New algorithm could improve diagnosis of rare diseases

Today, diagnosing rare genetic diseases requires a slow process of educated guesswork. Gill Bejerano, Ph.D., associate professor of developmental biology and of computer science at Stanford, is working to speed it up.

In a paper published July 12 in Genetics in Medicine, Bejerano and his colleagues describe an algorithm they’ve developed that automates the most labor-intensive part of genetic diagnosis: that of matching a patient’s genetic sequence and symptoms to a disease described in the scientific literature. Without computer help, this match-up process takes 20-40 hours per patient: The expert looks at a list of around 100 of the patient’s suspicious-looking mutations, makes an educated guess about which one might cause disease, checks the scientific literature, then moves on to the next one.

The algorithm developed by Bejerano’s team cuts the time needed by 90 percent.

“Clinicians’ time is expensive; computer time is cheap,” said Bejerano, who worked with experts in computer science and pediatrics to develop the new technique. “If I’m a busy clinician, before I even open a patient’s case, the computer needs to have done all it can to make my life easier.”

A Phrank approach

The algorithm’s name, Phrank—a mashup of “phenotype” and “rank”—hints at how it works: Phrank compares a patient’s symptoms and gene data to a knowledge base of medical literature, generating a ranked list of which rare genetic diseases are most likely to be responsible for the symptoms. The clinician has a logical starting point for making a diagnosis, which can be confirmed with one to four hours of effort per case instead of 20-40 hours.

The mathematical workings of Phrank aren’t tied to a specific database, a first for this type of algorithm. This makes it much more flexible to use.

Phrank also dramatically outperforms earlier algorithms that have tried to do the same thing, according to the paper. Bejerano’s team validated Phrank on medical and genetic data from 169 patients, an important advance over earlier studies in the field. Prior studies had tested algorithms on made-up patients instead because real-patient data for this research is hard to come by.

“The problem is that this test [using synthetic patients] is just too easy,” Bejerano said. “Real patients don’t look exactly like a textbook description.” On data from real patients, one older algorithm ranked the patient’s true diagnosis 33rd, on average, on the list of potential diagnoses it generated; Phrank, on average, ranked the true diagnosis fourth.

Phrank also holds potential for helping doctors identify new genetic diseases, Bejerano said. For example, if a patient’s symptoms can’t be matched to any known human diseases, the algorithm could check for clues in a broader knowledge base. “You might get the result that mouse experiments cause phenotypes similar to your patient, that you may have found the first human patient that suffers from this disease,” Bejerano said.

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Team finds missing immune cells that could fight lethal brain tumors

Glioblastoma brain tumors can have an unusual effect on the body’s immune system, often causing a dramatic drop in the number of circulating T-cells that help drive the body’s defenses.

Where the T-cells go has been unclear, even as immunotherapies are increasingly employed to stimulate the body’s natural ability to fight invasive tumors.

Now researchers at Duke Cancer Institute have tracked the missing T-cells in glioblastoma patients. They found them in abundance in the bone marrow, locked away and unable to function because of a process the brain stimulates in response to glioblastoma, to other tumors that metastasize in the brain and even to injury.

The findings, published online Aug. 13 in the journal Nature Medicine, open a new area of exploration for adjunct cancer drugs that could free trapped T-cells from the bone marrow, potentially improving the effectiveness of existing and new immunotherapies.

“Part of the problem with all these immunotherapies—particularly for glioblastoma and other tumors that have spread to the brain—is that the immune system is shot,” said lead author Peter E. Fecci, M.D., Ph.D., director of the Brain Tumor Immunotherapy Program in Duke’s Department of Neurosurgery. “If the goal is to activate the T-cells and the T-cells aren’t there, you’re simply delivering therapy into a black hole.”

Fecci said the research team began its search for the missing T-cells after observing that many newly diagnosed glioblastoma patients have the equivalent immune systems of people with full-blown AIDS, even before they undergo surgery, chemotherapy and radiation.

Where most people have a CD-4 “helper” T-cell count upwards of 700-1,000, a substantial proportion of untreated glioblastoma patients have counts of 200 or less, marking poor immune function that makes them susceptible to all manner of infections and potentially to progression of their cancer.

