchers from Fajgenbaum’s lab gather in a video call to discuss Covid-19 treatment data.

A global repository for Covid-19 treatment data

Researchers working with his lab have reviewed published data on more than 150 drugs doctors around the world have to treat nearly 50,000 patients diagnosed with Covid-19. They’ve made their analysis public in a database called the Covid-19 Registry of Off-label & New Agents (or CORONA for short).

It’s a central repository of all available data in scientific journals on all the therapies used so far to curb the pandemic. This information can help doctors treat patients and tell researchers how to build clinical trials.

The team’s process resembles that of the coordination Fajgenbaum used as a medical student to discover that he could repurpose Sirolimus, an immunosuppressant drug approved for kidney transplant patients, to prevent his body from producing deadly flares of immune-signaling cells called cytokines.

The 13 members of Fajgenbaum’s lab recruited dozens of other scientific colleagues to join their coronavirus effort. And what this group is finding has ramifications for scientists globally.

Based on their database, the team published the first systematic review of Covid-19 treatments in the journal Infectious Diseases and Therapy in May.

In that first analysis of the data, the team reviewed 2,706 journal articles published on the topic between December 1, 2019, and March 27, 2020. Just 155 studies met the team’s criteria for being included in the meta-review based on standards such as the size of the cohort, the nature of the study and the end points researchers chose for concluding their inquiries.

“It’s frustrating because we all want a drug that works for everyone,” he said. But that isn’t happening because the coronavirus affects people in ways that are much more complex.

They’re sorting through oceans of data

The first key thing to consider, Fajgenbaum said, was the huge variety of Covid-19 patient experiences. It’s hard to zero in on one particular therapy because there can be such significant differences in the timing of when the drug is administered, how severely Covid-19 strikes a given individual and the stage at which the disease has progressed.

Any change in one of those variables can render an otherwise effective drug impotent. But with massive amounts of patients, the clinical data was bearing out a few noticeable themes, he said.

First, the Covid-19 patients with more severe cytokine storms were more likely to need drugs targeted toward suppressing the immune system. Those with less severe cytokine storms were likely to benefit from an immune-boosting drug.

Outside of drugs designed to boost or suppress the immune system, another major category is antiviral therapies. Various antivirals hit the “viral cascade,” Fajgenbaum said. Some work by stopping the virus from infecting cells, others by halting replication within cells. Other antivirals act in between cells and the virus.

Keeping the database is a huge undertaking, given how stunning the pace of global scientific progress and collaboration has been in the face of the disease’s human toll.

“We set the really ambitious goal of just getting this started,” Fajgenbaum said.

In the three months since the cutoff date for their first paper, the team has reviewed more than 5,000 additional papers published by scientists around the world.

One of their biggest challenges has been fitting the puzzle pieces of the different studies. With each study designed differently, one data set can’t necessarily be grafted neatly onto another. That’s especially tricky when most people diagnosed with Covid-19 eventually get better anyway. It’s hard to parse out if a particular drug was effective and saved lives.

The goal of the CORONA database isn’t to find a wonder drug per se, but to help design better clinical trials that can establish a real cause-and-effect relationship between a drug agent and an individual’s survival.

In the war against the coronavirus, Fajgenbaum hopes CORONA aims to help light the way so the heavy artillery on the front lines can better know what to shoot at Covid-19.

“It’s hard to fight a war if you’re not keeping track of what weapons are being used against the enemy,” he said.


Shown here is one of the researchers’ computer screens as they review Covid-19 treatment data while on a video call. The left side shows a spreadsheet where they tabulate data from the studies. The right side shows the study they’re currently analyzing.

They’re collaborating with FDA analysts

Fajgenbaum’s CORONA database dovetails with ongoing work at the US Food and Drug Administration. For years, the agency has been developing an app called CURE ID, a platform designed to help health care providers capture novel uses of already approved drugs.

The app launched in December with two goals in mind: The first was to help advise physicians searching for new treatment ideas, prescription guidelines and emergency use advisories for drugs across hundreds of diseases. The agency’s second aim was to build a structure by which health providers in the trenches could quickly input anonymized information about their patients so that other doctors around the world could quickly see whether they had been successful using an off-label drug.

The app was ready just in time for the pandemic, and Fajgenbaum gave the keynote speech at its launch.

“It’s really been a terrific collaboration,” said a health policy analyst with the FDA. “His life follows very much the model we hope to use.”

Now that he and his team are working on the coronavirus, the urgency of their partnership has strengthened.

“Nobody wants to go to a database with no data in it,” the analyst said. “Rather than reinventing the wheel, he was kind enough to provide all his data.”

And while the CORONA database project is primarily intended to aid researchers, it’s tapping into major currents in health economics that explain weak points in the way the public and private sector develop therapies together.

“Covid-19 illustrates a market failure in how we build vaccines,” said Amitabh Chandra, a health economist with joint appointments as a professor at the Harvard Kennedy School and Harvard Business School. “We haven’t given firms the correct incentives to make vaccines before a pandemic. Vaccines are very hard to test before the pandemic hits.”

There aren’t old vaccines sitting on a shelf waiting to be dusted off to save the world from the coronavirus. But there are hundreds of FDA-approved drugs at your local pharmacy that can save lives immediately.

When teaching classes, Chandra uses a 2017 New York Times story profiling Fajgenbaum to illustrate the value of drug repurposing and motivate his students to think boldly about how to create economic incentives to cure diseases, particularly when a “invisible medicine” might be right under your nose.

“There’s no substitute for a good story to get people motivated,” he said.
Many drugs are beginning to stand out.

