Study confirms racial differences in response to prostate cancer treatment

patient

A study designed to enroll an equal number of Black and white men with advanced prostate cancer confirms key findings that have been evident in retrospective analyses and suggest potential new avenues for treating Black patients who disproportionately die of the disease.

Researchers at Duke Cancer Institute enrolled 50 Black and 50 white men with advanced prostate cancer to test whether there were outcome differences on treatment with the hormone therapy abiraterone acetate plus the steroid prednisone. In retrospective data reviews, the Duke researchers had previously found racial differences in PSA responses among advanced prostate cancer patients.

Publishing online in the journal Cancer, the researchers confirmed trends indicating that Black men’s PSA levels dropped further and more frequently than those of white men undergoing the therapy. These PSA changes, however, did not result in differences in disease progression or overall survival times.

But the survival finding has an important subtlety, said lead author Daniel George, M.D., professor in the departments of Medicine and Surgery at Duke University School of Medicine. George noted that most drug studies among prostate cancer patients include a small fraction of Black men that is far lower than their numbers in the larger population.

Exclusions typically result because Black men with prostate cancer are more likely to have other illnesses such as diabetes and high blood pressure, which study leaders often fear could put them at higher risk for complications. Additionally, there are deep historic and cultural reasons that Black men tend to decline participation in clinical studies.

For their study, however, the Duke team—including senior author Andrew Armstrong, M.D., professor in the departments of Medicine and Surgery—found that Black men were eager to join the clinical trial.

They were able to enroll a much larger proportion of Black men than what most studies include, in part because the study was addressing a question pertaining to race. And they did not exclude men with co-existing conditions, asserting that since the treatment is FDA approved for this population, they should be inclusive of the patients they see in practice.

“When you look at the overall survival data for our study, they’re equal between Black and white men,” George said. “But given the prevalence of coexisting conditions in the Black men we enrolled, mortality should have actually been higher for them.

“Our finding that it was not higher is telling—it suggests Black men with prostate cancer can fare just as well as whites, even with other health issues,” George said. “And it signals that future studies should consider enrolling Black men despite these often-disqualifying conditions.”

George said the researchers also identified a possible marker of ancestry-dependent treatment outcomes that could help explain why Black men respond more readily to hormone therapy, potentially pointing to new ways to address advanced prostate cancer in Black men.

“We need to understand how genetic ancestry might affect treatment outcomes—especially disease responsiveness in prostate cancer—because we are now using and studying these therapies earlier in the disease where we have the opportunity to cure patients,” George said.

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Study examines movement in children with autism

UTEP study examines movement in children with autism

For more than a year, researchers at The University of Texas at El Paso’s Stanley E. Fulton Gait Research & Movement Analysis Lab in the College of Health Sciences have been using real-time 3-D animation to investigate motor impairments in children who have autism spectrum disorder (ASD). Their aim is to understand how children with autism can learn motor skills, so that they can receive effective therapies.

The results of their study, titled “Children With Autism Exhibit More Individualized Responses to Live Animation Biofeedback Than Do Typically Developing Children,” were recently published in the journal of Perceptual and Motor Skills. The paper’s release coincides with National Autism Awareness Month in April.

“The greatest takeaway from this study is that when teaching or coaching new movements to an individual with autism, the teacher or coach needs to understand the individual with autism’s specific motor learning characteristics,” said Jeffrey Eggleston, Ph.D., assistant professor of kinesiology and Gait lab director. He is the study’s lead author. “They need to look specifically at each child’s needs because each child is different.”

The study’s other authors include Alyssa N. Olivas, a student in the doctoral biomedical engineering program; Heather R. Vanderhoof and Emily A. Chavez, students in the Interdisciplinary Health Sciences (IHS) doctoral program; Carla Alvarado, M.D., board certified psychiatrist; and Jason B. Boyle, Ph.D., associate professor and interim chair of Kinesiology at UTEP.

More than 80% of children with ASD have gross motor skills issues, such as problems with balance and coordination, which can interfere with their communication and social interactions.

