Stories about: Pediatrics

Earlier treatment may help reverse autism-like behavior in tuberous sclerosis

research in Purkinje cells may help complete the puzzle of autism
(IMAGE: PETER TSAI)

New research on autism has found, in a mouse model, that drug treatment at a young age can reverse social impairments. But the same intervention was not effective at an older age.

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Genomic sequencing for newborns: Are parents receptive?

BabySeqCasie Genetti, MS, CGC is a licensed genetic counselor with the Manton Center for Orphan Disease Research at Boston Children’s Hospital. She is first author of a recently published paper on the BabySeq Project.

The idea of genomic sequencing for every newborn has many in the scientific community buzzing with excitement, while leaving others wary of the ethical and social implications. But what do the parents think? The BabySeq Project has been exploring parental motivations and concerns while assessing their willingness to participate in a pilot newborn sequencing study.

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Typing medulloblastoma: From RNA to proteomics and phospho-proteomics

medulloblastoma proteomics study
Medulloblastoma (CREDIT: ARMED FORCES INSTITUTE OF PATHOLOGY/WIKIMEDIA)

Medulloblastoma is one of the most common pediatric brain tumors, accounting for nearly 10 percent of cases. It occurs in the cerebellum, a complex part of the brain that controls balance, coordination and motor function and regulates verbal expression and emotional modulation. While overall survival rates are high, current therapies can be toxic and cause secondary cancers. Developing alternative therapeutics is a priority for the field.

As early as the 1990s, the lab of Scott Pomeroy, MD, PhD, neurologist-in-chief at Boston Children’s Hospital, discovered molecules in medulloblastoma tumors that could predict response to therapies. In 2010, Pomeroy and colleagues uncovered four distinct molecular subtypes of medulloblastoma.

The World Health Organization updated the brain tumor classification scheme in 2016 to include these molecular and genetic features. In the new scheme, tumor subtypes with a good molecular prognosis receive less radiation and chemotherapy. But the creation of targeted therapeutics has remained a challenge, since some of the genetic pathways implicated in these subtypes are found in non-cancerous cells.

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Finally in the game: Patient in drug trial for PTEN mutation seems to benefit

The first patient to receive everolimus for PTEN hamartoma tumor syndrome
Preston Hall is the first Boston Children’s Hospital patient with PTEN hamartoma tumor syndrome to be treated with everolimus. At left, Siddharth Srivastava, MD. (PHOTO: SEBASTIAN STANKIEWICZ/BOSTON CHILDREN’S HOSPITAL)

From the time of Preston Hall’s birth at 30 weeks, his parents navigated multiple diagnoses, surgeries and sometimes life-threatening medical issues. At 11 months, Preston underwent skull revision surgery for trigonocephaly (a fusion of the skull bones causing a triangular-shaped forehead). After surgery, his doctors discovered serious airway and gastrointestinal issues that led to his failure to thrive. Preston eventually bounced back, but the underlying cause of his complex medical problems remained a mystery. All the while, his fraternal twin Luke overcame more typical preemie issues by age 3.

“At one point Preston had 20 different diagnoses,” his mother, Jennifer Hall, says. “It wasn’t until he was about 4 years old that we started to think his delays were not due to prematurity alone.”

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Putting patients first in the translational research pipeline

During a follow-up visit, pediatric hematologist/oncologist Sung-Yun Pai, MD, hugs a patient who received gene therapy for X-linked severe combined immunodeficiency.
During a follow-up visit at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, pediatric hematologist/oncologist Sung-Yun Pai, MD, hugs a patient who received gene therapy for X-linked severe combined immunodeficiency.

This is part II of a two-part blog series recapping the 2018 BIO International Convention. Read part I: Forecasting the convergence of artificial intelligence and precision medicine.

The hope to improve people’s lives is what drives many members of industry and academia to bring new products and therapies to market. At the BIO International Convention last week in Boston, there was lots of discussion about how translational science intersects with patients’ needs and why the best therapeutic developmental pipelines are consistently putting patients first.

As a case in point, Mustafa Sahin, MD, PhD, of Boston Children’s discussed his work to improve testing and translation of new therapies for autism spectrum disorder (ASD). As a member of PACT (Preclinical Autism Consortium for Therapeutics) and director of Boston Children’s Translational Neuroscience Program, Sahin aims to bridge the gap between drug discovery and clinical translation.

“Our mission is to de-risk entry of new therapies in the ASD drug discovery and development space,” said Sahin, who is also a professor of neurology at Harvard Medical School.

One big challenge, says Sahin, is knowing how well — or how poorly — autism therapies are actually affecting people with ASD. Externally, ASD is recognized by its core symptoms of repetitive behaviors and social deficits.

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Mothers’ life experiences may affect their newborns’ telomeres — especially boys’

mother and newborn with telomeres

A new study adds to a growing body of evidence that mothers’ experiences affect their babies’ chromosomes. For the first time, it also shows a gender difference — with male babies more susceptible to maternal influence. And it even implicates experiences dating back to the mother’s own childhood.

The study, led by psychologist Michelle Bosquet Enlow, PhD, at Boston Children’s Hospital, may help explain why stress can have intergenerational effects within a family. It was published last month in the journal Psychoneuroendocrinology.

The researchers enrolled 151 socioeconomically diverse mothers and their infants, all born at Beth Israel Deaconess Medical Center in Boston. The mothers completed in-depth interviews during pregnancy. Cord blood was collected from the newborns so that their chromosomes could be examined — and in particular, the little caps at their tips known as telomeres.

