Johns Hopkins Medicine-Led Study Shows Mutations May Cause Brain Tumors to Resist Therapy

About one-third of all brain tumors are gliomas, cancerous growths that originate in the glial cells that surround and support neurons in the brain. The prognosis for patients with gliomas is not good, with the average survival time being 12–18 months. Recent research by Johns Hopkins Medicine looked at why gliomas that have responded to one specific treatment — known as a BRAF inhibitor — sometimes become resistant to the drug and grow back.

In their study published Aug. 25, 2021, in the journal Clinical Cancer Research, Karisa Schreck, M.D., Ph.D., assistant professor of neurology, oncology and neurosurgery at the Johns Hopkins University School of Medicine, and her colleagues evaluated 15 glioma cases treated with BRAF inhibitors — drugs for attacking the BRAF gene that produces B-Raf, an enzyme that can lead to abnormal cell growth. However, the BRAF inhibitors didn’t always work as expected in all the patients studied.

“Three out of 100 glioma cases have a mutation in the BRAF gene,” says Schreck. “While we’ve seen people with this mutated gene and gliomas whose tumors shrink when they are treated with BRAF inhibitors, sometimes the drug just stops working. We wanted to find out why that happens.”

Schreck and her colleagues — including researchers Theodore Nicolaides, M.D., at NY Langone Health, and Jean Mulcahy Levy, M.D., at Children’s Hospital Colorado — found that 9 of the 15 patients with gliomas that grew back after BRAF inhibitor treatment had new mutations. The researchers hypothesized that these mutations might explain why there was resistance to the BRAF inhibitors, allowing the gliomas to grow back. They confirmed their theory with laboratory tests involving tissues and cells isolated from the patients with the mutated BRAF gene.

The researchers next tried different combinations of other targeted therapies to see if they could overcome the resistance. Some combinations did so, signaling that gliomas withstanding a specific BRAF inhibitor might be better treated with a combination of inhibitors.

“Anyone who knows someone with this type of cancer also knows it’s currently incurable,” Schreck says. “This study helped us understand what the next steps in treatments might be. It suggests that each patient’s cancer will likely need a personalized approach to therapy.”

Schreck says the team next plans to perform more testing in cell cultures and mouse models to determine which inhibitor combinations might be most useful for patients.

Schreck is available for interviews.


COVID-19 NEWS: Study to Investigate Impacts of COVID Vaccines on Menstruation

Johns Hopkins Medicine’s Department of Gynecology and Obstetrics is one of five institutions selected by the National Institutes of Health (NIH) to conduct research to explore the potential impacts of COVID-19 vaccination on menstruation. The five one-year grants, totaling $1.67 million, are funded by NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development and the NIH Office of Research on Women’s Health.

The NIH research grants were established after many women reported irregular menstrual periods and other menstrual changes after getting the COVID-19 vaccines.

“There may be several reasons why a woman might experience unscheduled menstrual bleeding, abnormal periods or bleeding that is heavier than usual,” says lead investigator Mostafa Borahay, M.D., Ph.D., associate professor of gynecology and obstetrics at the Johns Hopkins University School of Medicine. “This research will help us better understand if there’s a real link between the COVID-19 vaccines and these menstrual changes, or if it’s something else, such as lifestyle changes or pandemic-related stress.”

Borahay and his team hypothesize that the immune response following vaccination may bring immune cells into the endometrium (uterus). This, say the researchers, may result in the menstrual irregularities that women are reporting.

“If there’s a relationship between the COVID-19 vaccines and the menstrual changes, we need to know how it happens,” says Borahay. “Therefore, we plan to examine the response of the endometrium to the COVID-19 vaccination at the biological level.”

Menstruation, or a period, is part of a woman’s monthly reproductive cycle. Each month, a woman’s uterus prepares for pregnancy and thickens its walls by increasing the levels of two hormones, estrogen and progesterone. But when pregnancy does not occur, the uterus sheds its lining as the blood and mucus making up the menstrual flow that leaves the body through the vagina during the period.

For the study, the researchers will collect data from different sources. “Through a collaboration with Clue, a period and ovulation tracking app, we will gather unidentifiable data from users about their menstrual cycle before and following COVID vaccination,” says Malak El Sabeh, M.D., a postdoctoral fellow working on the project in Borahay’s laboratory.

Borahay is available for interviews.


