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Ludwig cancer research study shows how novel drug screen can individualize cancer therapy

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JUNE 8, 2021, NEW YORK – A study conducted by researchers at the Ludwig Center at Harvard has demonstrated how a drug screening method known as dynamic BH3 profiling can be used to quickly identify potentially effective combinations of existing drugs for personalized cancer therapy.

“We know that cancer cells and healthy cells have different metabolisms,” said Ludwig Harvard investigator Anthony Letai who, with former postdoctoral researcher Veerle Daniels, led the study reported in the current issue of Science Signaling. “Using BH3 profiling, we found a specific metabolic dependency in triple negative breast cancer cells obtained from a patient that we could target with an existing drug, making the cells more susceptible to death and priming them for a second targeted drug that could then trigger their death.”

Daniels, Letai and colleagues also showed that the strategy suppresses growth of triple negative breast cancer (TNBC) in mice bearing patient-derived tumors.

Though tumors often have unique metabolic adaptations on which they depend, specifically targeting those vulnerabilities with drugs has proved challenging. Such drugs have often failed in clinical trials because they were poorly targeted or too toxic at the doses required to kill cancer cells when used as single agents.

“We wanted to see which of the drugs known to perturb metabolism would bring the TNBC cells closer to dying, but leave normal cells unaffected,” said Daniels. The researchers reasoned that such cells could then be selectively targeted by existing therapies known as BH3 mimetics to push them over the edge. Because the initial priming treatment requires low doses of the drug, this strategy could lower the risk of toxicities that have troubled the development of drugs targeting cancer metabolism.

Therapy often induces in cancer cells a type of programmed death known as apoptosis, which is orchestrated by an elaborate protein machinery. Cells, however, also produce anti-death proteins that inhibit key elements of that machinery. Whether a stressed cell dies or survives depends on the balance of pro-death and anti-death proteins, and cancer cells tend to produce large quantities of the latter to escape apoptosis and resist therapy.

BH3 mimetics inhibit anti-death proteins, tipping the balance in favor of cell suicide. Notably, one BH3 mimetic has already been approved for the treatment of certain blood cancers, and other such drugs are in various stages of development.

Dynamic BH3 profiling (DBP), developed in Letai’s laboratory, measures that same balance of pro-death and anti-death proteins to gauge how primed a patient’s tumor cells are for apoptosis following exposure to a drug. It thus represents a potentially rapid and unbiased method for screening hundreds of drugs at a time to find those most likely to treat a given patient’s tumors.

Daniels, Letai and colleagues used DBP to examine a “library” of 192 compounds that perturb metabolism–developed in the laboratory of Ludwig Harvard Co-Director Joan Brugge–for their effects on normal and TNBC cells. Eight disrupted cancer cell metabolism but left normal cells unperturbed.

Two of these drugs target an enzyme known as NAMPT, which participates in one of three biochemical pathways that produce NAD+, a molecule of critical importance to metabolism. Some sensitive TNBC cell lines, the researchers showed, were dependent on the pathway involving NAMPT. They also ran a DBP screen to find out which specific anti-death proteins the TNBC cells depended on for survival following NAMPT inhibition. They used this information to identify the most effective BH3 mimetic drug to use in combination with NAMPT inhibitors.

Using two mouse models of patient-derived TNBC tumors developed in Brugge’s lab, the researchers showed that only the mice bearing NAMPT-dependent tumors responded to a combination of the NAMPT inhibitor and the BH3 mimetic. They propose that the NAMPT inhibitor, which proved too toxic as a single agent, might be repurposed as a combination therapy given at lower doses with BH3 mimetics.

“What we’ve shown overall is that we can use DBP to find metabolic regulators of apoptotic priming and specific anti-apoptotic dependencies in tumors–and so identify powerful combinations of metabolic compounds and BH3 mimetics for therapy,” said Daniels.