Initially, the researchers hunted for the missing T-cells in the spleen, which is known to pathologically harbor the cells in certain disease states. But the spleens were abnormally small, as were the thymus glands—another potential T-cell haven. They decided to check the bone marrow to see if production was somehow stymied and instead found hordes of T-cells.

“It’s totally bizarre—this is not seen in any disease state,” Fecci said. “This appears to be a mechanism that the brain possesses for keeping T-cells out, but it’s being usurped by tumors to limit the immune system’s ability to attack them.”

When examining the stashed T-cells, Fecci and colleagues found that they lacked a receptor on the cell surface called S1P1, which essentially serves as a key that enables them to leave the bone marrow and lymph system. Lacking that key, they instead get locked in, unable to circulate and fight infections, let alone cancer.

Fecci said the research team is now working to learn exactly how the brain triggers the dysfunction of this S1P1 receptor. He said the current theory is that the receptor somehow is signaled to retract from the cell surface into the cell interior.

“Interestingly, when we restore this receptor to T-cells in mice, the T-cells leave the bone marrow and travel to the tumor, so we know this process is reversible,” Fecci said.

His team is collaborating with Duke scientist Robert Lefkowitz, M.D., whose 2012 Nobel Prize in Chemistry honored discovery of the class of receptors to which S1P1 belongs. They are working to develop molecules that would restore the receptors on the cells’ surface.

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Machine-learning system determines the fewest, smallest doses that could still shrink brain tumors

MIT researchers are employing novel machine-learning techniques to improve the quality of life for patients by reducing toxic chemotherapy and radiotherapy dosing for glioblastoma, the most aggressive form of brain cancer.

Glioblastoma is a malignant tumor that appears in the brain or spinal cord, and prognosis for adults is no more than five years. Patients must endure a combination of radiation therapy and multiple drugs taken every month. Medical professionals generally administer maximum safe drug doses to shrink the tumor as much as possible. But these strong pharmaceuticals still cause debilitating side effects in patients.

In a paper being presented next week at the 2018 Machine Learning for Healthcare conference at Stanford University, MIT Media Lab researchers detail a model that could make dosing regimens less toxic but still effective. Powered by a “self-learning” machine-learning technique, the model looks at treatment regimens currently in use, and iteratively adjusts the doses. Eventually, it finds an optimal treatment plan, with the lowest possible potency and frequency of doses that should still reduce tumor sizes to a degree comparable to that of traditional regimens.

In simulated trials of 50 patients, the machine-learning model designed treatment cycles that reduced the potency to a quarter or half of nearly all the doses while maintaining the same tumor-shrinking potential. Many times, it skipped doses altogether, scheduling administrations only twice a year instead of monthly.

“We kept the goal, where we have to help patients by reducing tumor sizes but, at the same time, we want to make sure the quality of life—the dosing toxicity—doesn’t lead to overwhelming sickness and harmful side effects,” says Pratik Shah, a principal investigator at the Media Lab who supervised this research.

The paper’s first author is Media Lab researcher Gregory Yauney.

Rewarding good choices

The researchers’ model uses a technique called reinforced learning (RL), a method inspired by behavioral psychology, in which a model learns to favor certain behavior that leads to a desired outcome.

The technique comprises artificially intelligent “agents” that complete “actions” in an unpredictable, complex environment to reach a desired “outcome.” Whenever it completes an action, the agent receives a “reward” or “penalty,” depending on whether the action works toward the outcome. Then, the agent adjusts its actions accordingly to achieve that outcome.

Rewards and penalties are basically positive and negative numbers, say +1 or -1. Their values vary by the action taken, calculated by probability of succeeding or failing at the outcome, among other factors. The agent is essentially trying to numerically optimize all actions, based on reward and penalty values, to get to a maximum outcome score for a given task.

The approach was used to train the computer program DeepMind that in 2016 made headlines for beating one of the world’s best human players in the game “Go.” It’s also used to train driverless cars in maneuvers, such as merging into traffic or parking, where the vehicle will practice over and over, adjusting its course, until it gets it right.

The researchers adapted an RL model for glioblastoma treatments that use a combination of the drugs temozolomide (TMZ) and procarbazine, lomustine, and vincristine (PVC), administered over weeks or months.

The model’s agent combs through traditionally administered regimens. These regimens are based on protocols that have been used clinically for decades and are based on animal testing and various clinical trials. Oncologists use these established protocols to predict how much doses to give patients based on weight.

