Body

EL PASO, Texas - Sreenath Chalil Madathil, Ph.D., assistant professor in industrial manufacturing and systems engineering (IMSE) at The University of Texas at El Paso, is working to streamline the process and ease the patient experience at COVID-19 vaccination clinics in the United States to ensure faster vaccine distribution.

Madathil led a team of UTEP faculty, staff and students who observed several of El Paso's drive-though and walk-in clinics in early 2021. The team identified areas that likely created bottlenecks, which produce delays and other issues. They used the information from their observations to develop simulation models to experiment with a clinic's performance to further identify potential slowdowns, calculate resource utilization and reduce patient waiting time.

"We are truly pleased to have Dr. Madathil's expertise informing COVID-19 vaccination clinic design and implementation," said Patricia Nava, Ph.D., interim dean of UTEP's College of Engineering. "It's great that his team is so diverse in specialties and includes a student. Moreover, it is exciting to have a project that is so clearly impactful for our community. Learning about this project's existence will help demonstrate to potential students that engineering really is about using your creativity to harness science, math, and technology to make things better for humans and their environment."

Using simulation models, UTEP researchers can track various performance measures such as wait time, number of people in the queue and resource utilization.

"This quantitative scientific methodology will help university and community leaders efficiently plan for resources," Madathil said. "Our experts from IMSE, the College of Business Administration, the College of Health Sciences, the School of Nursing, and UTEP administration collaborated to develop these models. Moreover, the administration can test various 'What-if' scenarios if they need to test for potential increased capacity or working time. These models help stakeholders plan and design their vaccination event so that its implementation is carried out seamlessly. Developing such a decision support system is one small example of how we help our community."

Madathil fervently believes in the need to streamline health systems to reduce patient wait times and improve the overall patient experience. He is helping a few hospital systems in El Paso and Washington, D.C., to implement drive-through vaccination clinics. He anticipates the need for similar projects to continue to grow.

"We identified simple bottlenecks that, if not adequately addressed, will result in over mile-long traffic blocks and long waiting times. It is a huge inconvenience and unfair to the current priority population who receive the vaccines to have to wait for over two hours in a car," Madathil said. "We cannot afford to not learn from the mistakes of vaccine distribution to our senior people and improve the process. We must do it correctly the first time. We hope that this simple model helps improve patient experience and speedy recovery of our COVID-19 infected world."

Patients with lupus are more likely to have metabolic syndrome and insulin resistance - both factors linked to heart disease - if they have lower vitamin D levels, a new study reveals.

Researchers believe that boosting vitamin D levels may improve control of these cardiovascular risk factors, as well as improving long-term outcomes for patients with systemic lupus erythematosus (SLE).

Given that photosensitivity is a key feature of SLE, the scientists say that a combination of avoiding the sun, using high-factor sunblock and living in more northerly countries may contribute to lower levels of vitamin D in lupus patients. Patients with more severe disease also had lower vitamin D levels.

An international research team, led by experts at the University of Birmingham and University of Manchester, studied vitamin D levels in 1,163 SLE patients across 33 centres in 11 countries (UK, USA, Canada, Spain, The Netherlands, Sweden, Iceland, Switzerland, Turkey, South Korea and Mexico), publishing its findings in Rheumatology.

Report co-author Dr John A Reynolds, Clinical Senior Lecturer in Rheumatology at the University of Birmingham, commented: "Our results suggest that co-existing physiological abnormalities may contribute to long-term cardiovascular risk early on in SLE.

"We found a link between lower levels of vitamin D and metabolic syndrome and insulin resistance. Further studies could confirm whether restoring vitamin D levels helps to reduce these cardiovascular risk factors and improve quality of life for patients with lupus."

Lupus is an uncommon incurable immune system illness, more common in women, where the immune system is overactive, causing inflammation anywhere in the body. Untreated, the condition threatens irreversible damage to major organs including kidneys, heart, lungs and brain.

Metabolic syndrome is a combination of diabetes, high blood pressure (hypertension), abnormal cholesterol levels, and obesity. People with metabolic syndrome are at greater risk of getting coronary heart disease, stroke and other conditions affecting the blood vessels.

The researchers note that patients with SLE have an excess cardiovascular risk, up to 50 times that seen in people without the condition - this cannot be attributed to traditional cardiovascular risk factors, such as high blood pressure or smoking, alone.

The mechanisms underlying the association between high blood pressure and low vitamin D in SLE are not clear, but researchers believe they may be linked to impact of vitamin D deficiency on the renin-angiotensin hormone system, which regulates blood pressure, fluid and electrolyte balance, as well as systemic vascular resistance.

"This is the largest-ever study examining associations between vitamin D levels and metabolic syndrome in SLE; it also has the advantage of being an international cohort with diverse racial and ethnic backgrounds - generating results that will be applicable across many settings," commented Dr. Reynolds.

University of Maryland School of Medicine (UMSOM) researchers have identified the most toxic proteins made by SARS-COV-2--the virus that causes COVID-19 - and then used an FDA-approved cancer drug to blunt the viral protein's detrimental effects. In their experiments in fruit flies and human cell lines, the team discovered the cell process that the virus hijacks, illuminating new potential candidate drugs that could be tested for treating severe COVID-19 disease patients. Their findings were published in two studies simultaneously on March 25 in Cell & Bioscience, a Springer Nature journal.

"Our work suggests there is a way to prevent SARS-COV-2 from injuring the body's tissues and doing extensive damage," says senior author of the study Zhe "Zion" Han, PhD, Associate Professor of Medicine and Director of the Center for Precision Disease Modeling at UMSOM. He notes that the most effective drug against Covid-19, remdesivir, only prevents the virus from making more copies of itself, but it does not protect already infected cells from damage caused by the viral proteins.

Prior to the pandemic, Dr. Han had been using fruit flies as a model to study other viruses, such as HIV and Zika. He says his research group shifted gears in February 2020 to study SARS-COV-2 when it was clear that the pandemic was going to significantly impact the U.S.

SARS-COV-2 infects cells and hijacks them into making proteins from each of its 27 genes. Dr. Han's team introduced each of these 27 SARS-CoV-2 genes in human cells and examined their toxicity. They also generated 12 fruit fly lines to express SARS-CoV-2 proteins likely to cause toxicity based on their structure and predicted function.

