Why are males more prone to bladder cancer than females?

A microscopic view of human testis tissue. Researchers have discovered why males are more likely to get bladder cancer than females.
A microscopic view of human testis tissue. Researchers have discovered why males are more likely to get bladder cancer than females. IMAGE: ADOBE STOCK

New research helps explain why men are three to five times more likely to develop bladder cancer than women.

Using mouse models and human patient data, Boston Children’s Hospital researchers in the urology department, Xue Sean Li, PhD, and Satoshi Kaneko, PhD, found that inherent genomic differences contribute to the contrast in bladder cancer rate between males and females.

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A life-saving adjustment in IV nutrition cleared by the FDA

Fourteen years after Charles Rolfe received an experimental IV fish-oil solution, Omegaven has been approved by the FDA. (PHOTOS: WEBB CHAPPELL/ROLFE FAMILY)

In 2004, a surgeon and a hospital pharmacist went against the prevailing dogma. They began revising the IV nutrition formula being given to children unable to take food by mouth. In doing so, they saved many lives. Yet, it wasn’t until last month that their intervention, a new fat emulsion called Omegaven, gained formal approval from the Food and Drug Administration.

Children with intestinal failure due to gastroschisis, necrotizing enterocolitis or other diseases are typically placed on parenteral nutrition, an intravenous method of feeding. Without it, they would die. But prolonged use of IV nutrition — using the traditional formula — had a massive side effect: injury to the liver. The majority of children either died from liver failure or required a liver transplant.

By 2001, surgeon Mark Puder, MD, at Boston Children’s Hospital was tired of watching babies slowly die from liver disease that should be preventable. He suspected something needed to be adjusted in the IV nutrition formula — particularly the fat component, derived from soybean oil and known as Intralipid.

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Patients with epilepsy and inflammatory bowel disease to get DNA sequenced in study

3000 exomes study to sequence patients with epilepsy, IBD
ILLUSTRATION: ADOBE STOCK

Boston Children’s Hospital has embarked on a strategic initiative to accelerate and expand its research genomics gateway, with plans to sequence the DNA of 3,000 patients with epilepsy or inflammatory bowel disease and their family members. Patients will have access to enroll in this pilot study if their condition is of likely genetic origin but lack a diagnosis after initial clinical genetic testing.

Sequencing will cover the entire exome, containing all of a person’s protein-coding genes. The Epilepsy and IBD were chosen for the pilot because Ann Poduri, MD, MPH and Scott Snapper, MD, PhD, have already made huge inroads into the genetics of these respective disorders. Both have built large, well characterized patient databases for research purposes, have disease-specific genetic expertise and have begun using their findings to inform their patients’ care.

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Gene mutation in children with microcephaly reveals an essential ingredient for brain development

This electron microscope image shows two multivesicular bodies in the dendrites of neighboring neurons in the cerebellum of a normal mouse. Each contains vesicles bearing sonic hedgehog. (Michael Coulter/Boston Children’s Hospital)

In 2012, researchers in the Boston Children’s Hospital lab of Christopher Walsh, MD, PhD, reported a study of three unrelated families that had children with microcephaly. All had smaller-than-normal brains — both the cerebrum and the cerebellum were reduced in size— and all had mutations that knocked out the function of a gene called CHMP1A.

It was clear that CHMP1A is needed for the brain to grow to its proper dimensions. But the study stopped there.

“Then I came along, and my goal was to figure out what this gene is doing in brain during development, and why, when you lose it, you have a small brain,” says Michael Coulter, MD, PhD, who joined the Walsh lab as a student in 2012.

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A perfect genetic hit: New gene mutation implicated in rare congenital diarrhea

Normal intestinal organoids (left) in contrast to intestinal organoids derived from patients (right) with a newly-discovered gene mutation linked to congenital diarrhea.
Normal intestinal organoids (left) in contrast to intestinal organoids derived from patients (right) with a newly-discovered gene mutation linked to congenital diarrhea.

When the 1-year-old boy arrived from overseas, he was relying on total parenteral nutrition — a way of bypassing the digestive system to provide nutrients and calories completely intravenously — to survive. From the time of his birth, he had experienced unexplainable diarrhea. Answers were desperately needed.

Sequencing his genes in search of clues, neonatologists and collaborators at the Manton Center for Orphan Disease Research at Boston Children’s Hospital identified a new gene mutation responsible for chronic congenital diarrhea — even finding a similar mutation in two other children as well.

Using patient-derived intestinal organoids in the laboratory, the team discovered that the newly-identified gene mutation, WNT2B, appears to stifle intestinal stem cells’ normal function and growth. The findings were published in the American Journal of Human Genetics.

