RNA quality control factors nucleate Clr4/SUV39H and trigger constitutive heterochromatin assembly
Khanduja JS, Joh RI, Perez MM, Paulo JA, Palmieri CM [et al.], Motamedi M
Published in Cell on 5/21/2024 | *Summary available | Press Release

Noninvasive assessment of organ-specific and shared pathways in multi-organ fibrosis using T1 mapping
Nauffal V, Klarqvist MDR, Hill MC, Pace DF, Di Achille P [et al.], Ellinor PT
Published in Nature Medicine on 5/28/2024 | *Summary available

Affinity gaps among B cells in germinal centers drive the selection of MPER precursors
Ray R, Schiffner T, Wang X, Yan Y, Rantalainen K [et al.], Batista FD
Published in Nature Immunology on 5/30/2024

Two genome-wide interaction loci modify the association of nonsteroidal anti-inflammatory drugs with colorectal cancer
Drew DA, Kim AE, Lin Y, Qu C, Morrison J [et al.], Gauderman WJ
Published in Science Advances on 5/31/2024 | *Summary available

Effects of Low-Level Light Therapy on Resting-State Connectivity Following Moderate Traumatic Brain Injury: Secondary Analyses of a Double-blinded Placebo-controlled Study
Chan ST, Mercaldo N, Figueiro Longo MG, Welt J, Avesta A [et al.], Gupta R
Published in Radiology on 5/31/2024 | *Summary available

Stepped Palliative Care for Patients with Advanced Lung Cancer: A Randomized Clinical Trial
Temel JS, Jackson VA, El-Jawahri A, Rinaldi SP, Petrillo LA [et al.], Greer JA
Published in JAMA on 6/2/2024 | *Summary available | Press Release

Genetic Architecture and Clinical Outcomes of Combined Lipid Disturbances
Gilliland T, Dron JS, Selvaraj MS, Trinder M, Paruchuri K [et al.], Natarajan P
Published in Circulation Research on 6/3/2024 | *Summary available

KLRG1 Cell Depletion as a Novel Therapeutic Strategy in Patients with Mature T-Cell Lymphoma Subtypes
Assatova B, Willim R, Trevisani C, Haskett G, Kariya KM [et al.], Jain S
Published in Clinical Cancer Research on 6/3/2024 | *Summary available

Comparative analysis of Bcl-2 family protein overexpression in CAR T cells alone and in combination with BH3 mimetics
Korell F, Olson ML, Salas-Benito D, Leick MB, Larson RC [et al.], Maus MV
Published in Science Translational Medicine on 6/5/2024 | *Summary available

Hofbauer cells and fetal brain microglia share transcriptional profiles and responses to maternal diet-induced obesity
Batorsky R, Ceasrine AM, Shook LL, Kislal S, Bordt EA [et al.], Edlow AG
Published in Cell Reports on 6/6/2024 | *Summary available | Press Release

Vedolizumab for the prevention of intestinal acute GVHD after allogeneic hematopoietic stem cell transplantation: a randomized phase 3 trial
Chen YB, Mohty M, Zeiser R, Teshima T, Jamy O, Maertens J, Purtill D, Chen J, Cao H, Rossiter G, Jansson J, Fløisand Y
Published in Nature Medicine on 6/6/2024 | *Summary available

Tau propagation in the brain olfactory circuits is associated with smell perception changes in aging
Diez I, Ortiz-Terán L, Ng TSC, Albers MW, Marshall G [et al.], Sepulcre J
Published in Nature Communications on 6/6/2024 | *Summary available

MSGene: a multistate model using genetic risk and the electronic health record applied to lifetime risk of coronary artery disease
Urbut SM, Yeung MW, Khurshid S, Cho SMJ, Schuermans A [et al.], Natarajan P
Published in Nature Communications on 6/7/2024 | *Summary available

Dynamics of collagen oxidation and cross linking in regenerating and irreversibly infarcted myocardium
Akam-Baxter EA, Bergemann D, Ridley SJ, To S, Andrea B [et al.], Sosnovik DE
Published in Nature Communications on 6/10/2024 | *Summary available | Press Release

Patient Navigation for Lung Cancer Screening at a Health Care for the Homeless Program: A Randomized Clinical Trial
Baggett TP, Sporn N, Barbosa Teixeira J, Rodriguez EC, Anandakugan N [et al.], Rigotti NA
Published in JAMA Internal Medicine on 6/10/2024