The researchers found that a viral protein, known as Orf6, was the most toxic killing about half of the human cells. Two other proteins (Nsp6 and Orf7a) also proved toxic, killing about 30-40 percent of the human cells. Fruit flies that made any one of these three toxic viral proteins in their bodies were less likely to survive to adulthood. Those fruit flies that did live had problems like fewer branches in their lungs or fewer energy-generating power factories in their muscle cells.

For the remaining experiments, the researchers focused on just the most toxic viral protein, so they could figure out what cell process the virus hijacks during infection. Dr. Han's team found that the virus' toxic Orf6 protein sticks to multiple human proteins that have the job of moving materials out of the cell's nucleus--the place in the cell that holds the genome, or the instructions for life.

They then discovered that one of these human moving proteins, targeted by the virus, gets blocked by the cancer drug selinexor. The researchers tested selinexor on human cells and fruit flies making the toxic viral protein to see if the drug could help reverse the damage. Selinexor, like many cancer drugs is itself toxic. However, after accounting for its toxic effects, the drug improved human cell survival by about 12 percent. Selinexor prevented early death in about 15 percent of the flies making the toxic viral protein. The drug also restored branches in the lungs and the energy-generators in the muscle cells. Selinexor is FDA-approved to treat certain blood cancers.

"More than 1,000 FDA-approved drugs are in clinical trials to test as treatments for Covid-19, and luckily a trial testing selinexor, the drug used in our study, is being performed already," says Dr. Han. "If this trial proves to be successful, our data will have demonstrated the underlying mechanism for why the drug works."

Albert Reece, MD, PhD, MBA, Executive Vice President for Medical Affairs, University of Maryland Baltimore, and the John Z. and Akiko K. Bowers Distinguished Professor and Dean, University of Maryland School of Medicine, commented, "Although we now have vaccines, it may still be a while before we will have Covid-19 infections under control, especially with the new variants emerging. We will need to tap into every tool in the arsenal available to protect people from needless sickness, disability or even death, and this study guides us towards a new target for potential therapeutics."

March 23, 2021-- A new study published online in the Annals of the American Thoracic Society examines if the source of physician payment for a medical opinion influences whether the physician finds that a coal miner has black lung disease. The study is the first to look at this relationship in the workers' compensation process.

In "Association Between Financial Conflicts of Interest and ILO Classifications for Black Lung Disease," Lee S. Friedman, PhD, associate professor, School of Public Health, Division of Environmental and Occupational Health Sciences, University of Illinois Chicago and colleagues looked at which party reimbursed B-readers--physicians trained and licensed by the National Institute for Occupational Safety and Health (NIOSH) and approved by the U.S. Department of Labor (USDOL) to evaluate miners' chest X-rays during workers' compensation proceedings--and correlated the payments with diagnoses of black lung disease.

"Our findings demonstrate that B-readers who were ever hired by employers were substantially less likely to classify an absence of coal workers' black lung disease (pneumoconiosis) when they were contracted by the USDOL, compared to later classifications when hired by the employer," said Dr. Friedman. "We did not observe this disparity among physicians ever hired by a miner."

These physicians are hired by the USDOL for the initial evaluation. The miner and/or employer (mine operator), at their own expense, then has the option to request a supplemental evaluation if they feel the initial USDOL-funded classification is incorrect. They may pick any B-reader they choose.

The researchers looked at 63,780 X-ray classifications made by 264 B-reader physicians between 2000 and 2013 for U.S. coal miners' black lung claims. Of these, 7,656 court decisions for the period 2002-2019 were used to evaluate financial conflict of interest for each physician.

"The more frequently a physician is hired by an employer to provide a medical opinion on workers' compensation cases for black lung disease, the more likely that physician will not identify black lung disease on a chest X-ray," said Dr. Friedman. "And the more a physician works with a miner on their claim process, the more likely they will identify black lung disease."

Dr. Friedman noted that many miners cannot afford a supplemental evaluation following the evaluation by the B-reader selected by USDOL, so, often, the only additional classification submitted to the court is from the employer. "While bias is present in both sets of physicians, a vast majority of classifications submitted to these courts are paid for by mine operators. The employers will throw a lot of resources at these cases to discourage miners from filing for compensation by making the process protracted and painful."

One-fifth of all classifications submitted to USDOL were made by physicians who classified 95 percent of their cases in one direction - absence or presence of pneumoconiosis. The average B-reader noted the presence of pneumoconiosis in a third of X-rays. The vast majority of the physicians who classified X-rays in a singular direction were hired by employers and were reporting an absence of pneumoconiosis.

These evaluations are done through the Federal Black Lung Program, which is administered by the USDOL and charged with managing claims by coal miners for workers' compensation for totally disabling coal mine dust disease (black lung disease). Earlier reports raised concerns that financial conflicts of interest may systematically bias physicians when they are classifying chest X-rays for the absence, presence or severity of black lung disease.

Dr. Friedman and his colleagues concluded that their analysis demonstrates the need to reduce subjectivity in the classification of chest X-rays for black lung disease. "There remains a need for empirical analyses specific to the workers' compensation system, which is wholly lacking," they state. "All parties involved deserve a compensation system that is objective and expeditious."

They recommend a series of systematic reforms, as discussed in the paper.

BOSTON -- Researchers report in Science Advances that they have uncovered a new function for odontoblasts, the cells that form dentin, the shell beneath the tooth's enamel that encases the soft dental pulp containing nerves and blood vessels. "We found that odontoblasts, which support the shape of the tooth, are also responsible for sensing cold," says pathologist Jochen Lennerz, MD, PhD, one of the paper's senior authors and medical director of the Center for Integrated Diagnostics at Massachusetts General Hospital (MGH). "This research contributes a new function to this cell, which is exciting from a basic-science standpoint. But we now also know how to interfere with this cold-sensing function to inhibit dental pain."

