Publisher Health

Researchers at University of California San Diego School of Medicine and in Japan have used an ancient fish to reel in new insights about human biology and, in particular, how and why a widely used medication works to abort pregnancies (in people, not fish).
The findings published in the February 11, 2022 online issue of ACS Pharmacology & Translational Science.
The elephant shark (Callorhinchus milii) is an unusual looking and uncommon animal model. Known by several names, such as ghost shark, elephant fish and silver trumpeter, the species is found in waters off southern Australia. The smooth-skinned, cartilaginous fish grows to a maximum size of four feet and poses no threat to humans. Their distinctive hoe-shaped, proboscis-like snout is used to detect prey, primarily shellfish and bottom-dwelling invertebrates, through movement and weak electrical fields.
But it’s a different attribute that makes elephant sharks suitable for certain kinds of research: They belong to the oldest group of jawed vertebrates and have the slowest evolving genome of all known vertebrates, which make them ideal for investigating how some biological systems have evolved in bony vertebrates, including humans. The latest study, comparing progesterone receptor (PR) activation in elephant sharks and humans, provides insights in how steroid activation evolved in the latter, and why it works the way it does today.
Progesterone is a hormone that, in women, regulates the menstrual cycle, preparation for conception and maintaining a pregnancy. The effects of progesterone are mediated by its nuclear receptor, PR. Researchers found that PR activation in elephant sharks requires a different mix of hormones and steroids than PR activation in humans, with the latter requiring fewer but more specific hormonal and steroidal triggers.
More interestingly, they discovered that RU486, a medically approved clinical compound that blocks or terminates pregnancy in humans and is commonly called “the abortion pill,” does not have the same effect in elephant sharks. It does not inhibit progesterone activation of elephant shark PR.
The findings, said senior author Michael Baker, PhD, research professor at UC San Diego School of Medicine, illuminate the divergent evolutionary paths of fish and humans, and offer insight about how other more popular animal models, specifically zebrafish, might be problematic when attempting to parse the pathology of endocrine disruption (when natural or manmade chemicals mimic or interfere with hormones that regulate development, reproduction and other basic functions) or develop new drugs.
Co-authors include: Xiaozhi Lin, Shigeho Ijiri and Yoshinao Katsu, Hokkaido University, Japan; and Wataru Takagi and Susumu Hyodo, University of Tokyo
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Materials provided by University of California – San Diego. Original written by Scott La Fee. Note: Content may be edited for style and length.

Traumatic injuries are the leading cause of death in the U.S. among people 45 and under, and such injuries account for more than 3 million deaths per year worldwide. To reduce the death toll of such injuries, many researchers are working on injectable nanoparticles that can home in on the site of an internal injury and attract cells that help to stop the bleeding until the patient can reach a hospital for further treatment.
While some of these particles have shown promise in animal studies, none have been tested in human patients yet. One reason for that is a lack of information regarding the mechanism of action and potential safety of such particles. To shed more light on those factors, MIT chemical engineers have now performed the first systematic study of how different-sized polymer nanoparticles circulate in the body and interact with platelets, the cells that promote blood clotting.
In a study of rats, the researchers showed that particles in an intermediate size range, around 150 nanometers in diameter, were the most effective at stopping bleeding. These particles also were much less likely to travel to the lungs or other off-target sites, which larger particles often do.
“With nano systems, there is always some accumulation in the liver and the spleen, but we’d like more of the active system to accumulate at the wound than at these filtration sites in the body,” says Paula Hammond, an MIT Institute Professor, head of the Department of Chemical Engineering, and a member of MIT’s Koch Institute for Integrative Cancer Research.
Hammond; Bradley Olsen, the Alexander and I. Michael Kasser Professor of Chemical Engineering; and George Velmahos, a professor of surgery at Harvard Medical School and chief of trauma, emergency surgery, and surgical critical care at Massachusetts General Hospital, are the senior authors of the study.
MIT graduate student Celestine Hong is the lead author of the paper, which appears in the journal ACS Nano.