The glutathione S-transferase Gstt1 drives survival and dissemination in metastases
Ferrer CM, Cho HM, Boon R, Bernasocchi T, Wong LP [et al.], Mostoslavsky R
Published in Nature Cell Biology on 6/11/2024 | *Summary available | Press Release

Genetic drivers and cellular selection of female mosaic X chromosome loss
Liu A, Genovese G, Zhao Y, Pirinen M, Zekavat SM [et al.], Machiela MJ
Published in Nature on 6/12/2024 | *Summary available

Household material hardship and distress among parents of children with advanced cancer: A report from the PediQUEST Response trial
Eche-Ugwu IJ, Orellana L, Becker D, Bona K, Avery M [et al.], Wolfe J
Published in Cancer on 6/12/2024 | *Summary available

Clinical Decision Support as a Prevention Tool for Medication Errors in the Operating Room: A Retrospective Cross-Sectional Study
Amici LD, van Pelt M, Mylott L, Langlieb M, Nanji KC
Published in Anesthesia & Analgesia on 6/13/2024 | *Summary available | Press Release

A blood-brain barrier-penetrant AAV gene therapy improves neurological function in symptomatic mucolipidosis IV mice
Sangster ML, Bishop MM, Yao Y, Feitor JF, Shahriar S [et al.], Grishchuk Y
Published in Molecular Therapy – Methods and Clinical Development on 6/13/2024 | *Summary available | Research Spotlight

Exclusion of sulfide:quinone oxidoreductase from mitochondria causes Leigh-like disease in mice by impairing sulfide metabolism
Kanemaru E, Shimoda K, Marutani E, Morita M, Miranda M [et al.], Ichinose F
Published in Journal of Clinical Investigation on 6/13/2024 | *Summary available

Base editing strategies to convert CAG to CAA diminish the disease-causing mutation in Huntington's disease
Choi DE, Shin JW, Zeng S, Hong EP, Jang JH [et al.], Lee JM
Published in eLife on 6/13/2024 | *Summary available

Induction of DEPP1 by HIF Mediates Multiple Hallmarks of Ischemic Cardiomyopathy
Wyant GA, Jiang Q, Singh M, Qayyum S, Levrero C, Maron BA, Kaelin WG Jr
Published in Circulation on 6/17/2024 | *Summary available

Differential cortical layer engagement during seizure initiation and spread in humans
Bourdillon P, Ren L, Halgren M, Paulk AC, Salami P [et al.], Cash SS
Published in Nature Communications on 6/17/2024

Near-Infrared II Photobiomodulation Preconditioning Ameliorates Stroke Injury via Phosphorylation of eNOS
Yokomizo S, Kopp T, Roessing M, Morita A [et al.], Kashiwagi S, Atochin DN
Published in Stroke on 6/18/2024 | *Summary available | Press Release

Dysfunction of infiltrating cytotoxic CD8+ T cells within the graft promotes murine kidney allotransplant tolerance
Yokose T, Szuter ES, Rosales I, Guinn MT, Liss AS [et al.], Alessandrini A
Published in Journal of Clinical Investigation on 6/18/2024 | *Summary available

3-Hydroxykynurenine targets kainate receptors to promote defense against infection
Parada-Kusz M, Clatworthy AE, Goering ER, Blackwood SM, Shigeta JY [et al.], Hung DT
Published in Nature Chemical Biology on 6/19/2024 | *Summary available

APOE3 Christchurch Heterozygosity and Autosomal Dominant Alzheimer's Disease
Quiroz YT, Aguillon D, Aguirre-Acevedo DC, Vasquez D, Zuluaga Y [et al.], Arboleda-Velasquez JF
Published in New England Journal of Medicine on 6/20/2024 | *Summary available

Brigatinib in NF2-Related Schwannomatosis with Progressive Tumors
Plotkin SR, Yohay KH, Nghiemphu PL, Dinh CT [et al.], Blakeley JO; INTUITT-NF2 Consortium
Published in New England Journal of Medicine on 6/21/2024 | *Summary available | Press Release

RNA quality control factors nucleate Clr4/SUV39H and trigger constitutive heterochromatin assembly
Khanduja JS, Joh RI, Perez MM, Paulo JA, Palmieri CM [et al.], Motamedi M
Published in Cell on 5/21/2024 | Press Release

The human genome contains many repetitive regions which have to be maintained in a ‘silent’ state to preserve its stability. Loss of silencing at repeats increases mutations and is linked to several human pathologies, especially cancers. How cells establishing silencing at repeats is not well understanding. Here we show that special RNA molecules, called long noncoding RNAs, act as scaffolds for the recruitment of all the factors needed to assemble silencing at repetitive DNA elements. This discovery has important ramification for understanding how healthy cells maintain the fidelity of our genome and will help unearth new drug targets for killing cancer cells specifically in future studies.

