What's New in Research: July/August 2022 - Brigham Clinical & Research News

What’s New in Research: July/August 2022

Dynamic Lighting Helps Reduce Rates of Falls for Older U.S. Adults

Leilah Grant and Shadab Rahman

Falls are the leading cause of injury-related death for older adults (age 65+) in America. Since current interventions to reduce falls are multifactorial and require significant time and resources, pushes have been made to find alternative low-cost and low-burden solutions. In four long-term care homes totaling 758 residents, investigators at Brigham and Women’s Hospital, led by Shadab Rahman, PhD, MPH, and Leilah Grant, PhD, of the Division of Sleep and Circadian Disorders, studied whether changing the intensity and spectrum of lighting across the day — which impacts neurocognitive processes such as alertness, mood, and sleep — can reduce the rate of falls in elderly care-home residents.

In the homes, specifically, the short-wavelength (blue) content of ambient lighting was changed dynamically across the day and night at two sites, with fall rates at these sites then compared to the fall rates from the two other control sites, where the intensity and spectrum were fixed throughout the day and night. Overall, the researchers found a 43% reduction in the rate of falls for those who were exposed to the dynamic lighting versus those who were not.

“The ability to significantly reduce the rate of falls in long-term, care-home residents by implementing a relatively low-cost, passive, environmental intervention such as changing the spectrum and intensity of lighting throughout the day as a preventative strategy has major implications for improving health and well-being in this at-risk population,” said Rahman, the corresponding author of the study.

Supplemental Vitamin D Did Not Lower Risk of Fractures in Healthy U.S. Adults

JoAnn Manson

Meryl LeBoff

Although vitamin D supplements are widely prescribed and used to benefit bone health, definitive data on whether these supplements reduce fractures in the general population have been inconsistent. To advance scientific understanding on this subject, a team of researchers at Brigham and Women’s Hospital conducted an ancillary study to the VITamin D and OmegA-3 TriaL (VITAL), a clinical trial of more than 25,000 adults, also led by investigators from the Brigham. A total of 1,991 incident fractures in 1,551 participants were confirmed over a median follow-up of 5.3 years. Compared to placebo, supplemental vitamin D₃ (2000 IU/day) did not reduce total, non-vertebral, or hip fractures. The analyses also showed that there were no effects of supplemental vitamin D₃ on major osteoporotic fractures, wrist fractures, or pelvic fractures. Effects were not modified by baseline age, sex, race, body mass index, baseline vitamin D blood levels, and personal use of supplemental calcium and/or vitamin D.

“Overall, the results from this large clinical trial do not support the use of vitamin D supplements to reduce fractures in generally healthy U.S. men and women,” said lead author Meryl LeBoff, MD, Chief of the Calcium and Bone Section in the Endocrine Division at the Brigham. “These findings do not apply to adults with vitamin D deficiency or low bone mass or osteoporosis. Most participants in the trial were not deficient and may have already reached the vitamin D level needed for bone health. Our ongoing studies are focusing on whether free vitamin D levels or genetic variation in vitamin D absorption, metabolism, or receptor function will provide information about individuals who may benefit from supplemental vitamin D on musculoskeletal health.”

JoAnn Manson, MD, co-author and chief of the Division of Preventive Medicine at the Brigham said, “Although VITAL was originally designed to look at cardiovascular and cancer outcomes, this is a wonderful example of how it has shed light on health outcomes far beyond its original goals.”

Clonal Barcoding Approach Assists in Live Cancer Cell Tracking

Sandra McAllister

Cell lineage tracking serves many useful purposes for understanding clonal dynamics within complex cell populations, including cancers. To aid in this process, a team of researchers led by investigators at the Brigham integrated short, noncoding DNA sequences into the genomes of individual cancer cell clones to serve as a mechanism for molecular barcoding. From there, the team employed SunCatcher, an approach which differs from other barcoding methods by specifically generating individual clones before the barcoding. This allows for detection, quantification, and isolation of precise clones of interest. For this study, the SunCatcher method was applied within human breast cancer cell lines and used to track important biological processes. The technique was effective at detecting and identifying clones responsible for tumor formation, as well as early spontaneous metastases. Because SunCatcher enables isolation of clones for further analysis, the team was able to study metastatic clones as well as clones that were eliminated during the experiment. The researchers envision that SunCatcher will have the potential to be employed as a beneficial tool in other cell-based studies.

“We offer a new molecular barcoding approach with a Q-PCR-based detection method that is rapid, affordable, sensitive, and accurate,” said senior author Sandra McAllister, PhD, an associate scientist in the Hematology Division at the Brigham. “Another important point is that our technology enables functional analysis of live cells. We’re excited for anyone doing cell-based work that can use this technology – it’s applicable to more than just cancer research.”

Key Differences in Presentation, Outcomes for Distal versus Proximal Deep Vein Thrombosis Uncovered

Behnood Bikdeli

Deep vein thrombosis (DVT) occurs when a blood clot forms in a large (deep) vein. Proximal DVTs occur in deep veins above the knee and isolated, distal DVTs can occur when smaller blood clots form in the veins below the knee. But the differences between the clinical presentation, short-term and long-term outcomes for patients with isolated distal DVT (smaller thrombi in veins below the knee) versus proximal DVT have been unclear. A new study led by investigators from Brigham and Women’s Hospital highlights key differences in clinical features and co-morbidities, as well as short-term and also long-term outcomes for patients with distal DVT versus proximal DVT. The team found that patients with isolated distal DVT had lower co-morbidity burden and a lower risk of 90-day mortality. They were also at lower risk of developing a pulmonary embolism or a new venous thromboembolism in one year. The authors note that some of the differences in the outcomes are attributable to the risk profile of these patients. Patients with distal DVT were younger, more likely to have had DVT in the setting of transient provoking factors such as surgery or hormonal use but less likely to have serious co-morbidities such as cancer or anemia.

