Publisher Health

In a new study, researchers from the Case Western Reserve University School of Medicine have identified the structure of protein fibrils linked to a hereditary form of human prion disease. This insight, they say, reveals the mechanism for how prions can jump between some animal species, while retaining a transmissibility barrier between other species.
While their findings have no immediate implications for the development of new therapies for more common human prion disorders such as Creutzfeldt-Jakob disease, the work does suggest the potential for disease to be transmitted from one species to another can be predicted based on structural information.
“One of the major remaining questions in the field of prion diseases has been why these diseases are transmissible between some animal species but not others,” said Witold Surewicz, a professor in the Department of Physiology and Biophysics at the School of Medicine and the study’s senior author. “Our findings explain how this works.”
The study, funded by the National Institutes of Health, was published Sept. 12 in the scientific journal Nature Structural & Molecular Biology. Qiuye Li, a postdoctoral fellow at the School of Medicine, was lead author. The study was co-authored by Christopher Jaroniec, a professor of chemistry and biochemistry at Ohio State University.
Prion diseases, also known as “transmissible spongiform encephalopathies,” are a group of infectious brain-wasting disorders that include, among others, Creuzfeldt-Jakob disease in humans, bovine spongiform encephalopathy (mad cow disease) in cattle and chronic wasting disease in deer and elk.
These fatal disorders are unique because of their infectious pathogen — which is not a virus but an abnormally shaped form of the prion protein.

Children who were exposed to cannabis in the womb continue to show elevated rates of symptoms of psychopathology — depression, anxiety and other psychiatric conditions — even as, at ages 11 and 12, they head toward adolescence, according to research from the Department of Psychological & Brain Sciences’ BRAIN Lab, led by Ryan Bogdan, associate professor in Arts & Sciences at Washington University in St. Louis.
The findings, published Monday, Sept. 12, 2022 in the Journal of the American Medical Association, Pediatrics, is a follow-up to 2020 research from the Bogdan lab that revealed younger children who had been prenatally exposed to cannabis were slightly more likely to have had sleep problems, lower birth weight and lower cognitive performance, among other things.
In both cases, the effect is strongest when looking at exposure to cannabis after the pregnancy was known.To determine whether or not these associations persisted as the children aged, David Baranger, a postdoctoral researcher in the BRAIN Lab, returned to the more than 10,500 children from the 2020 analysis. They averaged 10 years old in 2020.
The data on the children and their mothers came from the Adolescent Brain and Cognitive Development Study (ABCD Study), an ongoing study of nearly 12,000 children, beginning when they were 9-10 years old, and their parent or caregiver. The study, which is funded by the National Institutes of Health and their federal partners, began in 2016, when participants were enrolled at 22 sites across the United States.
This seemingly small change in age — from 10 to 12 — is an important one. “During the first wave, they were just children. Now they’re edging up on adolescence,” Baranger said. “We know this is a period when a large proportion of mental health diagnoses occur.”
An analysis of the more recent data showed no significant changes in the rate of psychiatric conditions as the children aged; they remain at greater risk for clinical psychiatric disorders and problematic substance use as they enter the later adolescent years.
“Once they hit 14 or 15, we’re expecting to see further increases in mental health disorders or other psychiatric conditions — increases that will continue into the kids’ early 20s,” Baranger said.
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Materials provided by Washington University in St. Louis. Original written by Brandie Jefferson. Note: Content may be edited for style and length.