(Summary submitted by Mo Motamedi, PhD, Krantz Family Center for Cancer Research, Mass General Cancer Center)

Noninvasive assessment of organ-specific and shared pathways in multi-organ fibrosis using T1 mapping
Nauffal V, Klarqvist MDR, Hill MC, Pace DF, Di Achille P [et al.], Ellinor PT
Published in Nature Medicine on 5/28/2024

In over 40,000 individuals, we quantified liver, pancreas, heart, and kidney fibrosis (i.e., tissue scarring) using magnetic resonance imaging. We found that a high burden of fibrosis in ≥3 organs is independently associated with a 3-fold increased risk of mortality, underscoring the critical need to understand the biologic mechanisms that contribute to fibrosis. Through genetic association studies, we identified 58 independent genetic regions associated with fibrosis, 10 of which overlapped across multiple organs. This body of work paves the way for studies aimed at therapeutic targeting of identified biologic pathways and promises to have a widespread impact on multiple diseases.

(Summary submitted by Victor Nauffal, MD, Brigham and Women's Hospital)

Two genome-wide interaction loci modify the association of nonsteroidal anti-inflammatory drugs with colorectal cancer
Drew DA, Kim AE, Lin Y, Qu C, Morrison J [et al.], Gauderman WJ
Published in Science Advances on 5/31/2024

Using genetic data from more than 72,500 people, we identified alterations in genetic sequences that help us identify which individuals are more, or most, likely to benefit from using a low-dose aspirin regularly to help prevent their future risk of colorectal cancer that may help doctors make more accurate recommendations in the future and reduce the potential harms that may be associated with taking these medications regularly.

(Summary submitted by David A. Drew, PhD, Clinical & Translational Epidemiology Unit and Division of Gastroenterology, Department of Medicine)

Effects of Low-Level Light Therapy on Resting-State Connectivity Following Moderate Traumatic Brain Injury: Secondary Analyses of a Double-blinded Placebo-controlled Study
Chan ST, Mercaldo N, Figueiro Longo MG, Welt J, Avesta A [et al.], Gupta R
Published in Radiology on 5/31/2024

Traumatic brain injury (TBI) results from physical impact to the head. Low-level light therapy (LLLT) is emerging as a potential treatment for TBI. A prospective clinical trial was performed to evaluate the effect of LLLT on neuronal repair in humans who had suffered moderate TBI (injury serious enough to alter brain function or be visible on imaging). Thirty-eight patients were randomized to receive either active LLLT or “sham” LLLT, which was administered via a wearable helmet within 72 hours of injury. Compared to sham-treated patients, those receiving LLLT demonstrated an increase in brain connectivity within the first two weeks following the injury. Additional research is needed to evaluate the long-term impact of LLLT on cognitive outcomes.

(Summary submitted by Suk-Tak Chan, PhD, Martinos Center for Biomedical Imaging, Department of Radiology)

Stepped Palliative Care for Patients with Advanced Lung Cancer: A Randomized Clinical Trial
Temel JS, Jackson VA, El-Jawahri A, Rinaldi SP, Petrillo LA [et al.], Greer JA
Published in JAMA on 6/2/2024 | Press Release

Many patients with advanced cancer do not receive early palliative care, which is a key component of evidence-based cancer care. This study demonstrates that early palliative care can be effectively tailored to patients' cancer and care needs to maximize their quality of life while utilizing fewer palliative care resources. Implementing this patient-centered approach to delivering early palliative care will allow more patients to access essential early palliative care services. Importantly, as patients are living longer with advanced cancer, tailoring early palliative care to their healthcare needs is increasingly important to deliver patient-centered cancer care and increase access to palliative care services.