Letai’s laboratory is using DBP to methodically identify other drug combinations for the treatment of a variety of cancers. Because it is a functional drug screen–examining only whether a given drug primes cancer cells for death–DBP does not require prior knowledge of a cancer’s inner workings or genetic aberrations.

“We don’t have to be limited to drug targets that are identifiable only by genetic mutations, which are only a tiny fraction of the true targets out there in the cancer world,” said Letai.

He and his colleagues are also planning a clinical trial using DBP to identify tailored therapies for individual patients diagnosed with myelogenous leukemia.

Letai and Daniels note that the regular inter-lab meetings and collaborative model of the Ludwig Harvard Center were critical to the conception, design and conduct of the study.

“It was a way of combining a unique set of expertise,” said Letai. “I’m good at cell death, not good at metabolism. Veerle is good at metabolism and cell death, but was lacking some key tools to do her initial screening, so we turned to other members of the Ludwig Harvard Center who actually had those tools. We wouldn’t have been aware of that expertise if we weren’t at the Center because Harvard is a very big place.”

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Anthony Letai is a Professor in Medicine at Harvard Medical School and the Dana Farber Cancer Institute.

Veerle Daniels is now a research scientist at Flamingo Therapeutics in Leuven, Belgium.

This study was supported by Ludwig Cancer Research, the U.S. National Institutes of Health, the Terri Brodeur Breast Cancer Foundation, Alex’s Lemonade Stand Foundation, Tap Cancer Out, Brazil’s National Council for Scientific and Technological Development, The Breast Cancer Research Foundation, Breast Cancer Coalition of Rochester and the American Association for Cancer Research.

About Ludwig Cancer Research

Ludwig Cancer Research is an international collaborative network of acclaimed scientists that has pioneered cancer research and landmark discovery for 50 years. Ludwig combines basic science with the ability to translate its discoveries and conduct clinical trials to accelerate the development of new cancer diagnostics and therapies. Since 1971, Ludwig has invested nearly $3 billion in life-changing science through the not-for-profit Ludwig Institute for Cancer Research and the six U.S.-based Ludwig Centers. To learn more, visit http://www.ludwigcancerresearch.org.

For further information please contact Rachel Reinhardt, [email protected] or +1-212-450-1582.

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Source: https://bioengineer.org/ludwig-cancer-research-study-shows-how-novel-drug-screen-can-individualize-cancer-therapy/

Bioengineer

No health worries for children born to mothers given seasonal flu vaccine in pregnancy

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uOttawa/CHEO study finds no increased risk of early childhood health issues following exposure to seasonal flu vaccination during pregnancy

A population-based study, published today in JAMA, has found flu vaccination during pregnancy does not lead to an increased risk of adverse early childhood health outcomes.

Although pregnant people are not more susceptible to acquiring influenza infection, they are at an increased risk of severe illness and complications if they get the flu during pregnancy. For this reason, all pregnant people are advised to receive a flu shot each year, yet only 36 percent received it according to a study monitoring four flu seasons in Nova Scotia. Safety concerns are reportedly a leading reason people may not receive influenza vaccination in pregnancy.

Dr. Deshayne Fell, an Associate Professor of Epidemiology in the Faculty of Medicine at uOttawa and a Scientist at the CHEO Research Institute, a pediatric healthcare and research centre, led the study along with researchers in Ontario and at Dalhousie University in Nova Scotia. The study followed over 28,000 children from birth up to an average age of 3 ½ years, with the results suggesting that maternal influenza vaccination during pregnancy was not associated with:

– Immune-related health conditions, such as asthma, ear infections or other types of infection.

– Non-immune-related health problems like neoplasms, sensory impairment.

– Nonspecific health needs such as Emergency Department visits and hospitalizations did not increase.

“This study adds to what we know from other recent studies showing no harmful effects of flu vaccination during pregnancy on the longer-term health of children,” says Dr. Fell, whose other recent work includes studying the effectiveness and safety of COVID-19 vaccines during pregnancy. “This is important because we know that getting the flu shot during pregnancy not only protects the pregnant person, but has the added bonus of protecting newborn babies from getting the flu during their first few months of life, which is when they are most susceptible to respiratory infections but still too young to get the flu shot themselves.”

