Snapshot of Science for February 2023

Welcome to our Snapshot of Science for February 2023.

Here's a quick look at some recent publications, press releases and stories about the Mass General Research Institute community.

In this issue we highlight:

30 new studies published in high-impact journals, along with 28 summaries submitted by the research teams
7 new research-related press releases
16 posts from the Mass General Research Institute blog
5 research spotlights

Publications

The Function of Hepatocyte TfR1 in Liver Iron Level Homeostasis
Regulation of Iron Homeostasis by Hepatocyte TfR1 Requires HFE and Contributes to Hepcidin Suppression in β-thalassemia
Xiao X, Moschetta GA, Xu Y, Fisher AL, Alfaro-Magallanes VM [et al.], Babitt JL
Published in Blood on January 26, 2023

Novel Method to Isolate and Capture Mammalian Stomach Stem Cells
Dissection of Gastric Homeostasis in Vivo Facilitates Permanent Capture of Isthmus-like Stem Cells in Vitro
Huebner AJ, Gorelov RA, Deviatiiarov R, Demharter S, Kull T [et al.], Hochedlinger K
Published in Nature Cell Biology on January 30, 2023 | *Summary available

Blood Pressure Drug May Prevent Immunotherapy-Induced Brain Swelling in Patients with Glioblastoma
Losartan Controls Immune Checkpoint Blocker-induced Edema and Improves Survival in Glioblastoma Mouse Models
Datta M, Chatterjee S, Perez EM, Gritsch S, Roberge S [et al.], Jain RK
Published in PNAS on February 1, 2023 | *Summary available | Press Release

Hybrid Approach (CLAMP) to Identify Multiple DNA Targets in a Single Reaction Tube
CRISPR-Enhanced Hydrogel Microparticles for Multiplexed Detection of Nucleic Acids
Roh YH, Lee CY, Lee S, Kim H, Ly A [et al.], Lee H
Published in Advanced Science on February 1, 2023 | *Summary available

Protective DNA Variant Provides Substantially Lower Lifelong Exposure to LDL-C
Association of Rare Protein-Truncating DNA Variants in APOB or PCSK9 With Low-density Lipoprotein Cholesterol Level and Risk of Coronary Heart Disease
Dron JS, Patel AP, Zhang Y, Jurgens SJ, Maamari DJ [et al.], Khera AV
Published in JAMA Cardiology on February 1, 2023 | *Summary available

Breathing Polysulfides Prevents Mice from Experiencing Delayed Paraplegia after Temporary Blood Flow Restriction to the Spinal Cord
Intranasal Administration of Polysulfide Prevents Neurodegeneration in Spinal Cord and Rescues Mice from Delayed Paraplegia after Spinal Cord Ischemia
Kanemaru E, Miyazaki Y, Marutani E, Ezaka M, Goto S [et al.], Ichinose F
Published in Redox Biology on February 1, 2023 | *Summary available | Press Release

The Regulation of STING Trafficking and Examining the Mediated Responses
ESCRT-dependent STING Degradation Inhibits Steady-state and cGAMP-induced Signalling
Gentili M, Liu B, Papanastasiou M, Dele-Oni D, Schwartz MA [et al.], Hacohen N
Published in Nature Communications on February 4, 2023

Link Between Red Pigment and Parkinson’s in Both Periphery and the Brain
DOPA Pheomelanin is Increased in Nigral Neuromelanin of Parkinson's Disease
Cai W, Wakamatsu K, Zucca FA, Wang Q, Yang K [et al.], Chen X
Published in Progress in Neurobiology on February 4, 2023 | *Summary available

Super-sustainable Bioimaging Using Protein-sized Graphene Quantum Dots with Unprecedented Photostability
Planted Graphene Quantum Dots for Targeted, Enhanced Tumor Imaging and Long-term Visualization of Local Pharmacokinetics
Yan H, Wang Q, Wang J, Shang W, Xiong Z [et al.], Yun SH
Published in Advanced Materials on February 5, 2023 | *Summary available

New Sensing Technology That Can Detect Sepsis in an Hour
Dual-Enhanced Plasmonic Biosensing for Point-of-Care Sepsis Detection
Chin LK, Yang JY, Chousterman B, Jung S, Kim DG [et al.], Im H
Published in ACS Nano on February 6, 2023 | *Summary available

Protein That's Crucial to Tumor Cells' Metabolism and Immune Evasion Identified
Discovery of Targets for Immune-Metabolic Antitumor Drugs Identifies Estrogen-Related Receptor Alpha
Sahu A, Wang X, Munson P, Klomp JPG, Wang X [et al.], Flaherty KT
Published in Cancer Discovery on February 6, 2023 | *Summary available | Press Release

How Prostate Tumors Trick Immune Cells into Supporting Tumor Growth
Dissecting the Immune Suppressive Human Prostate Tumor Microenvironment via Integrated Single-cell and Spatial Transcriptomic Analyses
Hirz T, Mei S, Sarkar H, Kfoury Y, Wu S [et al.], Sykes DB
Published in Nature Communications on February 7, 2023 | *Summary available