Teeth that hurt from exposure to cold can occur for many reasons. Many people have experienced intense pain from cold when they have a hole in a tooth from an untreated cavity, for example. But teeth can also become very sensitive to cold from gum erosion due to aging. Some cancer patients treated with platinum-based chemotherapies have extreme cold sensitivity all over their bodies. "A breeze on the face registers as extreme pain in the teeth, which may even cause some patients to stop therapy," says Lennerz.

Tooth pain has been notoriously difficult to study. A tooth's hardness makes it a challenging tissue to study and inducing tooth pain in humans requires opening the tooth. The team of researchers, therefore, conducted experiments on mice whose molars were drilled under anesthesia. Mice with dental injuries manifest pain with their behavior; they drink up to 300% more sugar water than their litter mates without dental injuries, for example. In previous research, the team of investigators had discovered TRCP5, a protein encoded by the TRCP5 gene that is expressed in nerves in many parts of the body. Their earlier discovery allowed the researchers to zero in on TRCP5 as a mediator of pain from cold.

By studying genetically altered mice that did not have the TRCP5 gene, the researchers found that the mice with injured teeth did not manifest the increased drinking behavior and behaved like mice without dental injuries.

"We now have definitive proof that the temperature sensor TRCP5 transmits cold via the odontoblast and triggers nerves to fire, creating pain and cold hypersensitivity," says Lennerz. "This cold sensitivity may be the body's way to protect a damaged tooth from additional injury."

Specifically, in response to cold, the TRCP5 protein opens channels in the membrane of odontoblasts, enabling other molecules, such as calcium, to enter and interact with the cell. If the tooth's pulp is inflamed from a deep cavity, for example, TRCP5 is overabundant, causing increased electrical signaling via the nerves emerging from the root of the tooth and running to the brain, where pain is perceived. When gums recede from aging, teeth can become hypersensitive because the odontoblasts are sensing cold in a newly exposed region of the tooth. "Most cells and tissues slow their metabolism in the presence of cold, which is why donor organs are put on ice," says Lennerz. "But TRPC5 makes cells more active in cold, and the odontoblasts' ability to sense cold via TRPC5 makes this discovery so exciting."

Lennerz confirmed the presence of the TRPCS protein in extracted human teeth, which was a technical tour de force. "Our teeth aren't meant to be cut into ultra-thin layers so they can be studied under the microscope," says Lennerz, who first had to decalcify the teeth and put them in epoxy resin before slicing them and identifying the TRPC5 channels in the odontoblasts.

The research team also identified a pharmacological target for minimizing tooth sensitivity to cold. For centuries, oil of cloves has been used as a remedy for tooth pain. The active agent in oil of cloves is eugenol, which happens to block TRCP5. Toothpastes containing eugenol are already on the market, but the findings of this study may lead to more potent applications to treat teeth that are hypersensitive to cold. And there may be novel applications for eugenol, such as treating patients systemically for extreme cold sensitivity from chemotherapy. "I'm excited to see how other researchers will apply our findings," says Lennerz.

Colorectal cancer risk does not rise after bariatric surgery, a study from the University of Gothenburg shows. This finding is important for patients with obesity, and their healthcare professionals, when deciding upon such an operation.

Obesity is a known risk factor for several types of cancer, including colorectal cancer (affecting the colon or rectum). It is already established that bariatric surgery leads to a decrease in overall cancer risk in patients with obesity.

However, some studies on colorectal cancer have shown an elevated cancer risk after bariatric surgery, while others have reported a risk reduction. These conflicting results have raised concerns about this surgery and highlighted the need for more long-term studies analyzing the effect of bariatric surgery on colorectal cancer risk.

The current study, published in PLOS ONE, is based on data from the SOS (Swedish Obese Subjects) study, which began in 1987 and is led and coordinated from the Sahlgrenska Academy, University of Gothenburg, as well as data from the Swedish Cancer Register, kept by the National Board of Health and Welfare.

The scientists studied a group of 4047 individuals with obesity; 2,007 underwent bariatric surgery (surgery group) and 2,040 individuals received non-surgical obesity treatment (control group). The groups were comparable in terms of sex, age, body composition, risk factors for cardiovascular disease, psychosocial variables, and personality traits.

The median follow-up period of the study exceeded 22 years. Over this time, the surgery group underwent a significant weight loss, while the controls broadly retained their original weight. During the follow-up period, there were 57 cases of colorectal cancer in the surgery group and 67 in the control group.

"In this very long-term study, we could not verify that bariatric surgery is associated with changes in colorectal cancer risk in patients with obesity. This result is of high clinical relevance", states Magdalena Taube, associate professor at the department of Molecular and Clinical Medicine at Sahlgrenska Academy and the lead author of the study.

The SOS study is the only prospective, controlled study in the world that examines the very long-term effects of obesity surgery compared with conventional obesity treatment. This very long-term follow-up has been crucial for the conclusion of this study: the risk of colorectal cancer does not increase after bariatric surgery.

"Bariatric surgery leads to a substantial weight loss and better health in most patients, but it's still important to keep up healthy living habits and go for regular check-ups after the operation too," Taube concludes.

Australian researchers have discovered a new way to target an aggressive childhood cancer, neuroblastoma, one of the most common and dangerous cancers in young children.

The discovery may also have important implications for some other aggressive cancers in children, including certain brain tumours, as well as some adult cancers, including ovarian and prostate cancer.

The new research, led by scientists at Children's Cancer Institute and published in Nature Communications, has discovered that a cellular protein called ALYREF plays a crucial role in accelerating the effects of the cancer driver gene, MYCN, in neuroblastoma.

Scientists have known for some time that the one third of children with neuroblastoma who have very high levels of MYCN in their cancer cells have a much poorer prognosis. However, MYCN has proven to be an unreachable target for drug design. Instead, scientists have turned their attention to finding other molecules that work in close partnership with MYCN.

In the new research, Children's Cancer Institute scientists have shown that MYCN depends on ALYREF to drive the growth of neuroblastoma cells. According to Dr Zsuzsi Nagy and lead researchers Professor Glenn Marshall AM and Dr Belamy Cheung, this is a world-first discovery.

"We have been able to show for the first time that ALYREF binds to and actually controls MYCN function in neuroblastoma cells," explains Professor Marshall. "This means we now have a new molecule that we can target... a new way to get at MYCN and stop it from driving aggressive cancer growth."