The combination of antivirals lopinavir and ritonavir is the Covid-19 treatment protocol with the most number of studies published so far. As of mid-June, the team had looked at papers on that drug pairing involving more than 4,500 patients.

Next, corticosteroids have shown particular promise, making appearances in studies with another 4,000 patients. At the cellular level, antivirals work for a variety of reasons, each with its own specialty in attacking the virus at different points in its life cycle. Corticosteroids are different, however.

“Steroids tend to act the same, with replicating cortisol,” Fajgenbaum said.

He feels particularly elated about a recent United Kingdom-based study on the steroid dexamethasone. The study garnered headlines for its result showing that a low-dose 10-day regimen of the drug could reduce the risk of death by a third among hospitalized patients requiring ventilation.

In their spreadsheets, the numbers around dexamethasone were like a beacon.
“We built CORONA to help uncover something like dexamethasone,” he said. “It’s a cheap repurposed drug that’s been around for 60 years. This is what it’s all about.”

Studies need rigor

Because Covid-19 is so new, many of the studies are observational or anecdotal. These types of studies obviously matter as scientists are building a foundation of knowledge.

But the best insights come from running double-blind placebo-controlled studies. One shortfall is that many of the published studies just don’t have the level of rigor to inform larger-scale scientific decision-making.

“There are a lot of biases in these observational studies,” Fajgenbaum said.
One drug, the anti-malarial drug hydroxychloroquine, has famously received a lot of boosterism from US President Donald Trump. But in the published studies available for Fajgenbaum’s team to review, the drug hasn’t outperformed others.

Two French studies on hydroxychloroquine drew red flags for the University of Pennsylvania-based team because of the clinical end point the researchers chose: the time when the coronavirus cleared the body. It can be problematic to base an argument for a drug’s success only on that particular metric, because it leaves out crucial details from a person’s longer-term experience following infection.

“‘Virally cured’ is a challenging term,” Fajgenbaum said. “We don’t know if they’re discharged how they fared after leaving the hospital.”

On top of that, the reviewers were skeptical because the virus took a long time to leave the patients’ bodies, which they refer to as “a high time to viral clearance.”

That indicator that could suggest the drug was slow to take effect, or that other factors, including the patient’s own immune system, played a larger role in expelling the pathogen.

Know how to sort through the data

With dozens of people working full time to sort through thousands of studies, it’s obviously impossible for a single frontline health provider to keep abreast of all there is to know about Covid-19 while also treating patients at the same time.

It’s even harder for the average person following the story in the news, especially if you’re not equipped with a graduate degree in statistical analysis.

“Covid threw the world in flux,” said Sheila Pierson, associate director for clinical research at the CSTL. A biostatistician originally hired to study Castleman disease, she’s accepted the new mission along with her colleagues.

“There’s a lot of great science being done,” she explained. With that pace of innovation, it’s incredibly difficult for the average person to stay up to date, so the CORONA database helps everyone with a little extra scientific literacy amid headlines about new treatments that induce a form of intellectual whiplash.

“You should rely on multiple news sources,” Pierson said, in order to sort through what may appear to be conflated messages about whether a certain drug works or not for a certain group of people.

“It’s difficult when you’re only looking at one person’s view of a drug,” she said. “Look for a different write-up and a different view.”

He’s repeating the same methods that saved his life

As of June 27, Fajgenbaum has lived free of Castleman’s cytokine storms for 77.72 months. His last Castleman relapse ended on January 5, 2014. He’s a living experiment, and in his personal accounting he won’t round up to the next full month. Each new day is a precious moment with a daughter he feared he’d never meet.

The doctor and researcher remains immune compromised and won’t take risks with the coronavirus.
He hasn’t set foot in a building other than his home since March 13. And his life still relies on siltuximab and chemotherapy infusions administered monthly through a chest port.

“I’m reminded every time I touch the port in my chest of the cytokine storms I had,” he said. “I want so badly to solve (Covid-19) the way I did with Castleman. I have the same sense of urgency.”

Castleman disease nearly killed Fajgenbaum five times in his 20s while he was working his way through University of Pennsylvania’s Perelman School of Medicine and then earning an MBA at the University of Pennsylvania’s Wharton School.

Each time, the deadly disease triggered cytokine storms that led to multiple organ failure.

But the young man created a global organization to rally doctors, scientists and patients toward finding a cure. With intense study and brilliant partners, he zeroed in on an already available immunosupressant that could be repurposed to save his life.

Last year he published his memoir, “Chasing My Cure,” detailing a journey in which at one point a priest was brought to his hospital room to give his last rites.

Fajgenbaum’s story reads likes the teaser for a hit Netflix series. But if it were a show, all of that is really just season one. Because, spoiler alert — then a global pandemic hit.

A year ago you might have thought what the writers threw at him in a second season might be a bit unrealistic. But this project is the obvious next step.

“I see myself bringing our experiences with Castleman now over to the global fight against corona,” he said.

https://www.cnn.com/2020/06/27/health/coronavirus-treatment-fajgenbaum-drug-review-scn-wellness/index.html


Philip Britz-McKibbin, Professor of Chemistry & Chemical Biology, McMaster University Credit: JD Howell, McMaster University

A team of researchers at McMaster University has developed a reliable and accurate blood test to track individual fat intake, a tool that could guide public health policy on healthy eating.

Establishing reliable guidelines has been a significant challenge for nutritional epidemiologists until now, because they have to rely on study participants faithfully recording their own consumption, creating results that are prone to human error and selective reporting, particularly when in the case of high-fat diets.

For the study, published in the Journal of Lipid Research, chemists developed a test, which detects specific non-esterified fatty acids (NEFAs), a type of circulating free fatty acid that can be measured using a small volume of blood sample.