As the model explores the regimen, at each planned dosing interval—say, once a month—it decides on one of several actions. It can, first, either initiate or withhold a dose. If it does administer, it then decides if the entire dose, or only a portion, is necessary. At each action, it pings another clinical model—often used to predict a tumor’s change in size in response to treatments—to see if the action shrinks the mean tumor diameter. If it does, the model receives a reward.

However, the researchers also had to make sure the model doesn’t just dish out a maximum number and potency of doses. Whenever the model chooses to administer all full doses, therefore, it gets penalized, so instead chooses fewer, smaller doses. “If all we want to do is reduce the mean tumor diameter, and let it take whatever actions it wants, it will administer drugs irresponsibly,” Shah says. “Instead, we said, ‘We need to reduce the harmful actions it takes to get to that outcome.'”

This represents an “unorthodox RL model, described in the paper for the first time,” Shah says, that weighs potential negative consequences of actions (doses) against an outcome (tumor reduction). Traditional RL models work toward a single outcome, such as winning a game, and take any and all actions that maximize that outcome. On the other hand, the researchers’ model, at each action, has flexibility to find a dose that doesn’t necessarily solely maximize tumor reduction, but that strikes a perfect balance between maximum tumor reduction and low toxicity. This technique, he adds, has various medical and clinical trial applications, where actions for treating patients must be regulated to prevent harmful side effects.

Optimal regimens

The researchers trained the model on 50 simulated patients, randomly selected from a large database of glioblastoma patients who had previously undergone traditional treatments. For each patient, the model conducted about 20,000 trial-and-error test runs. Once training was complete, the model learned parameters for optimal regimens. When given new patients, the model used those parameters to formulate new regimens based on various constraints the researchers provided.

The researchers then tested the model on 50 new simulated patients and compared the results to those of a conventional regimen using both TMZ and PVC. When given no dosage penalty, the model designed nearly identical regimens to human experts. Given small and large dosing penalties, however, it substantially cut the doses’ frequency and potency, while reducing tumor sizes.

The researchers also designed the model to treat each patient individually, as well as in a single cohort, and achieved similar results (medical data for each patient was available to the researchers). Traditionally, a same dosing regimen is applied to groups of patients, but differences in tumor size, medical histories, genetic profiles, and biomarkers can all change how a patient is treated. These variables are not considered during traditional clinical trial designs and other treatments, often leading to poor responses to therapy in large populations, Shah says.

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Arsenic in combination with an existing drug could combat cancer

Investigators have discovered that arsenic in combination with an existing leukemia drug work together to target a master cancer regulator. The team, led by researchers at the Cancer Center at Beth Israel Deaconess Medical Center (BIDMC), is hopeful that the discovery could lead to new treatment strategies for diverse types of cancer. Their findings were published today online in Nature Communications.

Despite its current reputation as a poison, arsenic is considered one of the world’s oldest drugs, used for centuries as a treatment for ailments ranging from infection to cancer. While arsenic at certain levels in public drinking water has been linked conclusively to a variety of cancers, surprisingly, its presence at other doses has been linked to unusually low rates of breast cancer.

Researchers including Pier Paolo Pandolfi, MD, Ph.D., Director of the Cancer Center and Cancer Research Institute at BIDMC, also demonstrated that arsenic trioxide (ATO) – an oxide of arsenic that was approved by the US Food and Drug Administration in 1995—when used in combination with another drug called all-trans retinoic acid (ATRA), was effective against acute promyelocytic leukemia (APL), a discovery that has transformed the treatment of the disease from being highly fatal to being highly curable. However, it’s not fully clear what cellular target(s) these drugs act on, how they interact with each other, or whether they might be effective against other types of cancer.

Now, led by Kun Ping Lu, MD, Ph.D., and Xiao Zhen Zhou, MD, investigators at the Cancer Research Institute at BIDMC, discovered a previously unrecognized mechanism by which arsenic trioxide and all-trans retinoic acid work together to combat cancer. They found that the two drugs cooperate to destroy Pin1, a unique enzyme that the researchers discovered more than 20 years ago.

Together, when given at clinically safe doses, the drugs effectively inhibited numerous cancer-driving pathways and eliminated cancer stem cells in cell and animal models as well as patient-derived tumor models of triple-negative breast cancer, which has the worst prognosis of all breast cancer subtypes.

