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Cancer cells acquire genetic anomalies that allow them to grow and proliferate unchecked. Researchers have now found another difference between cancer cells and normal cells: the X chromosome, typically only inactivated in XX female cells, can be inactivated across different male-derived cancers. This work is publishing November 9 in the journal Cell Systems.
“To balance the expression of genes between the sexes, in normal development, one copy of the female X chromosome is inactivated at random across the human body. We wanted to know if this process that occurs in normal development goes awry in genetically unstable male or female cancer cells,” says senior author Srinivas Viswanathan, a cancer geneticist and medical oncologist at the Dana-Farber Cancer Institute.
By using publicly available datasets comprising of thousands of DNA samples from cancer patients around the world, the team of researchers stumbled upon the high expression of XIST — the gene responsible for shutting down gene expression on the X chromosome — in about 4% of the male cancer samples analyzed.
While XIST may be expressed in very early development in all sexes, X inactivation is thought to be a female-specific process later in development. It was previously shown that some female cancer cells may lose the ability to turn off one of the X chromosomes, leading to increased X-linked gene expression, but this ability of X inactivation had still only been studied primarily in female cells.
Within the 4% of anomalous male cancer samples identified, 74% were from reproductive cancers already shown to inactivate the X chromosome, but that left 26% of samples from other cancer types. These included liver, brain, skin, heart, lung, and thyroid cancers.
“We were very surprised by this result since XIST is a transcript typically used to classify female cancers, and so we wanted to ensure that this was not merely a result of mis-annotation. Yet, we do in fact see that some male cancers of diverse subtypes activate XIST and display features of X inactivation,” says Viswanathan.
“We have to be aware of the caveats of working with these types of datasets. These samples have been in many people’s hands, and there is more room for human error,” said co-corresponding author Cheng-Zhong Zhang, cancer biologist at the Dana-Farber Cancer Institute. “This is the biggest source of uncertainty for us; we have to be creative in how we look at the data and find controls.”
One possible explanation for why this phenomenon is occurring is genetic instability. Cancers often have multiple copies of chromosomes, and if two X chromosomes happen to be in one cell, then it may be necessary to inactivate one of them by activating XIST, regardless of whether that cell is in a female or male individual.
“Another possibility is there are some important genes on the X chromosome that, when silenced, enable the cancer to grow. We will investigate this in future studies,” says Viswanathan.
“In some ways, sex is the ultimate biomarker in that it subdivides the human population, but we often don’t think about how genetic differences between the sexes may inform cancer prognosis or response to therapy,” says Viswanathan.
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Materials provided by Cell Press. Note: Content may be edited for style and length.

New technology can trace which populations of breast cancer cells are responsible for the spread of the disease, and for the first time highlights how the location of cancer cells could be as important as mutations in tumour growth.
The method was created by a team from the Wellcome Sanger Institute, EMBL’s European Bioinformatics Institute (EMBL-EBI), the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ), the Science for Life Laboratory in Sweden, and collaborators. It could be used to help answer some of the big questions in cancer, such as why some cancer cells spread, how treatment resistance is formed, and why some therapies fail.
The new study, published today (9th November 2022) in Nature, shows how it is now possible to map how tumours have developed, combining the cancer cells’ genetic information, the surrounding cell types, and how they interact with their environment over time.
In the future, this approach could be used to see how treatments influence the cancer at not only the genetic level, but also any impact on how the tumour interacts with the immune system and the environment around it.
Breast cancer is one of the most common cancers in the UK, with around 55,500 women and around 370 men being diagnosed every year.1
Breast cancer commonly starts when cells start to grow uncontrollably, often due to mutations in the cells. Overtime the tumour becomes a patchwork of cells, called cancer clones, each with different mutations. As they are genetically different, they can have different reactions to treatments. For example, some of these cancer cells could become resistant to treatment, or some could spread around the body.