“Epidemiologists need better ways to reliably assess dietary intake when developing nutritional recommendations,” says Philip Britz-McKibbin, professor in the Department of Chemistry & Chemical Biology at McMaster University and lead author of the study.

“The food we consume is highly complex and difficult to measure when relying on self-reporting or memory recall, particularly in the case of dietary fats. There are thousands of chemicals that we are exposed to in foods, both processed and natural,” he says.

The study was a combination of two research projects Britz-McKibbin conducted with Sonia Anand in the Department of Medicine and Stuart Phillips in the Department of Kinesiology.

Researchers first assessed the habitual diet of pregnant women in their second trimester, an important development stage for the fetus. The women, some of whom were taking omega-3 fish oil supplements, were asked to report on their average consumption of oily fish and full-fat dairy and were then tested with the new technology. Their study also monitored changes in omega-3 NEFAs in women following high-dose omega-3 fish oil supplementation as compared to a placebo.

Researchers were able to prove that certain blood NEFAs closely matched the diets and/or supplements the women had reported, suggesting the dietary biomarkers may serve as an objective tool for assessment of fat intake.

“Fat intake is among the most controversial aspects of nutritional public health policies given previously flawed low-fat diet recommendations, and the growing popularity of low-carb/high-fat ketogenic based diets” says Britz-McKibbin. “If we can measure it reliably, we can begin to study such questions as: Should pregnant women take fish oil? Are women deficient in certain dietary fats? Does a certain diet or supplement lead to better health outcomes for their babies?”

Researchers plan to study what impact NEFAs and other metabolites associated with dietary exposures during pregnancy, might have on childhood health outcomes in relation to the obesity, metabolic syndrome and chronic disease risk later in life.

https://medicalxpress.com/news/2020-05-chemists-foolproof-track-fats.html


Branyas lives in Olot, a city in Catalonia.

By Jack Guy and Al Goodman

A 113-year-old woman, thought to be the oldest in Spain, has said she feels fine after surviving a brush with coronavirus.

Video footage of Maria Branyas, who was born on March 4 1907, shows the super-centenarian speaking to the director of the care home where she lives in Olot, Catalonia.

“In terms of my health I am fine, with the same minor annoyances that anyone can have,” said Branyas in the video. It was recorded Monday, a spokeswoman for the care home told CNN.

Branyas recovered after a mild case of Covid-19. Her battle started shortly after her family visited her on March 4 to celebrate her 113th birthday, the spokeswoman said.

The family has not been able to visit in person since then. Branyas has lived for 18 years in her own private room at the Santa Maria del Tura nursing home, which is run by the Institute of the Order of San Jose of Gerona, affiliated with the Roman Catholic Church, the spokeswoman said.

Branyas was born in San Francisco in the United States, where her father worked as a journalist, reports the AFP news agency.

Over the course of her long life she has survived two world wars as well as the 1918 flu pandemic, which killed more than 50 million people around the world.

Although Branyas recovered from coronavirus, two residents of the same home died of it. The situation at the care home has since improved, said the spokeswoman.

Spain’s state of emergency, in effect since March 14, has strict confinement measures that remain in place. But with the infection and death rates now declining, the government has lifted some lockdown measures in certain parts of the country, on what it says will be a gradual reopening of activity.

But the initial lifting of these restrictions did not apply to Olot, where Branyas lives.

https://www.cnn.com/2020/05/13/europe/spain-oldest-woman-coronavirus-survivor-scli-intl/index.html


Human cell types within corresponding organs that express the genes for both ACE2 and CTSL (green dot) or both ACE2 and TMPRSS2 (orange dot).

by Chris Baraniuk

When the SARS-CoV-2 virus enters the human body, it breaks into cells with the help of two proteins that it finds there, ACE2 and TMPRSS2. While there has been much discussion of viral infection in gut and lung cells, researchers have dug into massive gene expression datasets to show that other potential target cells also producing ACE2 and TMPRSS2 are scattered throughout the body—including in the heart, bladder, pancreas, kidney, and nose. There are even some in the eye and brain.

The results, published in a preprint on bioRxiv April 21, show that such cells are strikingly abundant. Many are epithelial cells, which line the outer surface of organs. The new findings add to an emerging picture of SARS-CoV-2 as a virus that can target cells in many places in the human body, rather than being focused on a particular organ or part of the respiratory tract.

Cardiologist Frank Ruschitzka at the University Hospital of Zürich and colleagues separately published a letter in The Lancet April 17 in which they described how virus particles had been found in the vascular endothelium, a thin layer of cells lining blood vessels in various organs of the body, for instance.

“This is not just a virus pneumonia,” Ruschitzka, who was not involved in the latest study, tells The Scientist, referring to COVID-19. “This is a disease like we have never seen before—it is not an influenza, it hits the vessels all over, it hits the heart as well.”

To uncover the locations of cells bearing ACE2 and TMPRSS2, the preprint researchers turned to the Human Cell Atlas, a project that has allowed scientists to pool together data on human cells since 2016.

By scouring single-cell sequencing records of around 1.2 million individual cells from human tissue samples, the team was able to find out which of those cells produce both ACE2 and TMPRSS2, and note their locations in the body. The analysis used 16 unpublished datasets of lung and airway cells and 91 published datasets spanning a range of human organs.

Coauthor Christoph Muus, a graduate student at Harvard University and the Broad Institute, explains that while the data show cells in many locations in the body produce SARS-CoV-2 receptors, it’s not certain that the virus can infect all of those tissues.

“Expressing the receptor is a necessary condition but not necessarily a sufficient condition,” he says. For example, potential target cells were found in the testes, but scientists still don’t know if SARS-CoV-2 infects and replicates in that part of the body.