Annual MRI screenings starting at ages 30 to 35 may reduce breast-cancer mortality by more than 50% among women who carry certain genetic changes in three genes, according to a comparative modeling analysis to be published Feb. 17, 2022, in JAMA Oncology.
The predictions involve pathogenic variants in ATM, CHEK2 and PALB2 genes — which collectively are as prevalent as the much-reported BRCA1/2 gene mutations. Authors of the study, published in JAMA Oncology, contend that their findings support MRI screening in some of these women earlier than existing preventive-care guidelines propose.
“Screening guidelines have been difficult to develop for these women because there haven’t been clinical trials to inform when to start and how to screen,” said Dr. Kathryn Lowry, an assistant professor of radiology at the University of Washington School of Medicine. She was the paper’s lead author.
The work was a collaboration of the Cancer Intervention and Surveillance Modeling Network (CISNET), the Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium, and the Breast Cancer Surveillance Consortium.
Using established breast-cancer simulation models, the researchers input age-specific risk estimates provided by CARRIERS and recent published data for screening performance. The CARRIERS data involved more than 32,000 breast-cancer patients and a similar number of patients who had no cancer.
“For women with pathogenic variants in these genes, our modeling analysis predicted a lifetime risk of developing breast cancer at 21% to 40%, depending on the variant,” Lowry said. “We project that starting annual MRI screening at age 30 to 35, with annual mammography starting at age 40, will reduce cancer mortality for these populations of women by more than 50%.”
The simulations compared the combined performance of mammography and MRI against mammography alone, and projected that annual MRI conferred significant additional benefit to these populations.

When acute myeloid leukemia (AML) relapses, it is more difficult to treat and outcomes are dismal. Scientists at St. Jude Children’s Research Hospital have discovered a mutation in pediatric AML that physicians can use to identify high-risk patients and better guide treatment. A paper on the work appeared today in Blood Cancer Discovery, a journal of the American Association for Cancer Research.
“We started broadly because it was clear that we didn’t have a deep enough understanding about why kids with AML relapse in the first place,” said co-corresponding author Jeffery Klco, M.D., Ph.D., St. Jude Department of Pathology. “We have a number of clinical trials at St. Jude for relapsed AML, so that gave us access to a large cohort of samples, and that is where the collaboration with our colleagues in Computational Biology became really beneficial to help us analyze the genetics.
“It became clear early on that there was a group of cases who had curious alterations in this gene UBTF, which had really only been superficially considered in the past,” Klco said.
A new high-risk subtype
The researchers evaluated the genomics of 136 St. Jude patients treated for relapsed AML. A specific type of mutation called a UBTF exon 13 tandem duplication (UBTF-TD) occurs in 9% of relapsed pediatric AML. This represents a significant and previously unrecognized subtype.
UBTF-TD AML is more common in children than adults. It is also associated with poor outcomes and an increased incidence of minimal residual disease (MRD). MRD refers to cancer cells that persist in small numbers after initial treatment, often giving rise to recurrence of the cancer.
Genetic analysis
The genomics of AML have been studied for many years, but this mutation has been mostly overlooked or undetected in previous work. Researchers at St. Jude developed the computational approaches to identify this, and potentially similar mutations, in AML and other cancers.
“This is an extremely difficult mutation to detect, so a lot of work went into developing the right algorithms. We had to develop our method from scratch,” said co-corresponding author Xiaotu Ma, Ph.D., St. Jude Department of Computational Biology. “Most of the existing methodologies assume there is only one event creating these kinds of mutations but, as with UBTF-TD, that isn’t always the case.”
“Now that we know what we’re looking for and how to find it, we can readily incorporate it into clinical genomics,” Ma said.
Clinical genomics can be used to screen for UBTF-TD mutations in AML to help identify high-risk patients. This process is already underway at St. Jude. The findings also open up new areas of investigation, including findings ways to target the protein created by UBTF-TD and determining how the aberrant peptide contributes to leukemia.