A new study from investigators at Brigham and Women’s Hospital, a founding member of Mass General Brigham, the University of Virginia School of Medicine, and the University of Pittsburgh, finds that COVID-19 “Test to Treat” sites — clinical centers launched based on a federal initiative to provide free testing, diagnosis, and immediate access to COVID-19 antiviral treatment with Paxlovid — may not be accessible to those who need it most. The study’s findings highlight major disparities in geographical access to these treatment centers, disproportionally affecting rural and American Indian and Alaskan Native communities. Results are published in JAMA Network Open.
“There are clear disparities in spatial access to Test to Treat sites, most notably in several communities which have experienced worse outcomes throughout the pandemic,” said lead author Rohan Khazanchi, MD, MPH, a resident in the Brigham’s Internal Medicine-Pediatrics Residency Program. “These findings challenge us to consider what opportunities exist for strategic placement of Test to Treat sites in closer proximity to the communities that may need this program most.”
This research extends from the Biden administration’s March 2022 announcement of the Test to Treat initiative, a public health program which launched one-stop locations where people can receive a COVID-19 test, speak to a clinician, obtain an antiviral prescription, and fill their prescription for free.
While the Test to Treat initiative aims to increase access to care, this research suggests that geography may play a vital role in achieving equity.
“Paxlovid is an oral antiviral which can reduce the risk of hospitalization or death among people with COVID-19 who have key risk factors like elderly age, being unvaccinated or not being up to date on COVID-19 vaccinations, or having one or more high-risk medical conditions,” said senior author Kathleen McManus, MD, MSc, an assistant professor of medicine in the UVA Health’s Division of Infectious Diseases and International Health. “Notably, these risk factors are disproportionately prevalent among minoritized and rural communities — some of which, as our study found, may have the poorest geographic access to Paxlovid treatment through Test to Treat sites.”
Investigators analyzed published geolocations of 2,227 unique COVID-19 Test to Treat sites from the healthdata.gov website, listed as of May 4, 2022. They then calculated the shortest travel time required from the population center of every census tract to reach one of the ten geographically closest sites. Finally, they linked census tract demographic characteristics with calculated driving distances to determine the national proportions of each demographic subgroup residing within a certain driving distance to each site.

Researchers at Oregon Health & Science University have discovered that the neurotransmitter adenosine effectively acts as a brake to dopamine, another well-known neurotransmitter involved in motor control.
Scientists found that adenosine operates in a kind of push-pull dynamic with dopamine in the brain; the discovery published today in the journal Nature.
“There are two neuronal circuits: one that helps promote action and the other that inhibits action,” said senior author Haining Zhong, Ph.D., scientist with the OHSU Vollum Institute. “Dopamine promotes the first circuit to enable movement, and adenosine is the ‘brake’ that promotes the second circuit and brings balance to the system.”
The discovery could immediately suggest new avenues of drug development to treat symptoms of Parkinson’s disease, a movement disorder where the loss of dopamine-producing cells has been widely implicated as a cause.
Scientists have long suspected that dopamine is influenced by an opposing dynamic of neuronal signaling in the striatum — a critical region of the brain that mediates movement along with reward, motivation and learning. The striatum is also the primary brain region affected in Parkinson’s disease by the loss of dopamine-producing cells.
“People for a long time suspected there has to be this push-pull system,” said co-author Tianyi Mao, Ph.D., a scientist at the Vollum who happens to be married to Zhong.
In the new study, researchers for the first time clearly and definitively revealed adenosine as the neurotransmitter that acts in an oppositional sense with dopamine. The study, involving mice, used novel genetically engineered protein probes recently developed in the Zhong and Mao labs. An example of that technology was highlighted last month in a study published in the journal Nature Methods.
Notably, adenosine is also well known as the receptor that caffeine acts upon.
“Coffee acts in our brain through the same receptors,” Mao said. “Drinking coffee lifts the brake imposed by adenosine.”