Working with neuroblastoma cells, Professor Marshall and his team found that ALYREF bound to MYCN directly to switch on another protein, USP3, which prevents MYCN being degraded. This maintains the extremely high levels of MYCN needed to drive the cancer, and so acts as an accelerant. These findings strongly suggest that ALYREF inhibition could interrupt this cycle and prove to be a very valuable new therapeutic strategy for high-risk neuroblastoma.

The next step will be to develop a potent and specific ALYREF inhibitor - a drug capable of inhibiting the actions of this molecule ? and to test this in laboratory models

"This research provides new knowledge as a basis for drug discovery," said Dr Cheung. "Once we find a suitable drug candidate, we can take this to clinical trial in children with high levels of MYCN and ALYREF in their tumours."

Excitingly, targeting ALYREF may also prove to be a useful therapeutic strategy for other types of cancer which, like high-risk neuroblastoma, are known to be MYCN-driven. These include blood cancers, medulloblastoma, glioblastoma, retinoblastoma, ovarian cancer, Wilms' tumour, and neuroendocrine prostate cancer. Further research will be needed to explore this potential.

Expectant women are more likely to give birth early if they have high blood levels of a chemical used in flame retardants compared with those who have limited exposure, a new study finds.

These polybrominated diphenyl ethers (PBDEs) are used in the manufacture of furniture, carpeting, and other products to reduce flammability. Previous studies have found that the substances can leach into household dust and build up in the body where they may interfere with the thyroid, an organ that secretes brain-developing hormones. Childhood exposure to PBDEs has been linked to learning disabilities, autistic symptoms, and behavioral issues, among other developmental problems.

In an investigation led by an NYU Long Island School of Medicine researcher, nearly all pregnant women enrolled in the study had detectable levels of PBDEs in their blood. The findings revealed that women with concentrations above 4 nanograms per milliliter of blood were roughly twice as likely to deliver their children early via cesarean section or intentionally induced labor due to safety concerns for the mother or infant. By contrast, there was no elevated risk for preterm birth among women with PBDE levels below that threshold.

"Our findings illustrate that flame retardants may have a tremendous impact on childbirth even if exposure occurred early on in the pregnancy," says study lead author Morgan Peltier, PhD. "Although PBDE chemicals are used with good intentions, they may pose a serious health concern that may have lasting consequences for children." Peltier is an associate professor in the departments of Clinical Obstetrics, Gynecology, and Reproductive Medicine at NYU Long Island School of Medicine, part of NYU Langone Health.

According to Peltier, preterm birth is a leading cause of newborn death and occurs annually in about 15 million pregnancies worldwide. Experts have linked the phenomenon to long-term neurological disorders including cerebral palsy, schizophrenia, and learning problems that can extend into adulthood. Earlier research has pointed to PBDE exposure as a possible culprit behind preterm birth. However, these investigations only looked at exposure to the chemicals late in pregnancy and only examined white and African-American mothers.

The new study, published online Dec. 1 in the Journal of Perinatal Medicine, is the first to explore the link between PBDE exposure in the first trimester of pregnancy, says Peltier. He notes that the investigation looked at a wider demographic group as well, adding Asian and Hispanic women to the analysis.

For the study, the research team analyzed blood samples from 3,529 California women, 184 of whom delivered their infants early. They measured the samples for levels of PBDE-47, a form of the chemical that commonly builds up in the household. The investigators then divided the mothers into four groups based on their amount of exposure.

The study also accounted for other risk factors linked to preterm birth, such as the mother's ethnicity, age, and whether she smoked during pregnancy.

Among the study findings, the group with the highest PBDE levels had a 75 percent increased risk for a spontaneous preterm birth compared with women who had the lowest exposure. Such births occur when women suddenly go into early labor after an otherwise normal pregnancy.

According to Peltier, the study findings also challenged previous beliefs about the role of thyroid hormones in the association between PBDEs and preterm birth. As part of the investigation, the researchers measured blood levels of thyroid stimulating hormone (TSH), a substance used to assess thyroid activity. If flame retardants indeed prevent the organ from working properly, thereby disrupting hormone function, then TSH levels should rise, says Peltier.

However, the study revealed that TSH levels remained normal, suggesting that another mechanism must be at work. Peltier says a possible explanation is that PBDEs may interfere with hormones in the placenta instead of the thyroid.

Peltier adds that the research team next plans to follow the children born to mothers in the study over time to explore how preterm birth linked to flame retardants may affect their long-term brain development.

He cautions that the findings do not prove a direct cause and effect, but strengthen the association between so-called endocrine disrupting chemicals and spontaneous premature birth.

A University of Arizona Health Sciences researcher examined the role of cholesterol in both Alzheimer's disease and Type 2 diabetes to identify a small molecule that may help regulate cholesterol levels in the brain, making it a potential new therapeutic target for Alzheimer's disease.

There is no known cure for Alzheimer's disease, which affects more than 5.5 million people in the United States. In the last decade, scientists have found increasing evidence linking the underlying causes of Type 2 diabetes and Alzheimer's disease.

Type 2 diabetes occurs when insulin becomes less efficient at removing glucose from the bloodstream, resulting in high blood sugar that can cause abnormal cholesterol levels. A similar situation occurs in Alzheimer's disease, but rather than affecting the body as a whole, the effects are localized in the brain.

"Alzheimer's and diabetes share many common causes," said Gregory Thatcher, PhD, professor of pharmacology and toxicology in the UArizona College of Pharmacy and the newly named R. Ken and Donna Coit Endowed Chair in Drug Discovery. "Our goal was to develop a way of identifying compounds that would counteract many detrimental changes that contribute to both Alzheimer's and Type 2 diabetes."

The paper, "Discovery of Nonlipogenic ABCA1 Inducing Compounds with Potential in Alzheimer's Disease and Type 2 Diabetes," was published in the journal ACS Pharmacology and Translational Science.

When cholesterol rises, due to insulin resistence or other factors, the body starts a process known as reverse cholestrol transport, during which specific molecules carry excess cholesterol to the liver to be excreted. Apolipoprotein E (APOE) is one of the proteins involved in reverse cholesterol transport.