Otolaryngology in Space: Johns Hopkins Medicine Studies Impact of Microgravity on Balance

The Inspiration4 spaceflight from Sept. 15–18, 2021, was historic for orbiting the first all-civilian crew without a professional astronaut. The mission also marked a milestone for Johns Hopkins Medicine otolaryngology — because it provided out-of-this-world data for an experiment designed by Johns Hopkins researchers. The objective: examining how the vestibular functions (the sense of balance and body position) of the four crew members were impacted by the microgravity of space.

“Since motion sickness and disorientation are common among astronauts going into space, this research is important because it may enable researchers in the future to predict from pre-flight testing how much at risk are astronauts to suffering performance-impacting balance problems,” says principal investigator Mark Shelhamer, Sc.D., professor of otolaryngology–head and neck surgery at the Johns Hopkins University School of Medicine.

As directed by Shelhamer and co-investigator and fellow Johns Hopkins Medicine otolaryngologist Michael Schubert, Ph.D., the Inspiration4 crew members used a computer tablet before taking off to conduct sensorimotor tests evaluating how their inner ears sense gravity on Earth, and how their brains use that sensory input to control their overall posture and the vertical and torsional (rotation along the line of sight) alignment of their eyes. Previous research has shown that both are components for proper sensorimotor function, and that in a near-weightless environment, this vestibular function must adjust to prevent balance impairment.

Shelhamer says the same Johns Hopkins Medicine sensorimotor tests will be performed on the astronauts now that they’ve returned to Earth (and again are experiencing the influence of gravity).

“This enables us to scientifically compare post-flight results to the information we gathered before launch, and perhaps, use those evaluations to establish protocols for predicting how people will perform in space,” he explains. “Standardized vestibular testing might one day help determine if a crew should be accompanied by an in-flight medical officer or receive other assistance to treat motion sickness and disorientation.”

Participating in the Inspiration4 mission, Shelhamer adds, has provided Johns Hopkins Medicine “with a tremendous opportunity to demonstrate our role in sensorimotor testing and space health research.”

Funding for this medical experiment, and the four others that were part of the Inspiration4 mission, came from Baylor College of Medicine’s Translational Research Institute for Space Health (TRISH). TRISH, a consortium between Baylor and two other academic institutions overseen and supported by NASA’s Human Research Program, studies ways to solve the challenges of human deep space exploration.

The Inspiration4 crew included commander Jared Isaacman, a billionaire entrepreneur, trained pilot and primary funder of the mission; medical officer Hayley Arceneaux, a physician assistant and childhood cancer survivor; mission specialist Chris Sembroski, an aerospace data engineer; and co-pilot Sian Proctor, a geoscientist, artist and science communicator.

Shelhamer is available for comment.


Johns Hopkins Medicine Team Creates Model to Help Show Path Toward Ending HIV Nationwide

A new Johns Hopkins Medicine mathematical model to predict how the human immunodeficiency virus (HIV) spreads in urban areas will play a major role in a federal initiative aiming to reduce the incidence of HIV infections in the United States by 90% between 2020 and 2030. As part of the Ending the HIV Epidemic in the U.S. (EHE) program, the model will be used to forecast HIV incidence in 32 U.S. cities when implementing specific interventions to reduce transmission of the virus.

In a study published Sept. 21, 2021, in the Annals of Internal Medicine, Anthony Todd Fojo, M.D., M.H.S., and colleagues describe their model, an algorithm that splits each city’s population into categories of race, age, sex and HIV risk factors, and estimates the number of HIV infections associated with each one.

“We calculated the number of HIV infections per subgroup and then predicted what would likely happen if cities adopt particular interventions,” Fojo says.

Fojo says potential citywide actions could include increasing viral suppression (reducing HIV virus counts to an undetectable level) among people with HIV, more frequent testing to diagnose HIV, and encouraging the use of pre-exposure prophylaxis (PrEP) — prescription drugs that prevent HIV infection.

“For some cities, it may make more sense to focus on getting people’s HIV controlled. For others, it may be more important to encourage preventive medications,” Fojo says. “To achieve a 90% reduction over the next 10 years, the model predicts it will likely take a combination of both, along with increased testing.”

The model described in the new study shows that if current trends continue, HIV incidence overall in the 32 cities might fall by 19% by 2030. With a modest increase in testing, preventive medications and better virus suppression across the population, those cities could improve that result to a reduction of between 34% and 67%.

Predictions of drops in HIV incidence also can be estimated for interventions in specific populations.

