The Brigham is home to nearly 5,000 researchers, including physician-investigators, biomedical scientists, and faculty, who publish new research papers on a range of scientific and medical subjects. Below are brief summaries of a selection of our community’s most recent work. If you have an upcoming Brigham publication, please contact bwhclinicalandresearchnews@partners.org.

Study Presents Drug Candidate for Reversing Mucosal Barrier Damage by HIV

Research in preclinical models suggests that recombinant molecule could act as a topical anti-HIV microbicide

A vaginal microbicide that could prevent sexual transmission of HIV-1 in women has tremendous potential for saving lives and helping staunch an epidemic. But the delicate milieu of microbes that naturally colonize the vagina and maintain a healthy mucosal barrier have made the search for such a microbicide challenging, thwarting clinical trials of the most promising candidates.

Investigators at Brigham and Women’s Hospital led by Raina Fichorova, MD, PhD, in collaboration with an international team, tested a laboratory-made version of a naturally occurring protein (recombinant fragment of human Surfactant Protein D or rfhSP-D) on bioengineered vaginal tissues, immune cells and microbes to determine if the drug candidate could help prevent HIV transmission safely. In a paper published in Frontiers in Immunology, the team reports on the technique’s success in preclinical testing, establishing it as a promising anti-HIV-1 vaginal microbicide.

“To find a new drug that can most effectively help the immune system without causing adverse effects is a formidable task that requires both fundamental understanding of the mucosal ecosystem and biotechnological knowhow,” said Raina Fichorova, MD, PhD, director of the Brigham’s Laboratory of Genital Tract Biology. “Our team was able to combine expertise in both of these areas to carry out this work and build a strong case for clinical trials of rfhSP-D as a topical anti-HIV microbicide.”

The team designed a model of sexual transmission of HIV through bioengineered, multi-layered vaginal tissue toward the underlying white blood cells. Two major events generally lead to HIV infiltration and transmission: inflammation and the breach of the mucosal barrier. The research team reports, for the first time, a genetic signature that is tied to this breach. The activity of genes involved in inflammation and the tightness of the barrier were altered in the presence of the virus, helping promote infection.

Fichorova and colleagues found that the drug candidate rfhSP-D not only prevented HIV transmission, but also reversed the genetic signature of vaginal tissue in the virus’ presence.  The molecule helped maintain vaginal tissue integrity and suppressed a pro-inflammatory response, preventing the virus from getting a foothold. In addition, multiple preclinical tests showed that the molecule could safely be applied without altering naturally occurring bacteria such as lactobacilli or disrupting vaginal mucosa.

“Our study offers a highly reproducible, cost-effective model to study the effectiveness of candidate microbicides. Our results provide a strong argument for further evaluation of rfhSP-D as a potential topical anti-HIV microbicide.”

The team worked with collaborators from the ICMR National Institute for Research in Reproductive Health in Mumbai, India; the Genome Informatics Research Group at Bionivid Technology Pvt Ltd, in Bengaluru, India and Brunel University, London, Uxbridge, England. For this project, Fichorova’s lab was chosen to host a predoctoral scholar by the UK HIV Research Trust, and a senior scientist supported by a program for Indo-US collaborative research. This study was partly supported by Medical Innovation Fund (Project no. 2011-16850) of Indian Council of Medical Research (ICMR), New Delhi, India.

Paper cited: Pandit H et al. “Surfactant Protein D Reverses the Gene Signature of Transepithelial HIV-1 Passage and Restricts the Viral Transfer Across the Vaginal Barrier” Frontier in Immunology DOI: 10.3389/fimmu.2019.00264 https://www.frontiersin.org/articles/10.3389/fimmu.2019.00264/full

–HB

Older Adults Starting Dialysis Die at Higher Rates than Previously Thought
Study results can help inform patient decisions, physician choice of treatment for end-stage kidney disease

Older adults with end-stage kidney disease who start dialysis — a treatment that keeps their blood free of toxins — appear to die at higher rates than previously thought, according to findings of a new study by researchers at Harvard Medical School, Brigham and Women’s Hospital, Veterans Affairs Boston Healthcare System and Icahn School of Medicine at Mount Sinai, among other institutions.

More than half of older adults who started dialysis died within a year of beginning treatment, according to the research, and nearly one in four succumbed to the disease within a month of doing so.

Results of the analysis are published April 22 in JAMA Internal Medicine.