The 18-month UTEP study incorporated live animation biofeedback to teach 15 children who have ASD and were between the ages of 8 and 17 how to do a squat, a strength exercise that works multiple muscle groups in the body’s lower extremities.

Researchers compared their movement patterns to children without the disorder. They found that children with ASD displayed highly individualized responses to the live animation biofeedback, much more so than children with typical development, Eggleston said.

In the lab, children had 1-inch cubes called inertial measurement unit (IMU) sensors strapped to their pelvis, thighs, lower legs and feet. They followed an animation model on a computer screen, which showed them how to squat. The children would then try to perform the squat without looking at the animation.

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Study probes COVID among vaccinated at US nursing home

covid

An unvaccinated worker infected with a COVID variant sparked an outbreak at a US nursing home where nearly all the residents had been inoculated, said a study out on Wednesday.

The dozens of cases, including 22 among fully vaccinated residents and staff, highlighted the importance of broad vaccine coverage and prevention measures, according to the research released by the Centers for Disease Control and Prevention.

During the March outbreak at a nursing home in the state of Kentucky, 46 cases were identified, with three residents dying, including two who were not vaccinated, the study said.

The spread was traced back to a worker who had symptoms and was not vaccinated. The variant was R.1, which is “not currently identified as a CDC variant of concern or interest,” the paper said.

While the researchers noted the flare up of the disease showed the strong effect the vaccine had in preventing symptoms in the sick, they also noted its limits.

“This underscores the importance… that all persons, including those who have recovered from COVID-19, be vaccinated,” the authors wrote.

“A continued emphasis on strategies for prevention of disease transmission, even among vaccinated populations, is also critical,” they added.

Their findings, released alongside a study of a similar outbreak at a Chicago nursing home, pointed to the results of vaccinated and unvaccinated people mixing.

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Study models economic impact of proposed law to regulate high-risk diagnostic tests

test tube

Legislation currently under consideration in the U.S. Congress would increase regulatory oversight of certain diagnostic tests, and a new study by researchers at Massachusetts General Hospital (MGH) and colleagues from several other institutions demonstrates that its potential impact will depend on key details in the bill’s final language. This study, published in JCO Oncology Practice, offers the first evidence-based analysis of how new rules proposed for the regulation of laboratory-developed tests (LDTs) could affect health care costs in the United States.

“The idea of having more oversight of LDTs is justified,” says Jochen Lennerz, MD, Ph.D., medical director of the MGH Center for Integrated Diagnostics (CID) and the study’s senior author. “But our results show that it’s very important to align the language in this new law with the intent of what it’s trying to accomplish.”

From a regulatory standpoint, there are two categories of in vitro clinical tests (IVCTs), which include diagnostic tests performed in a test tube, culture dish, or elsewhere outside a living organism. Manufactured tests for many different conditions are commercially available. The Food and Drug Administration (FDA) closely regulates these tests, requiring manufacturers to submit data for premarket approval before they can be sold. However, clinical laboratories at hospitals and in other health care settings can create their own IVCTs for use in-house, which are known as LDTs. Currently, the FDA does not require premarket approval of LDTs and exercises little oversight of their use.

LDTs serve a variety of purposes, but one critically important role is identifying patients for novel drug therapies that target specific DNA variations, particularly if a commercial test is not yet available. This form of therapy, known as personalized medicine, is becoming increasingly important in cancer treatment.

Unfortunately, faulty IVCTs can produce inaccurate results, causing some patients to forgo potentially beneficial treatments and others to receive unnecessary and potentially harmful therapies. The proposed legislation, currently known as the Verifying Accurate and Leading-edge IVCT Development (VALID) Act, clarifies the authority of the FDA over all diagnostics tests.

If passed, VALID would focus on so-called high-complexity IVCTs, which have the greatest potential for patient harm if the results are incorrect. To comply with VALID, clinical laboratories would have to demonstrate accuracy of their LDTs, which includes a process called technology certification.