The HSD3B1 gene could hold clues for predicting and treating endometrial cancer, according to a novel finding from the Cleveland Clinic’s Lerner Research Institute.
Researchers found a certain HSD3B1 genotype was more common in women with type 2 endometrial cancer, according to the results published in JNCI Cancer Spectrum. Those patients show lower survival rates than those diagnosed with type 1 endometrial cancer, likely driven by the fact that type 2 patient cells are less hormone-dependent.
The results are the latest step in untangling the role HSD3B1’s genotype plays in hormone-driven cancers, with previous research revealing associations with breast and prostate cancer. This body of work was in part led by Cleveland Clinic researchers and physician-scientists, and continues today with translational research and clinical trials.
HSD3B1 researchers are building a foundation for future options to treat and prevent cancer subtypes with a lower survival rate, says Nima Sharifi, MD, senior author of the paper and Director of the Lerner Research Institute’s Genitourinary Malignancies Research Center.
Despite being one of the most common cancers among women, there is no test or exam to screen for endometrial cancer. Incidence rates for this “underfunded and understudied” disease are rising in the United States, says Roberto Vargas, MD, co-author and assistant staff at the Cleveland Clinic’s Division of Gynecologic Oncology.
“Over the past three decades, we haven’t moved the bar on outcomes,” Dr. Vargas says. “Figuring out the interplay between this gene and endometrial cancer can pave a way to screen and treat it more effectively.”
HSD3B1 is a gene that regulates androgens and estrogens by producing the enzyme that converts adrenal steroid-precursors to androgens and estrogens. HSD3B1’s genotype is either adrenal-permissive, which amplifies the process, or adrenal-restrictive, which limits it.

President Biden has selected Dr. Renee Wegrzyn to lead the Advanced Research Projects Agency for Health, which is aimed at driving biomedical innovation.WASHINGTON — President Biden has selected Dr. Renee Wegrzyn, a Boston biotech executive with government experience, as the director of a new federal agency aimed at driving biomedical innovation, the White House said on Monday.Mr. Biden will announce his intention to appoint Dr. Wegrzyn, along with a series of steps to promote his so-called cancer moonshot initiative, during a speech at the John F. Kennedy Presidential Library and Museum in Boston on the 60th anniversary of the former president’s “moonshot” speech that ushered in an era of space travel.Mr. Biden, whose son Beau died of brain cancer in 2015, has a deep personal commitment to advancing cancer research. He helped create the cancer moonshot when he was vice president and proposed the new biomedical agency this year as part of an effort to reinvigorate the initiative and, he has said, to “end cancer as we know it.”Modeled after the Defense Advanced Research Projects Agency, the biomedical research agency is known as the Advanced Research Projects Agency for Health. (In the argot of Washington, where every agency has an acronym, the defense research agency is called DARPA and the health agency is ARPA-H.)Dr. Wegrzyn is currently a vice president of business development at Ginkgo Bioworks and the head of innovation at Concentric by Ginkgo, the company’s initiative to advance coronavirus testing and track the spread of the virus. She also worked at DARPA and its sister agency, the Intelligence Advanced Research Projects Activity.“Some of the problems we face every day — especially in health and disease — are so large they can seem insurmountable,” Dr. Wegrzyn said in a statement provided by the White House. “I have seen firsthand the tremendous expertise and energy the U.S. biomedical and biotechnological enterprise can bring to solve some of the toughest health challenges.”Congress has appropriated $1 billion for ARPA-H, which is housed within the National Institutes of Health. While its director is not a Senate-confirmed position, Mr. Biden may face pushback from Republicans, some of whom have argued that the new agency duplicates the N.I.H.’s efforts.The White House announcement drew praise from Ellen V. Sigal, the chairwoman of Friends of Cancer Research, a nonprofit that works with industry and government to advance new therapies. Ms. Sigal called Dr. Wegrzyn “an inspired choice,” adding, “She is a proven innovator and leader who knows science, knows how to make government work and understands the urgency for patients across the country.”In addition to announcing his intent to appoint Dr. Wegrzyn, Mr. Biden on Monday issued an executive order establishing a biotechnology and biomanufacturing initiative intended to position the United States as a leader in the field and to center drug manufacturing in the country. The coronavirus pandemic exposed critical weaknesses in the supply chain for drugs and live-saving therapies.“The United States has for too long relied heavily on foreign materials for bioproduction,” the White House said in a statement, “and our past offshoring of critical industries, including biotechnology, presents a threat to our ability to access key materials like including the active pharmaceutical ingredients for lifesaving medications.”

