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Researchers at UNC Lineberger Comprehensive Cancer Center have taken a major step forward in melding two key methods for studying breast cancer: one by genetic analysis and the second by looking at the architecture of cells, or their pathology. The investigators were able to link the two thanks to a decade-long effort made possible by the federally funded resource of The Cancer Genome Atlas (TCGA) Breast Cancer Data set. The scientists found much agreement between genetic and pathologic classifications but developed a novel way to use data from both systems to arrive at a classification method that divides breast cancers into 12 distinct biological groups.
The findings appeared December 8, 2021, in Cell Genomics.
“We’ve known for a long time that breast cancer is not one disease, and now through years of molecular research, added to decades of pathology knowledge, we have begun to integrate the two into one language,” said Charles Perou, PhD, co-director of the UNC Lineberger Breast Cancer Research Program, the May Goldman Shaw Distinguished Professor of Molecular Oncology, and corresponding author of the research. “This should greatly aid future research efforts and enable faster translation of molecular findings into the pathology lab for clinical use.”
The World Health Organization has long classified breast tumors into multiple types based on a tumor cell’s unique shape, structure and size. The most common type of breast cancer has been defined as invasive ductal breast carcinoma; it accounts for 70 percent to 80 percent of all breast cancers. While this predominant type of breast cancer was of interest to the researchers, it was the rarer types that held the most opportunity for new discoveries in this finding.
TCGA’s 10,000-plus tissue repository of 33 different types of cancer types allowed the investigators to explore the previously known, but rarer breast pathologies. However, obtaining a sufficient number of samples to adequately study rarer types and subtypes of cancer was a challenge. But the TCGA Breast Cancer team, led by Perou, was able to obtain enough samples for at least six rare breast cancer subtypes, each of which yielded interesting and unique molecular features.
Of particular note were rare metaplastic carcinomas, a breast cancer subtype with a poor clinical prognosis. Through comparison to the entire TCGA set of 10,000 tumors, the researchers found that some metaplastic cancers were related closely to melanomas, which are aggressive skin cancers, and to sarcomas, which are typically found in bone and connective tissue.
“Our effort finishes all planned analyses on TCGA, which has been a major undertaking,” said Aatish Thennavan, a PhD graduate student in Perou’s lab and first author of the article. “In our study, we validated our findings with other datasets that also had rarer subtypes. We would urge future studies to incorporate rarer subtypes so we can build on this foundational analysis.”
For their next efforts, the researchers plan to delve deeper into the molecular features and cellular origins of metaplastic breast cancers. They are also interested in why some of the 12 biological groups show evidence of immune cells that are capable of infiltrating tumor cells, and why others tend not to have these immune infiltrates. This line of research has therapeutic implications as there are treatments that have been developed that target immune cells in breast cancers.
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Materials provided by UNC Lineberger Comprehensive Cancer Center. Note: Content may be edited for style and length.

