Category Archives: Cell Medicine

Researchers have discovered a previously unknown way that pancreatic cells decide how much insulin to secrete. It could provide a promising new target to develop drugs for boosting insulin production in people with Type 2 diabetes.

In a pair of papers recently published in Cell Metabolism, scientists from the University of WisconsinMadison and their colleagues point to an overlooked enzyme known as pyruvate kinase as the primary way pancreatic beta cells sense sugar levels and release the appropriate amount of insulin.

From several proof-of-concept experiments in rodents and on human pancreatic cells, the team found that drugs stimulating pyruvate kinase not only increase the secretion of insulin but have other metabolically protective effects in the liver, muscle and red blood cells. The findings suggest that activating pyruvate kinase could be a new way to increase insulin secretion to counter Type 2 diabetes, but more research would be required before any new treatments were available.

Too much insulin can lower blood sugar to dangerous levels, and too little insulin can lead to diabetes, says Matthew Merrins, a professor of medicine at the UW School of Medicine and Public Health who led the work. The question were asking here is: How do nutrients like glucose and amino acids turn on beta cells in the pancreas to release just the right amount of insulin?

The work was accomplished by carefully dissecting the paradoxical timing of key biochemical events in the prevailing understanding of how pancreatic beta cells respond to nutrients in the blood. The researchers point to a new, richer model to understand how this important process is controlled that resolves these inconsistencies.

For decades, scientists believed that mitochondria, the energy generators in cells, initiated insulin secretion. It was a natural explanation, because mitochondria produce the high-energy molecule ATP, in the process depleting ATPs low-energy version, ADP. The drop in ADP stimulates calcium the ultimate trigger to release stored insulin.

But the timing didnt make sense. Mitochondria are most active after insulin secretion has already begun, not before. Plus, mitochondria would stall out before exhausting enough ADP to trigger insulin secretion.

A clue to solving these apparent paradoxes came from studies in the 1980s on heart muscle cells. At the time, scientists found that the enzyme pyruvate kinase which converts sugar into energy, independently of mitochondria could also severely deplete ADP. This process happens near ADP-sensing proteins involved in insulin release in the pancreas. Maybe, Merrins team thought, the pancreas took advantage of this proximity to fine-tune the release of insulin.

In initial experiments, the researchers supplied sugar and ADP to sections of pancreatic cells containing pyruvate kinase. The enzyme gobbled up both components, depleting ADP. Because pyruvate kinase was located near the ADP-sensing protein that triggers insulin secretion, it had a big effect.

Thats one of the important concepts in our paper: the location of metabolism is critical to its function, says Merrins.

Using mouse and human pancreatic islets, the clusters of cells that release insulin, the researchers tried stimulating pyruvate kinase activity. Drugs that activate the enzyme quadrupled the release of insulin, but only when there was enough sugar around a sign that pyruvate kinase cant be forced to release too much insulin.

Pyruvate kinase doesnt change how much fuel comes into the cell, it just changes how that fuel is used, says Merrins. Drugs that active pyruvate kinase strongly boost insulin secretion without causing too much insulin release that can lead to hypoglycemia.

In all, they discovered evidence of a more complex way in which pancreatic beta cells decide when and how much insulin to release, akin to a two-cycle engine. In the first cycle, blood sugar gets processed by pyruvate kinase, depleting ADP. Mitochondria keep the process going by feeding pyruvate kinase even more material, which causes ADP levels to crash, ultimately stimulating enough calcium entry into the cell to release insulin.

In the second cycle, mitochondria switch from feeding pyruvate kinase with material to producing the high-energy molecule ATP, which is needed to fully release insulin. Then the process resets.

In the companion study, led by Merrins colleagues at Yale University, the researchers examined how pyruvate kinase activators affected metabolism in healthy and obese rats. In a series of experiments, they found that activating pyruvate kinase increased both insulin secretion and insulin sensitivity while improving sugar metabolism in liver and red blood cells. Such treatments could be helpful for people with Type 2 diabetes, who dont produce enough insulin and have dysfunctional sugar metabolism as a result.

The therapeutic idea here is we could rewire metabolism to more efficiently trigger insulin secretion while improving the function of other organs at the same time, says Merrins.

This work was supported in part by the National Institutes of Health (grants R01DK092606, R01DK110181, K08DK080142, UL1RR-0024139, P30DK045735, K01DK101683, R01DK113103, R21AG050135, R01AG062328, F32DK116542, T32AG000213, T32DK007665) and the Health Resources and Services Administration (grant T32HP10010).

The rest is here:
'Rewiring' metabolism in insulin-producing cells may aid Type 2 diabetes treatment - University of Wisconsin-Madison

New Cell Signaling Center supports research on the most fundamental of cellular functionand development of therapeutics that target them

As Alexandra Newton took the stage late last year to give an invited lecture at the University of Dundee in Scotland, the event host introduced her as hailing from San Diego, the other top cell signaling community in the world.

Alexandra Newton (right) and members of her lab at UC San Diego School of Medicine (pictured pre-COVID-19 pandemic.

Until that moment, Newton hadnt thought of it that way. Yet it struck her as true.

We probably dont fully appreciate our own depth of expertise because its our normal, said Newton, Distinguished Professor in the Department of Pharmacology at UC San Diego School of Medicine. So, I figured if this university has a center dedicated to cell signaling, surely UC San Diego should as well.

And so Newton, with colleague Jin Zhang, professor of pharmacology, launched the Cell Signaling Center at UC San Diego. Their goal is to unite researchers passionate about understanding cell signaling, and leveraging it to treat disease.

Newton describes cell signaling as the language cells use to communicate among themselves and with the outside world. Say, a signal knocks on a cells outer door, so to speakinsulin, for example. The signal first needs to get the message inside the cell, then trigger a change in behavior, such as taking up glucose in this example, or growing, dividing or secreting.

That cascade of events is known as cell signaling, and its a language many scientists want to speak so that they can better understand the many ways it can go awry.