New Insights into How Blood Pressure Drug May Benefit Patients with Locally Advanced Pancreatic Cancer
Addition of Losartan to FOLFIRINOX and cChemoradiation Reduces Immunosuppression-associated Genes, Tregs and FOXP3+ Cancer Cells in Locally Advanced Pancreatic Cancer
Boucher Y, Posada JM, Subudhi S, Kumar AS, Rosario SR [et al.], Jain RK
Published in Clinical Cancer Research on February 7, 2023 | *Summary available | Press Release

Certain Social Factors Can Predict Early Death in Older Adults
Social Frailty Index: Development and Validation of an Index of Social Attributes Predictive of Mortality in Older Adults
Shah SJ, Oreper S, Jeon SY, Boscardin WJ, Fang MC, Covinsky KE
Published in PNAS on February 14, 2023 | *Summary available | Press Release

Identifying New Druggable Gene Candidates for End-stage Heart Failure
Single-nucleus RNA Sequencing in Ischemic Cardiomyopathy Reveals Common Transcriptional Profile Underlying End-stage Heart Failure
Simonson B, Chaffin M, Hill MC, Atwa O, Guedira Y [et al.], Ellinor PT
Published in Cell Reports on February 14, 2023 | *Summary available

Favorable Area-level Socioeconomic Status Associated with Almost 50% Lower T2D Prevalence in Those with High Genetic Risk
Association and Interaction of Genetics and Area-Level Socioeconomic Factors on the Prevalence of Type 2 Diabetes and Obesity
Cromer SJ, Lakhani CM, Mercader JM, Majarian TD, Schroeder P [et al.], Udler MS
Published in Diabetes Care on February 14, 2023 | *Summary available

Possibility of Non-invasive Treatment for Hydrocephalus
The Choroid Plexus Links Innate Immunity to CSF Dysregulation in Hydrocephalus
Robert SM, Reeves BC, Kiziltug E, Duy PQ, Karimy JK [et al.], Kahle KT
Published in Cell on February 16, 2023 | *Summary available

New Potential Treatment for Squamous Cell Carcinoma
The ULK3 Kinase Is a Determinant of Keratinocyte Self-renewal and Tumorigenesis Targeting the Arginine Methylome
Goruppi S, Clocchiatti A, Bottoni G, Di Cicco E, Ma M [et al.], Paolo Dotto G
Published in Nature Communications on February 16, 2023 | *Summary available

Investigating PTH Deficiency and Genetic Modification of Serine and Its Impact on Patient Calcium Levels
Homozygous Ser-1 to Pro-1 Mutation in Parathyroid Hormone Identified in Hypocalcemic Patients Results in Secretion of a Biologically Inactive Pro-hormone
Hanna P, Khatri A, Choi S, Brabant S, Gild ML [et al.], Jüppner H
Published in PNAS on February 16, 2023 | *Summary available

New Oral Treatment for Familial Dysautonomia
Development of an Oral Treatment That Rescues Gait Ataxia and Retinal Degeneration in a Phenotypic Mouse Model of Familial Dysautonomia
Morini E, Chekuri A, Logan EM, Bolduc JM, Kirchner EG [et al.], Slaugenhaupt SA
Published in American Journal of Human Genetics on February 20, 2023 | *Summary available

Genomic Architecture of the Cerebral Cortex
Multivariate Genomic Architecture of Cortical Thickness and Surface Area at Multiple Levels of Analysis
Grotzinger AD, Mallard TT, Liu Z, Seidlitz J, Ge T, Smoller JW
Published in Nature Communications on February 20, 2023 | *Summary available

Risk Factors for Developing Pancreatic Cancer
Uncinate Duct Dilatation Predicts Additional Risk for High-Grade Dysplasia or Invasive Carcinoma Among Fukuoka-Positive Intraductal Papillary Mucinous Neoplasms
Yang AZ, Kongboonvijit S, Fernandez-Del Castillo CF, Fong ZV, Zelga PJ [et al.], Qadan M
Published in Annals of Surgery on February 20, 2023 | *Summary available

New Data Help to Explain Why Certain Subgroups of HIV Patients Have Worse COVID-19 Outcomes
Impact of Host Factors and COVID-19 Infection on the Humoral Immune Repertoire in Treated HIV
Schnittman SR, Jung W, Fitch KV, Zanni MV, McCallum S [et al.], Grinspoon SK
Published in JCI Insight on February 20, 2023 | *Summary available

New Computer Tool Developed to Analyze Heterogeneous Clinical Brain MRI Scans
Robust Machine Learning Segmentation for Large-scale Analysis of Heterogeneous Clinical Brain MRI Datasets
Billot B, Magdamo C, Cheng Y, Arnold SE, Das S, Iglesias JE
Published in PNAS on February 21, 2023 | *Summary available