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Solving the DIPG puzzle a single cell at a time

Image depicting the cellular makeup of DIPG/DMG tumors vs normal brain tissue development
Scientists have discovered that DIPG/DMG tumors are made up of H3K27M-mutated cell populations that contain many cells stuck in a stem-cell-like state, fueling tumor growth. Cells that can differentiate despite the H3K27M mutation could hold the key to unlocking a new therapy for DIPG/DMG.

For more than 15 years, pediatric neuro-oncologist Mariella Filbin, MD, PhD, has been on a scientific crusade to understand DIPG (diffuse intrinsic pontine glioma). She hopes to one day be able to cure a disease that has historically been thought of as an incurable type of childhood brain cancer.

“While I was in medical school, I met a young girl who was diagnosed with DIPG,” Filbin recalls. “When I heard that there was no treatment available, I couldn’t believe that was the case. It really made a huge impression on me and since then, I’ve dedicated all my research to fighting DIPG.”

Her mission brought her to Boston Children’s Hospital for her medical residency program and later, to do postdoctoral research at the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center. Now, she’s starting her own research laboratory focused on DIPG — which has also been called diffuse midline glioma (DMG) in recent years — and continuing to treat children with brain tumors at the Dana-Farber/Boston Children’s pediatric brain tumor treatment center. She’s also a scientist affiliated with the Broad Institute Cancer Program.

This year, Filbin has made new impact in the field by leveraging the newest single-cell genetic sequencing technologies to analyze exactly how DIPG develops in the first place. Her latest research, published in Science, entailed profiling more than 3,300 individual brain cells from biopsies of six different patients.

Using what’s known as a single-cell RNA sequencing approach to interrogate the makeup of DIPG/DMG tumors, Filbin was able to identify a particularly problematic type of brain cell that acts forever young, constantly dividing over and over again in a manner similar to stem cells.

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Probing the brain’s earliest development, with a detour into rare childhood cancers

In early brain development there is an increase in ribosomes, contained in these nucleoli
Nucleoli, the structures in the cell nucleus that manufacture ribosomes, are enlarged in very early brain development, indicating an increase in ribosome production. Here, a 3D reconstruction of individual nucleoli. (Kevin Chau, Boston Children’s Hospital)

In our early days as embryos, before we had brains, we had a neural fold, bathed in amniotic fluid. Sometime in the early-to-mid first trimester, the fold closed to form a tube, capturing some of the fluid inside as cerebrospinal fluid. Only then did our brains begin to form.

In 2015, a team led by Maria Lehtinen, PhD, Kevin Chau, PhD and Hanno Steen, PhD, at Boston Children’s Hospital, showed that the profile of proteins in the fluid changes during this time. They further showed that these proteins “talk” to the neural stem cells that form the brain.

In new research just published in the online journal eLife, Lehtinen and Chau shed more light on this little-known early stage of brain development.

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Trial shows chemotherapy is helping kids live with pulmonary vein stenosis

Magnification of pulmonary vein tissue showing signs of pulmonary vein stenosis (plump abnormal cells stained dark magenta).
Magnification of pulmonary vein tissue showing signs of pulmonary vein stenosis (plump abnormal cells stained dark magenta). Credit: Boston Children’s Hospital Department of Pathology

Pulmonary vein stenosis (PVS) is a rare disease in which abnormal cells build up inside the veins responsible for carrying oxygen-rich blood from the lungs to the heart. It restricts blood flow through these vessels, eventually sealing them off entirely if left untreated. Typically affecting young children, the most severe form of PVS progresses very quickly and can cause death within a matter of months after diagnosis.

Until recently, treatment options have been limited to keeping the pulmonary veins open through catheterization or surgery. Yet this approach only removes the cells but does nothing to prevent their regrowth. Now, a clinical trial shows that adding chemotherapy to a treatment regimen including catheterization and surgery can deter abnormal cellular growth and finally give children with PVS a chance to grow up.

Results of the trial, run by the Boston Children’s Hospital Pulmonary Vein Stenosis Program, were recently published in the Journal of Pediatrics.

“Through this approach, we’ve created the first-ever population of survivors who are living with severe PVS,” says Christina Ireland, RN, MS, FNP, who has managed enrolling patients in the trial and treating new patients since the trial ended. “We’ve changed this disease from an acute killer to a chronic, manageable condition.”

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Very-low-carb diet can safely curb blood sugar in type 1 diabetes, study suggests

very-low-carb diet shows promise in type 1 diabetes

David Ludwig, MD, PhD, an endocrinologist at Boston Children’s Hospital, has written popular books espousing a low-glycemic, low-carbohydrate diet for weight control. He has argued that high-glycemic diets are contributing to the epidemic of type 2 diabetes.  But he hadn’t given much thought to carbohydrate restriction for type 1 diabetes until 2016.

At a conference, Ludwig met a surgeon with type 1 diabetes who maintains normal hemoglobin A1c levels (indicating high blood sugar control) on a very-low-carbohydrate diet. This surprised and impressed him: he had never seen any patient with type 1 diabetes able to completely normalize their hemoglobin A1cs. Moreover, most diabetes experts discourage very-low-carb diets, believing they pose a risk for hypoglycemia, or a dangerous drop in blood sugar.

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