More than 120,000 people in the United States started dialysis in 2015, half of them older than 65. Dialysis, which involves the use of a machine to purify a patient’s blood from toxins, is commonly used as a treatment for end-stage kidney disease. For some dialysis is a bridge to kidney transplantation, but most dialysis patients, particularly those who are older, do not get kidney transplants.

The newly reported death rates are almost twice as high as widely cited statistics from government data sources, a finding that suggests physicians and patients may be basing treatment decisions on overly optimistic survival estimates, the researchers said.

“Dialysis can seem like a magical cure for someone whose kidneys are failing, but our finding that half of older adults die within the first year after starting dialysis is sobering,” said lead author Melissa Wachterman, an assistant professor of medicine at Harvard Medical School, and a physician at VA Boston.

“When time is short, how you spend that time becomes even more important,” she said. “Spending the better part of three days a week doing dialysis may not be the right choice for everyone and people should factor this new evidence into their decisions.”

The results are based on an analysis of a small but representative sample of national outcomes data among Medicare patients, 65 and older, who started receiving dialysis between 1998 and 2014. The sample included outcomes for 391 such patients. Of those, 68 were 85 years of age or older, 89 required assistance with daily activities and 267 had four or more major medical problems. Of the 391 patients in the analysis, 286 (73 percent) started dialysis in the hospital rather than on outpatient basis. Nearly 23 percent of patients (88 people) died within a month of starting dialysis. Nearly 45 percent (173 people) died within six months, and nearly 55 percent (213) died within the year. The study also reveals higher death rates among several groups: those over age 85, those who had four or more major medical problems in addition to kidney failure, those who started dialysis in the hospital, and those who, even before starting dialysis, needed help from other people with basic tasks of daily living such as eating or bathing.

The most common source for mortality statistics for patients on dialysis is the U.S. Renal Data Registry (USRDS), maintained by the National Institutes of Health, which shows a mortality rate of approximately 30 percent among older adults starting dialysis. However, this source only includes patients well enough to receive dialysis outside of the hospital. In reality, almost three-quarters of patients start dialysis in the hospital, and some do not survive long enough to make it to outpatient dialysis, the researchers said. The new analysis includes outcomes among such hospitalized individuals. Including hospitalized dialysis patients in the final tally boosted the previously reported death rates to more realistic levels, Wachterman said.

The researchers say their findings should help older patients, their families and the physicians who treat them make better-informed choices based on more realistic outcomes.

Contrary to a popular belief among many patients, dialysis is not the only choice for end-stage kidney disease, Wachterman noted.  Another approach to managing kidney failure is conservative care in which patients receive medications and other therapies to relieve the symptoms of kidney disease, without starting dialysis.

People generally don’t live as long, but they can avoid the burden and potential harms of dialysis, the researchers said. This conservative approach to care, which focuses on aggressive management of symptoms such as pain and trouble breathing, is well-established in the United Kingdom and other countries, but, generally has not been developed as a common model of care in the U.S.

“The goal in difficult clinical situations like this is shared decision-making, where patients and clinicians can work together to make choices that best balance patients’ goals and values with the objective medical evidence,” Wachterman said.

“We may have been painting an overly rosy picture for some patients as to what things will look like after starting dialysis,” she said. “We hope this new evidence can help patients and families cope with what lies ahead and empower them to make informed treatment decisions that are most aligned with their goals and preferences.”

This study was supported by grant funding from the National Institute on Aging and the National Palliative Care Research Center.

Co-investigators included Ann O’Hare, Omari-Khalid Rahman, Karl Lorenz, Edward Marcantonio, Gabrielle Alicante and Amy Kelley.

Paper cited: Wachterman MW et al. “One-Year Mortality After Dialysis Initiation Among Older Adults,” JAMA Internal Medicine 22 Apr 2019.
-JZ

Investigators tested two prototype devices in a porcine model: 1) a temperature-triggerable flower-like system for esophageal drug delivery and 2) a temperature-triggerable flexible mechanical metamaterial as a macro-device dosage form for long-term GI drug delivery.

Investigators Explore Temperature-Triggered Devices for Gastrointestinal Therapies
Researchers hope orally administered devices can help shape future generation of stents, drug delivery systems

Gastrointestinal devices such as stents, endoscopic tubes, balloons and drug delivery systems can help clinicians treat patients with a range of conditions. But currently available methods for triggering where and when drugs are released or when a device is triggered to disassemble or change shape are often slow, which can restrict the utility of such tools. Investigators from Brigham and Women’s Hospital and MIT are designing devices that can be triggered by the ingestion of a warm liquid to break down into smaller segments that can be excreted. In proof-of-concept experiments in preclinical models, the team tested two devices — one that could be induced to change conformation in the esophagus to exit following the delivery of a drug, and the other that could reside unperturbed in the stomach until intentionally triggered. The team’s results are published in Science Translational Medicine.