“Our discovery strongly suggests an exciting new possibility of adding arsenic trioxide to existing therapies in treating triple-negative breast cancer and many other cancer types, especially when patients’ cancers are found to be Pin1-positive,” said Zhou. “This might significantly improve the outcomes of cancer treatment.”

Known to be a master regulator of cancer signaling networks, Pin1 activates more than 40 cancer-driving proteins and inactivates more than 20 tumor suppressing proteins. It has been found to be over-activated in most human cancers and is especially active in cancer stem cells—a subpopulation of cancer cells believed to drive tumor initiation, progression, and metastasis, but not effectively targeted by current therapies.

In their study, Zhou, Lu and their colleagues found that arsenic trioxide fights cancer by binding, inhibiting, and degrading Pin1. All-trans retinoic acid also binds and destroys the Pin1 enzyme, but in addition, it increases cells’ uptake of arsenic trioxide, increasing expression of a cell membrane protein that pumps ATO into cells. Mice that lack expression of Pin1 are highly resistant to developing cancer even when their cells overexpress oncogenes or lack expression of tumor suppressors. Notably, these animals display no obvious defects for over half of lifespan, suggesting that targeting this master switch of an enzyme may be safe.

The findings are especially promising when considering the wide-range effects of Pin1. Aggressive tumors are often resistant to targeted therapies aimed at blocking individual pathways, but targeting Pin1 would not only short circuit numerous cancer-promoting signals, but also eliminate cancer stem cells, the two major sources of cancer drug resistance. However, no effective Pin1 inhibitors have yet been developed.

“It’s gratifying to see this combination of all-trans retinoic acid and arsenic trioxide that my lab discovered to be curative in the treatment of acute promyelocytic leukemia translate into possible approaches for the treatment of other cancers,” said Pandolfi. “Indeed, it is interesting to speculate that this combination may even prove curative in other tumor types yet to be discovered.”

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Study of tick-borne disease dynamics could thwart future outbreaks

The Centers for Disease Control and Prevention (CDC) released a report earlier this year on the increase of tick-, flea- and mosquito-borne illnesses in the United States, but don’t panic.

Kurt Vandegrift, assistant research professor of biology at Penn State, works on emerging infectious diseases, and his lab studies ticks. Vandegrift’s lab is part of a National Science Foundation grant studying virus community dynamics. His research group is working to develop solutions that could help stop outbreaks of infectious diseases, like the ones mentioned in the recent CDC report, before they start.

“Mice that live in our houses and garages are reservoirs of some pretty nasty pathogens, like hantavirus,” said Vandegrift. “The only way viruses like these get discovered is if they get into humans and start causing illness.”

Zoonotic viruses, which can jump from animals to humans, like SARS, cost the global economy billions of dollars annually. Vandegrift and his colleagues aim to be more proactive and discover these viruses before they start causing illness in humans. According to Vandegrift, researchers are seeing more than two new emerging infectious diseases per year, most of which are viral, and most of which are zoonotic. 

“Most of the zoonotic viruses we know about have come from rodents, so it is really valuable to know what viruses are in these rodents,” said Vandegrift. “It would also behoove us to know what viruses are in ticks because they are essentially like dirty needles, poking all this wildlife biodiversity and then coming to us, humans, for their second feeding, presumably exposing us to the viruses that were infecting their first host.” 

Once the team has established the viral biodiversity, it aims to work out the dynamics within a host. Some of the viruses will be passed from tick to tick or mouse to mouse via “vertical transmission”—from mother to offspring—and some will be acquired by “horizontal transmission”—from other mice or, in the case of ticks, via blood meals upon hosts.

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To determine which viruses are transmitted vertically, the researchers take engorged adult ticks from hunter-killed deer and raise them in the lab, allowing them to lay eggs. The researchers then sequence the mother tick, her eggs, and the larvae that hatch. Any viruses that are found in common are vertically transmitted. Other viruses that are found only in nymphs and adults must have come from elsewhere and are horizontally transmitted. 

The same process is done with the mice, with the team testing both the mother and her offspring to determine what viruses they carry. The mice are then marked and can be retested in the future to see how the virus community assembles within an individual animal; the lab does the same with the ticks they study. 