Lennerz believes that the stringency of how VALID is interpreted, which is not currently defined in the bill, will influence whether the proposed law can improve the quality of LDTs without significantly increasing future health care costs. He joined lead author Richard Huang, MD, and several colleagues in an effort to model the overall expense of maintaining the technology certification framework under VALID for cancer diagnostics. They based their estimates on 2019 data from CID, which performs more than 10,000 high-complexity LDTs for MGH patients each year.

The study found that maintenance costs for a lab performing that volume of LDTs would be $638,000 a year under low stringency and slightly higher ($685,000) under moderate stringency, but soar to $1.2 million under highly stringent enforcement. Extrapolating that data to reflect the added expense for the nation’s 886 cancer treatment centers, complying with VALID would increase U.S. health care costs by $565 million, $606 million, or $1.1 billion over a three-year period, depending on stringency of enforcement.

Lennerz believes the study’s important contribution is putting a price tag on VALID, which no one has yet done. “The key finding is that maintaining this new infrastructure will come at a cost,” he says.

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Study helps unravel why pregnant women develop heart failure similar to older patients

pregnant women

Researchers at Penn Medicine have identified more genetic mutations that strongly predispose younger, otherwise healthy women to peripartum cardiomyopathy (PPCM), a rare condition characterized by weakness of the heart muscle that begins sometime during the final month of pregnancy through five months after delivery. PPCM can cause severe heart failure and often leads to lifelong heart failure and even death. The study is published today in Circulation.

PPCM affects women in one out of every 2,000 deliveries worldwide, with about a third of those women developing heart failure for life, and about five percent of them dying within a few years. Maternal mortality in the United States has doubled in the last 20 years, and PPCM is a leading cause of these deaths. Previously, the reasons behind why women developed PPCM remained a mystery until a 2016 study strongly suggested that some genetic mutations predispose women to the disease. Zoltan P. Arany, MD, PHD, the Samuel Bellet Professor of Cardiology in the Perelman School of Medicine at the University of Pennsylvania was also the senior author of that study. This newly released study shines a light on four more genetic variants that had not previously been associated with PPCM. It found that this genetic profile is highly similar to that found in patients with non-ischemic dilated cardiomyopathy (DCM), a very similar disease that typically impacts middle-aged men and women, and one that the medical community knows more about.

“This study provides the first extensive genetic and phenotype landscape of PPCM and has major implications for understanding how PPCM and DCM are related to each other,” said Arany. “It shows that predisposition to heart failure is an important risk factor for PPCM, suggesting that approaches being developed for DCM may also apply to patients with PPCM.”

For the study, Penn researchers identified nearly 470 women with PPCM, retrospectively, from several academic centers in the United States and abroad, and looked at clinical information and DNA samples. Then, they performed next-generation sequencing on 67 genes, including a gene known as TTN, which generates a large protein that controls how heart muscle cells contract and pump blood. 10.4 percent of the patients sampled showed shortened variants in the TTN gene, compared with just 1.2 percent of the reference population. Researchers also found overrepresentation of shortened variants in three other genes not previously associated with PPCM, but previously associated with DCM.

Researchers hope this will push for changes to allow physicians to follow similar, well-established genetic testing practices and counseling guidelines already used for patients with DCM, as well as gene-specific therapies.

“We believe this study shows how important genetic screening and counseling are for women who develop PPCM, something that isn’t currently common practice, and perhaps even for their female family members of child-bearing age,” Arany said. “As a physician, knowing you have a patient with PPCM who shows these genetic mutations would lead you to make changes in care, such as lowering the threshold for defibrillator use in the case of high-risk variants, or counseling family members on their risk of developing PPCM.”

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UK researchers will deliberately reinfect people with COVID-19 in new ‘challenge study’

Researchers in the U.K. are looking for volunteers who have already had COVID-19 for a “challenge study” that will deliberately reexpose them to the novel coronavirus.

The goal of the study is to understand what immune response is needed to protect against reinfection with COVID-19, according to a statement from the University of Oxford, which has received approval to conduct the trial.