(Summary submitted by Jennifer Temel, MD, Mass General Cancer Center)

Genetic Architecture and Clinical Outcomes of Combined Lipid Disturbances
Gilliland T, Dron JS, Selvaraj MS, Trinder M, Paruchuri K [et al.], Natarajan P
Published in Circulation Research on 6/3/2024

Disturbances in blood lipid traits–including cholesterol and triglyceride levels–are commonly linked to heart disease. Individuals often have abnormal levels of multiple lipid traits simultaneously. In our study of over 400,000 individuals, we assessed six types of concurrent lipid disturbances, uncovering unique clinical features and genetic associations for each. Of note, the “combined hyperlipidemia” disturbance was associated with a 92% increase in heart disease risk. We also identified 72 genetic loci that had not been associated with lipid traits in previous genetic studies. This research highlights the importance of examining multiple lipid traits to better understand disease risks associated with these simultaneous disturbances.

(Summary submitted by Jacqueline Dron, PhD, Center for Genomic Medicine)

KLRG1 Cell Depletion as a Novel Therapeutic Strategy in Patients with Mature T-Cell Lymphoma Subtypes
Assatova B, Willim R, Trevisani C, Haskett G, Kariya KM [et al.], Jain S
Published in Clinical Cancer Research on 6/3/2024

This study highlights KLRG1, the immune senescence marker to be highly expressed in subtypes of T-cell and NK-cell lymphoma underscoring its potential as a new target. First-in-class anti-KLRG1 monoclonal antibodies were effective in eradicating lymphoma in highly aggressive models of T-cell lymphoma by harnessing the immune system. Their combination with duvelisib, an oral PI3K inhibitor abbreviated the tumor burden substantially by leveraging the potency of repolarized macrophages. These findings have been expediently translated to a multicenter phase I/II clinical trial for patients with relapsed and refractory T-cell large granular lymphocytic leukemia and is actively enrolling patients who suffer from anemia and/or neutropenia (NCT05532722).

(Summary submitted by Salvia Jain MD, Mass General Cancer Center)

Comparative analysis of Bcl-2 family protein overexpression in CAR T cells alone and in combination with BH3 mimetics
Korell F, Olson ML, Salas-Benito D, Leick MB, Larson RC [et al.], Maus MV
Published in Science Translational Medicine on 6/5/2024

Despite promising response rates and successes in the treatment of blood cancer, about half of patients have their tumor return, with a lack of durable activity of the engineered immune cell therapy. To address this problem, the Maus Lab CAR-T cells resistant to programmed cell death, making them resistant to approved drugs that trigger this kind of cell death mechanism in blood cancers. The new engineered CAR T cells displayed enhanced tumor control in mice alone and in combination with these drugs, thus representing a promising strategy to improve the durable effects of CAR-T cell therapy.

(Summary submitted by Marcela Maus, MD, PhD, Cellular Immunotherapy Program, Mass General Cancer Center)

Hofbauer cells and fetal brain microglia share transcriptional profiles and responses to maternal diet-induced obesity
Batorsky R, Ceasrine AM, Shook LL, Kislal S, Bordt EA [et al.], Edlow AG
Published in Cell Reports on 6/6/2024 | Press Release

Immune activation in pregnancy can occur in response to metabolic diseases like obesity, infections, exposure to pollution and environmental toxins, or even stress. Maternal immune activation can have negative effects on fetal brain immune cells (microglia). It’s not possible to monitor microglia within the fetal brain, but this work suggests fetal macrophages in the placenta (Hofbauer cells) can act as indicators of fetal brain microglial programming after exposure to maternal obesity. Assessing placental Hofbauer cells can reveal when maternal immune activation may alter the programs of fetal brain microglia, potentially helping identify newborns at greatest risk for developing neurodevelopmental disorders.