In a large-scale study of people from diverse ancestries, researchers narrowed down the number of genomic variants that are strongly associated with blood lipid levels and generated a polygenic risk score to predict elevated low-density lipoprotein cholesterol levels, a major risk factor for heart disease. The study, published in the journal Nature, was led by the Global Lipids Genetics Consortium. The authors include researchers at the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health.
Lipids are fat-like substances that can be found in blood and body tissues. They come in two major forms — cholesterol and triglycerides. Humans need a certain amount of lipids in the body for normal function, but elevated lipid levels may increase the risk of developing a heart condition. Polygenic risk scores provide an estimate of an individual’s risk for specific diseases, based on their DNA changes related to those diseases.
“Finding the set of genomic variants that are important for this trait is key for us to understand the biology and identify new drug targets,” said Cristen Willer, Ph.D., senior author and professor of human genetics at the University of Michigan, Ann Arbor. “These genomic variants then inform how well polygenic risk scores work to determine risk for such diseases.”
Since the field’s inception, the genomics community has performed over 6,000 studies looking at the association of specific genomic variants and cardiovascular disease. However, the design of these studies overwhelmingly included individuals from European ancestral populations.
To address this issue, researchers accumulated data from 201 previous genome-wide association studies, including about 1.65 million individuals from five ancestral groups: African, East Asian, European, Hispanic and South Asian. About 1.32 million of those studies were from European ancestry, and the remaining 350,000 were non-European. The studies contained data on blood levels of the different classes of cholesterol and triglycerides.
The research group calculated the polygenic risk scores using data from each of the different ancestral groups, either separately or all together. Then, they tested the risk scores in a diverse set of studies, including Africans enrolled from Ghana, Kenya and Nigeria as part of the Africa America Diabetes Mellitus study. Charles Rotimi, Ph.D., scientific director of the NHGRI Intramural Research Program, was the principal investigator of the study.
The results showed a polygenic risk score that includes diverse genomic data is much more predictive of whether a person of any ancestry will have elevated low-density lipoprotein cholesterol levels than a score that only includes European genomic data.
“The message couldn’t be more clear. To have a fuller understanding of the effects of genomic variation on disease, we simply must include as many diverse groups of people as possible,” said Rotimi, a co-author on the paper. “It is the single biggest way by which we can ensure that the gains of genomic medicine and technologies are equitably deployed to serve the health needs of all human populations.”
For each ancestral group, the polygenic risk score that used data from all ancestries worked at least as well as or better than the risk scores derived from data from the same ancestral group.
“These results show that our concerted effort to include many diverse groups of people in genomic research will yield benefits such as new therapeutics and prevention strategies that improve the health of all people,” says Cashell Jaquish, Ph.D., a genetic epidemiologist and program officer within the Division of Cardiovascular Sciences at the National Heart Lung, and Blood Institute.
Funding for the study was provided by the National Heart, Lung and Blood Institute, part of the National Institutes of Health.
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Materials provided by NIH/National Human Genome Research Institute. Original written by Prabarna Ganguly, Ph.D.. Note: Content may be edited for style and length.

Scientists have determined for the first time the structure of the molecule associated with amyotrophic lateral sclerosis (ALS) and multiple other neurodegenerative diseases. The scientists at the Medical Research Council (MRC) Laboratory for Molecular Biology in Cambridge, UK, who led the study, say this discovery could enable targeted development of new medical interventions and diagnostic tests.
ALS is the most common form of adult-onset motor neuron disease and is characterised by the deterioration of neurons responsible for controlling voluntary muscle movements such as walking, talking, chewing, and breathing. There is no cure for ALS and no effective treatment to halt or reverse disease progression.
While the cause of ALS is unclear, it is known that the abnormal clumping of a protein, known as TDP-43, in nerve cells is the defining pathological hallmark of ALS. The TDP-43 clumps are also a hallmark of frontotemporal dementia (the second most common form of early-onset dementia after Alzheimer’s disease) and common in other neurodegenerative diseases, including Alzheimer’s and Parkinson’s.
TDP-43 is found in healthy cells throughout our bodies, but in the brains of patients with these diseases it clumps together forming ‘aggregates’ in the brain.
Although scientists have been aware of this for some time, the potential to translate this information into treatments has been limited as, until now, the molecular structure of the TDP-43 aggregates has been unknown.
Now, the team of scientists at the MRC Laboratory for Molecular Biology, working with researchers at the Tokyo Metropolitan Institute of Medical Science and the Aichi Medical University in Japan, have used cryo-electron microscopy to determine the first molecular structure of TDP-43 aggregates extracted from the donated brains of two individuals who had ALS.

Just as a home security system can alert a homeowner to the presence of an intruder, a protein called polyglutamine binding protein-1 (PQBP1) found in brain cells can alert the body to the presence of “intruding” viruses like human immunodeficiency virus (HIV). Now, researchers in Japan have shed new light on the role of PQBP1 in the detection of dysfunctional proteins associated with neurodegenerative disorders.
In a new study published in Nature Communications, researchers from Tokyo Medical and Dental University (TMDU) have revealed the role of intracellular receptor PQBP1 in response to Tau, a protein found primarily in neurons that plays a key role in the progression of neurodegenerative disorders like Alzheimer’s disease.
PQBP1 has been previously shown to sense and bind HIV DNA and trigger an immune pathway known as the cGAS-STING pathway to initiate an inflammatory response. While PQBP1 has also been shown to interact with dysfunctional proteins such as those implicated in the neurodegenerative disorder Huntington’s disease, the specific role of PQBP1 in neurodegenerative inflammatory responses was unclear. To better understand this relationship, researchers from TMDU set out to clarify the nature of the interaction between PQBP1 and Tau.
“By characterizing the relationship between PQBP1 and Tau, we were able to clarify a mechanism of inflammation in the brain that functions in both viral infection and neurodegenerative disease,” says senior author of the study, Hitoshi Okazawa.
The researchers performed in vitro analyses using microglia, which are PQBP1-expressing immune cells found in the brain, to demonstrate that Tau interacts with PQBP1 and that this interaction drives an immune response via activation of the cGAS-STING pathway. Their study revealed that the PQBP1-cGAS-STING pathway functions in parallel with TREM2-mediated pathway, whose mutation is known to associate with Alzheimer’s disease genetically.
They went on to use a mouse model in which PQBP1 was conditionally inactivated in microglia to show that expression of PQBP1 is necessary for a Tau-induced inflammatory response in vivo.
“We were pleased to find that inactivating PQBP1 in microglia in the mouse model reduced brain inflammation in response to the injection of Tau into the brain,” says Okazawa.
The team further found that mutations in the PQBP1-binding regions of Tau reduced the inflammation in the brain in response to Tau injection. These findings indicate that PQBP1 may represent a potential target for the development of therapeutics for the treatment of Tau-mediated neurodegenerative diseases.
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Materials provided by Tokyo Medical and Dental University. Note: Content may be edited for style and length.