“Since we have sequenced a portion of each mother tick’s clutch, we know what viruses are present, and so we can attach these ticks with known viruses to mice with known viruses and see who gives what to whom,” said Vandegrift. “We also collect these now-engorged ticks as they fall off of the mice and can molt a portion of them into nymphs, which we then can attach to a pathogen-free lab variety of our mice to see if what they picked up can be transmitted onward in the nymphal blood meal.”

Ticks are responsible for transmitting Borrelia (Lyme disease), Babesia and anaplasma, which are known bacterial infections. 

“There is no known rhyme or reason for how much bacteria is sucked up or spat out by the tick, and so we want to determine if these viruses play a role in this transmission,” said Vandegrift.

Through their method, the researchers think they will be able to test if viruses have a role in what bacteria is transmitted by the ticks.

“Some of our larvae will pick up these pathogens during that first blood meal on our wild-caught mice. These three bacteria will then be transmitted to the lab mice, and we can measure how much relative to what viruses were also along for the ride,” said Vandegrift.

Tips for avoiding ticks

In addition to studying ticks and tick-borne diseases, Vandegrift also has some practical advice to help both people and pets avoid ticks in the first place.

Despite having found hundreds of ticks attached to him over the years, Vandegrift said he has never tested positive for Lyme disease, a fact that he attributes to three things: diligence, luck and permethrin—an insecticide that kills ticks on contact. 

“Some people, like myself, react strongly to ticks and get very itchy even if they just walk on the skin, so I know nearly immediately that I have picked up an unwanted visitor,” Vandegrift said. “Many people do not notice, but there are some things you can do to help avoid tick bites, like wearing light-colored clothing to help you see the ticks. If you are in brush, constantly check yourself—particularly your legs. Wear DEET repellants or permethrin. If you do use permethrin, do not get it in water, however, as it will kill more than just ticks, and you should be aware that it will also kill bees.” 

The blacklegged tick, commonly known as the deer tick, now abundant in Pennsylvania, carries the bacteria that causes Lyme disease. In fact, Pennsylvania ranks No. 1 in instances of Lyme disease in the country. The vast majority of people are diagnosed as positive for Lyme disease in June and July from bites that likely occur from late April through June, when ticks are in the nymph stage.

“Ticks have three stages of life,” said Vandegrift. “The second stage of development—the nymph stage—poses the most significant threat of transmission of disease-causing bacteria to people. Ticks in the nymph stage are small, and they could be feeding on a person and go unnoticed for a more extended period compared to an adult tick due to their size. Ticks do not immediately transmit the bacteria that causes Lyme disease, so a person has time to check themselves over.”

Vandegrift said it’s important to also check our four-legged friends, as pets can be particularly good at collecting ticks, and to consult a veterinarian for recommended preventive treatments that can be used to safeguard your pet’s health and help prevent ticks from being carried into the home.

If you do find that a tick has attached to you or a pet, Vandegrift said the best way to remove it is with a fine-tipped pair of tweezers.

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Obesity could set stage for heart issues in pregnancy

(HealthDay)—Young pregnant women who are obese may face a higher risk of changes in heart structure and function, a small new study suggests.

The changes seen might lead to a pregnancy complication known as preeclampsia, according to the researchers. This disorder is a dangerous form of high blood pressure that can develop during the second half of pregnancy.

Preeclampsia can put both mother and baby at risk, according to the American College of Obstetricians and Gynecologists. Obesity is a known risk factor for preeclampsia.

“The main goal of this ongoing study is to follow women through pregnancy to detect whether there are differences in how an obese woman’s cardiovascular system changes during pregnancy that might explain their predisposition to preeclampsia and other cardiovascular complications,” said the study’s lead author Dr. Katherine Shreyder. She’s a medical resident at Texas Tech University Health Sciences Center in Odessa.

“It seems that the obese patients will be more likely to deteriorate during pregnancy, because we started to observe higher blood pressure (although still in the normal range), an increase in [the size of an area of the left heart], and diminished pumping strength and relaxation,” Shreyder said in an American Heart Association news release.

Obesity is defined as a body mass index (BMI) above 30. Body mass index is a rough estimate of a person’s body fat based on height and weight. For someone who is 5-feet 9-inches tall, a weight over 203 pounds is considered obese, according to the U.S. Centers for Disease Control and Prevention.