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Acute myeloid leukaemia, which affects blood and bone marrow cells, is a particularly dangerous form of cancer. More than half of patients under the age of 60 die. This proportion rises to 85% for patients over 60. A team from the University of Geneva (UNIGE), Switzerland, and from Inserm, in France, have identified a previously unknown mechanism that could lead to the development of new therapies. The selective activation of AMPK, a key enzyme in the energy balance of tumour cells, would indeed lead to their death by triggering the cells stress response. Moreover, the scientists have successfully exploited this energy gap in an animal model of the disease: a combination of two drugs — one of which is already on the market — has indeed shown promise. However, their effectiveness has yet to be confirmed on leukaemia stem cells, which have the ability to escape many treatments to restart tumour growth. These results can be found in the journal Cell Reports.
Jérôme Tamburini, an associate professor in the Department of Medicine and in the Translational Research Centre in Onco-Haematology (CRTOH) of UNIGE Faculty of Medicine and at the Swiss Cancer Center Léman (SCCL) and a professor at Université de Paris, is working on the energetic mechanisms of tumour cells in acute myeloid leukaemia. A cell signalling pathway called AMPK is of particular interest to him. “AMPK is the main detector of the cells energy level,” explains Jérôme Tamburini. “This pathway is activated when energy is lacking and initiates the degradation of certain nutrients to produce the necessary energy — a process called catabolism. As without energy, no cell can survive, could it be possible to selectively manipulate this mechanism in tumour cells to cause their destruction, while preserving healthy cells?”
In 2015, Jérôme Tamburini and his colleagues at Inserm in Paris participated in the development with the GlaxoSmithKline (GSK) laboratory of a pharmacological component — GSK621 — which proved to be an excellent activator of AMPK in vitro. “After this initial proof of principle, we had to decipher the biochemical mechanisms at work in order to understand them in detail, and in particular which cellular pathways did GSK621 activate in leukaemia cells, the first step in hoping to exploit this phenomenon for therapeutic purposes,” explains Jérôme Tamburini.
An effective combination of two drugs
The first step was to perform a gene expression analysis of human tumour cells, which identified an enzyme, PERK, particularly activated in response to the presence of GSK621. This is a key element in the stress response of the endoplasmic reticulum, an intracellular structure specialised in the metabolism of proteins and lipids. “The activation of AMPK thus triggers the activation of PERK, followed by a chain of reactions leading to apoptosis, the programmed death of the cell,” explains Jérôme Tamburini. “In addition, the activation of AMPK by GSK621 sensitises the cells to the effects of another pharmacological drug, the venetoclax, which is now widely used to treat acute myeloid leukaemia, although with limited effectiveness when used alone.”
The scientists then combined the two drugs in mice carrying human tumour cells, and found that this combination controlled tumour development much more effectively than in monotherapy. While GSK621 was not designed to be a drug, other products are currently in clinical trials to combat metabolic diseases, which activate the AMPK pathway. “Understanding the mechanism involved has brought to light potential therapeutic targets that were previously unknown,” explains Jérôme Tamburini. “We will now be able to review all the drugs known to have an effect on these pathways and determine which combinations would be the most effective.”
What about leukaemic stem cells?
Leukaemic stem cells consists in a small population of cells within the tumour that can only be detected by their ability to spread again the tumour after an initially successful treatment. The main cause of relapse, these cells are sensitive to very few of the therapies usually used in leukaemia. Furthermore, evidence is still lacking to determine the effect that massive activation of AMPK would have on them. “Before testing drug combinations targeting this AMPK/PERK mechanism in human beings, we need to determine their effect on leukaemic stem cells,” the authors conclude.
Several laboratories were involved in this research, including Institut Cochin (Inserm/CNRS/University of Paris), the Cancer Research Center of Lyon (Inserm/CNRS/Claude Bernard Lyon 1 University/Léon Bérard Centre) and the Toulouse Cancer Research Center (Inserm/CNRS/Toulouse III — Paul Sabatier University)
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Materials provided by Université de Genève. Note: Content may be edited for style and length.