If I talked super-fast or way too slowly, youd have trouble understanding me, Newton said. Similarly, a change in cell signaling can lead to miscommunication, and ultimately to disease.

Within the complex language of cells, there are a few commonly used phrasesphosphorylation is one key example. In phosphorylation, enzymes called kinases add phosphate groups to proteins and other enzymes called phosphatases remove them, changing protein conformation or activity back and forth like a switch. Whether or not a phosphate group is present in a particular place and time can drastically change cell behavior.

Cell signaling malfunctions can lead to a variety of diseases. For example, a sped-up kinase in one pathway might allow cells to divide out of control, leading to cancer. A slowdown of the same kinase may contribute to untimely cell death, as might occur in neurodegenerative diseases, such as Alzheimers.

If we know what has gone wrong, we are in a better position to fix it, Newton said.

Lets say you are repeatedly inserting a wrong word in your sentences, Newton said. We need to find the wrong word and replace it with the correct wordthats what were doing with targeted therapeutics.

Often, very small changes are sufficient to disrupt the normal balance of cell signaling. If just a few atoms in one amino acid, the building block of proteins, are off in a kinase, it could cause the enzyme to start spitting out phosphate groups 30 percent faster, changing the behavior of the cell, causing Alzheimers or some other disease, and we need therapeutic drugs to slow it down.

Graduate students in Alexandra Newtons lab hold a model of Protein Kinase C (pictured pre-COVID-19 pandemic).

There are more than 500 protein kinases operating in our cells, and many current and experimental drugs work by inhibiting these enzymes. One example is the drug imatinib (brand name Gleevec), a kinase inhibitor that has been a game-changer in treating some types of leukemia.

For decades, many researchers had also attempted to develop drugs that inhibit Protein Kinase C (PKC), Newtons favorite cell signaling molecule, as a means to treat cancer. But in 2015, Newtons team reversed this 30-year paradigm when they reported evidence that PKC actually suppresses, rather than promotes, tumors. Their work implied that anti-cancer drugs would actually need to do the oppositeboost PKC activity.

PKC enzymes are the perfect example of the need to understand the complex biochemistry of our target molecules before we start targeting them in therapies, Newton said.

UC San Diegos global reputation as a leader in cell signaling research grew out of decades of discoveries.

Susan Taylor, professor in the Department of Pharmacology and Department of Chemistry and Biochemistry, is best known for solving the first crystal structure of a protein kinase (PKA, a relative of PKC) in 1991. The structure revealed how kinases are shaped, how their various pieces come together and how they perform their enzymatic reactions.

Ill never forget sitting as a group in the San Diego Supercomputer Center one afternoon, looking at a screen together and seeing PKA in 3Dit was so amazing to realize that we were the only people in the world to see the structure, and to know it was just the beginning of a big family of enzymes, Taylor said.

PKA is still considered the poster child for kinases today.

The crystal structure of Protein Kinase A (PKA), shown here, was first solved by Susan Taylor and team in 1991. Its still considered the gold standard for kinase structures today.

Taylor originally came to UC San Diego as a postdoctoral researcher in 1971, training in the lab of biochemist Nathan Kaplan. There, she worked alongside a number of talented, eager scientists, including graduate student J. Craig Venter and fellow postdoc Jack Dixon.

Venter went on to lead the effort to sequence the human genome. He is currently CEO of the J. Craig Venter Institute.

Dixon became the first to clone, express and characterize a number of phosphatases (the enzymes that do the opposite of kinasesremove phosphate groups). He also discovered the substrate of the tumor-suppressing enzyme PTEN, which shares some structural similarities with the phosphatases he studied. Dixons work suggested cell signaling pathways that could be targeted to treat cancers lacking PTEN. He is now Distinguished Professor of Pharmacology, Cellular and Molecular Medicine, and Chemistry and Biochemistry at UC San Diego, where his team is studying a largely overlooked family of secreted kinases.

In the late 1970s, Taylor also taught Dr. Brian Druker when he was an undergraduate and then a medical student at UC San Diegobefore he went on to help develop the kinase-inhibitor drug Gleevec, the first FDA-approved therapeutic that works by specifically targeting a molecular defect unique to cancer cells, making it more effective and less damaging to healthy cells.

In addition to kinases and phosphatases, UC San Diego School of Medicine is home to many experts on G-protein coupled receptors (GPCRs), molecules that span cell membranes, where they transmit messages between cells and their environments.

Like kinases, many therapeutic drugs work by influencing GPCRs. Joan Heller Brown, Distinguished Professor of Pharmacology, for example, is known for fundamental contributions to the understanding of GPCRs and how they regulate cell growth and survival in healthy and various disease states, while Dr. Paul Insel, Distinguished Professor of Pharmacology and Medicine, is an expert in the genomics of GPCRs. Silvio Gutkind, who recently succeeded Heller Brown as chair of the Department of Pharmacology, and team are developing innovative anti-cancer prevention and treatment options that work by targeting GPCRs.

Much of todays cell signaling research relies heavily on leading-edge tools that have grown out of the work of late Nobel Laureate and UC San Diego Professor Roger Tsientools that allow researchers to eavesdrop on cellular conversations.

Tsien, recruited to UC San Diego in 1989, shared the 2008 Nobel Prize in Chemistry for the discovery and application of green fluorescent protein (GFP), which allows some jellyfish to glow. While colleagues discovered and isolated the GFP gene, Tsien found ways to tweak its makeup, making it glow more brightly and consistently. Then, he created a full color palette of fluorescent proteins that scientists could use to track the molecular goings-on within a cell.

GFP and its many colorful cousins (with names like mCherry and mOrange) quickly became indispensable tools in life sciences labs around the world. Tsien, who died in 2016, often called these fluorescent tags molecular spies because they allow researchers to listen in on cellular communications, to watch molecules interact in real-time and ask questions once thought impossible.