(Summary submitted by Andrea G Edlow, MD, MSc, Division of Maternal-Fetal Medicine, Department of Obstetrics, Gynecology, and Reproductive Biology)

Vedolizumab for the prevention of intestinal acute GVHD after allogeneic hematopoietic stem cell transplantation: a randomized phase 3 trial
Chen YB, Mohty M, Zeiser R, Teshima T, Jamy O, Maertens J, Purtill D, Chen J, Cao H, Rossiter G, Jansson J, Fløisand Y
Published in Nature Medicine on 6/6/2024

Acute graft-vs-host disease (GVHD) remains a significant complication after allogeneic hematopoietic cell transplantation (HCT). Acute GVHD generally can involve the skin, liver or intestine with lower gastrointestinal (GI) involvement being responsible for the vast majority of morbidity and mortality associated. Vedolizumab is a monoclonal antibody approved for the treatment of inflammatory bowel disease which targets proteins which control lymphocyte trafficking – i.e. how lymphocytes go to different anatomical locations. GRAPHITE was a phase 3 international trial investigating the addition of vedolizumab to conventional GVHD prevention with the aim of reducing the incidence of acute lower GI GVHD. Due to the effects of the COVID-19 pandemic, the trial was closed after 343 of a planned 558 patients had enrolled. However, even with this smaller sample size, the addition of vedolizumab was associated with a significant reduction in cases of acute GI GVHD or death at 6 months after HCT (85.5% with vedolizumab vs. 70.9% with placebo) with the effect primarily driven by much lower cases of clinically significant acute GI GVHD (2 cases vs. 12). This is the first phase 3 trial showing an intervention can specifically modulate acute GVHD in an organ-specific manner and adds to the growing options that practitioners can use. Over the last decade, prevention of acute GVHD has significantly improved with the routine use of several new agents including cyclophosphamide and abatacept, and now vedolizumab, as well as active investigation into methods of graft manipulation through cell sorting. The challenge ahead will be how we can incorporate these advances to continue to improve overall outcomes for patients undergoing HCT.

(Summary submitted by Yi-Bin Chen, MD, Mass General Cancer Center)

Tau propagation in the brain olfactory circuits is associated with smell perception changes in aging
Diez I, Ortiz-Terán L, Ng TSC, Albers MW, Marshall G [et al.], Sepulcre J
Published in Nature Communications on 6/6/2024

Smell loss in aging may be a clue to brain changes preceding Alzheimer Disease (AD) associated pathological accumulation and memory loss. In this study longitudinal neuroimaging and odor identification measures were used to better understand the association between smell loss and neurodegeneration. Odor identification decreased after seventh decade of life and was associated with tau accumulation (hallmark of AD) in olfactory pathways. Olfactory measures were able to predict longitudinal brain atrophy, cognitive decline and tau progression beyond olfactory regions. While amyloid accumulation due to xenobiotics or infections could facilitate the appearance and spreading of tau in the olfactory system, accelerating neurodegeneration, the study points to tau tangles spreading from the brainstem.

(Summary submitted by Ibai Diez Palacio, PhD, Gordon Center for Medical Imaging, Department of Radiology)

MSGene: a multistate model using genetic risk and the electronic health record applied to lifetime risk of coronary artery disease
Urbut SM, Yeung MW, Khurshid S, Cho SMJ, Schuermans A [et al.], Natarajan P
Published in Nature Communications on 6/7/2024

Cardiovascular disease (CVD) remains the leading cause of death in the U.S., claiming countless lives each year. Traditional clinical risk models often assume static patient profiles and provide fixed window estimates, failing to capture the dynamic nature of patient health over time. To address this, the research team developed MSGene, a novel multistate model that incorporates changing electronic health record (EHR) data throughout a patient's life. This model dynamically updates remaining lifetime risk predictions and expected treatment benefits, such as statin therapy, reflecting the evolving nature of patients' lives.

(Summary submitted by Sarah M. Urbut, MD, PhD, Division of Cardiology, Department of Medicine)

Dynamics of collagen oxidation and cross linking in regenerating and irreversibly infarcted myocardium
Akam-Baxter EA, Bergemann D, Ridley SJ, To S, Andrea B [et al.], Sosnovik DE
Published in Nature Communications on 6/10/2024 | Press Release

Heart attacks damage heart muscle, and the body repairs it with scar tissue. This scar tissue, unlike healthy muscle, can't pump blood effectively. This scar tissue is irreversible and deadly in humans. Unlike humans, zebrafish can amazingly remove this scar tissue and fully regrow a healthy heart. We recently discovered the key difference that makes scar tissue degradable! In mice, the scar tissue has "locked" connections, while zebrafish have "open" connections. This finding opens the door to designing therapies that "unlock" these connections and potentially heal human hearts after a heart attack

(Summary submitted by Eman Akam-Baxter, PhD, Cardiovascular Research Center, Department of Medicine)