APOE is also the strongest risk factor gene for Alzheimer's disease and related dementia, and an independent risk factor for Type 2 diabetes and cardiovascular disease. Similarly, reduced activity of another cholesterol transporter, ATP-binding cassette transporter A1 (ABCA1), correlates with increased risk of cardiovascular disease, Type 2 diabetes and Alzheimer's disease.

"While most people are aware of so-called 'good cholesterol,' and 'bad cholesterol,' associated with risk of heart attack and stroke, these broad concepts are also applicable to a healthy brain," said Dr. Thatcher, who has been working to develop advanced therapeutics for Alzheimer's for more than 20 years. "Moving cholesterol to where it is needed in the body has positive effects on many physiological processes and can help clear misfolded proteins that accumulate in the brain."

Increasing the activity of ABCA1 is expected to positively influence insulin signaling and reduce inflammation in the brain, making it a potential therapy for both Type 2 diabetes and Alzheimer's disease. In this study, Dr. Thatcher and the research team designed a way to identify small molecules that improve the function of ABCA1 in the body while avoiding unwanted effects to the liver.

In a March 20 paper in the journal EBioMedicine, "Metabolomic analysis of a selective ABCA1 inducer in obesogenic challenge provides a rationale for therapeutic development," Dr. Thatcher's team honed in on a specific small molecule, CL2-57, due to its ability to stimulate ABCA1 activity with positive effects on liver and plasma triglycerides. The use of this compound showed improved glucose tolerance and insulin sensitivity, as well as reduced weight gain, among other beneficial effects.

Their future research will seek to improve the properties of the small molecules to increase the levels in the brain. Their long-term goal is to understand which patients suffering from the cognitive and neuropsychiatric symptoms of Alzheimer's and dementia will benefit from the treatment.

"During the Covid-19 pandemic we hear about the mounting deaths in nursing homes and it's important to remember that Alzheimer's and related dementia is a major cause of the elderly moving to nursing homes," Dr. Thatcher said. "It would be good to think of a future in which healthspan was extended, especially a healthy brain; maybe that's more important than lifespan."

New clues to a long-pursued drug target in cancer may reside within immune cells, researchers at the University of Michigan Rogel Cancer Center have discovered.

The findings, which appear in Nature Immunology, not only shed new light on cancer immunology, they also suggest clinical trials related to this key target -- an interaction that destabilizes the important p53 tumor suppressor protein -- may unnecessarily be excluding a large number of patients.

The researchers are optimistic that the findings could help make immunotherapy treatment more effective against cancer.

"Everyone agrees this interaction is really important. The question is why, after so many years of work by biologists, biochemists and pharmacologists at universities and major drug companies, why don't we have a drug that works?" says senior study author Weiping Zou, M.D., Ph.D., the Charles B. de Nancrede Professor of Pathology, Surgery, Immunology and Biology at the University of Michigan.

The answer, says Zou, is that it's not just what's happening inside a patient's tumor cells that needs to be taken into consideration -- their immune cells play a vital role, too.

"We decided to look at the problem from the perspective of immunology," he says. "We thought that even if this important interaction is understood in tumor cells, there may still be a problem in the immune system. So we sought to better understand what was happening in T cells -- the soldiers of the immune system. And what we found was quite unexpected."

The 'guardian of the genome'

To better understand the U-M team's findings, it may be helpful to introduce the key players in this biological drama.

The gene TP53 has been called the "guardian of the genome" because the protein it makes -- p53 -- is essential for DNA repair and cell division. About half of all cancers are critically driven by mutations in this single gene that disrupt its ability to function as a tumor suppressor.

Yet that leaves another 50% of cancers that arise in patients whose tumors carry intact TP53.

For these patients, scientists have long sought to develop medicines that can disrupt the interaction between p53 and Mdm2, which is involved in keeping p53 levels in check. The idea is that disrupting their interaction would make more p53 available to suppress cancer.

These trials have generally excluded patients with p53 mutations because a lack of functional p53 means that interaction isn't happening inside their cancers.

"You want to stop the degradation of p53, that's the goal," explains Zou, who is also director of the Center of Excellence for Immunology and Immunotherapy at the U-M Rogel Cancer Center. "This is a very simple concept, but people have been working on this for years and we still don't have any FDA-approved drugs."

This is where Zou and his colleagues tried something new. Their experiments sought to probe the interaction between p53 and Mdm2 not just inside tumor cells, but also inside immune cells.

Mdm2: bad in tumor cells, but essential in immune cells

Although disrupting the p53-Mdm2 interaction in tumor cells was generally positive, the U-M team found that if disrupting the interaction between the same proteins inside T cells results in less Mdm2 in T cells, then the T cells will be functionally impaired.

"We discovered that while Mdm2 is bad in the context of tumor cells because it gets rid of p53, it's also essential for T cell function and survival," Zou says. "T cells need Mdm2."

Likewise, immunotherapy needs T cells. The approach harnesses and boosts the power of the body's immune cells to kill cancer cells. Without working T cells, the body can't mount an immune response. This could be one reason why immunotherapy drugs do not work in more than half of patients.

The findings also have important implications for ongoing drug discovery efforts, Zou stresses.

"Our study suggests that when you design and screen a drug candidate, you have to take not only the tumor cells into consideration, but also the T cells," he says. "Although there's a feeling that Mdm2 in tumor cells is a bad thing, drug developers need to make sure Mdm2 is not abolished in T cells or it will contribute to poor clinical outcomes."

Along with experiments using mouse models lacking either MDM2 or p53 in their T cells, the scientists tested a promising new compound called APG115. APG115 interferes the interaction between Mdm2 and p53, causing an increase in Mdm2 expression in T cells. Thus, APG115 showed T cell-dependent anti-tumor activity in mouse models.

APG115 was discovered in the lab of Shaomeng Wang, Ph.D., a critical collaborator on the project and the Warner-Lambert/Parke-Davis professor and a professor of internal medicine and pharmacology at the U-M Medical School; Wang also holds an appointment in the U-M College of Pharmacy.

The compound was licensed from U-M by Ascentage Pharma and is currently in several clinical trials for the treatment of human cancer, including in combination with pembrolizumab in patients with metastatic melanomas or advanced solid tumors. Wang is a co-founder of Ascentage and its chief scientific advisor.