With support from Bristol Meyers Squibb, the new Cell Signaling Center is proud to offer an Annual Roger Tsien Cell Signaling Distinguished Lecture Series in his honor.

Today, several of Tsiens trainees, including Zhang, Nathan Shaner, associate professor of neurosciences, and others are carrying on his legacy at UC San Diego School of Medicine. Shaner, original developer of the GFP-related fruit series, continues to engineer and optimize fluorescent proteins for use with newer imaging techniques. Zhang has devised a new set of fluorescent biosensors.

Our biosensors are unique in that we put in the DNA and cells assemble them for us, Zhang said. They allow us to follow a molecule of interest in a live cell, and see what it does, how, when and where.

Ultrasensitive biosensors developed by Jin Zhang and team help scientists track kinase activity in live mice.

Hardly a week goes by in which there isnt a new cell signaling study by UC San Diego School of Medicine researchers published in top scientific journals. In just the last few months:

When thinking about the future of the cell signaling field, Taylor said shes perhaps most excited about recent leaps in imaging capabilities in the past few years, especially when combined with computational and engineering expertise.

For example, researchers were (virtually) lining up to collaborate with new assistant professor Johannes Schneberg after he presented his work in quantitative 4D imaging at a recent meeting. His technology can, for example, fly viewers through the mitochondria in a live human brain organoid grown in a lab.

People across disciplines have always worked together well here at UC San Diego, even from the very beginning, and that has been enhanced by many cross-campus joint appointmentslike both Johannes Schneberg and Roger Tsien, who held faculty appointments in both the School of Medicines Department of Pharmacology and the Department of Chemistry and Biochemistry on the main campus, Taylor said.

That collaborative spirit is the basis for the new Cell Signaling Center. According to Zhang, the center will act as a hub for researchers in the field to better connect with each other, as well as a one-stop-shop for local biopharmaceutical companies and colleagues around the world looking for the types of experts and resources that UC San Diego can provide.

Together, we are taking not a sledgehammer approach to treating disease, but a precise fine-tuning of cell signaling processes to correct their mis-regulation in disease, Zhang said. Thats the basis of precision, or personalized, pharmacology, and it starts with the kind of work were doing here at UC San Diego.

Read more from the original source:
When the Language of Cells is Interrupted - UC San Diego Health

More than 100 different cancers can arise all over the body, but two universal metabolic pathways may tie them all together, researchers from the Perelman School of Medicine report in a new study published online in Cell Metabolism. Researchers have long believed all cancers are governed by a common set of fundamental processes. Exactly what those were, however, has remained elusive.

Having a unifying mechanism could inform new therapeutic approaches to prevent normal cells from transforming into any type of tumor, be it breast, prostate, or colon, for example.

The team discovered how the transformation from a phenotypically normal cell to a cancerous one involves the enhancement of two key elements: antioxidant defense and nucleotide synthesis. Genes associated with cancer, they found, are super charging some cells to fight off oxidative stress and synthesize nucleotides, which cells need to survive and rapidly grow, respectively.

Since the early 1980s, numerous cancer genes have been identified. However, they often affect multiple cellular processes, which makes it very hard to really summarize what exactly turns cells cancerous, says senior author Xiaolu Yang, a professor of cancer biology in the Perelman School of Medicine. We took a unique approach and looked at the cellular changes driven by a particular metabolic enzyme, which turned out to be the key here. Strikingly, we found that for a phenotypically normal cell to become a cancer cell, all it needs to do is to be equipped with the extra capacity to endure oxidative stress and produce nucleotides.

Shut down these metabolic pathways, the study suggests, and the cells dont become cancerous.

Read more at Penn Medicine News.

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Researchers discover two key events that turn normal cells into cancer - Penn Today

There are four common cold coronaviruses that we all catch at some stage. We generate antibodies to them, but our immune memory of them fades over time, and we get re-infected.

Their names are all too easily forgottenOC43, HKU1, 229E, and NL63but our immune systems may nevertheless remember them for a time. There have been hints that exposure to these common coronaviruses might offer some protection from COVID-19, mostly by looking at signs of immune memory in blood samples taken from before the pandemic. A study in the Journal of Clinical Investigationreports the first clinical evidence linking recent endemic coronavirus infections to less severe COVID-19 and even a reduced death rate in patients.

The COVID-19 disease is actually much less severe in those patients who had documented endemic coronavirus infections.

Manish Sagar, Boston Medical Center

The authors at Boston University School of Medicine found evidence for this by poring over the medical records of thousands of patients who had visited Boston Medical Center as inpatients or outpatients, most probably for respiratory illnesses, between 2015 and 2020. Each person had been assessed for infection using a PCR test that screens for bacteria and viruses, including the four endemic coronaviruses.

In total, 15,928 patients had at least one such PCR test. Of them, 875 tested positive for an endemic coronavirus (this group was called eCoV+), while the remaining 15,053 people never had a documented coronavirus infection (termed eCoV-).

Of the entire cohort, a total of 1,812 (11.4 percent) later returned for a SARS-CoV-2 test during the initial COVID-19 surge in Boston between March 12 and June 12.

Our study is the first to examine people with known endemic coronavirus infections, and compare them to people who, as far as we know, dont have any recent documented coronavirus infections, says Manish Sagar, the lead author of the study and a virologist at Boston Medical Center.

The infection rate for SARS-CoV-2 was no different between those who had a recently recorded endemic coronavirus infection (eCoV+) and those who did not have a positive test (eCoV-). This led the authors to conclude that a recent infection with endemic coronaviruses did not keep SARS-CoV-2 at bayboth groups were just as likely to become infected with the pandemic virus.

When the researchers peered closer at the data, they observed an important difference between the two groups. The COVID-19 disease is actually much less severe in those patients who had documented endemic coronavirus infections, says Sagar. The odds of intensive care unit (ICU) admission were significantly lower in eCoV+ than in eCoV- patients, and there was a trend towards lower odds of mechanical ventilation, the authors write in their report.