“If we could understand, in this really careful controlled way, exactly what kind of immune response is needed for protection [against reinfection], then we will be able to look at people who have natural infection and say whether or not they’re protected” against another infection, study chief investigator Dr. Helen McShane, a professor of vaccinology at the University of Oxford, said in a video about the study

In a challenge study, people who are at low risk of serious outcomes are intentionally exposed to a pathogen in a controlled lab environment. Earlier this year, other researchers in the U.K. began challenge studies in people who hadn’t been infected with COVID-19, deliberately exposing them to very small doses of the novel coronavirus SARS-CoV-2. 

For the new study, the researchers are recruiting healthy people ages 18 to 30 who were infected with COVID-19 at least three months prior to entering the study and have antibodies against the novel coronavirus, according to The Guardian.

The study will have two phases. The first phase, which will include 24 volunteers, aims to determine the lowest dose of SARS-CoV-2 that can cause an infection while producing little or no symptoms in the volunteers. 

“We start with a really, really small amount of the virus … and we check that that’s safe,” and then increase the dose if necessary (if it’s too low to cause an infection in any of the volunteers), McShane said in the video. 

“Our target is to have 50% of our subjects infected but with no, or only very mild, disease,” McShane told The Guardian.

The second phase will involve another 10 to 40 participants who will receive the dose determined in the first phase. The researchers hope to learn what levels of antibodies, T cells and other immune system components protect against reinfection.

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After being exposed to the virus, all of the participants will be quarantined for 17 days and  monitored closely. They will undergo numerous tests, including CT scans of their lungs and MRIs of their hearts, the researchers said.

Any participants who develop symptoms of COVID-19 will be treated with Regeneron’s monoclonal antibodies, which have been shown to reduce the risk of hospitalizations from COVID-19.

The participants will be followed for at least eight months after they recover from their second infection. Each participant will receive nearly $7,000 (£5,000) for being included in the study, The Guardian reported.

The first phase of the study is expected to start this month, and the second phase is expected to begin in the summer, the researchers said.

Originally published on Live Science.   

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Study ratifies link of processed meat to cardiovascular disease and death

processed meat

A global study led by Hamilton scientists has found a link between eating processed meat and a higher risk of cardiovascular disease. The same study did not find the same link with unprocessed red meat or poultry.

The information comes from the diets and health outcomes of 134,297 people from 21 countries spanning five continents, who were tracked by researchers for data on meat consumption and cardiovascular illnesses.

After following the participants for almost a decade, the researchers found consumption of 150 grams or more of processed meat a week was associated with a 46 percent higher risk of cardiovascular disease and a 51 percent higher risk of death than those who ate no processed meat.

However, the researchers also found moderate levels of consumption of non-processed meats had a neutral effect on health.

“Evidence of an association between meat intake and cardiovascular disease is inconsistent. We therefore wanted to better understand the associations between intakes of unprocessed red meat, poultry, and processed meat with major cardiovascular disease events and mortality,” said Romaina Iqbal, first author of the study and an associate professor at the Aga Khan University in Karachi, Pakistan.

“The totality of the available data indicates that consuming a modest amount of unprocessed meat as part of a healthy dietary pattern is unlikely to be harmful,” said Mahshid Dehghan, investigator for the Population Health Research Institute (PHRI) of McMaster University and Hamilton Health Sciences.

The Prospective Urban Rural Epidemiology (PURE) study was launched in 2003 and is the first multinational study that provides information on the association between unprocessed and processed meat intakes with health outcomes from low, middle and high-income countries.

“The PURE study examines substantially more diverse populations and broad patterns of diet, enabling us to provide new evidence that distinguishes between the effects of processed and unprocessed meats,” said senior author Salim Yusuf, executive director of the PHRI.

Participants’ dietary habits were recorded using food frequency questionnaires, while data was also collected on their mortality and major cardiovascular disease events. This allowed researchers to determine the associations between meat consumption patterns and cardiovascular disease events and mortality.

The authors believe that additional research may improve current understanding of the relationship between meat consumption and health outcomes. For example, it is unclear what study participants with lower meat intakes were eating instead of meat, and if the quality of those foods differed between countries.