In addition to Zhong and Mao, Lei Ma, Ph.D. of the Vollum Institute is the first author. Co-authors include Julian Day-Cooney, Ph.D., Michael A. Muniak, Ph.D., and Maozhen Qin of the Vollum; and, Omar Jaidar Benavides, Ph.D., and Jun B. Ding, Ph.D., of Stanford University.
This work was supported by two BRAIN Initiative awards to Zhong and Mao through the National Institutes of Health, awards U01NS094247 and R01NS104944; as well as three awards through the National Institute of Neurological Disorders and Stroke of the NIH, award R01NS081071 to Mao and R21NS097856 and R01NS127013 to Zhong.
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Materials provided by Oregon Health & Science University. Original written by Erik Robinson. Note: Content may be edited for style and length.

Alzheimer’s, Parkinson’s and many other neurodegenerative diseases are marked by damaging clusters of proteins in the brain. Scientists have expended enormous effort searching for ways to treat such conditions by clearing these toxic clusters but have had limited success.
Now, researchers at Washington University School of Medicine in St. Louis have found an innovative way to improve waste clearance from the brain, and thereby possibly treat or even prevent neurodegenerative conditions. They showed that immune cells surrounding the brain influence how efficiently waste is swept out of the brain, and that such immune cells are impaired in old mice, and in people and mice with Alzheimer’s disease. Further, they found that treating old mice with an immune-stimulating compound rejuvenates immune cells and improves waste clearance from the brain.
The findings, published Nov. 9 in Nature, suggest a new approach to halting some of the effects of aging on the brain.
“Alzheimer’s has been studied for many years from the perspective of how neurons die, but there are other cells, such as immune cells on the periphery of the brain, that also may play a role in Alzheimer’s,” said senior author Jonathan Kipnis, PhD, the Alan A. and Edith L. Wolff Distinguished Professor of Pathology & Immunology and a BJC Investigator. “It doesn’t look likely that we will be able to revive dead or dying neurons, but the immune cells that sit on the borders of the brain are a feasible target for treating age-related brain diseases. They’re more accessible, and could be drugged or replaced. In this study, we treated aged mice with a molecule that can activate aged immune cells, and it worked in improving fluid flow and waste clearance from the brain. This holds promise as an approach to treating neurodegenerative diseases.”
Kipnis is an expert in the blossoming field of neuroimmunology, the study of how the immune system affects the brain in health and disease. In 2015, he discovered a network of vessels that drains fluid, immune cells and small molecules from the brain into the lymph nodes, where many immune system cells reside. Last year, he and colleagues showed that some investigational Alzheimer’s therapies are more effective in mice when paired with a treatment geared toward improving drainage of fluid and debris from the brain.
For this study, Kipnis and Antoine Drieu, PhD — a postdoctoral researcher and the paper’s lead author — set out to understand the role played by the immune cells that live along the brain’s vasculature and in the leptomeninges, the tissues immediately surrounding the brain and spinal cord. They termed these cells parenchymal border macrophages, because they sit at the interface between cerebrospinal fluid and brain tissue.
Studying mice, Kipnis, Drieu and colleagues discovered that such macrophages regulate the motion of blood arteries that, in turn, controls the cleansing flow of fluid through the brain. When these macrophages were depleted or impaired, debris built up in the brain.
“Cerebrospinal fluid flow is impaired in numerous neurodegenerative diseases, such as Alzheimer’s, stroke, Parkinson’s and multiple sclerosis,” Drieu said. “If we can restore fluid flow through the brain just by boosting these macrophages, maybe we can slow the progression of these diseases. It’s a dream, but who knows? It might work.”
Further investigation revealed that parenchymal border macrophages are altered in people with Alzheimer’s disease and mice with an Alzheimer’s-like condition: The immune cells are less able to consume and dispose of waste, and cannot efficiently regulate fluid flow.
Starting at about age 50, people start experiencing a decline in brain fluid flow as part of normal aging. The same thing happens in older mice. Kipnis, Drieu and colleagues showed that the kind of border macrophage most important for waste clearance and fluid flow are scarce in older mice. When they treated old mice with a protein that boosts macrophage activity, the border macrophages started behaving more like those from younger mice. Further, the treatment improved fluid flow and waste clearance from the mice’s brains.