The data also show that among hospitalized patients who had previous positive test results for endemic coronavirus, 4.8 percent of them died compared with 17.7 percent among those in the group without such a test result.

Local immune memory may help explain these results. Such heterotypic immunity, says immunologist Joseph Mizgerd, director of the pulmonary center at Boston University School of Medicine, occurs when immune memory is etched into the lungs and/or nose. Its common after other types of respiratory infections and might offer protection against SARS-CoV-2 if elicited by endemic coronaviruses. Although the Boston group did not measure this type of immunity in patients, they now hypothesize that local immunity gained from endemic coronaviruses helps limit lung injury during COVID-19. We are testing that in ongoing experiments, Mizgerd says by email. He adds that such cross-reactive immunity is often mediated by memory T cells, which can localize in the lung, and he notes that lung-localized heterotypic T cells can prevent severe lung infection during pneumonias caused by other types of respiratory pathogens.

If indeed prior infection does ramp up protection against SARS-CoV-2, the study could not answer how long it takes for any such benefit to taper off. Nor did the work shed light on which of the four endemic coronaviruses in particular might be offering protection against the pandemic virus. The scientists are seeking funding to expand their research and include data from other institutions.

Mizgerd and his team did not look into which immune components may be responsible for an endemic coronavirus influencing a persons immune response to SARS-CoV-2. This is something that immunologist Dennis Burton at the Scripps Research Institute in La Jolla, California, and his colleagues have investigated.

Since the start of the pandemic, they have been interested in whether pre-existing immune responses to seasonal coronaviruses could influence antibody responses to SARS-CoV-2. In a study published in September as a preprint on bioRxiv, Burton and colleagues compared serum antibodies and antibody-producing B cells from 36 donors sampled prior to the pandemic to see whether those antibodies reacted with the spike protein from the new pandemic virus. Very few antibodies from before the pandemic reacted to SARS-CoV-2, the team found. The vast majority did not bind strongly to the new virus, although they did identify one antibody that could neutralize SARS-CoV-2.

The group also detected memory B cells in blood samples from before the pandemic that were turned on by the presence of SARS-CoV-2. This activation triggered them to make antibodies that reacted against some proteins made by SARS-CoV-2. That would suggest that there is some cross reactivity there, says Burton.

A cross-protective vaccine that protects against SARS-CoV-2 plus the endemic coronaviruses would be a really great boon.

Manish Sagar, Boston Medical Center

A recent Sciencestudy reported that 5 percent of 302 adults and 43 percent of 48 children had antibodies that reacted against certain proteins produced by SARS-CoV-2. Children are more prone to common cold coronavirus infections, perhaps explaining why they might harbor such antibodies, and why they suffer less severe COVID-19 symptoms.

We do not know yet if the presence of such antibodies modifies the risk of becoming infected or the severity of disease, senior author George Kassiotis at the Francis Crick Institute in London explains by email. There are conserved parts of the S2 peptide of the spike protein, such as the fusion peptide, in most coronaviruses that are targeted by such cross-reactive and potentially cross-protective antibodies, Kassiotis notes. This may hold promise for a universal vaccine protecting against current, as well as future CoVs, the authors write in their Sciencepaper.

Kassiotis says that concerns that antibody immunity might be short-lived have now been allayed by recent studies and adds that even if antibodies fell below detectable levels, the cells that made them will still be there and will respond faster and better to re-infection.

Antibodies and B cells are part of only one aspect of our immune memory to viruses. Multiple investigations since the beginning of the pandemic have suggested that between 20 percent and 50 percent of people who had never encountered SARS-CoV-2 had T cells that nevertheless seemed to react against peptides from this virus, as noted recently in a Sciencepaper.

In another study in Nature, researchers in Singapore identified memory T cells in patients who had recovered from SARS back in 2003. These were reactive to proteins from SARS-CoV-2, supporting the idea that T cell memory from infections with human coronaviruses may play a role in the response to an infection with the new pandemic virus.

An additional study recently published in Scienceused human blood samples from before the pandemic to locate parts of SARS-CoV-2 that stimulated existing T cells. The study found a range of memory T cells that could react to both the new virus but also to the four common cold coronaviruses, again suggesting that existing T cells against common coronaviruses could play a role in the immune response to SARS-CoV-2 in some patients.

Immunologist Stanley Perlman of the University of Iowa who was not involved in any of these studies says that everybody should have memory B cells against common cold coronaviruses. We may also have memory T cells that remember these viruses and perhaps help with fighting SAR-CoV-2. However, Perlman emphasized that the implications of this for COVID-19 is still a work in progress.

Burton says he hopes to dig into a molecular understanding of the cross-reactivity of antibodies, which might help design a vaccine against not just SARS-CoV-2, but common cold coronaviruses too. These viruses usually cause mild symptoms, but not always.

A cross-protective vaccine that protects against SARS-CoV-2 plus the endemic coronaviruses would be a really great boon, says Sagar. These coronaviruses are causes of the common cold, but they are also really important causes of pneumonia, pneumonia hospitalizations, and pneumonia deaths.

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Common Cold Coronaviruses Tied to Less Severe COVID-19 Cases - The Scientist

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The Wayne County Prosecutor's Office will ask an outsidemedical examiner to review the autopsy report of a woman who died earlier this year in the Harper Woods jail.

Priscilla Slater, 38, of Detroit, died inthe Harper Woods jail on June 10. Her deathprompted protests, the firing of two police officers for altering the police report detailing the discovery of her body, and the resignation of the city's longtimemayor after he told a meeting that he understood how someone could become a white supremacist.

Priscilla Slater, 38, of Detroit, died in the Harper Woods jail on June 10.(Photo: LaTasha Slater)

Slater was arrested about 1:30 a.m. on June 9 at the Parkcrest Inn in Harper Woods, after her boyfriend, Lewis Nichols, 27, also of Detroit, allegedly fired 18 shots into the parking lot.She died the next day.