Jeremy Kamil, a virologist at Louisiana State University Health Shreveport, says the preprint provides important details about the human body that may help scientists understand how SARS-CoV-2 infects hosts. By finding viral protein fragments in tissue samples from patients who died because of COVID-19, scientists might be able to firm up which organs are genuine sites of infection, he adds.

“I’d say this paper gives people a roadmap at where you might want to look in the body to understand where this virus is going,” he says.

One limitation of the work is that relatively little metadata about the people who donated tissue samples were available for the various datasets, though information about age and gender were included in many. The researchers don’t know, for example, whether there was an ethnicity bias in the data, whether patients had pre-existing conditions, or whether they were taking any medications. All of these things could affect gene expression in particular cells.

Smoking status was available for a subset of the data, and the team used this to show that smoking is correlated with a greater expression of the ACE2 gene in the upper airway, but lower expression in certain lung cells. Further research is needed to understand whether this affects smokers’ susceptibility to COVID-19. Data from China suggest that smokers are 14 times more likely to develop a severe form of the disease.

Some researchers from the same group using similar data have also recently published papers in Cell and Nature. In those cases, the researchers focused on certain groups of cells. The study reported in Nature examined cells potentially involved in viral transmission and found that nasal epithelial cells, in particular, were associated with expression of ACE2 and TMPRSS2. The authors report that the virus might exploit cells that secrete fluids in the nasal passage, which might help it spread from one person to another in droplets released, say, when someone sneezes.

The Cell study, meanwhile, also found ACE2 and TMPRSS2 transcripts in nasal, gut, and lung cells but the researchers also found that the protein interferon activated ACE2 expression in vitro. The human body uses interferon to fight infections, so it is not clear whether the protein is of overall benefit or detriment to COVID-19 patients.

The use of so many different data sources backs up the validity of the preprint authors’ findings, says Marta Gaglia, a molecular biologist at Tufts University. She agrees with the researchers that discovering ACE2- and TMPRSS2-producing cells in various places around the body does not prove the virus can always infect such cells.

“I think the reality is that most of the problems come from the lung,” she adds. Plus, while doctors treating COVID-19 patients may detect problems in multiple organs, those issues might not necessarily be caused directly by SARS-CoV-2 infection, says Gaglia. A problematic immune system response, for instance, could damage certain tissues in the body as an indirect consequence of viral infection.

https://www.the-scientist.com/news-opinion/receptors-for-sars-cov-2-present-in-wide-variety-of-human-cells-67496?utm_campaign=TS_DAILY%20NEWSLETTER_2020&utm_source=hs_email&utm_medium=email&utm_content=87213170&_hsenc=p2ANqtz-_vGzY0JSZbqON-CbrWnU2wp22vNPAa-zcPDPoSZR69MA0qXhi3ukYIXekJJKZ_A_GfMi8lV1cuO5y2DnnkhV-rdYFrPQ&_hsmi=87213170

A medical device based on technology developed by three faculty members from Case Western Reserve University and University Hospitals Cleveland Medical Center (UH) has won a prestigious 2020 Edison Best New Product Award.

EsoCheck, a device designed to help detect precancerous changes in the esophagus, was named a “Silver” winner of the 2020 Edison Best New Product Awards in the “Medical/Dental – Testing Solutions” subcategory.

Esophageal adenocarcinomas have increased more than five-fold in recent years and are a highly lethal cancer, with less than 20% 5-year survival. These cancers arise from a precursor lesion of Barrett’s esophagus (BE), which is an abnormal cell type that arises in the lower esophagus.

EsoCheck is a swallowable balloon-based device that, in a simple five-minute outpatient exam, can collect cells from the lower region of the esophagus to help determine if Barrett’s disease is present. Unlike endoscopy, the current method for examining the esophagus, EsoCheck does not require a patient to undergo sedation, lose a day of work or need a companion for transportation.

The EsoCheck device works together with EsoGuard, a companion molecular assay that tests the DNA from the cells retrieved by EsoCheck for the presence of genetic changes indicative of the presence or absence of Barrett’s disease.

Lucid Diagnostics, a subsidiary of New York-based PAVmed Inc., licensed the EsoCheck and EsoGuard technology through the Case Western Reserve University Technology Transfer Office in 2018.

The EsoCheck device and EsoGuard DNA test were co-invented by Amitabh Chak, MD, (Professor of Medicine at the Case Western Reserve School of Medicine and gastroenterologist at the University Hospitals Digestive Health Institute); Sanford Markowitz, MD, PhD, (Ingalls Professor of Cancer Genetics and Medicine at the School of Medicine and an oncologist at University Hospitals Seidman Cancer Center); and Joseph Willis, MD,(Professor of Pathology at the School of Medicine and Pathology Vice-Chair for translational research at UH).

The technology was developed as part of the Case Comprehensive Cancer Center’s GI SPORE (Gastrointestinal Specialized Program of Research Excellence) and BETRNet (Barrett’s Esophagus Translational Research Network) programs led by Markowitz and Chak, and was first tested in humans in a clinical trial led by Chak at University Hospitals.

Further support for the clinical assay development was derived from a National Cancer Institute award led by Willis. The development was also supported by the Case-Coulter partnership and the State of Ohio Third Frontier Technology Validation Start-up Fund.

Last fall, the new EsoCheck method for examining the esophagus received clearance from the U.S. Food and Drug Administration for clinical use, and, this February, the companion EsoGuard DNA test for Barrett’s detection received breakthrough designation from the FDA.

Since 1987, the Edison Awards, named after Thomas Alva Edison, have recognized some of the most innovative products and business leaders in the world. They’re among the most prestigious accolades, honoring excellence in new product and service development, marketing, design and innovation.