The study included 11 women with a BMI of nearly 34. Their average age was 30. For comparison, the researchers also recruited 13 women with a BMI of 25.5, which is considered slightly overweight. Their average age was 26 years.

All of the women were in the first trimester of a first-time pregnancy. Eighty-five percent of the women were Hispanic. None had any known heart conditions, high blood pressure or diabetes. None were carrying twins or triplets.

Compared to normal weight women, the researchers found that the obese women had a thicker left ventricle, which is the heart’s main pumping chamber. Obese women also didn’t pump blood as efficiently as normal weight women.

In addition, blood pressure was higher in the obese women—125/80 mm Hg, compared to 109/69 mm Hg, on average.

Dr. Robert Eckel, a spokesperson and past president of the American Heart Association, reviewed the study findings.

“Obese women have a higher risk of preeclampsia and other complications like gestational diabetes. There are lots of reasons why obesity and pregnancy might not be a perfect marriage,” Eckel said.

But, he emphasized that this is a very small study with “modest differences” between the groups.

Eckel said these differences “may not play out in a larger sample.” He added that he would have liked to have seen a control group of non-pregnant obese women to see how obesity affects pregnancy. It would also be interesting to see how the differences between obese and non-obese women change throughout pregnancy, he said.

Dr. James Catanese, chief of cardiology at Northern Westchester Hospital in Mount Kisco, N.Y., said this study was very interesting, especially because obesity and preeclampsia will be seen more in the future.

“This study already saw changes so early on in pregnancy from obesity, so it may help us find out months before who’s going to get preeclampsia,” he said.

Catanese noted that if these findings are replicated with a larger group of women, it might indicate a need to start blood pressure medications early in pregnancy.

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Estrogen could promote healthy development of preterm infants

Premature birth alters the balance of interneurons in the cerebral cortex that can be restored with estrogen treatment, according to a study of human brain tissue and preterm rabbits published in JNeurosci.

Infants born prior to a full-term pregnancy are at increased risk of neurobehavioral disorders linked to defects in interneurons, which continue to develop through the end of the third trimester. Prematurity is also associated with a large reduction in levels of the hormone estrogen.

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Potential new MS drug could regenerate myelin

Scientists from the University at Buffalo in New York find that the receptor muscarinic type 3 (M3R) is a “key regulator” of remyelination, which is the process that replenishes lost myelin.

M3R is found on the surface of oligodendrocyte progenitor cells (OPCs), the precursors to the cells that make myelin.

A receptor is a cell-surface protein that triggers certain cell functions when it encounters and binds to a matching unique molecule.

The scientists showed that blocking M3R increased remyelination in mice that had human OPCs transplanted into them.

Senior study author Fraser J. Sim, an associate professor of pharmacology and toxicology, and his colleagues report their findings in a paper now published in The Journal of Neuroscience.

Multiple sclerosis and myelin loss

Multiple sclerosis (MS) is a disease that destroys the myelin sheath that surrounds nerve fibers in the central nervous system, which is made up of the brain, spinal cord, and optic nerve.

Many experts believe that the disease develops because the immune system attacks myelin and the cells that make it as though they were a threat.

As myelin is destroyed, it forms lesions that weaken signals that travel along the nerve fibers, leading to disrupted communication between brain cells. Scientists have learned that the disease also damages the nerve cells themselves.

MS has many symptoms, and they can range from mild to severe and depend on which part of the central nervous system is affected.

Common early symptoms include: problems with vision and pain in the eye; weak and stiff muscles, sometimes with painful spasms; tingling in the limbs, face, and trunk; difficulties with balance; and bladder problems.

As the disease progresses, these symptoms may be accompanied by extreme fatigue, changes in mood and concentration, and difficulties with planning and decision-making.

The symptoms can come and go, or they can persist and worsen. They may also vary from person to person, and they can also change in the same individual over time.

Estimates suggest that there are up to 350,000 people living in the United States who have been diagnosed with MS, with women twice as likely to be affected as men.

Oligodendrocytes and myelination

MS arises not just because the myelin degrades, but also because there is a failure to repair it. This has made scientists wonder if destruction of the cells responsible for remyelination might not be the only factor.

They started to investigate the possibility that the precursors of myelinating cells — the OPCs — were failing to multiply and mature. The result would be a shortage of cells for repairing myelin damage.

Eventually, they discovered that blocking muscarinic receptors was a powerful way to get OPCs to mature and speed up remyelination.