The Michigan State Police investigated Slater's death. Their findings have been turned over to Wayne County Prosecutor Kym Worthy's office, which is conducting its own investigation.

A Wayne County Medical Examiner's report reached no certain conclusion about the cause of Slater's death. In the absence of pathological findings, the report speculated that an irregular heartbeat caused by abnormally angled coronary arteriescould have resulted in Slater's sudden death.

Protesters gather outside of Harper Wood Police Department while marching through Harper Woods for Priscilla Slater on July 24, 2020. Slater was found unresponsive in a Harper Woods Police Department holding cell in June 2020.(Photo: Ryan Garza, Detroit Free Press)

But Oakland County ChiefMedical Examiner Ljubisa Dragovic, M.D., who reviewed the autopsy report at the Free Press' request, calledthat theory "nonsense."

Because of the condition of Slater's liver, Dragovic said in an interview this week, "the most likely diagnosis that one can propose, without being able to see the details ofthe microscopic slides, is that she died from alcoholwithdrawal.If she was not monitored in the cell, thatis a big problem."

The autopsy report notes that video of the jail cell appears to show Slater having a seizure about 5:10 a.m. Her body was discovered in the cellmore than seven hourslater,at12:30 p.m.,

Oakland County (Mich.) Medical Examiner Ljubisa Dragovic.(Photo: ASSOCIATED PRESS)

The report does not state a time of death,but says the seizure may have occurred as Slater died.

Dragovic saidSlater's apparent seizure was not consistentwith the heart condition the Wayne County report says killed her.

"The presenting terminal events are not in concordance with a sudden onset of arrhythmia," he said.

Worthy said Wednesday that her office had not previouslybeen aware of the possibility that Slater died of alcohol withdrawal. Alcohol withdrawal is not mentioned in the Wayne County Medical Examiner's report.

"This information was not part of any investigation," she said. "Because of this new information, we feel we need to get an independent medical examinerto review the report."

Worthy added that the need to enlist an additional expert would delay the completion of her own office's report.

Edward Jouney, an addiction specialist and assistant clinical professor in the psychiatry department at Michigan Medicine, said jails should screen people who are in custody at intake to identify substance abuse and the risk of withdrawal. He noted he was speaking generally ofjail practices.

Demonstrators march down the streets of Harper Woods on July 15, 2020, demanding to know what happened to Priscilla Slater while she was in police custody. Slater was arrested by Harper Woods police and taken into custody on June 9, 2020.(Photo: Rodney Coleman-Robinson, Detroit Free Press)

"The first thing that should be done is to take a history to see if the individual has been using any alcoholor drugs, then quantify to see how much they're using," he said. "The body acclimates to drugs or alcohol, and experiences a change in physiology. When you go into jail, you're obviously not provided with alcohol. Thebody is going to react, and go into whats called alcohol withdrawal syndrome."

Most people, he said, will survive alcohol withdrawal with a minimum of care. But some will require medical treatment, and the condition can be life-threatening.

"Some people may necessitate admission to an ICU, and can experience severe problems. If they have a history of regular alcohol use, they (jailofficials)need to regularly assess them for symptoms of alcohol withdrawal."

It's unclear whether Slater was screened for drug or alcohol use, or whether she was offered any treatment while in custody. The Wayne County Prosecutor's Office denied a Freedom of Information Act request for police reports related to Slater's arrest and time in custody, citing the ongoing investigation.

LaTasha Slater, Priscilla Slater's sister, said Wednesday that Dragovic'sexplanation makes sense. Priscilla Slater worked hard, but she played hard, LaTasha said and that often meant drinking hard.

LaTasha had rejected the idea that her sister died of a previously undetected heart abnormality. But she said Dragovic's theory provides amore plausible explanation for her sister's death.

"That makes more sense to me thananything Ive heard about the whole situation," LaTasha said.

Nancy Kaffer is a columnist and member of the Free Press editorial board. She has covered local, state and national politics for two decades. Contact: nkaffer@freepress.com. Become a subscriber.

Read or Share this story: https://www.freep.com/story/news/local/michigan/wayne/2020/11/12/priscilla-slater-autopsy-jail-harper-woods/6251487002/

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Expert poses new theory on what really killed woman in Harper Woods jail - Detroit Free Press

We hypothesized that pT3a stage at nephrectomy can be accurately predicted in cT1N0M0 clear cell-renal cell carcinoma (cc-RCC) patients. Of 236 patients, treated with either partial or radical nephrectomy (2005-2019), 25 (10. 6%) harbored pT3a stage. Multivariable logistic regression models predicting pT3a were fitted using age, tumor size, tumor location and exophytic rate. The new model was 81% accurate. In calibration plots, minimal departures from ideal prediction were recorded. In decision curve analyses, a net-benefit throughout all threshold probabilities was recorded relative to the treat-all or treat-none strategies. Using a probability cut-off of 21% for presence of pT3a stage, 38 patients (16.1%) were identified, in whom pT3a rate was 36.8%. Conversely, in 198 patients (83.9%) below that cut-off, the rate of pT3a was 5.6%. Alternative user-defined cut-offs may be selected. The new model more accurately identifies a subgroup of cT1N0M0 cc-RCC patients with substantially higher risk of pT3a stage than average.