Back pain affects many people at some point in their lives, and a common cause is damage to the squishy discs or flexible, rubbery tissues of the spine. However, observing this damage at an early stage is difficult with current imaging methods. Now, researchers reporting in ACS Nano can see microscopic soft tissue destruction in animal spines by targeting denatured collagen with fluorescent molecules. 
Anywhere along the spine, from the neck to tail bone, can become uncomfortable when its soft and protective tissues, including the cartilage and jelly-like intervertebral discs, become damaged and lose their structure. Daily wear-and-tear, as well as some disorders, such as facet joint osteoarthritis or ankylosing spondylitis, can degrade and unfurl the collagen proteins that give these tissues their bounce and flexibility. Detecting compromised collagen early could help patients get relief before the pain becomes severe, but this is very difficult to do with existing medical technologies, such as X-rays and magnetic resonance imaging (MRI). Previously, Yang Li and colleagues developed a collagen hybridizing peptide (CHP) probe that specifically binds unfurled collagen molecules, which happens when they deteriorate and lose their ability to cushion vertebrae. So, Li, Kuibo Zhang, Hong Shan and colleagues wanted to test if CHP labeled with fluorescent tags could be used as an imaging method to identify collagen destruction in the body.
To make the peptide probe more stable in the body, the researchers modified CHP by substituting a hydroxyl group with fluorine and then attaching a fluorescent dye to it. When healthy mice and rats were injected with the fluorescent dye-labeled CHP and imaged with near-infrared fluorescence (NIRF), the team could confirm that the fluorescing molecules accumulated on the soft tissues between the vertebrae. Then the researchers removed a portion of the animals’ spines and imaged them with light sheet fluorescence microscopy. This technique produced precise 3D maps, which revealed denatured collagen. Because CHP is known to specifically target damaged collagen, the team says their imaging experiments show that even healthy animals can have a modest degree of deteriorated collagen around load-bearing joints, especially in the lower back. In additional experiments, both the NIRF images and 3D maps generated with the new method detected collagen deterioration in animal models of spinal injury before structural changes were visible in tissues on MRI scans. Finally, the researchers applied dye-labeled CHP as a stain to intervertebral disc slides from people that had undergone spinal surgeries. The fluorescence intensity of the stain rose substantially as the level of disc degeneration increased. Based on these results, the researchers say that their molecular-level technique could be developed in clinical studies for earlier diagnosis and targeted therapeutic treatments for patients with back pain.
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Materials provided by American Chemical Society. Note: Content may be edited for style and length.

Physical exercise is great for a mouse’s brain, and for yours. Numerous studies conducted in mice, humans and laboratory glassware have made this clear. Now, a new study shows it’s possible to transfer the brain benefits enjoyed by marathon-running mice to their couch-potato peers.
Stanford School of Medicine researchers have shown that blood from young adult mice that are getting lots of exercise benefits the brains of same-aged, sedentary mice. A single protein in the blood of exercising mice seems largely responsible for that benefit.
The discovery could open the door to treatments that — by taming brain inflammation in people who don’t get much exercise — lower their risk of neurodegenerative disease or slow its progression.
In the study, to be published Dec. 8 in Nature, the Stanford researchers compared blood samples from exercising and sedentary mice of the same age. They showed that transfusions of blood from running mice reduced neuroinflammation in the sedentary mice and improved their cognitive performance. In addition, the researchers isolated a blood-borne protein that appears to play an important role in the anti-neuroinflammatory exercise effect.
Inflammation and cognitive health
Neuroinflammation has been strongly tied to neurodegenerative diseases in humans, said Tony Wyss-Coray, PhD, professor of neurology and neurological sciences. Animal studies have indicated that neuroinflammation precipitates neurodegenerative disorders and that reversing or reducing neuroinflammation can prolong cognitive health, he said.