But as the authors note, translating this laboratory success into the clinic has been constrained by “poor understanding” of the muscarinic receptor subtype involved and questions about “species differences between rodents and humans.”

In earlier work, the team had reported that solifenacin — a drug that was already approved for treating bladder problems — blocked the receptor and promoted remyelination in animals.

However, in that study it was not clear “which specific receptor the drug worked on,” explains Prof. Sim. In order to limit undesirable side effects, it would be better to know precisely which receptor subtype to target.

M3R has role in myelin production

In the latest study, the researchers worked with mouse OPCs, human OPCs, and mice with human OPCs transplanted into them.

They discovered that activating the M3R receptor led to cell signals in OPCs that “act to delay differentiation and remyelination.”

Further experiments demonstrated that blocking M3R increased remyelination by human OPCs transplanted into mice.

Prof. Sim explains that their new findings put the field in a better position for carrying out clinical trials of drugs that target M3R in MS patients.

This work establishes that M3R has a functional role and if blocked, could improve myelin repair.”

Prof. Fraser J. Sim

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Drugs that block structural changes to collagen could prevent lung fibrosis

Scientists have found that it is the structure of collagen, rather than the amount, that leads to the devastating condition of lung fibrosis, according to a report in the journal eLife.

The study provides the first evidence in humans that altered collagen structure affects tissue stiffness during progression of lung fibrosis and identifies a potential new target for drugs to prevent the condition.

It is widely thought that fibrosis occurs when components that hold together a tissue’s architecture (called the extracellular matrix (ECM)) build up in the tissue and lead to tissue stiffness. But recently evidence has suggested that this increased stiffness causes the build-up of yet more ECM components, resulting in a cycle that causes more scar tissue.

“We knew that stiffness is an important factor in the build-up of scar tissue in the lung,” explains lead author Mark Jones, NIHR Clinical Lecturer in Respiratory Medicine at the NIHR Southampton Biomedical Research Centre and University of Southampton, UK. “But we didn’t understand what specifically causes increased stiffness in diseased human tissue. Given that excessive build-up of collagen is considered a hallmark of fibrosis, we wanted to see whether this molecule has a role in tissue stiffness.”

They started by looking at the biological and mechanical features of lung tissue from people with lung fibrosis and compared this to healthy lung tissue. They found that the lung fibrosis samples were much stiffer than those from healthy people but, surprisingly, had similar levels of collagen.

However, when they looked at enzymes that give collagen its unique ‘cross-linked’ structure within the ECM, they found that a family of these enzymes (the LOXL family) was more abundant in the fibrosis samples. This led them to further investigate the types of collagen structures found in the fibrosis samples—which are broadly grouped into immature and mature collagen cross-links. They found that increased lung tissue stiffness only occurred where there were higher amounts of the mature cross-linked collagen and that, in these samples, the structure of each collagen building block—or fibril—was altered. This suggested that it is collagen structure, controlled by the LOXL family, that determines tissue stiffness.

Having made this discovery, the team tested whether they could alter the structure of collagen by blocking the LOXL enzymes, with a view to preventing lung fibrosis. They tested a compound called PXS-S2A that blocks LOXL-2 and LOXL-3 in lung tissue cells isolated from people with fibrosis. They found that the number of cross-linked collagen molecules declined with an increasing dose of PXS-S2A.The compound also reduced tissue stiffness, even at low concentrations, suggesting that blocking LOXL-2/LOXL-3 could be an effective way to reduce tissue stiffness.

Finally, they tested the LOXL-2/3 inhibitor in rats with lung fibrosis and found that although there was no effect on total collagen content in the lungs, the treated rats had reduced fibrosis and improved lung function, with no adverse effects.

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Cell ‘chatter’ discovery could open clinical trial opportunity for fatal childhood brain tumour

Brain tumours are hard to treat. But even this is a harrowing understatement for some forms of the disease.

Diffuse intrinsic pontine glioma (DIPG) is one such example. These rare brain tumours almost exclusively affect children, and they’re invariably fatal.

“Almost all children with DIPG sadly die within a couple of years of diagnosis,” says Professor Chris Jones from the Institute of Cancer Research, London, a Cancer Research UK-funded expert on the disease.

“There aren’t any effective treatments.”