The glutathione S-transferase Gstt1 drives survival and dissemination in metastases
Ferrer CM, Cho HM, Boon R, Bernasocchi T, Wong LP [et al.], Mostoslavsky R
Published in Nature Cell Biology on 6/11/2024 | Press Release

Pancreatic cancer is the second leading cause of cancer-related death, with less than 5% survival after 5 years; although patients succumb to metastases, there are no specific diagnostic markers or therapeutic strategies aimed at treating metastases. Using a combination of comparative transcriptomics and a novel functional screen, we identified a novel gene called Gstt1 as upregulated in metastatic lesions, which inhibition completely halted the growth of metastases without affecting the primary tumors; furthermore, this gene alters the matrix surrounding the metastatic cells, so they can grow in these foreign niches, indicating that these lesions evolve by acquiring non-genetic adaptations. Our results provides new avenues to change treatment for this devastating disease.

(Summary submitted by Raul Mostoslavsky, MD, PhD, Krantz Family Center for Cancer Research, Mass General Cancer Center)

Genetic drivers and cellular selection of female mosaic X chromosome loss
Liu A, Genovese G, Zhao Y, Pirinen M, Zekavat SM [et al.], Machiela MJ
Published in Nature on 6/12/2024

With age, women can lose one X chromosome (called mLOX) in their white blood cells. To understand its causes and consequences, we studied mLOX in 883,574 females from eight biobanks. We found that 12 percent of females exhibited mLOX in approximately 2 percent of cells, and identified 56 common mLOX-associated germline variants, implicating genes associated with chromosomal missegregation, cancer risk, and autoimmune diseases. Our findings show that germline variants increase mLOX risk in women, with the remaining X chromosome's allelic content possibly shaping how much a population of mLOX-positive cells expands.

(Summary submitted by Aoxing Liu, PhD, Analytic and Translational Genetics Unit, Department of Medicine)

Household material hardship and distress among parents of children with advanced cancer: A report from the PediQUEST Response trial
Eche-Ugwu IJ, Orellana L, Becker D, Bona K, Avery M [et al.], Wolfe J
Published in Cancer on 6/12/2024

Families of children with cancer often struggle to meet basic needs, causing distress for both parents and children. It is unclear if parents of children with advanced cancer face even greater challenges. To find out, we studied 150 parents of children with advanced cancer from multiple centers. We discovered that 40% of these parents could not meet their basic family needs, which was linked to high levels of stress. The threat of homelessness was the biggest issue contributing to this stress. Supporting families in meeting basic needs is an essential part of comprehensive cancer care.

(Summary submitted by Joanne Wolfe, MD MPH, Department of Pediatrics)

Clinical Decision Support as a Prevention Tool for Medication Errors in the Operating Room: A Retrospective Cross-Sectional Study
Amici LD, van Pelt M, Mylott L, Langlieb M, Nanji KC
Published in Anesthesia & Analgesia on 6/13/2024 | Press Release

Medication errors in the operating room have high potential for patient harm. Clinical decision support (CDS) involves comprehensive software algorithms that provide evidence-based information to clinicians at the point-of-care to enhance decision-making and prevent errors. While CDS improves both efficiency and quality of care in operating rooms, it is not yet widely used. In this study, two independent reviewers analyzed 80 intraoperative medication-related safety reports to determine whether the medication errors were preventable by GuidedOR, a CDS software platform that was developed at MGH. The reviewers found that 95% of the intraoperative medication errors were preventable by GuidedOR, representing an important opportunity to improve the safety of patients undergoing surgery and anesthesia.

(Summary submitted by Karen C. Nanji, MD, MPH, Department of Anesthesia, Critical Care, and Pain Medicine)

A blood-brain barrier-penetrant AAV gene therapy improves neurological function in symptomatic mucolipidosis IV mice
Sangster ML, Bishop MM, Yao Y, Feitor JF, Shahriar S [et al.], Grishchuk Y
Published in Molecular Therapy – Methods and Clinical Development on 6/13/2024 | Research Spotlight

Mucolipidosis IV (MLIV) is a rare neurologic disease of childhood with extremely high unmet need. Here, Grishchuk, Bei, and colleagues show that AAV-CPP16-mediated gene transfer of the MLIV causative MCOLN1 gene to symptomatic MLIV mice restores neurofunction, delays paralysis, and alleviates brain pathology, indicating a promising therapeutic approach for clinical development.