“We are intrigued by a simple question: when you ingest a hot liquid, what happens as it travels down your esophagus and into the stomach?” said co-corresponding author C. Giovanni Traverso, MB, BChir, PhD, a gastroenterologist and biomedical engineer in the Division of Gastroenterology at the Brigham. “What we’ve found is that there are essentially two zones — the esophageal and the gastric — which means that we may be able to control and trigger gastrointestinal devices in these two regions with precision using warm water.”

The first device the team tested was inspired by a blooming flower. This capsule-sized esophageal system with petal-like structures can close up like a bud when a warm fluid is ingested. The prototype, which was tested in pigs, unfurled in the esophagus, making contact with the esophageal wall and releasing milli-needles loaded with model drugs. When warm water was administered, the prototype fully closed and passed from the esophagus into the stomach.

The second device tested was a highly flexible, gastric resident device capable of releasing drug of extended— a device intended to stay in the stomach and release a regular dosage of a drug for weeks. Ingesting a warm liquid did not disturb the functioning of the device, but directly spraying warm water into the stomach with the aid of endoscope helped break down the device into pieces that could safely pass through the gastrointestinal tract in the pig model.

“Our approach was to employ design principles of transformable architected materials (mechanical metamaterials) whose shape and volume can be considerably altered through thermal actuation, as a new approach for developing gastrointestinal (GI) technologies with fast and robust response,” said first author Sahab Babaee, a postdoctoral associate in the Langer Lab at MIT.

The authors note that the current work provides a proof of concept, but additional testing will be needed to characterize heat dissipation in humans. The team is currently identifying and prioritizing conditions to optimize this new approach for where it is needed most.

“Currently, many gastric devices need to be removed by pulling them out through the esophagus. We anticipate that temperature-triggered systems could usher in the development of the next generation of stents, drug delivery and sensing systems housed in the gastrointestinal tract,” said Traverso.

Co-authors of this work include: Simo Pajovic, Ameya R. Kirtane, Jiuyun Shi, Ester Caffarel-Salvador, Kaitlyn Hess, Joy E. Collins, Siddartha Tamang, Aniket V. Wahane, Alison M. Hayward, Hormoz Mazdiyasni and Robert Langer.

Funding for this work was provided by the Bill and Melinda Gates Foundation (grant numbers OPP1139921 and OPP1139937) and NIH grant EB000244. Several co-authors are co-inventors on provisional application numbers 62/767,749, 62/767,954, and 62/767,798, filed by MIT related to this work. Complete details of all relationships for profit and not for profit for Traverso can be found here. A list of entities with which Langer is involved, compensated, or uncompensated, can be found here.

Paper cited: Babaee, S et al. “Temperature-responsive biometamaterials for gastrointestinal applications” Science Translational Medicine DOI: 10.1126/scitranslmed.aau8581
-HB

“Seeing the Brain Thinking”

Fundamentally New MRI Method Developed to Measure Brain Function in Milliseconds
MRI elastography could offer a new way to see extremely fast neuronal activity in the brain

The speed of the human brain is remarkable — in a fraction of a second, neurons are activated, propagating thoughts and reactions to stimuli. But the speed at which we can noninvasively follow brain function using an MRI is not as impressive. Functional MRI (fMRI), which measures changes in blood oxygen levels, has revolutionized the field of neuroscience by revealing functional aspects of the brain. But the changes that fMRI is sensitive to can take up to six seconds in humans — a veritable eon in brain time. Investigators from Brigham and Women’s Hospital, in collaboration with colleagues at King’s College London and INSERM-Paris, have discovered a fundamentally new way to measure brain function using a technology known as magnetic resonance elastography (MRE), an approach that creates maps of tissue stiffness using an MRI scanner.  In a paper published in Science Advances, the team presents data from preclinical studies indicating that the technique can track brain function activity on a time scale of 100 milliseconds. Studies of the technique in human participants are now underway.

“What excites me most is that this an entirely new method, and I’ve always been intrigued by new science,” said co-corresponding author Sam Patz, PhD, a physicist in the Brigham’s Department of Radiology and professor of Radiology at Harvard Medical School. This work, which started out as a hunch and is now being borne out by rigorous experiments, represents the collaborative work of an international team dedicated to the pursuit of this new way of imaging brain function. “The data we are publishing was obtained in mice, but translation of this technology to humans is straightforward and initial studies are currently underway.”