About University Hospitals / Cleveland, Ohio

Founded in 1866, University Hospitals serves the needs of patients through an integrated network of 18 hospitals, more than 50 health centers and outpatient facilities, and 200 physician offices in 16 counties throughout northern Ohio. The system’s flagship academic medical center, University Hospitals Cleveland Medical Center, located in Cleveland’s University Circle, is affiliated with Case Western Reserve University School of Medicine. The main campus also includes University Hospitals Rainbow Babies & Children’s Hospital, ranked among the top children’s hospitals in the nation; University Hospitals MacDonald Women’s Hospital, Ohio’s only hospital for women; University Hospitals Harrington Heart & Vascular Institute, a high-volume national referral center for complex cardiovascular procedures; and University Hospitals Seidman Cancer Center, part of the NCI-designated Case Comprehensive Cancer Center. UH is home to some of the most prestigious clinical and research programs in the nation, including cancer, pediatrics, women’s health, orthopedics, radiology, neuroscience, cardiology and cardiovascular surgery, digestive health, transplantation and urology. UH Cleveland Medical Center is perennially among the highest performers in national ranking surveys, including “America’s Best Hospitals” from U.S. News & World Report. UH is also home to Harrington Discovery Institute at University Hospitals – part of The Harrington Project for Discovery & Development. UH is one of the largest employers in Northeast Ohio with 28,000 physicians and employees. Advancing the Science of Health and the Art of Compassion is UH’s vision for benefitting its patients into the future, and the organization’s unwavering mission is To Heal. To Teach. To Discover. Follow UH on LinkedIn, Facebook @UniversityHospitals and Twitter @UHhospitals. For more information, visit UHhospitals.org.

https://finance.yahoo.com/news/medical-device-developed-cwru-uh-123000489.html

by Rose Reeb

Increased weekly working hours are associated with a higher risk for hypothyroidism in workers with no evidence of thyroid autoimmunity, according to study results published in Thyroid.

To determine if long work hours are associated with thyroid function, researchers conducted a cross-sectional study using data from 2160 South Korean adults (69.9% men). Individuals who had provided blood and urine samples, were working ≥36 hours per week and <12 hours per day, were not pregnant, did not have a history of thyroid disease, did not have a positive thyroid peroxidase antibody test, did not have isolated hypothyroidism or hyperthyroidism, and were not missing relevant data were included.

Hypothyroidism was defined as a serum thyrotropin level above the upper reference limit with a normal or low free thyroxine level. Hyperthyroidism was defined as a serum thyrotropin level below the lower reference limit with a normal or high free thyroxine level.

The median age of the included individuals was 42.4 years (interquartile range, 33.0- 52.1). The median weekly number of work hours was 47.1 (interquartile range, 39.8-54.9) and 15.4% of included individuals were shift workers. Overall, hypothyroidism was observed in 2.1% and hyperthyroidism was observed in 2.9% of the cohort.

Rates of both hypothyroidism (3.6%) and hyperthyroidism (3.5%) were highest in the group with the highest work hours (P =.03 for trend). The mean number of work hours per week in euthyroid, hypothyroid, and hyperthyroid individuals were 49.5±0.3, 53.4±1.5, and 51.6±1.6 hours, respectively (P =.012). There was a significant association between hypothyroidism and longer work hours per week, even after adjusting for all biological and lifestyle covariates (adjusted odds ratio [aOR], 1.46; 95% CI, 1.12-1.90) and excluding outliers in number of work hours per week (aOR, 1.99; 95% CI, 1.19-3.31) and individuals with overt thyroid dysfunction (aOR, 1.44; 95% CI, 1.11-1.88). Hyperthyroidism was not significantly associated with the number of hours worked per week.

Moreover, hypothyroidism was approximately 2.6 times more prevalent in individuals who worked 53 to 83 hours per week compared with those who worked 36 to 42 hours per week.

As the study was cross-sectional and observational in nature, causation could not be determined. The researchers suggested that “[f]urther research is needed to clarify the causal relationship and the underlying mechanism” of hypothyroidism in connection to longer working hours.

Reference

Lee YK, Lee D-E, Hwangbo Y, Lee YJ, Kim HC, Lee EK. Long work hours are associated with hypothyroidism: a cross-sectional study with population-representative data [published online March 31, 2020]. Thyroid. doi:10.1089/thy.2019.0709


OUTRUNNING CANCER: Tumors on the lungs of sedentary mice (left) and animals that ran on wheels (right) after injection with melanoma cells.
L. PEDERSEN ET AL., CELL METAB, 2016

Bente Klarlund Pedersen

Mathilde was diagnosed with breast cancer at the age of 44. Doctors treated her with surgery, chemotherapy, and radiation, and Mathilde’s physician informed her that, among many other side effects of her cancer treatment, she could expect to lose muscle mass. To fight muscle wasting, Mathilde began the intensive physical training program offered to cancer patients at the Rigshospitalet University Hospital of Copenhagen. The program consists of 3.5-hour sessions of combined resistance and aerobic training, four times a week for six weeks. Although the chemotherapy made her tired, Mathilde (a friend of mine, not pictured, who requested I use her first name only) did not miss a single training session.

“In a way it felt counterintuitive to do intensive, hard training, while I was tired and nauseous, but I was convinced that the training was good for my physical and mental health and general wellbeing,” Mathilde told me in Danish. She followed the chemo- and radiotherapy strictly according to the prescribed schedule. She was not hospitalized, acquired no infections, and did not develop lymphedema, a failure of the lymphatic system that commonly occurs following breast cancer surgery and leads to swelling of the limbs.