European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology. 2020 Nov 05 [Epub ahead of print]

Luigi Nocera, Lara F Stolzenbach, Claudia Coll Ruvolo, Mike Wenzel, Zhe Tian, Giuseppe Rosiello, Carlo A Bravi, Luigi Candela, Giuseppe Basile, Alessandro Larcher, Shahrokh F Shariat, Roberto Bertini, Umberto Capitanio, Andrea Salonia, Francesco Montorsi, Alberto Briganti, Pierre I Karakiewicz

Cancer Prognostics and Health Outcomes Unit, Division of Urology, University of Montreal Health Center, Montreal, Quebec, Canada; Division of Experimental Oncology/Unit of Urology, URI, Urological Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy. Electronic address: ., Cancer Prognostics and Health Outcomes Unit, Division of Urology, University of Montreal Health Center, Montreal, Quebec, Canada; Martini-Klinik Prostate Cancer Center, University Hospital Hamburg-Eppendorf, Hamburg, Germany., Cancer Prognostics and Health Outcomes Unit, Division of Urology, University of Montreal Health Center, Montreal, Quebec, Canada; Department of Neurosciences, Reproductive Sciences and Odontostomatology, University of Naples Federico II, Italy., Cancer Prognostics and Health Outcomes Unit, Division of Urology, University of Montreal Health Center, Montreal, Quebec, Canada; Department of Urology, University Hospital Frankfurt, Frankfurt am Main, Germany., Cancer Prognostics and Health Outcomes Unit, Division of Urology, University of Montreal Health Center, Montreal, Quebec, Canada., Division of Experimental Oncology/Unit of Urology, URI, Urological Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy., Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; Departments of Urology, Weill Cornell Medical College, New York, NY, USA; Department of Urology, University of Texas Southwestern, Dallas, TX, USA; Department of Urology, Second Faculty of Medicine, Charles University, Prag, Czech Republic; Institute for Urology and Reproductive Health, I.M. Sechenov First Moscow State Medical University, Moscow, Russia; Division of Urology, Department of Special Surgery, Jordan University Hospital, The University of Jordan, Amman, Jordan.

PubMed http://www.ncbi.nlm.nih.gov/pubmed/33168336

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Predicting the risk of pT3a stage in cT1 clear cell renal cell carcinoma. - UroToday

At the very heart of our Biblical tradition is this commandment from the Book of Leviticus: You shall not stand idly by the blood of your fellow. (Leviticus 19:16)

If we see our sisters or brothers in danger, our job is simple: Provide that help, come to their aid, do what is in our power to protect them and save them.

In the midst of a global pandemic, we feel the call to protect and promote the health and well-being of others even more urgently. Right now, we hear the call to uphold the ultimate Jewish value of pikuach nefesh (saving a life).

Sometimes, we live out that value in an immediate way. We donate blood today, which can save lives in real time. We provide support for basic needs to ensure that people in our community have enough to eat right now. But if we truly wish to move the needle in the work of pikuach nefesh, we must also provide resources to fund research over many years, even decades, that will, ultimately, yield dramatic results.

To truly make a difference, to be Gods partners in bringing healing to the world, we must not stand idly by in both immediate and long-term ways.

California voters have an opportunity to do just this by voting yes on Proposition 14, which will advance the California Institute of Regenerative Medicines stem cell research to help those who are affected by ailments including heart disease, diabetes, Alzheimers, Parkinsons disease, sickle cell disease, spinal cord injuries, Covid-19, and so many other chronic illnesses and injuries.

Funding for this important and vital medical research helps save lives, and it will provide immediate economic stimulus, as well. Even as it funds long-term strategies to alleviate human suffering, Prop. 14 will create jobs during this challenging time. Recent studiessuggest that Prop. 14 would generate approximately $20 billion in increased economic activity in California, yielding more than 100,000 new jobs at every level. This far surpasses Prop. 14s estimated cost of $5.5 billion in bonds.

Critics of the proposition question the need for such funding on a state level today. They argue that Proposition 71, the initiative that originally created the California Institute of Regenerative Medicine, was passed in 2004 only because President George W. Bush had banned federal funding for stem cell research. Now that federal funding for stem cell research is allowed, the critics charge, its no longer Californias responsibility to fund such research; private and federal funding should be used to continue this important work.

However, relying on federal and private funds is too risky. Many in our country wish to stifle and limit stem cell research on religious grounds. Far more importantly, Jewish law on this matter is unequivocal: stem cell research is not just permitted, but, arguably, required as a matter of pikuach nefesh. Numerous halachic authorities have made this clear. It should, therefore, come as no surprise that some of the most exciting work in stem cell research is currently being done in Israel.

Medical experts agree that stem cell research and therapies will save lives and alleviate human suffering. In fact, it already has. One example is the stem cell work Dr. Donald Kohn at UCLA conducted to cure ADA-SCID bubble baby disease.

This work is too important for us to leave it to chance or to allow it to be cut off or limited.

We see Prop. 14s opportunity to provide such resources for life-saving research as a blessing, the fulfillment of core Jewish values.

Just one chapter before the commandment to not stand idly by, our Torah reminds us that the purpose of mitzvot, the very goal of Judaism, is to enhance life. We are commanded: in the pursuit of My laws and statutes you shall live. (Leviticus 18:5) The Rabbis of the Talmud interpret this verse to mean that the ultimate value, above all else, is life itself.

To be sure, it will take many years to realize the promise of current research. But like the well-known story of Honi, who came upon an old man planting a tree that would not bear fruit for another 70 years, we recognize that our efforts are not for ourselves alone. Just as our ancestors sacrificed so that our lives would be better, we commit ourselves to doing the same for our descendants.

The voices of our sisters and brothers cry out to us: friends and family members with diabetes; co-workers fighting against cancer; loved ones slipping away due to the cruel ravages of Alzheimers.

They call out to us in their pain. They are searching for hope.

We cannot stand idly by. We must generously sacrifice so that they and subsequent generations might live and be well.

There are quite literally lives to be saved. Join us by voting yes on Prop, 14 on Nov. 3.

Read more:
We can't stand idly by: Vote 'yes' on Prop. 14 for stem cell research - The Jewish News of Northern California

One participant said, It seems like weve done 10 years of work in seven months!

Kevin Harrod, Ph.D.Jeanne Marrazzo, M.D., director of Infectious Diseases, got a text at the end of Wednesdays four-hour School of Medicine COVID-19 Research Symposium that highlighted the broad and breakneck work done at the University of Alabama at Birmingham since March 2020.

It seems like weve done 10 years of work in seven months! she told participants.