“Collectively, our results show that parenchymal border macrophages could potentially be targeted pharmacologically to alleviate brain clearance deficits associated with aging and Alzheimer’s disease,” said Kipnis, who is also a professor of neurology, of neuroscience and of neurosurgery. “I am discussing with colleagues how we can replace or rejuvenate those cells in aging brains and as a treatment for Alzheimer’s. I hope that one day we will be able to slow down or delay the development of age-related brain diseases with this approach.”

Take a wire paperclip. Now, bend it back and forth in the same spot 15, maybe 20 times. Chances are the paperclip will have broken before you finish. This is due to what’s called metal fatigue, which occurs when a metal component is cyclically stressed until it fails.
While the broken paperclip is a trivial example of metal fatigue, the phenomenon is a huge problem in the wider world. “Most unexpected failures — bridges, airplanes, oil rigs, heart valves — fail by that process,” said UC Santa Barbara materials science professor Tresa Pollock, who specializes in the mechanical and and environmental performance of materials in extreme environments. Virtually any structural metal that is subjected to cyclic stress — deformations, vibrations, extreme temperatures, impacts and the like — is vulnerable, with results that can cost hundreds of billions of dollars each year.
To forsee and avoid such catastrophic fates, Pollock and fellow researchers at UCSB, University of Illinois at Urbana-Champaign and Université de Poitiers in France have developed a theory that predicts the limits to which metals can be subjected to cyclic stress before failing. And they can predict failure from the first cycle. Their research is published in the journal Science.
Being able to predict when a metal component is likely to fail from cyclic stress has long been a priority when designing an engineered system, whether it’s an artificial heart valve or a nuclear power plant. However, according to Pollock, who also serves as the interim dean of the College of Engineering at UC Santa Barbara, the process of making this determination hasn’t changed much in almost two centuries.
“They take something, cycle it and measure the cycles to failure,” she said.
But these empirically-driven results often come without the deeper, quantitative insights that would enable predictions across a broad range of metals under various conditions. Further complicating the matter is that failures can often occur after millions or billions of cycles. “And if you have to test something for a year or 10 years before it fails, then it’s a little difficult to generate enough test results to design against that failure,” Pollock said.

By taking advantage of a phenomenon that leads to fractures in metal, MIT researchers have designed medical devices that could be used inside the body as stents, staples, or drug depots, then safely broken down on demand when they’re no longer needed.
The researchers showed that biomedical devices made from aluminum can be disintegrated by exposing them to a liquid metal known as eutectic gallium-indium (EGaIn). In practice, this might work by painting the liquid onto staples used to hold skin together, for example, or by administering EGaIn microparticles to patients.
Triggering the disintegration of such devices this way could eliminate the need for surgical or endoscopic procedures to remove them, the researchers say.
“It’s a really dramatic phenomenon that can be applied to several settings,” says Giovanni Traverso, the Karl van Tassel Career Development Assistant Professor of Mechanical Engineering at MIT and a gastroenterologist at Brigham and Women’s Hospital. “What this enables, potentially, is the ability to have systems that don’t require an intervention such as an endoscopy or surgical procedure for removal of devices.”
Traverso is the senior author of the study, which appears in Advanced Materials. Vivian Feig, an MIT postdoc, is the lead author of the paper.
Breaking down metals
For several years, Traverso’s lab has been working on ingestible devices that could remain in the digestive tract for days or weeks, releasing drugs on a specific schedule.

Countless tiny hairs (cilia) are found on the outer wall of some cells, for example in our lungs or in our brain. When these micrometre-sized hairs coordinate their movement and produce wave-like movements together, they can cause currents on a microscale and thus pump fluid from one place to another. Until now, this could only be studied in large computer simulations. However, more than a few thousand hairs cannot be simulated in this way. Now a continuum theory of micro-hairs has been developed — a powerful and completely new approach.