This work is the culmination of a five-year collaboration between Patz, co-corresponding author Ralph Sinkus PhD, and many others. Sinkus, a physicist and professor at King’s College London and INSERM Paris, is a pioneer in the field of MRE and played a key role both in helping get the MRE research program started for preclinical testing in Patz’s Boston-based lab as well as in carrying out the research being reported. Both Patz and Sinkus point to each other as an example of how a true collaborative relationship should function.

Although initially interested in applying MRE to the lungs, the team decided to also run scans of the brain. The results from these scans revealed something surprising: The acoustic cortex was stiffening, for no apparent reason. “These results were so unexpected that we had to pursue them, and this observation is what sparked everything else,” said Sinkus. “It’s a true interest in science that made this happen.”

On a hunch, Patz plugged one of the mouse’s ear canals with a gel. Sure enough, when he took another “elastogram” image of the mouse’s brain, he could see that the auditory cortex on the side of the brain that processed sound from that ear had begun to soften. In repeated preclinical studies, this initial observation has been replicated, showing which regions of the brain stiffen or soften under different types of stimulus timing.

“The intriguing novelty of this approach is that the stiffening/softening of specific brain regions persists even when stimuli as short as 100 milliseconds are presented to the mouse,” said Patz.

Both Sinkus and Patz agreed that the changes in stiffness parallel neuronal activity, allowing one to “see the brain thinking” in almost real-time.

The team is now interested in using MREs to observe neuronal activity in the human brain, which could have implications for diagnosing and understanding neurological pathologies in which neuronal activity may be slowed, disrupted our rerouted — such as Alzheimer’s, dementia, multiple sclerosis, or epilepsy.

The team’s approach leverages novel hardware to induce vibrations in the brain — an essential part to measure brain stiffness via MRI. Patz likens the elastography apparatus to holding an electric toothbrush against one’s head in order to create tiny mechanical waves that travel through the brain. Standard MRE methodology was used to measure the waves as they travel through the brain but a new mathematical approach by the Sinkus group was implemented to create the elastograms from the raw data. The team also used a new MRE protocol to compare the stiffness of the brain in two different functional states that correspond to a stimulus applied or not applied to the hind limb in mice. The researchers present data showing that modulating the stimulus influenced the location, phase and the intensity of the elasticity changes seen in the brain, meaning that they can visualize regional responses in the brain as they unfold at high speed.

“We believe this will transform our ability to observe neuronal functional activity with implications for neurological pathologies,” said Patz.

Funding for this work was provided by the National Institutes of Health (R21 EB030757), the European Union’s Horizon 2020 Research and Innovation program under grant agreement No 668039, German Research Foundation (DFG, SCHR 1542/1-1), Brigham and Women’s Hospital Department of Radiology and Boston University Department of Engineering, the Wellcome/EPSRC Centre for Medical Engineering (WT 203148/Z/16/Z), the European Union Seventh Framework Programme FP7/20072013 under grant agreement n° 601055.

Paper cited: Patz, S et al. “Imaging localized neuronal activity at fast timescales through biomechanics” Science Advances DOI: 10.1126/sciadv.aav3816

-HB

Christine Seidman and colleagues have found rare genetic variants associated with heart complications after cancer therapy

A New Role for Genetics in Cancer Therapy-Induced Cardiomyopathy

Scientists discover that rare gene variants are associated with development of adult and pediatric CCM

Recent advances in the development of cancer therapies have increased long-term survival and prognosis. However, the increased burden and prevalence of harmful side effects, including cardiomyopathy, have emerged alongside those therapeutic benefits. In particular, there have been increases in cancer therapy-induced cardiomyopathy (CCM) — a heart condition which may compromise a patient’s quality of life and long-term prognosis after the cancer has been treated. And while certain clinical risk factors for CCM are known, the factors that contribute to an individual’s susceptibility remain a mystery. A team of investigators from Brigham and Women’s Hospital and Harvard Medical School finds that genetics may be at play and elucidates rare genetic variants which may influence risk for developing CCM. Results are published in Circulation.

“With improved long-term survival of cancer patients and advancement in cancer therapies, we have been seeing more patients with cardiotoxicity from cancer therapy,” said Yuri Kim, MD, PhD, lead author and cardiology fellow at HMS. “Our study is the first to consider the association between rare genetic variants in a large set of cardiomyopathy genes and the occurrence of CCM.”