Physical exercise is increasingly being integrated into the care of cancer patients such as Mathilde, and for good reason. Evidence is accumulating that exercise improves the wellbeing of these patients by combating the physical and mental deterioration that often occur during anticancer treatments. Most remarkably, we are beginning to understand that exercise can directly or indirectly fight the cancer itself.

An increasing amount of epidemiological literature strongly indicates that exercise training may lower the risk of cancer, control disease progression, amplify the effects of anticancer therapy, and improve physical function and psychosocial outcomes. For example, a 2016 study of more than 1.4 million individuals in the US and Europe found that people could reduce their cancer risk with moderate to vigorous leisure-time exercise training. The phenomenon held across several different cancers, including breast, colon, rectum, esophagus, lung, liver, kidney, bladder, and head and neck. And the combined results of approximately 700 unique exercise intervention trials, involving more than 50,000 cancer patients in total, leave little doubt that patients benefit from physical activity, showing improvements such as reduced toxicity of anticancer treatment, decreased disease progression, and enhanced survival. The same studies showed that exercise training improves mood, decreases loss of muscle mass, and helps cancer patients return to work earlier after successful treatment. Some studies show that 150 minutes per week of moderate exercise nearly double the chance of survival compared with breast cancer patients who don’t exercise during treatment.

Hundreds of animal studies, conducted over decades, suggest that the link is likely causal: in mice and rats, exercise leads to a reduction in the incidence, growth rate, and metastatic potential of cancer across a large variety of models of different human and murine tumor types. But how exercise helps fight cancer is a bit of a black box. Exercise may improve the efficacy of anticancer treatment by boosting the immune system and thereby attenuating the toxicity of chemotherapy and immunotherapy. Cancer patients are also likely to benefit from the overall health-promoting properties of physical activity, such as improved metabolism and enhanced cardiovascular function.

Uncovering the mechanisms whereby exercise induces anticancer effects is crucial to fighting the disease. Exercise-related factors that have a direct or indirect anticancer effect could serve as valuable biomarkers for monitoring the amount, intensity, and type of exercise required to best aid cancer treatment. Such research could also potentially highlight novel therapeutic targets.

Each workout matters

Regardless of the nature of the training, the primary setting of exercise’s effect on cancer is the bloodstream. Long-term training has been associated with a reduction in the blood levels of systemic risk factors, such as sex hormones, insulin, and inflammatory molecules. However, this effect is only seen if exercise training is accompanied by weight loss, and researchers have not yet established causal direct links between regular exercise training and the reductions in the basal levels of these risk factors. Alternatively, the anticancer effect of exercise could also be the result of something that occurs within individual sessions of exercise, during which muscles are known to release spikes of various hormones and other factors into the blood.

To learn more about the effects of individual bouts of exercise versus long-term training regimens, Christine Dethlefsen, a graduate student in my laboratory, incubated breast cancer cells with serum obtained from cancer survivors at rest before and after a six-month training intervention that began after patients completed primary surgery, chemotherapy, and radiotherapy. For comparison, she incubated other cells with serum obtained from blood drawn from these patients immediately after a two-hour acute exercise session during their weeks-long course of chemotherapy. Her study revealed that serum obtained following an exercise session reduced the viability of the cultured breast cancer cells, while serum drawn at rest following six months of training had no effect.

These data suggest that cancer-fighting effects are driven by repeated acute exercise, and each bout matters. In Dethlefsen’s study, incubation with serum obtained after a single bout of exercise (consisting of 30 minutes of warm-up, 60 minutes of resistance training, and a 30-minute high-intensity interval spinning session) reduced breast cancer cell viability by only 10 to 15 percent compared with control cells incubated with serum obtained at rest. But a reduction in tumor cell viability by 10 to 15 percent several times a week may add up to clinically significant inhibition of tumor growth. Indeed, in a separate study, my colleagues and I found that daily, voluntary wheel running in mice inhibits tumor progression across a range of tumor models and anatomical locations, typically by more than 50 percent.

Exercise’s molecular messengers

One prime candidate for helping to explain the link between exercise and anticancer effects is a group of peptides known as myokines, which are produced and released by muscle cells. Several myokines are released only during exercise, and some researchers have proposed that these exercise-dependent myokines contribute to the myriad beneficial effects of physical activity for all individuals, not just cancer patients, perhaps by mediating crosstalk between the muscles and other parts of the body, including the liver, bones, fat, and brain.

Exercise’s Anticancer Mechanisms

Researchers are beginning to understand that not only can exercise improve cancer patients’ overall wellbeing during treatment, but it may also fight the cancer itself. Experiments on cultured cells and in mice hint at some of the mechanisms that may be involved in these direct and indirect effects.

1) Exercising muscles release multiple compounds known as myokines. Several of these have been shown to affect cancer cell proliferation in culture, and some, including interleukin-6, slow tumor growth in mice.

2) Exercise stimulates an increase in levels of the stress hormones epinephrine and norepinephrine, which can both act directly on tumors and stimulate immune cells to enter the bloodstream.

3) Epinephrine also stimulates natural killer cells to enter circulation.

4) In mice, interleukin-6 appears to direct natural killer cells to home in on tumors.

5) In lab-grown cells and in mice, epinephrine, norepinephrine, and some myokines hinder tumor growth and metastasis.