Presentations by eight leading UAB researchers buoyed that sentiment. Among the work:

One hallmark of all eight presentations? An extreme interdisciplinary collaboration of researchers and clinicians across the hospital and university campus, that co-convener Etty Tika Benveniste, Ph.D., called remarkable. Research presented by Fran Lund, Ph.D., for example, involved eight different labs and 30 researchers.

Here are brief highlights of each presentation.

The first two presenters, Lund and Paul Goepfert, M.D., looked at how two kinds of the immune systems white blood cells respond in patients with COVID-19.

Lund, an international expert in B cell biology, was able to isolate B cells from patients that made antibodies against the SARS-CoV-2 virus spike protein. Her team found that many of these antibodies were cross-reactive against the spike proteins from SARS or MERS, which suggested that the antibody protection might wane. She also briefly mentioned her work to test the Altimmune Inc. intranasal vaccine candidate that would be the first intranasal vaccine for COVID-19 and might be effective at preventing transmission.

Steven Rowe, M.D.Goepferts team found a surprising result: Peripheral T follicular helper cells against SARS-CoV-2 continue to increase during convalescence, and they are more activated in severe patients who are in intensive care.

Immunologic studies like those of Lund and Goepfert are vital for understanding how the body responds to SARS-CoV-2 infection, as a prelude to learning how to better treat the disease.

In the section on optimizing diagnosis and treatment, Erdmann talked about several other clinical trials besides the remdesivir trial. He noted that UAB has been quite successful in minority enrollment for inpatient trials, and said UAB researchers have been able to enroll 159 convalescent patients and 846 hospitalized patients for donations of high-quality biological samples like peripheral blood monocytes, blood plasma, urine and oral saline rinses.

After he finished, Marrazzo said, You highlighted the absolutely herculean efforts to do this exceptionally collaborative work at UAB.

Besides the creation and expansion of the UAB COVID-19 test, Leal described how his team was able to adapt that test to screen 250,000 students who were returning to Alabama colleges in August, by using a pooled-sample method. Now, as flu season approaches, the clinical lab is adjusting its test to detect both SARS-CoV-2 and seasonal influenza in a single test. They are also beginning to incorporate prognostic tests of things like interferon-beta or various cytokines into the COVID-19 test. The goal is being able to identify those who are more at risk for severe disease.

In Harrods drug screening, he identified tocopherol polyethylene glycol succinate (TPGS) an existing drug that is a Vitamin E precursor as a drug that acts in synergy with remdesivir. This is important because the TPGS could then lessen the amount of remdesivir needed to treat patients. Remdesivir is in short supply. Intriguingly, his team also found that ivacaftor, a cystic fibrosis drug, is effective against SARS-CoV-2 in the cell culture assays, opening the door to studying its mechanism of action.

The second presenter in basic science discovery, along with Harrod, was Steven Rowe, M.D., director of the Gregory Fleming James Cystic Fibrosis Research Center at UAB. He is testing ferrets as an animal model of severe COVID-19 disease, to fill the urgent need for such a model. His team has found that infection with SARS-CoV-2 disrupts mucociliary clearance in the ferret trachea, as measured by micro-optical coherence tomography, which is similar to the laser eye test that creates a profile of a patients retina. This test is now being adapted to quantify mucociliary clearance the escalator-like movement of mucus from the lungs to the throat in patients with COVID-19.

Paul Goepfert, M.D.,Nathan Erdmann, M.D., and Fran Lund, Ph.D.The final section of the symposium focused on COVID-19 and health disparities.

Mona Fouad, M.D., noted that COVID-19 deaths are higher in African Americans and Hispanics than whites, and she said that, as the pandemic arrived, the UAB Minority Health and Health Disparities team pivoted to COVID-19. They created a Community Mobile Testing Model with three parts: engaging and educating communities about COVID-19 and dispelling myths; bringing mobile testing to vulnerable communities; and creating patient navigators to help people with COVID-19. Navigators are people who have had experiences similar to those of the communitys people and understand their needs.

Jefferson County CARES Act funding expanded the program to 33 test sites in 18 communities in the county. Of the adults tested, Hispanics had a 29 percent positivity rate, African Americans 9 percent and whites 5 percent.

The final UAB presenter was Selwyn Vickers, M.D., dean of the UAB School of Medicine. He said a meeting he had with 13 Black medical leaders nationwide identified COVID-19 as a crisis within a crisis. African Americans already had health disparities, caused in part by disparities in education and socio-economic determinants, before the added burden of a pandemic.

The deadly combination of COVID-19 with the preexisting social determinants was like throwing gasoline on a fire, he said, a combination of smoldering chronic disease and an acute respiratory infection. Even more than African Americans, the worst-hit in the United States are Native Americans.

To help address disparities, Vickers said we need to prepare for a second surge of COVID-19, ensure equitable treatment and vaccine availability, invest in public health, and invest in reducing the social determinants of health disparities.

Mona Fouad, M.D., Selwyn Vickers, M.D., andSixto Leal, M.D.At UAB, Marrazzo is the C. Glenn Cobbs, M.D., Endowed Professor in Infectious Diseases and a professor in the Department of Medicine; Benveniste is the senior vice dean for Basic Sciences in the School of Medicine, the Charlene A. Jones Endowed Chair in Neuroimmunology, and professor, Department of Cell, Developmental and Integrative Biology; Lund is the Charles H. McCauley Professor and chair, Department of Microbiology; Goepfert is director of the Alabama Vaccine Research Clinic and professor, Department of Medicine, Division of Infectious Diseases; and Erdmann is an assistant professor, Department of Medicine, Division of Infectious Diseases.

Also, Leal is assistant professor, Department of Pathology; Harrod is the Benjamin Monroe Carraway Endowed Chair and professor, Department of Anesthesiology and Perioperative Medicine; Rowe is professor, Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine; Fouad is senior associate dean of Diversity and Inclusion, professor, Department of Medicine, and director, Division of Preventive Medicine; and Vickers is the James C. Lee Jr. Endowed Chair, senior vice president for Medicine and dean, School of Medicine.