"This compound interferes with the interaction between p53 and Mdm2," Zou says. "And when we administered it, we saw two things happen: p53 expression was increased, which is exactly what you want; but Mdm2 levels also increased -- which was the opposite of what we expected."

The researchers mapped the molecular interactions, finding that inside T cells, Mdm2 plays another role besides interacting with p53. It stabilizes a protein called Stat5, which is, in turn, important for T cell survival and function.

So, this paradoxical result of increasing levels of Mdm2 in T cells actually enhances their tumor-fighting properties and could make immunotherapy treatment more effective, Zou says.

Moreover, the researchers found APG115 functioned regardless of whether tumors contained normal or mutated versions of TP53.

"So what this tells us is that clinical trials for drugs that target Mdm2, including those currently in development that target the interaction between p53 and Mdm2, could potentially be expanded to include patients who are currently excluded -- those whose tumors carry loss-of-function TP53 mutations," Zou says. "Right now, if a patient's tumor has mutated p53, then those patients wouldn't be eligible for clinical trials for drugs that target p53-Mdm2 interaction. What our research shows is that this is really unnecessary. Patients will have normal p53 and Mdm2 in their T cells, and that's where it's really important."

With this new finding, Zou and Wang believe that future clinical trials of APG115 and other Mdm2 inhibitors should include patients whose tumors harbor mutated p53.

More than half of the opioid tablets prescribed for patients who underwent orthopaedic or urologic procedures went unused in a new study by researchers at the Perelman School of Medicine at the University of Pennsylvania. Using an automated text messaging system that regularly checked in with patients on their pain and opioid use, the study also showed that most opioids are taken within the first few days following a procedure and may not be necessary to manage pain even just a week following a procedure. The study was published today in JAMA Network Open.

"Through simple text messaging we highlight a method which gives clinicians the information they need to reduce prescribing and manage pain," said co-lead author Anish Agarwal, MD, a clinical innovation manager in the Penn Medicine Center for Digital Health and an assistant professor of Emergency Medicine. "We found that more than 60 percent of the opioid tablets prescribed went unused, which tracks with the team's preliminary studies. We can begin to use these data in multiple ways: One approach would be to look at trends in patient-reported use and tailor future prescribing to meet the anticipated pain for the majority of patients undergoing a specific procedure."

In response to the opioid crisis, using text messaging to keep track of how many prescriptions patients actually take after a procedure - and to potentially right-size the amount prescribed - is relatively new but growing in popularity. The traditional ways that clinicians track their patients' opioid use could use a boost.

"Right now, care teams rely heavily on patient recall, which they may not be able to remember in detail; phone calls, which require a lot of effort in making calls; or tracking from the health system ordering, which does not provide information from the patients themselves about how much they are using, and how much pain they are in," explained co-lead author Daniel Lee, MD, an assistant professor of Urology. "So with these older methods, either the data we are getting could be inaccurate, or the way we get the data is not scalable for an entire health system."

Using automated text messaging systems, then, provides the opportunity for large-scale, near-real-time polling of patients. But as an emerging method, it requires study.

With that in mind, Agarwal, Lee, co-author Eric Hume, MD, director of Quality and Safety and an associate professor of Orthopaedic Surgery, and senior author M. Kit Delgado, MD, an assistant professor of Emergency Medicine and Epidemiology, and their team set out to test the text messaging system. Over a span of several months in 2019, they enrolled patients who'd had common orthopaedic and urologic procedures, ranging from knee arthroscopy to hand fracture fixes and vasectomies to prostatectomies.

A little more than 900 patients - approximately 45 percent of those eligible - participated in the study. About 80 percent were orthopaedic patients and just under 20 percent had urological procedures.

Participants were asked to rate their pain (on a scale of zero to 10), as well as if they felt able to manage that pain on the fourth day following their procedure. Subsequent texts went out on days seven, 14 and 21 to measure the change over time. Each of these texts also inquired about opioid tablet use which was matched to their initial prescription.

As time went on, the text messages showed that the average pain scores fell among patients of both classifications of procedures. At the same time, the ability to manage pain climbed, according to patients. However, this all seemed to be accomplished with fewer and fewer opioid pills, the study showed, and certainly far fewer than were prescribed. By day seven, most patients had actually stopped taking tablets (the average patient in the study took zero tablets by day seven).

The average Orthopaedic Surgery patient took six tablets across the entire study period, but had been prescribed 20. Among Urology patients, one tablet was the average amount used, compared to seven prescribed. The study showed that, across the board, 64 percent of patients didn't even use half of their prescription, and only 21 percent of Orthopaedic Surgery patients and 11 percent of Urology patients needed a refill a month out from their procedure.

"Having data on our prescription of opioids and the amount that was unused is eye-opening," said Hume. "This is so much more powerful and engaging than a generic message to reduce prescribing without an eye toward patient needs."

The team believes that knowing the difference between prescription rates and use, along with finding this reliable way to measure that difference, will be a game-changer in pain management for surgical procedures.

"The potential to translate these findings to tailor post-operative prescribing to patient needs and change national practice is high," said Delgado, who also serves as Co-Chair of the Penn Medicine Opioid Task Force. "This study has national implications, as it shows that patients only take a fraction of the amounts that we know are prescribed on average across the country. Previously we showed the median amount of opioid pills prescribed to be 40 tablets for knee arthroscopy and 20 tablets for prostate or bladder resections. We are in the process of rolling this automated text messaging platform to additional surgical groups within the health system and will continue to share our learnings to guide practice on a broader scale."

BOSTON - In the largest study of its kind to date, researchers at Massachusetts General Hospital, Brigham and Women's Hospital and the Ragon Institute of MGH, MIT and Harvard have found the new mRNA COVID-19 vaccines to be highly effective in producing antibodies against the SARS-CoV-2 virus in pregnant and lactating women. They also demonstrated the vaccines confer protective immunity to newborns through breastmilk and the placenta.