The best-characterized myokine is interleukin-6, levels of which increase exponentially during exercise in humans. At least in mice, interleukin-6 is involved in directing natural killer (NK) cells to tumor sites. But there are approximately 20 known exercise-induced myokines, and the list continues to grow. Preliminary studies show that myokines can reduce cancer growth in cell culture and in mice. For example, when treated with irisin, a myokine best known for its ability to convert white fat into brown fat, cultured breast cancer cells were more likely to lose viability and undergo apoptosis than were control cells. A study I led found that oncostatin M, another myokine that is upregulated in murine muscles after exercise, also inhibits breast cancer proliferation in vitro. And a team led by Toshikazu Yoshikawa of Kyoto Prefectural University determined that in a mouse model of colon cancer, a myokine known as secreted protein acidic and rich in cysteine (SPARC) reduced tumorigenesis in the colon of exercising mice. Overall, skeletal muscle cells may be secreting several hundred myokine types, but of these, only about 5 percent have been investigated for their biological effects. And researchers have tested fewer for whether they regulate cancer cell growth.

Not all of the molecular messengers released in response to exercise come from the muscles. Notably, exercise induces acute increases in epinephrine and norepinephrine, stress hormones released from the adrenal gland that are involved in recruiting NK cells in humans. Murine studies show that NK cells can signal directly to cancer cells. In Dethlefsen’s study, when breast cancer cells incubated with serum obtained after a bout of exercise were then injected into mice, they showed reduced tumor formation. The exercise-induced suppression of breast cancer cell viability and tumor formation were, however, completely blunted when we blockaded β-adrenergic signaling, the pathway through which epinephrine and norepinephrine work. These findings suggested that epinephrine and norepinephrine are responsible for the cancer-inhibiting effects we observed. Epinephrine and norepinephrine, which activate NK cells, have also been shown to act on cancer cells through the Hippo signaling pathway, which is known for regulating cell proliferation and apoptosis. Exercise-induced spikes in these stress hormones activate this pathway, which somehow inhibits the formation of new malignant tumors associated with metastatic processes.

Calling the immune system

In addition to acting directly on tumors, the myokines released during and after exercise are known to mobilize immune cells, particularly NK cells, which appear to be instrumental to the exercise-mediated control of tumor growth in mice.

The late molecular biologist Pernille Højman of the Centre for Physical Activity Research at Rigshospitalet was a leader in discerning this mechanism. In the study described above that compared tumor growth in active and sedentary mice, on which I was also an author, Højman looked more closely at the tumors and found that the running mice had twice as many cytotoxic T cells and five times more NK cells than those animals housed without a wheel.

Højman repeated the experiment on mice that had been engineered to lack cytotoxic T cells. Again, she found that mice with access to running wheels had smaller tumors. When she performed the same test on mice that had intact T cells but lacked NK cells, the tumors of all the mice grew to the same size. This suggested that the NK cells, and not the T cells, were the link between exercise and tumor growth suppression.

Work by other groups had demonstrated that epinephrine has the potential to mobilize NK cells, and Højman and the rest of our team wondered if epinephrine had a role in mediating the anticancer effects of exercise. We injected mice that had malignant melanoma with either epinephrine or saline and found that the hormone indeed reduced the growth of tumors, but to a lesser degree than what was observed in the mice that had access to a wheel. Something else had to be involved.


AND STAY OUT: Exercise activates natural killer cells (purple) and helps them home to tumors.

To find out what, our team tested the effects of interleukin-6, which we suspected was the additional exercise factor involved in tumor homing of immune cells. When we exposed inactive mice to both epinephrine and interleukin-6, the rodents’ immune systems attacked the tumors as effectively as if the animals had been running.

While much remains to be learned about how physical exercise influences cancer, evidence shows that exercise training is safe and feasible for patients with the disease and contributes to their physical and psychosocial health. (See “Exercise and Depression” on page 44.) Being active may even delay disease progression and improve survival. A growing number of patients, including Mathilde, are undergoing exercise training to fight physical deterioration during cancer treatment. As they do so, scientists are working hard to understand the pathways by which physical activity results in anticancer activity.

Exercise and Depression

Depression is a severe adverse effect of cancer and cancer therapy. The risk of depression can be as high as 50 percent for some cancer diagnoses, although this number varies a great deal depending on cancer type and stage (J Natl Cancer Inst Monogr, 32:57–71, 2004). In addition to its effects on a patient’s quality of life, depression can hinder compliance with treatment, and it’s a risk factor for mortality in cancer patients (Lancet, 356:1326–27, 2000). In recent years, healthcare providers have increasingly integrated physical exercise into the care of cancer patients with the aim of controlling disease and lessening treatment-related side effects, while researchers have amassed evidence supporting the assertion that such training can lower symptoms of depression in these patients (Acta Oncol, 58:579–87, 2019). The biological mechanisms behind this beneficial effect remain to be determined, although some clues have emerged.

For example, a study in mice found that exercise-dependent changes in metabolism result in reduced accumulation of some neurotoxic products (Cell, 159:33-45, 2014). In cancer patients, systemic levels of kynurenine, a neurotoxic metabolite associated with fatigue and depression, are upregulated (Cancer, 121:2129-36, 2015). In mice, exercise enhances the expression of the enzyme kynurenine aminotransferase, which converts kynurenine into neuroprotective kynurenic acid, thereby reducing depression-like symptoms.

Findings such as these, together with exercise’s well-documented effects in alleviating depression among patients without cancer, suggest that incorporating exercise into cancer treatment may benefit mental as well as physical health.

https://www.the-scientist.com/features/regular-exercise-helps-patients-combat-cancer-67317?utm_campaign=TS_DAILY%20NEWSLETTER_2020&utm_source=hs_email&utm_medium=email&utm_content=86607989&_hsenc=p2ANqtz-8W-OrX7bn_MULo5_Jx-u7E1c2gVfZwwWCD26RHtjZT7CoZ9KWhz0zOuCD53QkfOvre5WKYWWxP0plIm4Lf56uABjYb0A&_hsmi=86607989

By Olivia Konotey-Ahulu

A vaccine against the coronavirus could be ready by September, according to a scientist leading one of Britain’s most advanced teams.