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Study of NCOA3 yields novel findings of melanoma progression

melanoma

For the first time, activation of nuclear receptor coactivator 3 (NCOA3) has been shown to promote the development of melanoma through regulation of ultraviolet radiation (UVR) sensitivity, cell cycle progression and circumvention of the DNA damage response. Results of a pre-clinical study led by Mohammed Kashani-Sabet, M.D., Medical Director of the Cancer Center at Sutter’s California Pacific Medical Center (CPMC) in San Francisco, CA were published online today in Cancer Research, a journal of the American Association for Cancer Research.

“Our research suggests a previously unreported mechanism by which NCOA3 regulates the DNA damage response and acts as a potential therapeutic target in melanoma, whereby activation of NCOA3 contributes to melanoma development following exposure to ultraviolet light,” says Dr. Kashani-Sabet, who collaborated with scientists at CPMC’s Research Institute, the University Duisburg-Essen in Germany and the Knight Cancer Institute in Portland, OR for the study.

Epidemiological studies suggest a role for UVR in melanoma causation, supported by whole genome sequencing studies demonstrating a high burden of UV-signature mutations. But the precise molecular mechanisms by which melanoma develops following UVR remain poorly understood, necessitating the identification of additional molecular factors that govern both UV and melanoma susceptibility.

NCOA3 (also known as AIB1 or SRC-3) is a member of the nuclear hormone receptor coactivator family, and regulates gene expression through its interaction with various transcription factors. NCOA3 was initially shown to be amplified in breast cancer, and has a demonstrated oncogenic role in various solid tumors. However, a role for NCOA3 in UVR-mediated melanomagenesis has not been previously demonstrated.

By utilizing a combination of in vitro, in vivo and PDX modeling of melanomagenesis, Dr. Kashani and colleagues assessed the effects of regulating NCOA3 expression in human melanoma cells as well as in melanocytes, identifying multiple oncogenic pathways regulated by NCOA3 in melanoma progression.

Results showed that down-regulation of NCOA3 expression, either by genetic silencing or small molecule inhibition, significantly suppressed melanoma proliferation in melanoma cell lines and PDXs. NCOA3 silencing suppressed expression of xeroderma pigmentosum C and increased melanoma cell sensitivity to UVR. Suppression of NCOA3 expression led to activation of DDR effectors and reduced expression of cyclin B1, resulting in G2/M arrest and mitotic catastrophe.

A single nucleotide polymorphism in NCOA3 (T960T) was associated with decreased melanoma risk, given a significantly lower prevalence in a familial melanoma cohort than in a control cohort without cancer. Additional studies suggest this polymorphism decreases NCOA3 protein production, and is accompanied by increased sensitivity to ultraviolet light—resulting in cell death.

Taken together, these findings are consistent with a model of melanoma initiation whereby elevated NCOA3 expression promotes melanocyte survival following exposure to UVR. This survival advantage enables accumulation of UVR-mediated DNA damage. Over the lifetime of an individual who is susceptible to melanoma, significant exposure to UVR can result in both the high mutational burden and uncontrolled cellular proliferation that characterize the disease. By contrast, these effects are attenuated following expression of the T960T polymorphism, with increased sensitivity to UV-mediated cell death, thereby protecting against the carcinogenic effects of UVR.

“Our results demonstrate an unprecedented role for a molecular marker in distinct stages of tumor progression. These results identify NCOA3 as a candidate susceptibility marker for melanoma, as a potential diagnostic marker, as a prognostic marker of melanoma survival and as a target for therapy. We propose a critical role for NCOA3 in UVR-mediated melanomagenesis, and as a rational therapeutic target for melanoma,” says Dr. Kashani-Sabet.

Skin cancer is the most common type of cancer worldwide. Melanoma accounts for about 1% of skin cancers but causes a large majority of skin cancer deaths. This year, approximately 106,000 Americans will be diagnosed with melanoma.

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Cells burn more calories after just one bout of moderate aerobic exercise, study finds

Cells burn more calories after just one bout of moderate aerobic exercise, OSU study finds

In a recent study testing the effects of exercise on overall metabolism, researchers at Oregon State University found that even a single session of moderate aerobic exercise makes a difference in the cells of otherwise sedentary people.