Melanoma, a type of skin cancer, is often curable when detected and treated in its early stages. However, the disease can rapidly spread to other organs in the body and become deadly. According to the American Cancer Society, more than 7,600 people die of the disease each year in the United States.
Thankfully, immune checkpoint inhibitors (ICI), a type of immunotherapy, have transformed the treatment of certain cancers, including melanoma, and improved patient care. But despite the availability of this immunotherapy, doctors have been unable to predict who will benefit from ICI and who will not.
Now, a team of researchers at Wake Forest School of Medicine, led by David R. Soto-Pantoja, Ph.D., associate professor of surgery and cancer biology, has discovered blood biomarkers that can potentially predict patient response.
Results from the study are published online in Clinical Cancer Research, a journal of the American Association for Cancer Research.
“When immunotherapy works, it can be very successful and improve overall survival. About 20% to 40% of patients will respond,” Soto-Pantoja said. “But predictive biomarkers are urgently needed to guide treatment decisions and to develop new approaches to therapeutic resistance.”
For the study, scientists analyzed blood samples of two patient groups before treatment, both with stage III and IV melanoma. One group of patients responded to ICI treatment and had a complete or partial response. The other patient group did not respond to ICI treatment and had disease progression.
Scientists examined the bioenergetics or cellular metabolism of circulating immune cells called peripheral blood mononuclear cells and the metabolomic profiles of plasma.
Cancer cells consume abnormal nutrients and release factors that can be sensed by blood circulating cells. According to Soto-Pantoja, it’s possible that mitochondria of circulating cells can sense these metabolic changes. Soto-Pantoja’s team also examined how this organelle changes function in patients’ blood cells.
“We found functional and molecular metabolic biomarkers, which are associated with ICI response, can be detected in blood before treatment,” Soto-Pantoja said.
The circulating immune cells of patients who responded to treatment had an increased extracellular acidification rate, a measure of glucose metabolism. Investigators also found changes in mitochondrial shape and structure changes that were linked to the response. In addition, the team identified a common metabolic signature that distinguished responders and non-responders — increased lactate levels to pyruvate (specific lipid and amino acid metabolites) and an elevated glucose receptor in patients who responded to treatment.
“Our study shows new insight in the treatment of melanoma that can be extended to other cancer types,” Soto-Pantoja said. “These biomarkers can potentially lead to personalized treatment strategies to improve overall survival.”
Funding for the study was provided by the V Foundation V Scholar in Cancer 519 Research Award No. V2019-018 and NCI Grant No. P30CA012197.
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Materials provided by Wake Forest Baptist Medical Center. Note: Content may be edited for style and length.

The Latest on Vaccines for Kids Under 5Apoorva MandavilliReporting on the coronavirusBut isn’t there new data on the vaccine’s effectiveness in children under 5?As the trial continued through December, some children became infected with the Omicron variant, giving the companies insight into the vaccine’s performance in the real world, and prompting the Food and Drug Administration to consider authorizing two doses of the vaccine. But as the number of infections grew, the data did not support that decision.

Advanced imaging technology developed by Yale researchers has helped them confirm that the destruction of brain synapses underlies the cognitive deficits experienced by patients with Alzheimer’s disease, according to a study published Feb. 17 in the journal Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association.
For many years, scientists have assumed that the loss of connections between brain cells caused Alzheimer’s-related symptoms, including memory loss, but actual evidence of the role of synaptic loss had been limited to a small number of brain biopsies and post-mortem brain exams conducted on patients with moderate or advanced disease. However, the emergence of a positron emission tomography (PET) scanning technology, developed at Yale, has allowed researchers to observe the loss of synapses in living patients with even mild symptoms of Alzheimer’s disease.
The new glycoprotein 2A (SV2A) PET imaging scan allowed scientists to measure metabolic activity at the brain synapses of 45 people diagnosed with mild to moderate Alzheimer’s disease. The researchers then measured each person’s cognitive performance in five key areas: verbal memory, language skills, executive function, processing speed, and visual-spatial ability.