For example, the model predicts that, if 25% of young Black and Hispanic men who have sex with men used PrEP and were tested twice a year to more rapidly identify HIV, and 90% of those already with HIV could achieve viral suppression, cities could achieve a 13% to 68% reduction in HIV incidence across the whole population.

When interventions include people who inject drugs and all men who have sex with men, the incidence of HIV could be reduced from 48% to 90%. Thirteen of the 32 cities could achieve more than a 90% reduction in incidence with large-scale interventions that include heterosexuals. 

Fojo and his colleagues also have developed a web tool to help cities develop individualized plans. He says he hopes public health officials will use this resource to make cost-effective intervention decisions for their communities.

Fojo is available for interviews.


New Guidelines Seek Better Pregnancy Outcomes Related to Cardiovascular Health

Thanks largely to the efforts of Johns Hopkins Medicine researchers, the American Heart Association (AHA) recently announced recommendations for improving cardiovascular health outcomes in women before, during and after pregnancy. According to the U.S. Centers for Disease Control and Prevention (CDC), the United States has the highest maternal mortality rate among industrialized countries with an estimated 700 deaths a year due to pregnancy complications.

Additionally, the AHA reports that heart disease and stroke contribute to one in three of those deaths, primarily from cardiomyopathy (where the heart loses its ability to effectively pump blood), cerebrovascular disease (conditions that affect blood flow to the brain) or other cardiovascular disorders. For non-Hispanic Black and American Indian/Alaska Native women, it’s nearly two to three times higher than the rate for white women.

To bring more awareness to the problem and address it medically, an AHA working group, co-led by cardiologist Garima Sharma, M.D., director of the cardio-obstetrics program at the Johns Hopkins University School of Medicine, created the new guidelines and published them in a policy statement, “Call to Action: Maternal Health and Saving Mothers,” posted online Sept. 8, 2021, in the AHA journal Circulation.

The guidelines, says Sharma, also address the inequities hindering proper maternal health care for all.

“Regardless of a woman’s employment, housing, race or social status, she deserves a health system that ensures a healthy pregnancy, delivery and beyond childbirth as a healthy mom,” says Sharma. “With a concerted effort, the United States can save maternal lives by implementing simple changes in our patient and provider approach, as well as system overhauls to meet the needs of women in their reproductive years.”

In their statement, Sharma and her AHA colleagues outline the inequities that influence disparities, and propose approaches to improving maternal outcomes. Sharma says the guidelines act as a roadmap for policy makers and health care leaders to act on the issue.

“The wheels of science are powered by patient advocacy, and it cannot make an impact in the day-to-day lives of women until policy changes,” said Sharma. “This statement pulls together science from decades of data and translates that science into actionable items that could make real change that could ultimately save women’s lives.”

According to the World Health Organization, the global maternal mortality ratio (maternal deaths per 100,000 births) declined by 38% from 2000 to 2017. However, it has been steadily increasing in the United States from 7.2 deaths per 100,000 live births in 1987 to 17.4 deaths per 100,000 births in 2018. The CDC defines a pregnancy-related death as a woman who dies while pregnant or within one year postpartum.

The policy statement provides strategies to reduce overall deaths and address racial disparities in maternal health through a three-pronged approach focused on patients, health care providers and care systems. This approach includes:

.•    Addressing disparities and inequities by educating providers, improving reporting of maternal outcomes, expanding Medicaid funding in states where it doesn’t exist and increasing public awareness about activities to reduce heart disease (such as smoking cessation).
•    Modernizing maternal health care delivery by making women more aware of preconception counseling, expanding postpartum care for Medicaid participants to the first year after delivery and transforming provider payment so it prioritizes high quality, lower cost and removes unnecessary services.
•    Updating technology and systems by modernizing the public health care infrastructure in under-resourced communities and closing the health care gaps between urban and rural areas.

The policy statement has received support from the American College of Obstetricians and Gynecologists, as well as the Society for Maternal-Fetal Medicine. It will be presented at the annual AHA national conference in November.

Sharma is available for interviews.


Researchers Identify Inflamed Brain Cells Likely Involved in MS Nerve Degeneration

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system that leads to focal lesions (areas of localized damage) in the brain and spinal cord. Some patients with MS have lesions with “rims” of inflammation — known as chronic active lesions — that contribute to more rapid disability accumulation (when a patient with MS experiences multiple losses of physical abilities) than in people without rim lesions.

To better understand how lesion edge inflammation causes brain cells to degenerate in MS, researchers at Johns Hopkins Medicine and the National Institutes of Health’s National Institute of Neurological Disorders and Stroke (NINDS) have identified which brain cell types sustain the chronic inflammation that leads to the signature lesions.