Mitochondria are the part of the cell responsible for the biological process of respiration, which turns fuels such as sugars and fats into energy, so the researchers focused only on mitochondria function.

“What we found is that, regardless of what fuel the mitochondria were using, there were mild increases in the ability to burn off the fuels,” said Matt Robinson, lead author on the study and an assistant professor in the College of Public Health and Human Sciences.

OSU researchers recruited participants who do not follow a regular exercise routine and had them ride a stationary bike for an hour at a moderate intensity. They biopsied their muscles 15 minutes later to test how efficient the mitochondria were after the exercise was completed and compared those results with a resting day.

Post-exercise, study participants’ mitochondria burned 12-13% more fat-based fuel and 14-17% more sugar-based fuel. While the effects were not drastic, they were consistent, Robinson said.

“It’s pretty remarkable that even after just one hour of exercise, these people were able to burn off a little more fuel,” he said.

Previous research in the field has long established that regular exercise creates lasting change in people’s metabolism, making their bodies burn more energy even when they’re not working out.

Prior studies have looked at highly trained or athletic people, but Robinson’s team wanted to look specifically at singular bouts of exercise in people who were generally active and disease-free but who did not have structured exercise regimes. These people were on the lower end of fitness, which is associated with low mitochondrial abundance and energy production. Participants were monitored while working out at approximately 65% of their maximal effort, where they could keep up the cycling pace for an hour or more and still comfortably carry on a conversation.

Robinson said they’re hoping these results help break down the mental barrier of people thinking they need to be elite athletes for exercise to make an impact on their health.

“From a big picture health perspective, it’s very encouraging for people to realize that you can get health benefits from a single session of exercise,” Robinson said. “We’re trying to encourage people, ‘You did one, why don’t you try to do two? Let’s do three.’

“We know that exercise is good for you, in general. But those benefits of that single bout of exercise seem to fade away after a day or two. You get the long-term benefits when you do that exercise again and again and you make it a regular habit.”

In this study, Robinson’s research team focused narrowly on mitochondria to find out how big a role mitochondria play in the overall function of muscle metabolism. Other studies are looking at changes in blood flow to the muscle and how the muscle metabolizes fats versus sugars.

From a disease perspective, Robinson said it’s clear that obesity and diabetes involve impairments in metabolism. Physiologically, when the body undergoes exercise, sugars tend to be burned off first while fats are stored, but in cases of diabetes and obesity, there is some dysregulation in metabolism that causes the body to not be able to switch between the two types of fuel.

Exercise can help reset that system, he said.

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Gene therapy using ‘zinc fingers’ may help treat Alzheimer’s disease, animal study shows

brain

Researchers have used a genetic engineering strategy to dramatically reduce levels of tau—a key protein that accumulates and becomes tangled in the brain during the development of Alzheimer’s disease—in an animal model of the condition. The results, which come from investigators at Massachusetts General Hospital (MGH) and Sangamo Therapeutics Inc., could lead to a potentially promising treatment for patients with this devastating illness.

As described in Science Advances, the strategy involves a gene regulation technology called zinc finger protein transcription factors (ZFP-TFs), which are DNA-binding proteins that can be harnessed to target and affect the expression of specified genes. In this case, the therapy was designed to target and silence the expression of the gene that codes for tau. Mice with Alzheimer’s disease received a single injection of the treatment—which employed a harmless virus to deliver the ZFP-TFs to cells—directly into the hippocampus region of the brain or intravenously into a blood vessel. Treatment with ZFP-TFs reduced tau protein levels in the brain by 50% to 80% out to 11 months, the longest time point studied. Importantly, the therapy reversed some of the Alzheimer’s-related damage that was present in the animals’ brain cells.

“The technology worked just the way we had hoped—reducing tau substantially for as long as we looked, causing no side effects that we could see even over many, many months, and improving the pathological changes in the brains of the animals,” says senior author Bradley Hyman, MD, Ph.D., who directs the Alzheimer’s disease research unit at the MassGeneral Institute for Neurodegenerative Disease. “This suggests a plan forward to try to help patients.”

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