They found that the loss of synapses or connections between brain cells was strongly associated with poor performance on cognitive tests. They also found that synaptic loss was a stronger indicator of poor cognitive performance than the loss of overall volume of neurons in the brain.
Yale researchers can now track the loss of synapses in patients over time, providing better understanding of development of cognitive decline in individuals, said Christopher van Dyck, a professor of psychiatry, neurology, and neuroscience at Yale School of Medicine, director of the Yale Alzheimer’s Disease Research Center, and senior author of the paper.
“The findings help us understand the neurobiology of the disease and can be an important new biomarker to test the efficacy of new Alzheimer’s drugs,” said Adam Mecca, assistant professor of psychiatry and lead author of the paper.
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Materials provided by Yale University. Original written by Bill Hathaway. Note: Content may be edited for style and length.

We all know exercise is good for us, but that still leaves plenty of questions. How much exercise? Who benefits the most? And when in our lives? New research led by University of Pittsburgh psychologists pools data from dozens of studies to answer these questions, showing that older adults may be able to prevent declines in a certain kind of memory by sticking to regular exercise.
“Everyone always asks, ‘How much should I be exercising? What’s the bare minimum to see improvement?’ ” said lead author Sarah Aghjayan, a Clinical and Biological Health Psychology PhD student in the Kenneth P. Dietrich School of Arts and Sciences. “From our study, it seems like exercising about three times a week for at least four months is how much you need to reap the benefits in episodic memory.”
Episodic memory is the kind that deals with events that happened to you in the past. It’s also one of the first to decline with age. “I usually like to talk about the first time you got behind the wheel of a car,” said Aghjayan. “So you might remember where you were, how old you were, who was in the passenger seat explaining things to you, that feeling of excitement.”
Exercise that gets the heart pumping has shown promise in increasing brain health, and experiments in mice show that it improves memory — but studies looking at the same link in humans have come out mixed.
Seeking clarity in the muddy waters of the scientific literature, the team pored over 1,279 studies, eventually narrowing them down to just 36 that met specific criteria. Then they used specialized software and no small number of Excel spreadsheets to transform the data info a form where the different studies could be directly compared.
That work paid off when they found that pooling together those 36 studies was enough to show that for older adults, exercise can indeed benefit their memory. The team, including Aghjayan’s advisor Kirk Erickson in the Department of Psychology and other researchers from Pitt, Carnegie Mellon University and the University of Iowa, published their results in the journal Communications Medicine on Feb. 17.

Denisse Takes’s world is very small these days. She makes a living by producing songs from her living room, plays “Animal Crossing” online with friends and leaves her home in Burbank, Calif., only occasionally to walk her dog.Even as her social media feeds are flooded with friends and family members returning to their normal lives, she sees no one except for her husband, who donated his kidney in 2015 so that Ms. Takes, 37, could receive a compatible donor’s kidney in return.The medication that keeps her immune system from rejecting the organ also suppresses it from creating antibodies in response to a coronavirus vaccine. Her body is so bad at fighting off infection that she has gone to the emergency room with common colds, she said. She is certain that Covid-19 would kill her.But the isolation and depression — amplified as the rest of the world seemingly moves on from the pandemic without her — have also taken their toll. “I keep trying to hold on for my husband, honestly,” Ms. Takes said.Millions of Americans with weakened immune systems, disabilities or illnesses that make them especially vulnerable to the coronavirus have lived this way since March 2020, sequestering at home, keeping their children out of school and skipping medical care rather than risk exposure to the virus. And they have seethed over talk from politicians and public health experts that they perceive as minimizing the value of their lives.As Year 3 of the pandemic approaches, with public support for precautions plummeting and governors of even the most liberal states moving to shed mask mandates, they find themselves coping with exhaustion and grief, rooted in the sense that their neighbors and leaders are willing to accept them as collateral damage in a return to normalcy.