The study, Association of Maternal Influenza Vaccination During Pregnancy with Early Childhood Health Outcomes, is published in JAMA.

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About the University of Ottawa
The University of Ottawa is home to over 50,000 students, faculty and staff, who live, work and study in both French and English. Our campus is a crossroads of cultures and ideas, where bold minds come together to inspire game-changing ideas. We are one of Canada’s top 10 research universities–our professors and researchers explore new approaches to today’s challenges. One of a handful of Canadian universities ranked among the top 200 in the world, we attract exceptional thinkers and welcome diverse perspectives from across the globe. http://www.uottawa.ca

About CHEO
Dedicated to the best life for every child and youth, CHEO is a global leader in pediatric health care and research. Based in Ottawa, CHEO includes a hospital, children’s treatment centre, school and research institute, with satellite services located throughout Eastern Ontario. CHEO provides excellence in complex pediatric care, research and education. We are committed to partnering with families and the community to provide exceptional care — where, when and how it’s needed. CHEO is a partner of the Kids Come First Health Team, a network of partners working to create a high quality, standardized and coordinated system for pediatric health care that is centred around children, youth and their families. Every year, CHEO helps more than 500,000 children and youth from Eastern Ontario, western Quebec, Nunavut and Northern Ontario. http://www.cheo.on.ca

https://media.uottawa.ca/news/study-no-health-worries-children-born-mothers-who-received-seasonal-flu-vaccine-during

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Bioengineer

How your phone can predict depression and lead to personalized treatment

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Study used data from cell phone apps and watches, brain activity and lifestyle factors to generate predictions of depression; results could lead to individualized treatment plans for mental health

According to the National Alliance on Mental Illness and the World Health Organization, depression affects 16 million Americans and 322 million people worldwide. Emerging evidence suggests that the COVID-19 pandemic is further exacerbating the prevalence of depression in the general population. With this trajectory, it is evident that more effective strategies are needed for therapeutics that address this critical public health issue.

In a recent study, publishing in the June 9, 2021 online edition of Nature Translational Psychiatry, researchers at University of California San Diego School of Medicine used a combination of modalities, such as measuring brain function, cognition and lifestyle factors, to generate individualized predictions of depression.

The machine learning and personalized approach took into account several factors related to an individual’s subjective symptoms, such as sleep, exercise, diet, stress, cognitive performance and brain activity.

“There are different underlying reasons and causes for depression,” said Jyoti Mishra, PhD, senior author of the study, director of NEATLabs and assistant professor in the Department of Psychiatry at UC San Diego School of Medicine. “Simply put, current health care standards are mostly just asking people how they feel and then writing a prescription for medication. Those first-line treatments have been shown to be only mild to moderately effective in large trials.

“Depression is a multifaceted illness, and we need to approach it with personalized treatment whether that be therapy with a mental health professional, more exercise or a combination of approaches.”

The one-month study collected data from 14 participants with depression using smartphone applications and wearables (like smart watches) to measure mood and lifestyle variables of sleep, exercise, diet and stress, and paired these with cognitive evaluations and electroencephalography, using electrodes on the scalp to record brain activity.

The goal was not to make any comparisons across individuals, but to model the predictors of each person’s daily fluctuations in depressed mood.

The researchers developed a new machine-learning pipeline to systematically identify distinct predictors of low mood in each individual.

As an example, exercise and daily caffeine intake emerged as strong predictors of mood for one participant, but for another, it was sleep and stress that were more predictive, while in a third subject, the top predictors were brain function and cognitive responses to rewards.

“We should not be approaching mental health as one size fits all. Patients will benefit by having more direct and quantified insight onto how specific behaviors may be feeding their depression. Clinicians can leverage this data to understand how their patients might be feeling and better integrate medical and behavioral approaches for improving and sustaining mental health,” said Mishra.