The levels of long-term blood sugar, HbA1c, can be used to accurately determine the risk of a person with type 1 diabetes developing eye- and kidney complications. A study from Linköping University, Sweden, has shown that this level should be lower than 53 mmol/mol (7%). The study has followed individuals for more than 30 years after the onset of type 1 diabetes, and the results have been published in Diabetes Care.
People with diabetes may experience damage to the small blood vessels in various organs. The reasons for this are unclear, but it has been known since the 1990s that good control of blood sugar levels reduces the risk of complications. It has, however, not been clear what level of long-term sugar, HbA1c, people with type 1 diabetes should have in order to avoid serious damage to blood vessels in the eyes and kidneys.
“Our study determines accurately the levels of long-term sugar that can avoid complications. This knowledge can increase a person’s motivation to keep their blood sugar level under control,” says Hans Arnqvist, professor emeritus at Linköping University and leader of the study.
Researchers in the current study, known as VISS (Vascular Diabetic Complications in Southeast Sweden), have followed all children and adults younger than 35 years who developed type 1 diabetes during the period 1983-1987, and who received care in the South-East Healthcare Region of Sweden. All 447 newly diagnosed persons in the region during this period were included in the study. The researchers have followed the patients’ HbA1c values, which reflect their average blood sugar levels during a longer period. They have also monitored the development of eye- and kidney damage in these patients for a period of between 32 and 36 years after diagnosis.
The small blood vessels in the eye are particularly susceptible to damage in type 1 diabetes. Nearly all patients experience small haemorrhages in the eye that do not affect their vision. In some cases, new blood vessels develop in the retina. The latter is known as ‘proliferative retinopathy’, and can lead to blindness. Another effect of diabetes concerns the area known as the ‘macula’ of the retina, where high-focus vision is located. Damage here leads to blurred vision.
The kidneys are not as sensitive to high blood sugar levels as the eye, but the important small blood vessels here can also be damaged. One consequence of such damage is the excretion of blood proteins in the urine. Albumin is the protein with highest concentration in the blood, and when it is present in the urine the condition is known as ‘albuminuria’. The damage to the kidneys eventually leads to impaired kidney function and, in serious cases, kidney failure. This is a fatal condition if untreated, and the patient must either undergo dialysis or receive a kidney transplant.
The blood sugar level in a healthy person is very closely controlled, with a maximum HbA1c level of 42 mmol/mol (6.0%).
“The results of our study show that people with type 1 diabetes for at least 32 years should keep their mean long-term sugar level below 53 mmol/mol (7.0%), if they are to completely avoid serious damage. The risk of eye- and kidney complications increases as the level increases. Our conclusions relate to avoiding complications arising from blood vessel damage. But if a patient has problems with low blood sugar, hypoglycaemia, it’s not possible to control the blood sugar level so strictly,” says Hans Arnqvist.
The target level for HbA1c that is suggested by the results of the VISS study agrees with the individual targets recommended by the American Diabetes Association. In Sweden, target levels are given for groups, rather than individuals.
The previous follow-up by the research group was conducted 20 years after the onset of disease. Now after 30 years, the results show that damage has arisen at lower blood sugar levels than was the case after 20 years. More patients have experienced damage, despite having blood sugar levels that are not higher than those they have previously had. In other words, it seems that the threshold for developing complications falls gradually with time. This means that the study does not allow any conclusions for the recommended blood sugar levels of people with type 1 diabetes longer than 30 years after diagnosis.
The VISS study has received funding from the Swedish Child Diabetes Foundation and the Foundation Funds of Region Östergötland.
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Materials provided by Linköping University. Original written by Karin Söderlund Leifler. Note: Content may be edited for style and length.

