Author: Nancy Fliesler

How celastrol sensitizes brains to leptin, curbing hunger and obesity

celastrol path of action
Celastrol increases numbers of IL1R1 receptors in the brain, allowing leptin to act. (ILLUSTRATION: ELLA MARU STUDIO)

Here’s what’s known about celastrol, widely hailed in 2015 for its potent anti-obesity effects. It’s derived from the roots of the thunder god vine. It increases the brain’s sensitivity to leptin, the hormone that signals we’ve had enough to eat. It has curbed food intake by nearly 80 percent in obese mice, producing up to a 45 percent weight loss. It’s now in Phase 1 clinical trials conducted by ERX Pharmaceuticals; phase 2 studies are slated to begin this year.

What hasn’t been known is how celastrol makes the brain more sensitive to leptin. A study in today’s Nature Medicine finally provides an answer.

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50-year-old mystery solved — with clues to making more red blood cells

why steroids boost red blood cell production
Red blood cells produced by a single progenitor cell (IMAGE COURTESY HOJUN LI / DANA-FARBER/BOSTON CHILDREN’S VIA CELL PRESS)

Back in the 1950s, doctors began using steroids to treat Diamond-Blackfan anemia, or DBA, a severe condition in which patients cannot make enough red blood cells. There was no real rationale for using steroids, but there was no other good option, aside from regular transfusions. At the time, steroids were being thrown at seemingly everything.

But steroids worked in most patients, at least for a time — at the expense of serious side effects such as weight gain, bone loss, hypertension, diabetes and an increased risk of infections. A new study published yesterday in Developmental Cell finally explains why steroids work — and could provide a foothold for developing safer and better treatments for DBA. It could even pave the way to treatments for other types of bone marrow failure.

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EEG data classify ‘autism’ into two distinct groups

[IMAGES FROM BMC NEUROLOGY (DOI 10.1186/s12883-019-1254-1)]

The Diagnostic and Statistical Manual, 5th edition (DSM-5) established a single diagnosis of autism spectrum disorder (ASD) that includes Asperger’s syndrome, formerly considered a separate condition. The change was meant to eliminate diagnostic ambiguities, but it has encouraged schools to take a “one size fits all” approach, putting all children with autistic features in the same classroom.

This concerns many parents and professionals. “Typically, such classrooms focus on the more severely impaired, often non-verbally communicative children without helping the higher functioning children, such as those with Asperger’s,” says Heidelise Als, PhD, a psychologist at Boston Children’s Hospital.

Als and her co-investigator Frank Duffy, MD, a neurologist at Boston Children’s, decided to take an unbiased look at children diagnosed with autism, using data from their EEGs. In a paper in BMC Neurology, they conclude that autism is not a single entity, but falls into two distinct clusters — ripe for additional investigation.

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Eavesdropping on mitochondria, tissue by tissue

mitochondria
(IMAGE: ADOBE STOCK)

First in a two-part series on mitochondria. See part 2.

Mitochondria are essential to life: they produce energy, synthesize building blocks critical to cell function and help regulate cellular activity, including programmed cell death. Mitochondrial diseases can cause severe metabolic disorders in children and dysfunctional mitochondria are thought to play a role in cancer, diabetes, heart attack, stroke, Parkinson’s disease and more.

A new research tool offers an unprecedented glimpse at the workings of these tiny, dynamic organelles, and could aid in the study of mitochondrial dysfunction.

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How the antidepressant ketamine rapidly awakens the brain, and why its effects vary more in women

(CREDIT: NATHALIE PICARD / BOSTON CHILDREN’S HOSPITAL)

In small doses, the anesthetic ketamine is a mildly hallucinogenic party drug known as “Special K.” In even smaller doses, ketamine relieves depression — abruptly and sometimes dramatically, steering some people away from suicidal thoughts. Studies indicate that ketamine works in 60 to 70 percent of people not helped by slower-acting SSRIs, the usual drugs for depression.

Two ketamine-like drugs are in the clinical pipeline, and, as of this week, one appears close to FDA approval. With no significant new antidepressant in more than 30 years, anticipation is high. Yet no one has pinned down how low-dose ketamine works. Studies have implicated various brain neurotransmitters and their receptors — serotonin, dopamine, glutamate, GABA receptors, opioid receptors — but findings have been contradictory.