(Summary submitted by Yulia Grishchuk, PhD, Center for Genomic Medicine)

Exclusion of sulfide:quinone oxidoreductase from mitochondria causes Leigh-like disease in mice by impairing sulfide metabolism
Kanemaru E, Shimoda K, Marutani E, Morita M, Miranda M [et al.], Ichinose F
Published in Journal of Clinical Investigation on 6/13/2024

Our bodies and gut bacteria produce hydrogen sulfide, which is used by mitochondria (the cell’s energy producers). Some children have a defective enzyme that can't properly use hydrogen sulfide, leading to a serious brain condition called Leigh syndrome, which can be fatal. In our research, we discovered that mice lacking this enzyme build up hydrogen sulfide in their brains. This build-up stops energy production and leads to a Leigh-like brain disease in the mice. When we treated these mice with antibiotics to kill gut bacteria or gave them a special diet to reduce hydrogen sulfide, the hydrogen sulfide levels decreased, and the mice recovered. We hope that similar treatments could help children with Leigh syndrome.

(Summary submitted by Fumito Ichinose, MD, PhD, Department of Anesthesia, Critical Care and Pain Medicine)

Base editing strategies to convert CAG to CAA diminish the disease-causing mutation in Huntington's disease
Choi DE, Shin JW, Zeng S, Hong EP, Jang JH [et al.], Lee JM
Published in eLife on 6/13/2024

An expanded CAG repeat in the huntingtin gene (HTT) is responsible for Huntington's disease (HD). Given that the CAG length-dependent repeat expansion is a key driver of HD, strategies for base editing to convert CAG repeats to CAA are expected to delay disease onset by reducing the mutation responsible for the disease. Aiming at reducing the length of the uninterrupted HTT CAG repeat, Choi et al. have developed innovative base editing methods to convert CAG into CAA. These base editing strategies for HD successfully introduced CAA interruptions without significant off-target effects, leading to a decrease in somatic CAG repeat expansion in model systems. This proof-of-concept study may pave the way for new disease-modifying therapies.

(Summary submitted by Jong-Min Lee, PhD, Center for Genomic Medicine)

Induction of DEPP1 by HIF Mediates Multiple Hallmarks of Ischemic Cardiomyopathy
Wyant GA, Jiang Q, Singh M, Qayyum S, Levrero C, Maron BA, Kaelin WG Jr
Published in Circulation on 6/17/2024

Ischemic cardiomyopathy is the major cause of heart failure and a significant cause of morbidity and mortality. HIF (hypoxia inducible factor) regulates many aspects of cardiac function. It has been previously shown that chronic HIF activation in the heart in mouse models phenocopies multiple features of ischemic cardiomyopathy in humans, including autophagy, lipid accumulation, and systolic cardiac dysfunction. Here, we have discovered DEPP1 is a key component in the cardiac remodeling that occurs with chronic ischemia and DEPP1 loss decreases cardiac dysfunction during chronic HIF activation. These studies provide key insight into the molecular changes that occur during chronic ischemia.

(Summary submitted by Gregory A Wyant, PhD, Cardiovascular Research Center, Department of Medicine)

Near-Infrared II Photobiomodulation Preconditioning Ameliorates Stroke Injury via Phosphorylation of eNOS
Yokomizo S, Kopp T, Roessing M, Morita A [et al.], Kashiwagi S, Atochin DN
Published in Stroke on 6/18/2024 | Press Release

The current stroke treatment is effective only for a minor fraction of patients. Here, we tried to find a new and effective therapy. We have discovered that treating the head with low-power invisible laser light improves the function of blood vessels in the brain via stimulating the production of the well-known gas molecule “nitric oxide (NO),” which is critical for blood vessel function and decreases stroke injury. Since laser therapy is widely used in medicine already and has proven to be safe with few side effects, we expect that we could advance this technology to clinical trials soon.