In a study published Sept. 8, 2021, in the journal Nature, the Johns Hopkins Medicine and NINDS team determined that microglia (tiny immune cells that specifically protect the brain) and astrocytes (special glial cells that perform numerous support functions for the central nervous system) are the specific cellular subtypes that are inflamed in MS chronic active lesions.

Using a new technique called single nucleus RNA sequencing, the researchers identified what the microglia and astrocyte cells are doing when inflamed. They determined how these inflammatory cells communicate with each other while damaging brain tissue, and used this insight to look for a means to stop the process.

The team — which included Johns Hopkins Medicine neurologists Martina Absinta, M.D., Ph.D.; Peter Calabresi, M.D., co-director of the Johns Hopkins Multiple Sclerosis Precision Medicine Center; and Daniel Reich, M.D., Ph.D., a Johns Hopkins trainee who now directs the Translational Neuroradiology Section at NINDS — focused its investigation on C1q, a molecule associated with the activation of the immune response in inflamed microglia. Using a series of experiments, the group determined that without C1q, the microglia do not activate and stay uninflamed.

“In theory, we suggest that inhibiting C1q in patients with MS could reduce the detrimental smoldering inflammation persisting in these chronic active brain lesions,” says study lead author Absinta. “The great thing is that we have imaging biomarkers [biological tags for detecting chronic inflammation with MRI scans], so we can see the hot spots and be able to identify patients who might benefit from such treatment.”

“This study highlights the power of precision medicine to not only identify patients at risk of more severe disease, but to leverage novel technologies to identify specific therapeutic targets for people with progressive MS, a form of the disease that is often resistant to treatment,” says Calabresi.

“We found commonalities in the inflamed microglia subpopulation with other neurodegenerative diseases like Alzheimer’s,” says Absinta. “We hope that this finding encourages clinicians to explore similar therapeutic approaches.”

Absinta says the next steps in this research are to design clinical trials using the MRI biomarker and potentially the precision medicine targets identified in this study.

This study was supported by the Intramural Research Program of NINDS, the Adelson Medical Research Foundation, the Conrad N. Hilton Foundation and the Cariplo Foundation.

Absinta is available for interviews.,


Eyeglasses for Students Boost Academic Performance, Raises Test Scores

In what may be the largest clinical study ever conducted in the United States of the impact of glasses on classroom performance, Johns Hopkins researchers report that students who received eyeglasses through a school-based program scored higher on reading and math tests. The findings, they say, could lead to improved learning for millions of children who suffer from vision impairment and lack access to pediatric eye care.

The study was published Sept. 9, 2021, in JAMA Ophthalmology.

“We rigorously demonstrated that giving kids the glasses they need helps them succeed in school,” says study senior author Megan Collins, M.D., M.P.H., a pediatric ophthalmologist at the Johns Hopkins Wilmer Eye Institute at the Johns Hopkins University School of Medicine, associate faculty at the Johns Hopkins Berman Institute of Bioethics, and co-director of the Johns Hopkins Consortium for School-Based Health Solutions.

The team studied students who received eye examinations and glasses through the Vision for Baltimore program — an effort launched in 2016 after Johns Hopkins researchers identified a need for vision care among the city’s public school students. At that time, as many as 15,000 of the city’s 60,000 pre-K through eighth grade students likely needed glasses, although many didn’t know it or have the means to get them.

Conducted from 2016 to 2019, the clinical trial analyzed the performance of 2,304 students in third through seventh grades who received screenings, eye examinations and eyeglasses from Vision for Baltimore. The research team studied the students’ scores on standardized reading and math tests, measuring both one-year and two-year impacts.

Reading scores increased significantly after one year for students who received glasses, compared with students who got them later. There also was significant improvement in math for elementary school students.

The researchers found particularly striking improvements for girls, special education students and students who had previously been among the lowest performing.

“The glasses offered the biggest benefit to the very kids who needed it the most — the ones who were really struggling in school,” Collins says.

The academic improvements seen after one year were not sustained over two years. The researchers suspect this could be a result of students wearing their glasses less over time, possibly due to losing or breaking them.

To maintain the academic achievement seen after the first year, the researchers say that — in addition to providing the initial exams and glasses — school-based vision programs should develop stronger efforts to make sure children are wearing the glasses received and replace them if needed.

Collins is available for interviews.

This news story is adapted from a Johns Hopkins University news release.