Cells in the developing embryo can sense the stiffness of other cells around them, which is key to them moving together to form the face and skull, finds a new study by UCL researchers.
In the study of frog embryos, published in Nature, researchers found that embryonic cells can navigate away from soft regions of the embryo and toward harder regions.
Facial malformations and death can arise in embryos where the cells are unable to distinguish soft regions from hard ones, and researchers say the discovery could help to understand and prevent harmful birth defects.
Lead author Professor Roberto Mayor (UCL Cell & Developmental Biology) said: “The features of human and animal faces, like the nose, lips and ears, are sculpted by the complex and precise movement of cells in a developing embryo.
“An error in the movement of these cells can have devastating consequences for the babies and their families, generating serious problems such as lip or palate cleft, facial palsy, cranial malformations or even death. These account for a third of all birth defects globally — over 3 million each year — and are the primary cause of infant mortality, so improving our understanding of what causes such birth defects could be life-saving.”
Scientists studying the neural crest (embryonic stem cells that form facial features) have mainly focused on the genes and molecules that control the movement of these cells. Now, an ongoing line of work led by Professor Mayor has shown that not only genes and molecules, but mechanical cues as well, are important for the movement of these cells.
The new study was conducted using frog embryos, as their neural crest cells behave in a similar way to those of humans and their movement is often used to study the spread of cancer. In addition, the embryo development of frogs can be studied without inflicting harm.
Professor Mayor and colleagues had previously found that the stiffening of embryonic cells precipitates the migration of neural crest cells to the front of the head to form the face. Here, they have identified for the first time how the cells can detect stiffness in their surrounding environment in order to move along a stiffness gradient.
The research team identified a network of chemical and mechanical signals that interact to cooperatively control cell migration in the embryo. They found that neural crest cells induced the stiffness gradient by relying on a protein known to be involved in cell-to-cell adhesion, and they sensed the gradient by interacting with the extracellular matrix (fibres around cells). In doing so, the cells are able to make their own path toward stiffer regions of the embryo.
Co-author Dr Adam Shellard (UCL Cell & Developmental Biology) said: “This newly identified behaviour is likely to be found not only in the cells that form our face, but in the cells that forms all our organs, and could play a central role in the dissemination of cancer cells during metastasis which hijack the behaviour.
“Understanding how these cells move is an important step toward developing therapies for craniofacial malformations and cancer progression.”
The study was supported by the Medical Research Council, the Biotechnology and Biological Sciences Research Council, and Wellcome.
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Materials provided by University College London. Note: Content may be edited for style and length.

Debilitating cluster headaches commonly begin in childhood, but patients are not typically diagnosed until they are adults, according to research from The University of Texas Health Science Center at Houston (UTHealth Houston).
A team of researchers led by Mark Burish, MD, PhD, assistant professor in the Vivian L. Smith Department of Neurosurgery with McGovern Medical School at UTHealth Houston, conducted the Cluster Headache Questionnaire, an international, internet-based survey of 1,604 participants with cluster headache. Results from the survey were recently published in Headache: The Journal of Head and Face Pain.
Cluster headache is a rare headache disorder, occurring in about one in every 1,000 individuals. They are extremely painful and occur in cyclical patterns known as cluster periods, with most attacks taking place at the same time each day. Cluster headache is diagnosed as “episodic” when the attacks occur in periods lasting between seven days and one year and are separated by pain-free periods lasting three months or longer. Meanwhile, in “chronic” cluster headache, attacks occur for more than one year without remission or with remissions lasting less than three months.
The headaches are similar to migraines, but there are some key differences. Unlike migraines, which can last an entire day or potentially several days if left untreated, cluster headaches typically last anywhere from 15 to 180 minutes. While it’s uncommon to have more than one migraine a day, it is possible for someone to have up to eight cluster headaches over a 24-hour period. Moreover, migraine pain can vary in location; by contrast, cluster headaches involve only one side of the head, typically at the temple or around the eye. Lastly, people who have migraines tend to rest in a quiet, dark room, whereas people who have cluster headaches tend to become restless and often pace around the room.
There is extremely limited information on several characteristics of cluster headache, namely pediatric-onset cluster headache and comparative effectiveness of cluster headache treatments.
“I hope that this study will change the traditional thinking that cluster headache only affects adult men,” said Burish, who is also with The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences. “Our study shows that it commonly starts in childhood, and that many children go years without the correct diagnosis, presumably suffering the entire time because they don’t have the correct treatments.”
Significantly, pediatric onset was found in 27.5% of survey participants, but only 15.2% of participants with pediatric onset were diagnosed before the age of 18.