“Our findings may have implications for risk stratification and for practice,” said corresponding author Behnood Bikdeli, MD, MS, of the Brigham’s Division of Cardiovascular Medicine. “While we find less ominous outcomes for isolated, distal DVTs, they are not entirely benign. Even among patients who received initial anti-coagulation treatment, almost half had signs or symptoms of post thrombotic syndrome, a chronic manifestation of these clots. Randomized clinical trials are needed to assess the best long-term management for patients who have had isolated, distal DVT.”

Novel Treatment for Rare Form of Kidney Cancer Uncovered

Chromophobe renal cell carcinoma (ChRCC) is a rare form of kidney cancer for which there are currently no proven treatments for metastatic or unresectable disease. In a study led by investigators from Brigham and Women’s Hospital, researchers report the first evidence that ChRCC can be targeted with ferroptosis — a type of programmed cell death that occurs when large amounts of iron cause lipid peroxides to accumulate in the cell membrane. The team successfully induced ferroptosis in ChRCC cells via cysteine deprivation and found evidence that this strategy may be an effective approach for treating ChRCC.

“Targeted therapies are urgently needed to treat chromophobe RCC,” said corresponding author Elizabeth P. Henske, MD, of the Division of Pulmonary and Critical Care Medicine at the Brigham. “Through our study, we’ve found strong evidence that ChRCC can be therapeutically targeted by taking advantage of the cells’ hypersensitivity to ferroptosis. This represents an important breakthrough in our understanding as we think about treatment for patients with this rare disease.”

Study Identifies T-Cell Populations that Predict Response to Immunotherapy

Jonathan D. Schoenfeld

Immune checkpoint blockade (ICB) therapy has shown promising potential for treating many types of cancer, including head and neck squamous cell cancers (HNSCCs). In a clinical trial of patients with high-risk oral cavity cancers treated with immunotherapy prior to surgery, most patients have continued to remain disease free even after a few years — better than expected outcomes with standard of care treatment. Investigators from Brigham and Women’s Hospital took advantage of the clinical trial’s unique design to study blood and tissue samples from these patients before and after immunotherapy and found that certain populations of immune cells, most notably a type of T-cell called resident memory T-cells, expanded after just a couple of weeks of immune therapy treatment. These responding T-cell populations could be found in both the tumors and the circulating blood, which could help treat the tumor and prevent recurrences.

“Specific populations of immune cells found in the blood even before treatment strongly predicted which patients would respond best with the majority or even all of the tumor found to be killed at the time of surgery just a few weeks later,” said co-senior author Jonathan D. Schoenfeld, MD, MPH, of the Department of Radiation Oncology. “These biomarkers could potentially be used to help select patients for future trials to further improve outcomes.”

Microbial Link Between Western-Style Diet and Incidence of Colorectal Cancer Uncovered

Shuji Ogino

New research builds the case that a Western-style diet — rich in red and processed meat, sugar and refined grains/carbohydrates — is tied to higher risk of colorectal cancer through the intestinal microbiota. Investigators from Brigham and Women’s Hospital with collaborators looked at data from more than 134,000 participants from two U.S.-wide prospective cohort studies. The team analyzed dietary patterns as well as DNA from Escherichia coli strains found in more than 1,000 colorectal tumors. The team looked for bacterial strains carrying a distinct genetic island known as polyketide synthase (pks). Pks encodes an enzyme that has been shown to cause mutations in human cells. Overall, the team found that Western diet was associated with colorectal tumors containing high amounts of pks+ E. coli but not with tumors containing little to no amount of pks+ E. coli.

“These findings support our hypothesis that Western-style diets increase colorectal cancer risk through its effect on pks+ E. coli,” said corresponding author Shuji Ogino, MD, PhD, MS, of the Program in Molecular Pathological Epidemiology in the Department of Pathology at the Brigham. “This is the first study to link Western diet with specific pathogenic bacteria in cancer. Our next question is which component of western-style diet and lifestyle relates to colorectal cancer containing this bacterial species.”

Study Uncovers Pancreas Cell Type-Specific Activities of IL18

Guo-Ping Shi

Both type 1 and type 2 diabetes are characterized by the loss of β cells and insulin secretion. Regenerating β cells from other cell types, such as α cells, has been proposed as a potential therapeutic strategy for diabetes. Inflammation is thought to be connected to diabetes progression, but many questions remain about the role of specific markers of inflammation, such as interleukin 18 (IL18) in the disease and in specific cell types. In a new study, researchers have found that in human and mouse pancreases, α cells express IL18, acinar cells express traditional IL18 receptors, and β cells express an alternative IL18 receptor known as the Na-Cl co-transporter (NCC). The team’s findings suggest that IL18, together with the glucagon-like peptide-1 (GLP1) from α cells, uses NCC and GLP1 receptor on β cells for β-cell development, insulin secretion, and insulin signaling. Like GLP1 agonists, IL18 may have therapeutic potential for patients with obesity and diabetes. Yet, interruption of IL18 interactions with its receptors has been shown to be effective at reducing atherosclerosis in experimental models. Therefore, targeting IL18 in patients with cardiovascular disease may damage β-cell functions.

“These findings provide insights into the role of IL18 signaling in regulating islet β cell proliferation and may help guide future efforts to protect these IL18 pathways as a potential strategy to expand β cells and increase islet mass in diabetes,” said senior author Guo-Ping Shi, ScD, a principal investigator in the Brigham’s Division of Cardiovascular Medicine.