Mount Sinai researchers have made two important discoveries about the mechanism by which bladder cancer cells foil attacks from the immune system. The research, published in Cancer Cell in September, could lead to a new therapeutic option for patients with these types of tumors.
Advanced bladder cancer is aggressive and patients generally have poor prognoses. Several immune checkpoint inhibitors have been approved by the Food and Drug Administration for bladder cancer, but they only sustain good responses in about 20 percent of patients.
When people get cancer, a type of immune cell called a “natural killer cell” swings into action to try to kill off the tumor cells. However, the tumor cells are often able to foil the attacks from the natural killer cells. The Mount Sinai researchers reported that they had found a subset of CD8 T cells that adapts to tumor evasion strategies by appropriating innate-like properties traditionally ascribed to natural killer cells, offering a strategy to reduce the tumor cells’ ability to fight them off.
To create additional killer cells, the researchers showed that they could induce CD8+ T cells to express a molecule known as NKG2A on their surface, allowing them to behave more like natural killer cells. This study showed that NKG2A is associated with improved survival and with responsiveness to a cancer-fighting immunotherapy known as PD-L1 checkpoint blockade.
The second discovery concerns cancer cells’ ability to resist PD-L1 checkpoint blockade therapy. The researchers noted that tumors can maintain expression of a protein called HLA-E on their surface that can resist the T cells because HLA-E binds to the NKG2A molecule and disables the T cells’ ability to fight. An immunotherapy that specifically targets the HLA-E/NKG2A axis could be an effective way to attack cancers in these patients, the researchers said.
“These findings suggest that antibodies that block both NKG2A and PD-L1 could be a more effective treatment strategy for patients whose bladder cancer tumors have both high levels of HLA-E and NKG2A-positive CD8+ T cells,” said lead and co-corresponding author Amir Horowitz, PhD, Assistant Professor of Oncological Sciences at The Tisch Cancer Institute at Mount Sinai and member of the Precision Immunology Institute at the Icahn School of Medicine at Mount Sinai. “These findings provide a framework for future clinical trials that combine a therapy that blocks NKG2A with other immunotherapies in these tumors.”
“Immune checkpoint blockade is a leading type of cancer immunotherapy that targets the PD1-PDL1 pathway in order to re-engage ‘exhausted’ CD8+ T cells in the fight against tumors,” said co-corresponding author Nina Bhardwaj, MD, PhD, Director of Immunotherapy, Co-Director of the Cancer Immunology Program and Professor of Medicine (Hematology and Medical Oncology) at The Tisch Cancer Institute at Mount Sinai. “In this paper, we show that responses to PD-L1 blockade in patients with bladder cancer are influenced by an additional immune checkpoint axis identified recently in other cancers: NKG2A-HLA-E.”
To conduct the study, the researchers profiled tumors and blood of bladder cancer patients across various stages of the disease, and studied all specimens immediately after surgical removal from patients to ensure they could capture live immune cells and examine their functioning. The study integrated several cutting-edge single-cell technologies and leveraged publicly available datasets through The Cancer Genome Atlas (TCGA) and the ImVigor210 trial of atezolumab, an anti-PDL1 immunotherapy.
Several collaborators contributed to this study, including Columbia University, Karolinska Institutet, Frederick National Laboratory for Cancer Research at the National Institutes of Health, Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, Harvard University, University of Genoa, University of Lausanne, Oslo University, Sema4, Genentech and Astra Zeneca. Funding from the U.S. Department of Defense, Parker Institute for Cancer Immunotherapy, the National Cancer Institute and the National Institute of Allergy and Infectious Diseases supported this work.

Researchers from Johns Hopkins Medicine and the Dana Farber Cancer Institute in Boston have shown that a hormone secreted into the blood during endurance, or aerobic, exercise reduces levels of a protein linked to Parkinson’s disease and halts movement problems in mice.
Parkinson’s disease, a neurologic condition that causes people to lose control over their muscles and movements, affects about 1 million people in the U.S.
If confirmed in additional laboratory research and clinical trials, the researchers’ study in mice engineered to have Parkinson’s disease symptoms could pave the way for a Parkinson’s disease therapy based on the hormone irisin.
Results of the researchers’ tests appeared Aug. 31 in Proceedings of the National Academy of Sciences.
Johns Hopkins Medicine’s Ted Dawson, M.D., Ph.D., and Dana Farber’s Bruce Spiegelman, Ph.D., worked together to look into the link between the exercise molecule irisin and Parkinson’s disease.
For unknown reasons, endurance exercise has long been found to alleviate symptoms of Parkinson’s disease. Dawson, whose research focuses on neurodegenerative diseases, including Parkinson’s disease, said one of the first clues to the link between exercise, Parkinson’s disease and irisin came from Spiegelman, whose first paper about irisin was published in 2012 in Nature and subsequently in other scientific journals, showing that a protein called an irisin peptide is released into the blood and increases with endurance exercise.