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A tissue engineered heart ventricle for studying rhythm disorders, cardiomyopathy

a tissue engineered heart ventricle
(Luke MacQueen and Michael Rosnach/Harvard University)

While engineered heart tissues can replicate muscle contraction and electrical activity in a dish, many aspects of heart disease can only adequately be captured in 3D. In a report published online yesterday by Nature Biomedical Engineering, researchers describe a scale model of a heart ventricle, built to replicate the chamber’s architecture, physiology and contractions. Cardiac researchers at Boston Children’s Hospital think it could help them find treatments for congenital heart diseases.

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“Teenage” red blood cells could hold the key to a malaria vaccine

A T cell (right) launches an attack on an immature red blood cell called a reticulocyte. This immune response could help design a malaria vaccine.
A T cell (right) launches an attack on an immature red blood cell (left) infected with a malaria parasite called P. vivax. At the arrow, the T cell breaches the infected cell’s membrane to deliver death-inducing enzymes. Credit: Lieberman lab/Boston Children’s Hospital

Malaria parasite infection, which affects our red blood cells, can be fatal. Currently, there are about 200 million malaria infections in the world each year and more than 400,000 people, mostly children, die of malaria each year.

Now, studying blood samples from patients treated for malaria at a clinical field station in Brazil’s Amazon jungle, a team of Brazilian and American researchers has made a surprising discovery that could open the door to a new vaccine.

“I noticed that white blood cells called killer T cells were activated in response to malaria parasite infection of immature red blood cells,” says Caroline Junqueira, PhD, a visiting scientist at Boston Children’s Hospital and Harvard Medical School (HMS).

For red blood cells, this activity is unusual.

“Infected red blood cells aren’t recognized by our immune system’s T cells in the same way that most other infected cells of the human body are,” says Judy Lieberman, MD, PhD, chair in the Program in Cellular and Molecular Medicine at Boston Children’s Hospital.

Digging deeper, Junqueira, Lieberman and collaborators have found a completely unexpected immune response to malaria parasites that infect immature blood cells called reticulocytes. The revelation could help to design a new vaccine that might be capable of preventing malaria.

Their findings, published today in Nature Medicineuncover special cellular mechanisms and properties specific to “teenaged” reticulocytes and a strain of malaria called Plasmodium vivax that enable our T cells to recognize and destroy both the infected reticulocytes and the parasites inside them.

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Inhibiting inhibitory neurons gets mice with spinal cord injury to walk again

Boosting KCC2 expression as a treatment for spinal cord injury
Boosting KCC2 expression: A cross section of a mouse spinal cord, stained two different ways, showing increased expression of KCC2 in inhibitory neurons. This increased expression, induced genetically or with a small-molecule drug, correlated with improved motor function, including ankle movement and stepping. (Zhigang He Lab)

Most people with spinal cord injury are paralyzed from the injury site down, even when the cord isn’t completely severed. Why don’t the spared portions of the spinal cord keep working, allowing at least some movement? A new study just published online by Cell provides insight into why these nerve pathways remain quiet. Most intriguingly, it shows that injection with a small-molecule compound can revive these circuits in paralyzed mice — and get them walking again.

“We saw 80 percent of mice treated with this compound recover their stepping ability,” says Zhigang He, PhD, of Boston Children’s Hospital’s F.M. Kirby Neurobiology Center, the study’s senior investigator. “For this fairly severe type of spinal cord injury, this is the most significant functional recovery we know of.”

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A huge leap for cloning

Two identical mice are pictured. Researchers have reported a new technique to improve mouse cloning efficiency.Animal cloning, the creation of a genetically identical copy of an individual organism, holds promise for many different reasons, including its use to conserve endangered species and to improve our understanding of developmental biology, which could eventually help us prevent or reverse developmental disorders from the get-go. Although more than 20 species of animals have been cloned so far, cloning efficiency, or the percent of successful live births, has remained universally low and economically out of reach for most practical applications.

But now, researchers at Boston Children’s Hospital have reported a new cloning technique that has yielded the highest efficiency ever reported in mouse cloning, capable of producing 13 to 16 times more mouse pups than previous methods. The findings were reported in Cell Stem Cell.

To improve mouse cloning efficiency, a team led by the study’s senior author Yi Zhang, PhD, corrected two factors that they had previously identified as having impact on successful development of cloned embryos.

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Skewed T-cell pathway may help explain transplant rejection, autoimmune diseases

Th17 transplant rejection
Researchers discover a pathway that controls our T helper cell profiles (Fawn Gracey illustration)

Second in a two-part series on transplant tolerance. (See part one.)

Our immune system has two major kinds of T cells. T helper cells, also known as effector T cells, tend to rev up our immune responses, while T regulatory cells tend to suppress or downregulate them. Last week we reported that bolstering populations of T regulatory cells might help people tolerate organ transplants better. A new study turned its focus to T helper cells, and found that an imbalance of these cells causes an exaggerated immune response that may also contribute to transplant rejection.

The study also showed, in mice and in human cells in a dish, that the immune imbalance can be potentially reversed pharmacologically. Findings were published yesterday in the Journal of Clinical Investigation.

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