The study, published in the American Journal of Obstetrics and Gynecology (AJOG), looked at 131 women of reproductive age (84 pregnant, 31 lactating and 16 non-pregnant), all of whom received one of the two new mRNA vaccines: Pfizer/BioNTech or Moderna. The vaccine-induced titers - or antibody levels - were equivalent in all three groups. Reassuringly, side effects after vaccination were rare and comparable across the study participants.

"This news of excellent vaccine efficacy is very encouraging for pregnant and breastfeeding women, who were left out of the initial COVID-19 vaccine trials," says Andrea Edlow, MD, MSc, a maternal-fetal medicine specialist at MGH, director of the Edlow Lab in the Vincent Center for Reproductive Biology and co-senior author of the new study. "Filling in the information gaps with real data is key - especially for our pregnant patients who are at greater risk for complications from COVID-19. This study also highlights how eager pregnant and lactating individuals are to participate in research."

According to the Centers for Disease Control and Prevention, individuals who are pregnant are more likely to become severely ill with COVID-19, require hospitalization, intensive care or ventilation - and may be at increased risk for adverse pregnancy outcomes. The team also compared vaccination-induced antibody levels to those induced by natural infection with COVID-19 in pregnancy, and found significantly higher levels of antibodies from vaccination.

Vaccine-generated antibodies were also present in all umbilical cord blood and breastmilk samples taken from the study, showing the transfer of antibodies from mothers to newborns.

"We now have clear evidence the COVID vaccines can induce immunity that will protect infants," says Galit Alter, PhD, core member of the Ragon Institute and co-senior author of the study. "We hope this study will catalyze vaccine developers to recognize the importance of studying pregnant and lactating individuals, and include them in trials. The potential for rational vaccine design to drive improved outcomes for mothers and infants is limitless, but developers must realize that pregnancy is a distinct immunological state, where two lives can be saved simultaneously with a powerful vaccine. We look forward to studying all vaccine platforms in pregnancy as they become available."

The study was also able to provide insight into potential differences between the immune response elicited by the Pfizer vaccine compared to the Moderna vaccine, finding the levels of mucosal (IgA) antibodies were higher after the second dose of Moderna compared to the second dose of Pfizer.

"This finding is important for all individuals, since SARS-CoV-2 is acquired through mucosal surfaces like the nose, mouth and eyes," says Kathryn Gray, MD, PhD, an obstetrician at Brigham and Women's Hospital and a first author of the paper. "But it also holds special importance for pregnant and lactating women because IgA is a key antibody present in breastmilk."

People who are physically active on a regular basis recover better after surgery for colorectal cancer. However, starting to exercise only after the diagnosis is a fact had no effect on recovery, a University of Gothenburg thesis shows.

In working on his thesis, Aron Onerup, who obtained his doctorate in surgery at the University's Sahlgrenska Academy and is now a specialist doctor at Sahlgrenska University Hospital, carried out an observational study of 115 patients diagnosed with colorectal cancer.

The participants who had been physically inactive proved, three weeks after their surgery, to be at higher risk of not feeling that they had recovered physically. Among them, the risk of postoperative complications was also more than four times higher than it was for participants who had been physically active.

Studies with similar results were conducted for individuals scheduled for operations to treat breast cancer and biliary tract disease as well.

The question was whether the odds of recovery could be improved for patients diagnosed with colorectal cancer. In another study, 761 individuals were randomly assigned to either receive ordinary, routine care or follow an exercise program, on their own, for about two weeks before and four weeks after surgery for colorectal cancer.

However, this program - which included half an hour of moderate-intensity exercise daily - had no effect on the latter group's self-reported physical recovery, nor on their complication risk, repeat surgery, readmission to hospital, or length of hospital stay.

"Although the exercise study didn't show any effects in the brief postoperative period, it's possible that measures resulting in increased physical activity in the long term may have positive health effects. The key is not to introduce measures into health care until they've been scientifically evaluated," Onerup states.

However, the overall picture provides evidence that, at the point when it becomes clear that an operation for biliary tract disease or colorectal cancer is necessary, people's physical activity level is clearly connected with the subsequent course of their recovery.

"The research findings indicate that there are further reasons to work for a population that's as physically active as possible, besides the gains in terms of, for example, cardiovascular and mental health that are already known," Onerup says.

Oncotarget published "Phase 1 study of Z-Endoxifen in patients with advanced gynecologic, desmoid, and hormone receptor-positive solid tumors" which reported that Z-endoxifen administration was anticipated to bypass these variations, increasing active drug levels, and potentially benefiting patients responding sub-optimally to tamoxifen.

Patients with treatment-refractory gynecologic malignancies, desmoid tumors, or hormone receptor-positive solid tumors took oral Z-endoxifen daily with a 3 3 phase 1 dose escalation format over 8 dose levels.

Three patients had partial responses and 8 had prolonged stable disease; 44.4% of patients at dose levels 6–8 achieved one of these outcomes.

Six patients who progressed after tamoxifen therapy experienced partial response or stable disease for ≥ 6 cycles with Z-endoxifen; one with desmoid tumor remains on study after 62 cycles.

The Oncotarget article provides evidence that antitumor activity and prolonged stable disease are achieved with Z-endoxifen despite prior tamoxifen therapy, supporting further study of Z-endoxifen, particularly in patients with desmoid tumors.

The Oncotarget article provides evidence that antitumor activity and prolonged stable disease are achieved with Z-endoxifen despite prior tamoxifen therapy.

Dr. Alice P. Chen from The Division of Cancer Treatment and Diagnosis at The National Cancer Institute in Bethesda Maryland said, "Tamoxifen is a member of the selective estrogen receptor modulator (SERM) drug family and is approved by the FDA for the treatment of patients with estrogen receptor-positive (ER+) metastatic breast cancer, for adjuvant therapy of high-risk ER+/progesterone receptor-positive (PR+) breast cancer, and for chemoprevention in women at high risk of developing breast cancer."

However, only about 50% of women with metastatic ER breast cancer who receive treatment with tamoxifen derive benefit, and trials have yielded mixed results regarding the clinical benefit of tamoxifen based on dose or serum concentration.

Endoxifen and 4-hydroxy-tamoxifen have similar binding affinities for ERα and ERβ, which are approximately 100-fold higher than those of tamoxifen or NDM-tamoxifen, but endoxifen plasma concentrations following tamoxifen administration are 5- to 20-fold higher than 4-hydroxy-tamoxifen.

