Stories about: Therapeutics

Scientists find link between increases in local temperature and antibiotic resistance

Image representing the rise of antibiotic resistance
Illustration by Fawn Gracey

Over-prescribing has long been thought to increase antibiotic resistance in bacteria. But could much bigger environmental pressures be at play?

While studying the role of climate on the distribution of antibiotic resistance across the geography of the U.S., a multidisciplinary team of epidemiologists from Boston Children’s Hospital found that higher local temperatures and population densities correlate with higher antibiotic resistance in common bacterial strains. Their findings were published today in Nature Climate Change.

“The effects of climate are increasingly being recognized in a variety of infectious diseases, but so far as we know this is the first time it has been implicated in the distribution of antibiotic resistance over geographies,” says the study’s lead author, Derek MacFadden, MD, an infectious disease specialist and research fellow at Boston Children’s Hospital. “We also found a signal that the associations between antibiotic resistance and temperature could be increasing over time.”

During their study, the team assembled a large database of U.S. antibiotic resistance in E. coli, K. pneumoniae and S. aureus, pulling from hospital, laboratory and disease surveillance data documented between 2013 and 2015. Altogether, their database comprised more than 1.6 million bacterial specimens from 602 unique records across 223 facilities and 41 states.

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Elusive epilepsy mutations begin to yield up their secrets

mosaic epilepsy mutations concept
Fawn Gracey illustration

Anti-seizure drugs don’t work in about a third of people with epilepsy. But for people with focal epilepsy, whose seizures originate in a discrete area of the brain, surgery is sometimes an option. The diseased brain tissue that’s removed also offers a rare opportunity to discover epilepsy-related genes.

Many mutations causing epilepsy have been discovered by testing DNA taken from the blood. But it’s becoming clear that not all epilepsy mutations show up on blood tests. So-called somatic mutations can arise directly in tissues like the brain during early prenatal development. Even within the brain, these mutations may affect only a fraction of the cells — those descended from the original mutated cell. This can create a “mosaic” pattern, with affected and unaffected cells sometimes intermingling.

One of the first such mutations to be described, by Ann Poduri, MD, MPH, and colleagues at Boston Children’s Hospital in 2012, was in Dante, a young boy who was having relentless daily seizures. The entire right side of Dante’s brain was malformed and enlarged, and he underwent a drastic operation, hemispherectomy, to remove it. Only later, studying brain samples from Dante and similar children, did Poduri find the genetic cause: a mutation in the gene AKT3. It affected only about a third of Dante’s brain cells. 

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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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Science Seen: An intestinal toxin’s trick, a potential cancer fighter

Crystal structure of the C. difficile toxin bound to its receptor, causing intestinal damage
Adapted from Science May 11, 2018. DOI: 10.1126/science.aar1999

Clostridium difficile, also called “C. diff,” causes severe gastrointestinal tract infections and tops the CDC’s list of urgent drug-resistant threats. In work published in Nature in 2016, Min Dong, PhD, and colleagues found the elusive portal that enables a key C. diff toxin, toxin B, to enter the intestines’ outer cells and break down the intestinal barrier (above right).

Interestingly, the same portal, known as the Frizzled receptor, also receives signals that maintain the intestine’s stem cells. When toxin B docks, it blocks these signals, carried by a molecule known as Wnt. But exactly how it all works remained a puzzle — until new research published today in Science.

Liang Tao, PhD in Dong’s lab, working with the labs of Rongsheng Jin, PhD, at UC-Irvine, and Xi He, PhD, at Boston Children’s, captured the crystal structure of a fragment of toxin B (in orange above) as it joined to the Frizzled receptor (in green). The structure revealed lipid molecules within the Frizzled receptor (in yellow and red) that play a central role. Normally, when Wnt binds to Frizzled, it nudges these lipids aside. But the team showed that when the toxin fragment binds to Frizzled, it locks these lipids in place, preventing Wnt from engaging with the cell.

Just as stem cells rely on Wnt signaling for growth and regeneration, so do many cancers. Now that its mechanism is known, Dong thinks this toxin B fragment, which by itself isn’t toxic, could be a useful anti-cancer therapeutic. They’re currently developing a new generation of Wnt signaling modulators and testing them in animal models of cancer. (For further information, contact Rajinder.Khunkun@childrens.harvard.edu of Boston Children’s Technology & Innovation Development Office.)