Appealing to athletes’ sense of ‘future guilt’ through psychological intervention could prove a powerful weapon in the fight against doping, according to a new study.
Researchers discovered that making elite athletes picture how guilty they might feel about using banned performance enhancing drugs produced a more powerful initial reaction than initiatives educating sportspeople about the health risks of doping.
Working with 208 athletes across the UK and Greece, researchers carried out two six-month trials — one a psychological intervention focussing on emotions and personal choice, the other an education programme highlighting the risks and health consequences of doping.
Using real athlete stories and testimonies on video, they made participants aware of emotions experienced by sportspeople who had doped, contrasting those feelings with emotions experienced by successful athletes who competed clean.
Participants discussed the athletes’ stories — enhancing their understanding of the emotions linked to doping. Researchers explored the justifications athletes use for doping (moral disengagement) and drew attention to the consequences doping has for others — whether family, friends, teammates or other competitors.
While the psychological intervention was more powerful than its educational counterpart, the experts found that receiving useful information about doping, doping control processes, the risks of sport supplements, healthy nutrition, and the anti-doping rule violations strengthened athletes’ confidence to resist the temptation to dope.

There’s a lot that our eyes have to protect themselves from — dust and debris; viruses and bacteria; chemicals from things we use every day like soaps and lotions; ultraviolet radiation from the sun; and hours of looking at computer screens or devices. It might be surprising then to learn that parts of the eye that are central to vision — the lens, cornea and retina — are immune privileged, meaning they lack immune cells and the protection they offer. But then how do these critical tissues protect themselves?
A few years ago, Sue Menko, PhD, professor of Pathology, Anatomy and Cell Biology at Thomas Jefferson University and researchers in her lab were studying a mouse that was engineered to lack a key protein required for the perfectly clear structure of the lens. As they expected, without this protein, the lens was malformed. But to their surprise, they also observed immune cells in the lens trying to fix the damage. This was the first time immune cells had been found to be recruited to the lens, and it challenged decades of scientific dogma. Building on their evidence, last year the Menko lab, in a collaboration with Mary Ann Stepp’s lab at George Washington University, found that when the cornea was wounded, immune cells travelled to the surface of the lens to protect from further damage.
Now in a new study published in The FASEB Journal on Dec 7th, the researchers show that immune cells respond to the lens, not just following an acute injury in the eye, but also to long-lasting inflammation. In collaboration with Dr. Rachel Caspi’s lab at the National Eye Institute and the Stepp lab, they studied a mouse model of uveitis, a form of eye inflammation triggered by infection or injury, and is considered to be an autoimmune disease like diabetes. Left untreated, uveitis can lead to a number of complications, including retinal scarring, glaucoma and cataracts of the lens. However, because the lens was thought for so long to have immune privilege, the role of immune cells in cataracts associated with uveitis has never been explored.
Dr. Menko and her lab used high-resolution microscopy to look at the whole eye and the surface of the lens. The first thing the researchers wanted to know was, do immune cells interact with the lens in this experimental model of uveitis? They were shocked at what they saw.
“In our previous study in which the cornea was wounded, we saw a small number of immune cells on the surface of the lens, acting almost like sentinels,” says Dr. Menko. “In this case, it was like a battering ram. There were dozens of immune cells, and different types of them, including T-cells and macrophages. It’s clearly a robust immune response and could reflect in part that inflammation in uveitis is so severe.”
The researchers then monitored this immune response to the lens over the course of 26 days, as inflammation sets in at day 14, reaches its peak at day 19 and begins to resolve by day 26.