The studies, published in leading journals JAMA Internal Medicine and JAMA Neurology, monitored 78, 500 adults with wearable trackers — making these the largest studies to objectively track step count in relation to health outcomes.
The researchers from the University of Sydney, Australia and University of Southern Denmark found lowered risk of dementia, heart disease, cancer and death are associated with achieving 10,000 steps a day. However, a faster stepping pace like a power walk showed benefits above and beyond the number of steps achieved.
“The take-home message here is that for protective health benefits people could not only ideally aim for 10,000 steps a day but also aim to walk faster,” said co-lead author Dr Matthew Ahmadi, Research Fellow at the University of Sydney’s Charles Perkins Centre and Faculty of Medicine and Health.
‘For less active individuals, our study also demonstrates that as low as 3,800 steps a day can cut the risk of dementia by 25 percent,” said co-lead author Associate Professor Borja del Pozo Cruz from the University of Southern Denmark and senior researcher in health at the University of Cadiz.
Key points: Every 2,000 steps lowered risk of premature death incrementally by 8 to 11 percent, up to approximately 10,000 steps a day. Similar associations were seen for cardiovascular disease and cancer incidence. A higher number of steps per day was associated with a lower risk of all-cause dementia 9,800 steps was the optimal dose linked to lower risk of dementia by 50 percent, however risk was reduced by 25 percent at as low as 3,800 steps a day Stepping intensity or a faster pace showed beneficial associations for all outcomes (dementia, heart disease, cancer and death) over and above total daily steps.”Step count is easily understood and widely used by the public to track activity levels thanks to the growing popularity of fitness trackers and apps, but rarely do people think about the pace of their steps,” said senior author Emmanuel Stamatakis, Professor of Physical Activity, Lifestyle and Population Health at the University of Sydney.

The eye disease Age-related Macular Degeneration (AMD) is the most frequent cause of vision loss and blindness among elderly people in the Western world.
The most aggressive form is so-called ‘wet AMD’ — a disease in which the formation of new blood vessels in the underlying choroid of the retina results in fluid and swelling in the eye.
In a new study from Aarhus University which has just been published in the scientific journal Investigative Ophthalmology & Visual Science (IOVS), the authors have examined the past five years of studies in a model for the disease corresponding to 380 scientific articles. Research into the mechanisms behind the disease — and thus the development of new treatment modalities — is often based on laboratory animals, in which new blood vessels are artificially created in the retina, typically using lasers.
The review of the many studies shows an imbalance in the use of laboratory animals; researchers usually choose to use young, healthy male mice, even though they know that both the sex and the age of the mice play a role in the degree of vessel formation.
“It is predominantly young, healthy, male mice that are used for research on this type of vessel formation. This makes sense from an ethical, financial and time perspective, as mice are inexpensive compared with larger laboratory animals, and the studies can be carried out relatively quickly. The biological variation can also be limited. However, AMD is a disease that most frequently occurs in the elderly population, and the disease occurs just as frequently in women — perhaps even slightly more frequently, when you look at ‘wet AMD’,” says medical doctor and PhD student Bjørn K. Fabian-Jessing, who is first author on the study.
Previous studies have shown a discrepancy between the treatment effects seen in animal studies and in clinical trials in humans.

A new rodent study shows that even small quantities of alcohol can trigger epigenomic and transciptomic changes in brain circuitry in an area that is crucial in the development of addiction.
What’s more, the University of Illinois Chicago researchers who conducted the study say that the pathways involved in priming the brain for addiction are the same ones that are associated with the highs of drinking, like euphoria and anxiolysis, the clinical term for a level of sedation in which a person is relaxed but awake.
“This suggests that when the brain experiences the anti-anxiety effects of alcohol and the mood lift — the relaxation and the buzz — it is also being primed for alcohol use disorder,” said the study’s senior author Subhash Pandey, the Joseph A. Flaherty endowed professor of psychiatry and director of the Center for Alcohol Research in Epigenetics in the UIC College of Medicine.
While Pandey says the study does not suggest, for example, that one drink leads to addiction in humans, it does provide some clues as to why some people are more vulnerable to alcohol use disorder.
“We’re seeing that dependent behaviors may not always be from long-term, high-quantity habits but a result of rapid epigenetic changes in the brain, which we show in this study may start happening even at low doses,” said Pandey, who is also a senior research career scientist at the Jesse Brown Veterans Affairs Medical Center.
A paper published in Molecular Psychiatry details Pandey’s experiments, which studied rats under control and alcohol exposure conditions.