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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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A bold strategy to enhance CAR T-cell therapies, capable of targeting DIPG and other tough-to-treat cancers

CAR T-cell therapy uses a patient's own genetically modified T cells to attack cancer, as pictured here, where T cells surround a cancer cell.
T cells surround a cancer cell. Credit: National Institutes of Health

A Boston-based team of researchers, made up of scientists and pediatric oncologists, believe a better CAR T-cell therapy is on the horizon.

They say it could treat a range of cancers — including the notorious, universally-fatal childhood brain cancer known as diffuse intrinsic pontine glioma or DIPG — by targeting tumor cells in an exclusive manner that reduces life-threatening side effects (such as off-target toxicities and cytokine release syndrome). The team, led by Carl Novina, MD, PhD, and Mark Kieran, MD, PhD, of the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, calls their approach “small molecule CAR T-cell therapy.”

Their plan is to optimize the ability for CAR T-cell therapies, which use a patient’s genetically modified T cells to combat cancer, to more specifically kill tumor cells without setting off an immune response “storm” known as cytokine release syndrome. The key ingredient is a unique small molecule that greatly enhances the specificity of the tumor targeting component of the therapy.

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Failed cancer drug may extend life in children with progeria

child with progeria and damage to cell nucleus
Image: Wikimedia Commons. (Source: The Cell Nucleus and Aging: Tantalizing Clues and Hopeful Promises. Scaffidi P, Gordon L, Misteli T. PLoS Biology Vol. 3/11/2005, e395 doi:10.1371/journal.pbio.0030395)

Hutchinson-Gilford Progeria Syndrome, better known as progeria, is a highly rare genetic disease of premature aging. It takes a cruel toll: Children begin losing body fat and hair, develop the thin, tight skin typical of elderly people and suffer from hearing loss, bone problems, hardening of the arteries, stiff joints and failure to grow. They die at an average age of 14½, typically from heart disease resembling that of old age.

An observational study published yesterday in the Journal of the American Medical Association suggests that a drug called lonafarnib, originally developed as a potential cancer treatment, can extend these children’s lives.

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News Note: A fresh perspective on RNA with big implications for drug development 

RNA-based drugs are the future of therapeuticsRibonucleic acid, or RNA, has long been underappreciated for its role in gene expression. Until recent years, RNA has been thought of merely as a messenger, shuttling DNA’s instructions to the genetic machinery that synthesizes proteins.

But new discoveries of RNA functions, modifications and its ability to transcribe sections of the genome that were previously considered “junk DNA” has led to the discovery of a huge number of new druggable targets.

These new insights into RNA’s complex purposes have largely been uncovered through ever-increasingly sensitive and affordable sequencing methods. As a result, RNA-based drugs now stand to greatly extend our ability to treat diseases beyond the scope of what’s possible with small molecules and biologics.

Although several RND-based drug approaches have already been established, some barriers still prevent these strategies from working broadly. In a review paper for Nature Structural and Molecular Biology, Judy Lieberman, MD, PhD, of the Program in Cellular and Molecular Medicine of Boston Children’s Hospital, lays out where RNA-based drug development currently stands.

Lieberman, who has helped pioneer the RNA-based drug revolution herself, was the first scientist to show in an animal disease model that small, double-stranded RNAs could be used as drugs and leveraged to knock down genes in cells.

Read Lieberman’s review: “Tapping the RNA world for therapeutics.”

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For biomedicine startups, the road to commercialization is paved with mentors and winds through Boston

the road for biomedicine startups

Marina Freytsis, PhD, supports the Technology and Innovation Development Office (TIDO) at Boston Children’s Hospital in seeking industry partnerships for Boston Children’s technologies and intellectual property.

Last week, Boston Children’s Hospital’s Technology and Innovation Development Office (TIDO) had the privilege of hosting a Boston Biomedical Innovation Center (B-BIC) panel discussion on the path from academia to entrepreneurship. We heard from Jeffrey Arnold (an angel investor), Jonathan Thon (an academic-turned-CEO) and Pamela Silver (an entrepreneurial professor).

My top five takeaways for budding entrepreneurs:

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A new tactic for antibiotic-resistant pneumonia: Making neutrophils stronger, but fewer in number

bacterial pneumonia with neutrophils

Antibiotic resistance is a growing threat in bacterial pneumonia. While treatments that stimulate the immune system can help the body fight the invaders, these treatments can also cause inflammation that damages and weakens lung tissue.

Now, research in Science Translational Medicine suggests a way to have the best of both worlds: enhanced bacterial killing with reduced inflammation.

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