Multiple other factors, including age, body mass index, gender, and polypharmacy contribute to how patients metabolize tamoxifen into endoxifen.

Among patients who receive tamoxifen, levels of endoxifen are lower in poor metabolizers, a finding that appears to correlate with significantly reduced time to tumor recurrence in these patients compared to those with greater CYP2D6 metabolism following treatment with adjuvant tamoxifen.

The Chen Research Team concluded in their Oncotarget Research Output that additional preclinical and clinical data demonstrate that Z-endoxifen can elicit major responses in ER breast cancer that has progressed on tamoxifen.

Despite these data in breast cancer, the optimal dose or concentration of Z-endoxifen in other tumors is unknown; however, our observation that high dose Z-endoxifen elicits antitumor activity in patients with non-breast malignancies would be in keeping with the data already observed demonstrating Z-endoxifen antitumor activity in breast cancers that have progressed on tamoxifen.

Furthermore, the overall safety profile, achievable plasma concentrations of Z-endoxifen, and clinical efficacy seen in this trial indicate that this agent may particularly benefit patients who have progressed on tamoxifen treatment and suggest that further studies of Z-endoxifen should be considered in patients with non-breast malignancies.

Sign up for free Altmetric alerts about this article

DOI - https://doi.org/10.18632/oncotarget.27887

Full text - https://www.oncotarget.com/article/27887/text/

Correspondence to - Alice P. Chen - chenali@mail.nih.gov

Keywords -
Z-endoxifen,
phase 1,
tamoxifen,
pharmacokinetics

About Oncotarget

Oncotarget is a weekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology.

To learn more about Oncotarget, please visit https://www.oncotarget.com or connect with:

SoundCloud - https://soundcloud.com/oncotarget
Facebook - https://www.facebook.com/Oncotarget/
Twitter - https://twitter.com/oncotarget
LinkedIn - https://www.linkedin.com/company/oncotarget
Pinterest - https://www.pinterest.com/oncotarget/
Reddit - https://www.reddit.com/user/Oncotarget/

Oncotarget is published by Impact Journals, LLC please visit https://www.ImpactJournals.com or connect with @ImpactJrnls

Journal

Oncotarget

DOI

10.18632/oncotarget.27887

HOUSTON, TX - March 25, 2021 - Humans are born with tens of thousands of hematopoietic stem cells (HSCs) that collectively ensure lifelong production of blood and immune cells that protect us from infections. HSCs can either duplicate to produce more stem cell progeny or differentiate to produce distinct immune cell lineages, an extremely critical decision that ensures that the body achieves the fine balance between having enough immune cells to fight invaders while still retaining enough HSCs to maintain future blood production. As we age, HSCs accumulate mutations that lead to the emergence of genetically distinct subpopulations. This common phenomenon known as clonal hematopoiesis (CH) is known to start in early fifties and is frequently associated with loss of function mutations in the DNMT3A gene. CH is associated with a significantly higher risk of blood cancers, cardiovascular disease, stroke and all-cause mortality.

A study led by Dr. Katherine King, associate professor at Baylor College of Medicine and Texas Children's Hospital, shows for the first time that long-term infection and chronic inflammation drive CH mediated by the loss of Dnmt3a function. In addition, the study offers key insights into the mechanism by which chronic inflammation leads to CH and demonstrates the critical role of DNMT3a in regulating normal HSC responses to infections. The study was published in the journal Cell Stem Cell.

"Previously, we showed that chronic infection significantly impairs the ability of wild-type HSCs to remain in a quiescent stem cell state. Prolonged (lasting several months) exposure to a systemic bacterial infection promoted extensive differentiation of HSCs. While this produced sufficient immune cells to fight the infection, it also reduced the number of bone marrow HSCs by 90%," King said. "In contrast, HSCs in mice lacking Dnmt3a gene did not differentiate much. In fact, they underwent self-renewal to produce more HSCs. We undertook the current study to test our prediction that defective differentiation and increased duplication of Dnmt3a HSCs allows them to overtake and outcompete normal HSCs when fighting chronic infections or facing long-term inflammatory conditions."

To test their hypothesis, researchers used a combination of experimental and mathematical modeling experiments to test how HSCs from Dnmt3a mutant mice respond to long-term infection and chronic inflammation. For experimental validation, they generated mosaic mice that were generated by transplanting a mixture of whole bone marrow from Dnmt3a-mutant mice and normal mice into irradiated mice, which allowed them to track how each subpopulation of HSC contracts or grows relative to one another over time when infected for several months with Mycobacterium avium bacteria.

Using this model that mimics chronic infection in humans, they found long-term infection caused specific expansion of Dnmt3a-loss of function HSCs along with a concomitant reduction in their ability to differentiate into immune cells, which is contrary to the behavior exhibited by normal HSCs to chronic infection. Moreover, compared to the normal HSCs, Dnmt3a HSCs were more resistant to exhaustion and were less sensitive to stress-induced apoptosis ('cell death') upon chronic infection. Collectively, this indicates how a minor population of Dnmt3a HSCs could eventually overtake a major population of normal HSCs in the presence of chronic infection.

A number of viral or bacterial infections and chronic inflammatory stress conditions including tuberculosis, hepatitis, herpetic infections, and inflammatory bowel disease trigger the release of interferon gamma (IFNγ) by the immune system, which in turn, initiates a cascade of protective immune responses. The team found that compared to wild-type HSCs, Dnmt3a-loss of function HSCs exhibited an entirely opposite set of cellular responses and global changes in gene expression patterns in response to IFNγ, which tended towards preserving or even increasing the numbers of stem cells at the expense of mounting an effective response against imminent invaders or stress.

"We are excited by the findings of this study which opens several areas of future investigations. We have shown for the first time how chronic inflammation due to long-term infections or autoimmune conditions such as rheumatoid arthritis, ulcerative colitis or Crohn's disease dampen the body's immune response as we age. Moreover, it sheds light on the critically important role of DNMT3a in modulating immune responses during chronic infection or stress and also explains how aging and inflammation are linked to blood cancers," King concluded.