“Our study shows that we can use the technology and tools that are readily available, like cell phone apps, to collect information from individuals with or at risk for depression, without significant burden to them, and then harness that information to design personalized treatment plans.”

Mishra said next steps include examining if the personalized treatment plans guided by the data and machine learning are effective.

“Our findings could have broader implications than depression. Anyone seeking greater well-being could benefit from insights quantified from their own data. If I don’t know what is wrong, how do I know how to feel better?”

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Co-authors include: Rutvik Shah, Gillian Grennan, MariamZafar-Khan, Fahad Alim, Sujit Dey, all with UC San Diego; and Dhakshin Ramanathan with UC San Diego and the VA San Diego Medical Center.

Disclosure: Shah, Dey and Mishra have an Invention Disclosure filed for “Personalized Machine Learning of Depressed Mood using Wearables.”

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Source: https://bioengineer.org/how-your-phone-can-predict-depression-and-lead-to-personalized-treatment/

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The buck stops where? UNH research records longest-ever deer distance

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DURHAM, N.H.–Why did the deer cross the road? According to research from the University of New Hampshire to keep going and going and going. Researchers have discovered the longest distance ever recorded by an adult male white-tailed deer–300 kilometers, or close to 200 miles, in just over three weeks. The finding has important implications for population management and the transmission of disease, especially chronic wasting disease, a fatal neurological disease.

“Deer are one of the most abundant, well-known and intensely managed species of wildlife in the United States,” said Remington Moll, assistant professor of wildlife ecology and lead author. “So, to make this discovery despite the fact that they are so well studied is pretty surprising.”

In their study, published in the journal Ecology and Evolution, researchers analyzed data from GPS radio collars on more than 600 deer in Missouri. One dispersal, or long-distance journey, of an adult white-tailed deer stood out for its length, duration and age of the deer. The buck travelled close to 300 kilometers over 22 days by moving an average of 13.6 kilometers per day (almost eight and a half miles), crossing a major river seven times, an interstate highway, a railroad and eight state highways. To confirm the findings, the researchers surveyed the scientific literature for other dispersals of white-tailed deer. The deer, known as N17003, stood head and antlers above others; his walkabout was 174 kilometers longer than any other recorded for an adult male deer.

“This extraordinary movement just jumped out from the others we tracked,” said Moll. “At first, we thought it was an error. It looks like someone took the GPS collar and drove across the state of Missouri.”

The findings were remarkable not only for the deer’s range–he roamed a distance equal to that between New York City and Baltimore–but also because unlike juvenile males, who move to seek breeding opportunities, adult males tend to stay put. Movements were faster and more directional than those in their home territory and were faster and more directional at night than during the day when the deer frequently sheltered in forest cover. The journey, which happened in November 2017, occurred during hunting season.

“We call this a rare event, but we haven’t been putting collars out for that long, and not in these large numbers,” said Moll. “It’s entirely possible that it could be happening with greater frequency than we’ve known.”

Nearly eight million Americans hunt deer which contributes more than $20 billion to the U.S. economy. The researchers say that understanding the distance deer travel and how they do it is important for managing the species and controlling chronic wasting disease, a fatal neurological disease spread by direct contact and the environment. Knowing that deer are crossing county or even state lines highlights a need for regional management coordination.

Funding for this study was provided by the Missouri Department of Conservation, the U.S. Fish and Wildlife Service and the University of Montana.

Co-authors are Jon Roberts and Joshua Millspaugh, University of Montana; Kevyn Wiskirchen, Jason Sumners, Jason Isabelle and Barbara Keller, Missouri Department of Conservation; and Robert Montgomery, Michigan State University.

The >University of New Hampshire inspires innovation and transforms lives in our state, nation, and world. More than 16,000 students from all 50 states and 71 countries engage with an award-winning faculty in top-ranked programs in business, engineering, law, health and human services, liberal arts and the sciences across more than 200 programs of study. As one of the nation’s highest-performing research universities, UNH partners with NASA, NOAA, NSF and NIH, and receives more than $110 million in competitive external funding every year to further explore and define the frontiers of land, sea and space.