One of the main reasons that the outlook for DIPG is so poor is down to where it grows in the brain. These tumours start in the brainstem, which lies at the base of the brain and hooks up the spinal cord with deeper brain regions. This crucial piece of machinery controls many of the body’s vital processes, such as breathing and our heart beat.

That means surgery – a cornerstone treatment for many cancers – is out of the question. Drugs are also notoriously ineffective for brain tumours, because most are shut out by the protective blood brain barrier. DIPG is no exception, and Jones says that no chemotherapies have convincingly shown a beneficial effect, despite many different clinical trials testing a variety of drugs. This leaves radiotherapy as the only option, but it isn’t a cure.

“Radiotherapy is the only treatment that’s been shown to have any effect on DIPG,” he says.

“Usually patients will be given a drug as well in an attempt to find something that works, but the cancer usually comes back within 6-9 months.”

Difficult by name and by nature

This situation leaves a pressing need for new treatments. Behind every cancer treatment is research, but that’s where the nature of DIPG presents scientists with yet another challenge.

Studying samples of patients’ tumours in the lab helps scientists understand the biology of the disease and leads them towards new treatments. But for many years biopsy samples weren’t taken from children with DIPG, because the procedure was too dangerous due to the tumours’ delicate position. That left scientists with a shortage of tissue to work with and learn from.

“DIPG is diagnosed by imaging, so questions were raised over the need for invasive and risky biopsies. That set back the collection of tissue for study,” Jones says.

But the field was reawakened in 2012 when a new way of taking biopsy samples with a thin needle was shown to be safe. Using this brain tissue, and also samples taken from children who have died from the diseases, scientists can now grow DIPG cells in the lab and in mice, boosting research efforts and uncovering the genes and molecules that may fuel the disease.

And Jones’ latest research, published in Nature Medicine, is testament to how important these samples are.

More than meets the eye

Scientists already knew that DIPG doesn’t grow as a uniform bundle of cells. Instead, these tumours resemble a diverse patchwork of cells with distinct genetic and molecular fingerprints.

“Down the microscope it looks like adult glioblastoma,” says Jones. “So, a variety of drugs designed against the biology of this tumour type have been tried in DIPG patients, but none of them have worked.”

The tumour isn’t limited to the brainstem either; it spreads throughout the brain, seeding new patchworks of cancer cells in distant regions.

Armed with this knowledge, Jones and his team studied the brains of children who had died of DIPG, comparing the genetic features of different populations of cells. By creating a map of their DNA faults, the scientists showed that spreading cells move early in the tumour’s development, although they tended to grow slower than those in the original tumour.

Next, they grew up samples taken from the brains of children with DIPG into balls of cells in the lab, observing their behaviour and characteristics.

“We found that they were very different; some grew very fast while others didn’t, and some could spread extensively when others couldn’t,” Jones says.

But when they mixed cells together, those that previously had weaker characteristics became more aggressive. “We think these different populations are cooperating, helping one another to grow or spread,” he adds.

This helping hand seems to come from molecular signals that the cancer cells send out, since bathing cells in the liquid that more aggressive cells had been grown in also boosted their ability to divide and spread.

Trials and tribulations

Alongside revealing the intricacies of the disease, Jones hopes that his research brings new, smarter ways to treat DIPG.

“This work opens up a new way of thinking about how we may treat tumours,” he says. “If we can better understand what these different populations of cells are doing, and how they’re interacting, maybe we can identify which ones are the key to go after with drugs.”

With support from Cancer Research UK, the next stage of this research aims to find out precisely that. Hopefully, discoveries that emerge could make their way towards patients sooner, as Jones is also part of a Cancer Research UK-funded clinical trial that’s treating children with DIPG based on the biology of their disease. Because the study is designed to be adaptive, meaning the treatment a child receives on the trial isn’t set in stone, promising new treatments being developed could be added in and tested out in the trial as it progresses.

Supporting this type of research is exactly why we’ve made brain tumours a top priority, and why we’re committing an extra £25 million over the next 5 years specifically for research in this area.

“New, targeted drugs are now starting to make their way into clinical trials for DIPG,” says Jones.

“We don’t yet know whether they’ll work, but ultimately we want to combine targeted drugs with other treatments, such as radiotherapy or immunotherapy.

“For the first time, these kinds of trials are now opening for DIPG.”

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