Read more here:
Interdisciplinary work highlighted at COVID-19 Research Symposium - The Mix

Neurological diseases such as multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS) cause damage to nerve fibers that cant be reversed. Now, scientists at Ohio State University and the University of Michigan have discovered an immune cell they believe could be harnessed to partially reverse this damage and slow MS, ALS and other neurodegenerative disorders.

By studying mouse models, the researchers discovered a new type of white blood cell known as a granulocyte. Its similar to a neutrophilan infection-fighting white blood cellbut it secretes growth factors that helped axons of the central nervous system regenerate, the team reported in the journal Nature Immunology. They identified a subset of human immune cells with similar properties, they said.

The ability of this subset of granulocyte to stimulate the regrowth of severed nerve fibers is "really unprecedented," said Benjamin Segal, M.D., professor and chair of neurology at Ohio State College of Medicine and co-director of the Wexner Medical Center's Neurological Institute, in a statement. "In the future, this line of research might ultimately lead to the development of novel cell based therapies that restore lost neurological functions across a range of conditions."

RELATED: How the brain's immune cells could guide treatment of neurodegenerative diseases

The team observed that the newly discovered granulocytes were similar to immature neutrophils. To test whether the granulocytes might have therapeutic powers, the researchers injected them into mice with injured optic nerves or broken nerve fibers. Those animals regrew nerve fibers, while mice injected with mature neutrophils did not.

The notion that immunotherapy might offer solutions to brain diseases is a popular one in neurological research. Last year, Stanford University researchers described a subpopulation of CD8 T cells that could be boosted with a peptide to relieve MS symptoms in mice.

And just last month, researchers led by Mount Sinais Icahn School of Medicine reported that immune cells called microglia can tamp down excessive neuron activity in diseases such as Alzheimers and Huntingtons. Targeting microglia in neurodegenerative diseases is also the focus of startup Tranquis Therapeutics, which launched with $30 million in capital this summer.

The next step for the Ohio State and University of Michigan researchers is to collect the neuro-enhancing granulocytes they discovered and figure out how to enhance them in the lab. Ultimately, they hope to determine whether the cells could be injected into patients to reverse damage to the central nervous system.

Such an immunotherapy could be useful not just for treating diseases like MS and ALS, but also for treating traumatic injuries to the brain and spine, they suggested.

Visit link:
Newly discovered immune cell offers path to treating ALS, MS and other brain diseases - FierceBiotech

NATICK, Mass., Oct. 29, 2020 /PRNewswire/ -- AffyImmune Therapeutics today announced enrollment of the first patient in its Phase I clinical study evaluating AIC100, the company's novel affinity-tuned CAR-T cell product, in patients with advanced, refractory thyroid cancer. The trial is designed to test safety, biological activity and real-time assessment of CAR T cell localization in patients.

The study, entitled: 'Phase I study of AIC100 in relapsed and/or refractory advanced thyroid cancer and anaplastic thyroid cancer' is being conducted at Weill Cornell Medicine. Unlike most CAR-T cell products, AIC100 was designed to specifically target tumor cells overexpressing the target (ICAM-1) while avoiding normal cells expressing lower levels. This was accomplished by lowering the affinity of the targeting portion of the chimeric antigen receptor (CAR) of AIC100 through directed evolution to levels more comparable to physiological levels governing T cell interactions with their targets. Prior studies in animal models clearly showed that that these lower affinity CAR T cells not only spared normal cells but also persisted longer having greater anti-tumor activity in animal models.

Eric von Hofe, President of AffyImmune Therapeutics, stated: "After overcoming a few COVID-19 related delays we are excited to announce the enrollment of our first patient in the AIC100 trial, this marks another important step for us. Affinity tuning clearly provides a number of advantages over the traditional approach of designing CAR-T cells." He continued, "the resulting CAR-T cells are able to discriminate based on target expression, persist longer for better tumor cell killing and open the door to targeting antigens previously avoided for fear to on-target off-tumor toxicity. We are gratified in being able to bring this novel CAR-T product to the clinic for refractory thyroid cancers, which are notoriously aggressive with no good treatment options."

About AffyImmune Therapeutics, Inc.

AffyImmune is realizing the potential of cancer immunotherapy by extending the anti-cancer activity of CAR-T cell therapy to solid tumors, improving the safety and efficacy of CAR-T treatment. Based on Professor Moonsoo Jin's work at Weill Cornell Medicine, AffyImmune's proprietary technology allows fine-tuning of the affinity of CAR-T cells to selectively kill tumor cells while sparing healthy cells to reduce toxicity. AffyImmune scientists have also developed a tracking system that can be engineered into any CAR-T cell to allow for real-time localization of cells after administration to patients.

AffyImmune's lead asset, AIC100, is an affinity-tuned, 3rd generation CAR-T cell therapy co-expressing SSTR2. Preclinical studies in various solid tumor models demonstrated AIC100's robust and enduring tumor eradication and superior safety profile compared to standard, high-affinity CAR T cell therapy. In 2019, AffyImmune received Orphan Drug Designation by the FDA for AIC100 and began recruitment for a Phase 1 trial to treat advanced thyroid cancer.

Founded in 2016, AffyImmune is headquartered in Natick, MA and is incubated by ORI Capital.

About ORI Healthcare Fund L.P.

ORI Healthcare Fund is a $200 million venture capital fund focused on investing in innovative companies with disruptive technologies in the healthcare industry globally. The General Partner of the Fund was founded by Ms. Simone (Hong Fang) Song, the former head of China Healthcare Investment Banking at Goldman Sachs.

Contact information Eric von Hofe, [emailprotected] AffyImmune Therapeutics, Inc. 12 Michigan Drive Natick, MA 01760 +1 (617) 699-1965

SOURCE AffyImmune Therapeutics, Inc.

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AffyImmune Therapeutics Announces First Patient Enrolled in Phase I Clinical Trial of AIC100 CAR T cells for the Treatment of Advanced, Refractory...