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PHOTOS FOR DOWNLOAD

Image: http://unh.edu/sites/default/files/deer_distance_monroebuck_.jpg

Credit: Missouri Department of Conservation

Caption: Fleeting glimpse of an adult white-tailed deer, known as N17003, that traveled the longest distance ever recorded by a UNH researcher – over 200 miles in 22 days.

Image: http://unh.edu/sites/default/files/deer_map_300kdeerdispersal_.jpg

Credit: UNH

Caption: Map chronicling the multi-county journey of an adult white-tailed deer, known as N17003, traveling the longest distance ever recorded – over 300 kilometers in just over three weeks.

https://www.unh.edu/unhtoday/news/release/2021/06/08/buck-stops-where-unh-research-records-longest-ever-deer-distance

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Serenading Lusitanian toadfish drowned out by water traffic

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During spring, Lusitanian toadfish (Halobatrachus didactylus) suitors form choirs in Portugal’s Tagus estuary to serenade the females, vibrating their swim bladders to produce a call, known as a boatwhistle, which sounds like a vibrating cell phone. The males also listen in on each other to check whether anyone is intruding on their territory. But sadly, their performances are no longer conducted in hushed reverence. Revving motorboats and churning ferry propellors and engines fill the water with unwelcome noise, which made Clara Amorim, Daniel Alves, Manuel Vieira and Paulo Fonseca, from the Universidade de Lisboa, Portugal, wonder whether human noise pollution is playing havoc with the garrulous fish’s ability to communicate. They publish their discovery that toadfish serenades are being drowned out by water traffic that also disrupts their ability to croon together in Journal of Experimental Biology at https://journals.biologists.com/jeb.

‘We had previously measured how far toadfishes could communicate with each other’, says Alves, who worked with local fisherman to collect the vocal fish. Once the fish were comfortable in the lab, Alves and Fonseca tested their hearing by playing boatwhistles – which had been recorded at distances from 0.1-15 m – while logging the fishes’ brainwaves as they listened to the sound against a silent background. Then, the duo added the whine of an outboard motor or a rumbling ferryboat and rechecked the brainwaves, to find out whether the fish were still able to hear the serenades.

Unfortunately, the outboard motor almost completely drowned out the recordings of the males. One boatwhistle that had been clear up to 10.4 m away in absolute silence became inaudible over distances of more than 2.5 m and the range of another toadfish rumble fell to just 2.0 m. However, the ferryboat seemed to have less of an impact on the toadfishes’ hearing, cutting the range over which one boatwhistle could be heard by 4 m, to 6.3 m, while the other, which had been so badly affected by the outboard motor, could be heard over slightly longer distances (6.7 m). Water traffic is clearly affecting the ability of these vocal fish to hear one another, but does the sound of passing vessels affect how harmonising toadfish croon together?

To find out, Vieira, Amorim and Fonseca crossed the Tagus to a quiet toadfish breeding ground, providing the serenading residents with 12 custom-built concrete nests, each equipped with an underwater microphone to record their boatwhistles as they settled into duetting with nearby males to attract females. In peaceful waters, the neighbours coordinated well, slightly advancing or delaying their responses to each other’s calls depending on their proximity. However, when the scientists played recordings of passing ferries and motorboats to the courting males, the toadfishes’ coordination broke down entirely, with serenading duetters interjecting more randomly between their neighbour’s timed rumbles.

‘These results demonstrate that boat noise can severely reduce the distance at which the Lusitanian toadfish can communicate and affect how they produce sounds in their choruses’, says Vieira, who warns that noisy human water traffic could dramatically affect the Lusitanian toadfish’s love life.

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Source: https://bioengineer.org/serenading-lusitanian-toadfish-drowned-out-by-water-traffic/

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