Sarah Gilbert, professor of vaccinology at Oxford University, told The Times on Saturday that she is “80% confident” the vaccine would work, and could be ready by September. Experts have warned the public that vaccines typically take years to develop, and one for the coronavirus could take between 12 to 18 months at best.

In the case of the Oxford team, however, “it’s not just a hunch, and as every week goes by we have more data to look at,” Gilbert told the London newspaper.

Gilbert’s team is one of dozens worldwide working on a vaccine and is the most advanced in Britain, she told the Times. As the country looks set to begin its fourth week under lockdown, a vaccine could be fundamental in easing the measures and returning to normal life. Gilbert said human trials are due to start in the next two weeks.

Her remarks came as the death toll from the virus pushed past 100,000 globally. On Friday, the U.K. reported 980 fatalities, taking the total count from the virus to 8,958, and the government has repeatedly pleaded with the public to obey lockdown rules during the long Easter holiday weekend. As Prime Minister Boris Johnson begins his recovery after a spell in intensive care, Patrick Vallance, the government’s chief scientific adviser, warned he expects the number of deaths to increase for “a few weeks” yet.

Manufacturing the millions of vaccine doses necessary could take months. Gilbert said she’s in discussions with the British government about funding, and starting production before the final results are in, allowing the public to access the vaccine immediately if it proves to work. She said success by the autumn was “just about possible if everything goes perfectly.”

https://www.bloomberg.com/news/articles/2020-04-11/coronavirus-vaccine-could-be-ready-in-six-months-times

Looking for examples of true leadership in a crisis? From Iceland to Taiwan and from Germany to New Zealand, women are stepping up to show the world how to manage a messy patch for our human family. Add in Finland, Iceland and Denmark, and this pandemic is revealing that women have what it takes when the heat rises in our Houses of State. Many will say these are small countries, or islands, or other exceptions. But Germany is large and leading, and the UK is an island with very different outcomes. These leaders are gifting us an attractive alternative way of wielding power. What are they teaching us?

Truth

Angela Merkel, the Chancellor of Germany, stood up early and calmly told her countrymen that this was a serious bug that would infect up to 70% of the population. “It’s serious,” she said, “take it seriously.” She did, so they did too. Testing began right from the get go. Germany jumped right over the phases of denial, anger and disingenuousness we’ve seen elsewhere. The country’s numbers are far below its European neighbours, and there are signs they may be able to start loosening restrictions relatively soon.

Decisiveness

Among the first and the fastest moves was Tsai Ing-wen’s in Taiwan. Back in January, at the first sign of a new illness, she introduced 124 measures to block the spread, without having to resort to the lockdowns that have become common elsewhere. She is now sending 10 million face masks to the US and Europe. Ing-wen managed what CNN has called “among the world’s best” responses, keeping the epidemic under control, still reporting only six deaths.

Jacinda Ardern in New Zealand was early to lockdown and crystal clear on the maximum level of alert she was putting the country under – and why. She imposed self-isolation on people entering New Zealand astonishingly early, when there were just 6 cases in the whole country, and banned foreigners entirely from entering soon after. Clarity and decisiveness are saving New Zealand from the storm. As of mid-April they have suffered only four deaths, and where other countries talk of lifting restrictions, Ardern is adding to them, making all returning New Zealanders quarantine in designated locations for 14 days.

Tech

Iceland, under the leadership of Prime Minister Katrín Jakobsdóttir, is offering free coronavirus testing to all its citizens, and will become a key case study in the true spread and fatality rates of Covid-19. Most countries have limited testing to people with active symptoms. Iceland is going whole hog. In proportion to its population the country has already screened five times as many people as South Korea has, and instituted a thorough tracking system that means they haven’t had to lockdown… or shut schools.

Sanna Marin became the world’s youngest head of state when she was elected last December in Finland. It took a millennial leader to spearhead using social media influencers as key agents in battling the coronavirus crisis. Recognising that not everyone reads the press, they are inviting influencers of any age to spread fact-based information on managing the pandemic.

Love

Norway’s Prime Minister, Erna Solberg, had the innovative idea of using television to talk directly to her country’s children. She was building on the short, 3-minute press conference that Danish Prime Minister Mette Frederiksen had held a couple of days earlier. Solberg held a dedicated press conference where no adults were allowed. She responded to kids’ questions from across the country, taking time to explain why it was OK to feel scared. The originality and obviousness of the idea takes one’s breath away. How many other simple, humane innovations would more female leadership unleash?

Generally, the empathy and care which all of these female leaders have communicated seems to come from an alternate universe than the one we have gotten used to. It’s like their arms are coming out of their videos to hold you close in a heart-felt and loving embrace. Who knew leaders could sound like this? Now we do.

Now, compare these leaders and stories with the strongmen using the crisis to accelerate a terrifying trifecta of authoritarianism: blame-“others”, capture-the-judiciary, demonize-the-journalists, and blanket their country in I-will-never-retire darkness (Trump, Bolsonaro, Obrador, Modi, Duterte, Orban, Putin, Netanyahu…).

There have been years of research timidly suggesting that women’s leadership styles might be different and beneficial. Instead, too many political organisations and companies are still working to get women to behave more like men if they want to lead or succeed. Yet these national leaders are case study sightings of the seven leadership traits men may want to learn from women.

It’s time we recognised it – and elected more of it.

https://www.forbes.com/sites/avivahwittenbergcox/2020/04/13/what-do-countries-with-the-best-coronavirus-reponses-have-in-common-women-leaders/#456c3af43dec