(Summary submitted by Satoshi Kashiwagi, MD, PhD, Gordon Center for Medical Imaging, Department of Radiology)

Dysfunction of infiltrating cytotoxic CD8+ T cells within the graft promotes murine kidney allotransplant tolerance
Yokose T, Szuter ES, Rosales I, Guinn MT, Liss AS [et al.], Alessandrini A
Published in Journal of Clinical Investigation on 6/18/2024 | Press Release

The mechanisms that drive transplant tolerance, a state of long-term allograft survival without lifelong immunosuppressive drugs, are not fully understood. We have elucidated a new path towards tolerance that we have labeled defensive tolerance. The process involves the reprogramming of intragraft alloreactive immune cells initially set to reject the graft into innocuous cells that no longer present a threat. We show that IFN- plays a key role in defensive tolerance. A similar mechanism may explain how some tumors avoid being susceptible to an immune response. Understanding what drives defensive tolerance could provide us with new therapeutic targets to enhance allograft acceptance and eliminate malignancies.

(Summary submitted by Alessandro Alessandrini, PhD, Center for Transplantation Sciences, Department of Surgery )

3-Hydroxykynurenine targets kainate receptors to promote defense against infection
Parada-Kusz M, Clatworthy AE, Goering ER, Blackwood SM, Shigeta JY [et al.], Hung DT
Published in Nature Chemical Biology on 6/19/2024 | Press Release

Dysregulated host responses to infection (i.e., sepsis) have been estimated to cause 1 in every 5 deaths world-wide. We sought to identify host mechanisms that could be perturbed to promote survival during infection by chemically screening a whole organism vertebrate (zebrafish) infection model for antiinfectives. We found that the tryptophan metabolite, 3-hydroxykynurenine, rescues zebrafish from lethal bacterial challenge but does not act like a classical antibiotic. Rather, 3-HK targets kainate receptors (KARs), ligand-gated ion channels primarily expressed on neurons, to promote systemic control of infection, revealing a novel mechanism by which tryptophan metabolism and KARs intersect to promote host defense.

(Summary submitted by Anne Clatworthy, PhD, Department of Molecular Biology)

APOE3 Christchurch Heterozygosity and Autosomal Dominant Alzheimer's Disease
Quiroz YT, Aguillon D, Aguirre-Acevedo DC, Vasquez D, Zuluaga Y [et al.], Arboleda-Velasquez JF
Published in New England Journal of Medicine on 6/20/2024 | Press Release

An international team, including researchers from Mass General Brigham, has been searching for protective genetic variants in a family that includes more than 1,000 individuals who are genetically predisposed to develop early onset Alzheimer’s disease in their 40s. Previously, the researchers identified the “Christchurch variant” as potentially protective against Alzheimer’s based on one family member who had two copies of this variant and was expected to develop dementia in her 40s, but only developed cognitive impairment 30 years after the expected age. The new study finds that having just one copy of the APOE3 Christchurch variant is enough to confer a degree of protection, adding new evidence that the research could be pointing to a new therapeutic target.

(Summary submitted by Yakeel T Quiroz, PhD, Department of Psychiatry)

Brigatinib in NF2-Related Schwannomatosis with Progressive Tumors
Plotkin SR, Yohay KH, Nghiemphu PL, Dinh CT [et al.], Blakeley JO; INTUITT-NF2 Consortium
Published in New England Journal of Medicine on 6/21/2024 |Press Release

People with a condition called NF2-related schwannomatosis (NF2-SWN) have tumors that can grow along nerves. These tumors can cause a lot of problems, and there aren't any approved treatments for them yet. Scientists wanted to see if a drug called brigatinib could help. They gave brigatinib to 40 patients who had NF2-SWN and tumors that were getting worse. They checked the tumors to see if the drug was helping. They also looked at whether the patients had any side effects from the drug. They found that 10% of the main tumors and 23% of all the tumors got better with brigatinib. The tumors that improved the most were the ones in the brain and the ones that weren't on the hearing nerve. The growth of the tumors slowed down while the patients were taking the drug. Some patients also had better hearing, and some said they had less pain. Overall, brigatinib seemed to help with different types of tumors in people with NF2-SWN. This way of testing drugs in people with multiple different types of tumors allows scientists to quickly see if they can help with genetic conditions like NF2-SWN.

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Researchers have found promising evidence that brigatinib, a small molecule treatment approved for the treatment of lung cancer, helps to shrink the tumors of patients with NF2-related schwannomatosis. Using a highly innovative phase 2 platform-basket trial design, the multi-center team found that brigatinib shrunk 10% of growing tumors and 23% of all tumors. Some patients also experienced better hearing and said they had less pain.

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