“We felt it was time to figure this out once and for all,” says neuroscientist Takao Hensch, PhD.

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Blood stem cell transplants from any donor, without toxicity?

could stem cell transplants be made nontoxic?
(ADOBE STOCK)

Many blood disorders, immune disorders and metabolic disorders can be cured with a transplant of hematopoietic (blood-forming) stem cells, also known as bone marrow transplant. But patients must first receive high-dose, whole-body chemotherapy and/or radiation to deplete their own defective stem cells, providing space for the donor cells to engraft. These “conditioning” regimens are highly toxic: they wipe out the immune system, raising infection risk, and can cause anemia, infertility, other organ damage and cancers. And when the donor isn’t an exact match, patients’ immune systems must be suppressed for prolonged periods to prevent rejection.

As a result, most patients either don’t receive a transplant or must endure serious side effects. But if two new studies bear out in clinical trials, a far gentler conditioning treatment could enable stem-cell transplants for a much wider range of disorders, even possibly from unmatched donors.

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Children raised in institutions have impaired memory and executive functioning at age 16

long-term effects of child institutionalization

An estimated 8 million children worldwide live in institutions where they experience neglect and deprivation. Last fall, a study of children reared in Romanian orphanages reported high levels of mental health problems when they reached adolescence. In particular, they had more difficult behaviors such as rule-breaking, excessive arguing with authority figures, stealing or assaulting peers. But if they were placed early with carefully vetted foster families through the Bucharest Early Intervention Project (BEIP) , these problems were reduced.

A new BEIP study, published yesterday in the Proceedings of the National Academy of Sciences, examined cognitive functioning. It found that institutionalized children, at ages 8 and 16, also have impaired memory and executive functioning compared with peers placed early in foster homes.

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Using multiple data streams and artificial intelligence to ‘nowcast’ local flu outbreaks

(PHOTO: ADOBESTOCK)

Because influenza is so contagious, it’s been challenging to track and forecast flu activity in real time as people move about and travel. While the CDC continuously monitors patient visits for flu-like illness in the U.S., its information can lag by up to two weeks. A new study led by the Computational Health Informatics Program (CHIP) at Boston Children’s Hospital combined multiple approaches, providing what appear to be the most accurate local flu predictions to date.

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Overriding resistance to epigenetic inhibitors in neuroblastoma: Targeting PI3K

(IMAGE COURTESY NATIONAL CANCER INSTITUTE)

Children’s cancers pose unique challenges. They’re not caused by the same kinds of genetic mutations that cause adult cancers, and only a minority of their mutations can be targeted with drugs. In a recent study, Kimberly Stegmaier, MD, at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and her colleagues systematically deleted every gene in the genome in a number of childhood cancers. This led them to previously unknown — and targetable — genes that help drive tumor growth.

But Stegmaier is also interested in epigenetic regulators — proteins that help control the regulation of genes and contribute to many pediatric cancers. They’re a hot subject of research: Child cancers tend to arise in developing tissues, and epigenetic regulators are active during early development. Clinical trials are starting to test drugs that inhibit epigenetic cancer-promoting factors.

There’s a problem, though: Cancers often become resistant to targeted inhibitors, including epigenetic inhibitors. So, again using genome-wide approaches, Stegmaier set out to find ways to overcome this resistance.

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Newborn DNA sequencing finds actionable disease risks in nearly 10% of enrolled babies

BabySeq study sequenced the DNA of 159 newborns
(PHOTO: AdobeStock)

Current newborn screening tests a baby’s blood for several dozen known, treatable conditions. Can full-on DNA sequencing at birth add more benefit? Interpreting sequencing results is complex: having a genetic variant doesn’t always mean having the disease, and many of the conditions identified may not currently be treatable.

To explore what DNA sequencing might turn up, the BabySeq study, an NIH-funded project, was in launched in 2015. A team led by Ozge Ceyhan-Birsoy, PhD of Partners HealthCare and Alan H. Beggs, PhD, now reports the comprehensive results of whole-exome sequencing in 159 infants. Their analysis is published in the American Journal of Human Genetics.

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