To investigate the role of genetics in CCM, Kim and colleagues recruited 213 adult and child patients with CCM from three academic centers in Philadelphia, Madrid and London. These patients had diverse background malignancies, including breast cancer and leukemia. Most patients (90 percent) received anthracyclines — a cancer drug known to cause cardiotoxicity in up to 10 percent of patients. Next generation sequencing was conducted in all patients to identify rare pathogenic variants in CCM susceptibility genes. The team then compared results with reference populations.

Interestingly, investigators discovered that truncating variants in the gene TTN (TTNtv), which encodes the protein titin, were significantly increased in CCM patients compared to control cohorts. Clinical outcomes were also significantly impacted in patients with TTNtv.

“Adverse outcomes from cardiomyopathy, including heart failure, atrial fibrillation and impaired myocardial recovery were more prevalent in adult CCM patients with TTNtv than those without,” noted Kim.

One notable highlight in this study was the researchers’ ability to reproduce and validate their clinical findings in animal models. Mice with the TTNtv variant were also found to have increased susceptibility to the cardiotoxic effects of anthracyclines, displaying significantly decreased levels of left ventricular function compared to control.

While the authors are optimistic about their findings, they acknowledge certain limitations to their study, including the use of data from participants in the Cancer Genome Atlas, some of whom may have also developed CCM, as a control group. Inclusion of CCM patients in the control group would lower, not inflated statistical significance, and thus the reported findings represent a conservative association between genotype and CCM. In addition, they note that while the patient cohorts consisted of individuals of various ethnic backgrounds, Caucasian participants comprised nearly 80 percent of the group.

These caveats aside, the authors are excited about the potential clinical implications of their work. In light of the limited strategies that currently exist for diagnosing CCM in cancer patients, they hope that the identification of genetic risk factors may open up a new path to identify and better manage cancer patients at high risk for CCM.

“We believe that identification of cancer patients with high CCM risk based on genetic testing will enable health care providers to tailor their cardiovascular and oncological monitoring and treatment regimen, which will ultimately improve patients’ cardiovascular and oncological prognosis,” said Kim.

“Our next steps are to find ways to directly mitigate the adverse effects of TTNtv on cardiac biology, which would benefit not only CCM patients, but many cardiomyopathies that are caused by these prevalent and damaging human mutations,” said co-corresponding author Christine E. Seidman, MD, the director of the Cardiovascular Genetics Program and a cardiovascular medicine specialist at the Brigham, as well as the Thomas W. Smith Professor of Medicine at HMS.

Further research is needed to determine if early detection of risk for CCM through genetic testing can optimize patients’ cancer and cardiovascular outcomes.

Funding for this work was provided by Instituto de Salud Carlos III (ISCIII) (PI15/01551, PI17/01941 and CB16/11/00432 to P.G-P. and L.A-P.), the Spanish Ministry of Economy and Competitiveness (SAF2015-71863-REDT to P.G-P.), the John S. LaDue Memorial Fellowship at Harvard Medical School (Y.K.), Wellcome Trust (107469/Z/15/Z to J.S.W.), Medical Research Council (intramural awards to S.A.C. and J.S.W; MR/M003191/1 to U.T), National Institute for Health Research Biomedical Research Unit at the Royal Brompton and Harefield National Health Service Foundation Trust and Imperial College London (P.J.B., S.A.C., J.S.W.), National Institute for Health Research Biomedical Research Centre at Imperial College London Healthcare National Health Service Trust and Imperial College London (D.O.R., S.A.C., S.P., J.S.W.), Sir Henry Wellcome Postdoctoral Fellowship (C.N.T.), Rosetrees and Stoneygate Imperial College Research Fellowship (N.W.), Fondation Leducq (S.A.C., C.E.S., J.G.S.), Health Innovation Challenge Fund award from the Wellcome Trust and Department of Health (UK; HICF-R6-373; S.A.C., P.J.B., J.S. W.), the British Heart Foundation (NH/17/1/32725 to D.O.R.; SP/10/10/28431 to S.A.C), Alex’s Lemonade Stand Foundation (K.G.), National Institutes of Health (R.A.: U01CA097452, R01CA133881, and U01CA097452; Z.A.: R01 HL126797; B.K.: R01 HL118018 and K23-HL095661; J.G.S. and C.E.S.: 5R01HL080494, 5R01HL084553), and the Howard Hughes Medical Institute (C.E.S.).

Paper cited: Garcia-Pavia, P. et al. “Genetic Variants Associated with Cancer Therapy-Induced Cardiomyopathy” Circulation doi.org/10.1161/CIRCULATIONAHA.118.037934

-JZ