They are only very simple structures, but without them we could not survive: Countless tiny hairs (cilia) are found on the outer wall of some cells, for example in our lungs or in our brain. When these micrometre-sized hairs coordinate their movement and produce wave-like movements together, they can cause currents on a microscale and thus pump fluid from one place to another. Paramecia — unicellular organisms with numerous cilia — also use such effects to move around.
How the synchronisation of such micro-hairs comes about and what effects it has — such questions have so far only been studied in large computer simulations. However, more than a few thousand hairs cannot be simulated in this way. Sebastian Fürthauer from TU Wien has now taken a completely different approach: Together with research teams from the USA, he has developed a continuum theory of micro-hairs. This makes it possible to investigate questions that were previously completely out of reach. The theory has now been published in the scientific journal PNAS.
Micro-world and macro-world
“The complicated connection between the micro-world and the macro-world plays an important role in many areas of physics,” says Sebastian Fürthauer. Every air flow, every flow in a liquid can be understood as the movement of small particles — of atoms and molecules. It is possible to study the forces that act between the individual particles, how they collide and move together.
But it is also possible to disregard this view on the level of individual particles completely and look at things differently — using concepts like pressure, density and mean flow velocity. “In fluid mechanics, that’s exactly what you do,” says Sebastian Fürthauer. “You don’t care about the fact that every flow consists of individual particles, instead you look for mathematical equations that use terms like pressure or density to describe the entire flow in a continuous way.”
Collective waves instead of individual hairs

In Alzheimer’s disease, the degeneration of brain cells is linked to formation of toxic protein aggregates and deposits known as amyloid plaques. Similar processes play an important role also in type 2 diabetes. A research team under the lead of the Technical University of Munich has now developed “mini-proteins,” so-called peptides, which are able to bind the proteins that form amyloids and prevent their aggregation into cytotoxic amyloids.
Many cell- and neurodegenerative diseases are linked to the formation of toxic protein aggregates which cause cell death. Prominent representatives of these diseases are Alzheimer’s disease and type 2 diabetes mellitus, with worldwide more than 50 million and 400 million patients, respectively. Importantly, the number of Alzheimer’s and diabetes patients constantly rises, as the population becomes older. However, the two diseases remain so far incurable. Therefore, there is an urgent need for new therapeutic approaches.
Targeting the formation of harmful amyloid aggregates is a promising approach. A team led by Aphrodite Kapurniotu, a professor for Peptide Biochemistry at the Technical University of Munich (TUM), has now developed novel synthetic peptides, which are able in experimental models to block toxic amyloid aggregation linked to both diseases.
Molecular interactions between Alzheimer’s disease and type 2 diabetes
Previous studies showed that certain “cross-interactions” between the amyloidogenic proteins of the two diseases dramatically accelerate their amyloid aggregation process. These findings could possibly explain why people suffering from one of the two diseases might have an increased risk for the other disease as well.
The team developed synthetic peptides that could function as effective inhibitors of amyloid aggregation in both diseases. Prof. Kapurniotu says: “The designed peptides are in fact able to bind the amyloidogenic proteins linked to both diseases and to effectively suppress both cytotoxic amyloid aggregation and amyloid cross-accelerating interactions. Remarkably, although the mixed aggregates formed by interactions of the designed peptides with the amyloidogenic proteins look very similar to harmful amyloid aggregates, they are completely devoid of cytotoxic effects. Moreover, these amyloid-resembling mixed aggregates become more efficiently taken up by the phagocytic immune cells than amyloid aggregates.”
Future studies shall pave the way for medical application
Increasing evidence suggests that Alzheimer’s disease and type 2 diabetes are linked to each other. Prof. Kapurniotu believes thus that the designed peptides could be valuable candidates for the development of drugs for treating both diseases.
A patent application has been already filed by TUM. Additional studies are now planned to translate the findings from the experimental models into the clinic.
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Materials provided by Technical University of Munich (TUM). Note: Content may be edited for style and length.