“I can still see your world, but I live in a different world,” said Toby Cain, 31, of Decorah, Iowa, who has lymphatic cancer and went through six rounds of chemotherapy and radiation during the pandemic, making her especially vulnerable to Covid-19.Scenes on social media of other people living normal lives increase Ms. Cain’s sense of isolation and loss.Jenn Ackerman for The New York TimesShe lives alone, eats almost every meal alone and scrolls through social media alone, lamenting the family weddings and friends’ babies she has missed — at least until recently, when she quietly gave up on social media altogether. “It’s like living behind a veil while the rest of the world moves forward,” she said.More than seven million adults in the United States, or about 3 percent, are characterized by health professionals as immunocompromised because of a disease, medication or other treatment that weakens their body’s immune response, meaning that diseases such as Covid-19 can be more deadly to them, and that vaccines offer less protection.Tens of millions more Americans have at least one medical condition, such as asthma or diabetes, that puts them at greater risk from Covid. How much greater can vary widely; many live with little worry, while others at higher risk have felt the need to isolate from society.That is not what Aaron Vaughn, now 12, of East Lynne, Mo., hoped for when he received a heart transplant in June 2020. Born with half a heart, he thought a transplant would give him more freedom after years of long hospital stays. But with the virus still circulating, he has not been to school or a restaurant — his last trip was to Pizza Hut, his favorite at the time — since early 2020, and sees no one but his family and doctors.“If I could go to school, that would be cool,” Aaron said, adding, “I can’t go anywhere except the hospital.”Aaron Vaughn, left, and his siblings in their backyard in East Lynne, Mo. Aaron, who was born with half a heart, received a transplant in June 2020.Chase Castor for The New York TimesHe is vaccinated, but because of the drugs he takes to stop his body from rejecting the heart, his doctors have told him to act like he is not. His siblings, also vaccinated, went back to school in person last month, but they wear masks, making them stand out in their conservative community, where roadside signs urge people not to get a coronavirus vaccine.His parents said they had received hate mail for asking neighbors to wear masks or get vaccinated — some of the same neighbors who rallied around and prayed for Aaron when he needed a transplant. “It’s hard when people have turned something political, you know, that could kill my son,” said his mother, Sarah Vaughn.The rollback of mask mandates in states such as New York, Illinois and California is the latest source of stress for vulnerable Americans, who fear that the rest of the country is shedding precautions without any consideration of how to keep them safe. The federal Centers for Disease Control and Prevention said last week that it was too soon to abandon masks, in part because of the potential impact on vulnerable people, but the agency indicated on Wednesday that it would soon issue new guidelines.“Having everyone mask indoors always is not a forever strategy,” said Dr. Megan Ranney, an emergency physician and academic dean at the School of Public Health at Brown University, noting that immunocompromised people and others with vulnerabilities have always faced risks. But, she added, “We need to make sure that we have more stringent protections in place in places where people don’t have a choice about whether or not they go there.”The best protection in the long term, Dr. Ranney said, is to keep overall infections low: The less the virus is circulating, the less likely someone will be exposed. Vaccinating almost everyone would help, she said, but millions of Americans refuse, and not enough funding has been forthcoming for improved ventilation systems in public places.Aaron attends school virtually while his siblings go in person. Though he is vaccinated, his doctors advised him to act as if he isn’t because of his suppressed immune system.Chase Castor for The New York TimesThe fear and anger felt by many high-risk Americans burst into public view last month in response to remarks from the C.D.C. director, Dr. Rochelle Walensky. Citing a study that said only 0.003 percent of vaccinated people had died of Covid-19, she told ABC News that 75 percent of those who had died despite vaccination had “at least four comorbidities, so, really, these are people who were unwell to begin with.”That drove Imani Barbarin, who has several conditions that put her at high risk, including cerebral palsy and diabetes, to create the hashtag #MyDisabledLifeIsWorthy on social media, generating an outpouring from other people angry over the government’s approach.The Coronavirus Pandemic: Key Things to KnowCard 1 of 3The state of the virus in the U.S.