Nerve–immune Cell Interactions in the Lungs Drive the Development of Allergic Asthma
Lung Dopaminergic Nerves Facilitate the Establishment of T Helper 2 Resident Memory Cells in Early Life
Wang W, Garcia C, Shao F, Cohen JA, Bai Y, Fine A, Ai X
Published in The Journal of Allergy and Clinical Immunology on February 23, 2023 | *Summary available | Press Release

New Data Address a Longstanding Challenge in IBD Management
Gut Microbial Metabolism of 5-ASA Diminishes Its Clinical Efficacy in Inflammatory Bowel Disease
Mehta RS, Mayers JR, Zhang Y, Bhosle A, Glasser NR [et al.], Huttenhower C
Published in Nature Medicine on February 23, 2023 | *Summary available

Potential New TGF-β Pathway to Treat Small Cell Lung Cancer
TGF-β in the Microenvironment Induces a Physiologically Occurring Immune-suppressive Senescent State
Matsuda S, Revandkar A, Dubash TD, Ravi A, Wittner BS [et al.], Maheswaran S
Published in Cell Reports on February 23, 2023 | *Summary available

Study Resolves Long Standing Mystery in How Phosphate Levels Are Detected and Controlled
Kidney Glycolysis Serves as a Mammalian Phosphate Sensor That Maintains Phosphate Homeostasis
Zhou W, Simic P, Zhou IY, Caravan P, Vela Parada X [et al.], Rhee EP
Published in Journal of Clinical Investigation on February 23, 2023 | *Summary available

Potential of Learning Analytics to Support Competency-based Medical Education
Using Learning Analytics in Clinical Competency Committees: Increasing the Impact of Competency-based Medical Education
Carney PA, Sebok-Syer SS, Pusic MV, Gillespie CC, Westervelt M, Goldhamer MEJ
Published in Medical Education Online on February 23, 2023 | *Summary available

New Insights into Lung Cancer Metabolic Dependency
NRF2 Activation Induces NADH-reductive Stress, Providing a Metabolic Vulnerability in Lung Cancer
Weiss-Sadan T, Ge M, Hayashi M, Gohar M, Yao CH [et al.], Bar-Peled L
Published in Cell Metabolism on February 24, 2023 | *Summary available

Publication Summaries

The mammalian stomach is composed of several different specialized epithelial cell types that are replenished by long-lived stem cells. Our lab developed a novel method to isolate and capture these stem cells from both humans and mice as well as indefinitely expand them in culture. These cells maintain the ability to differentiate into many of the cell types normally found in the stomach and will provide new insights into the mechanisms that direct normal differentiation and homeostasis as well as provide a tractable model of gastric cancer initiation and progression.

(Summary submitted by Aaron Huebner, PhD and Konrad Hochedlinger, PhD, Center for Regenerative Medicine)

We have found that patients with glioblastoma – the deadliest form of primary adult brain cancer – not only respond poorly to immunotherapy, but also suffer an increase in brain swelling (cerebral edema) from the treatment. Currently, this swelling is controlled with the use of potent steroids, but these drugs counteract the effectiveness of immunotherapy. In our studies, we have found that the blood pressure drug losartan prevents this brain swelling and also improves the overall effectiveness of immunotherapy, even eradicating some tumors in mouse models of glioblastoma. These results serve as a foundation for future clinical trials testing losartan with immunotherapy in glioblastoma patients.

(Summary submitted by Rakesh Jain, PhD, Department of Radiation Oncology)

Many factors can contribute to risk for obesity and type 2 diabetes, but it can be difficult to determine how these factors interact. We studied the interplay of genetic and neighborhood-level socioeconomic risk factors in large biobanks from the Mass General Brigham and the United Kingdom. Genetics and socioeconomic factors were both associated with higher disease rates on their own, and the combination of the two was even greater than the sum of its parts. People in the highest vs lowest quintiles of both genetic and socioeconomic risk had more than seven-fold increased rates of type 2 diabetes (22.2% vs. 3.1%) and more than three-fold higher rates of obesity (69.0% vs. 20.9%). We believe this research calls for a whole-person approach to obesity and diabetes prevention and suggests public health interventions may be most impactful if targeted to those who also have elevated genetic risk.

(Summary submitted by Sara J. Cromer, MD, Endocrine Division, Department of Medicine)

CRISPR/Cas has become a powerful tool to detect specific DNA sequences. However, it has been difficult to identify multiple DNA targets in a single reaction tube. To solve this problem, we designed a hybrid approach named CLAMP (Cas-Loaded Annotated Micro-Particles). This method uses tiny gel particles to carry out the CRISPR/Cas reaction. Each particle, imprinted with an ID code, becomes fluorescent when it comes into contact with the target DNA. By referencing this ID and measuring the fluorescent signal, we could resolve multiple DNA targets at once. We successfully applied CLAMP to detect human papillomavirus in Pap-smear samples.

(Summary submitted by Hakho Lee, PhD, Center for Systems Biology)

Low-density lipoprotein cholesterol (LDL-C) is a leading risk factor for coronary heart disease (CHD). While some individuals inherit high risk based on genetics, a small subset of the population inherits a protective DNA variant that inactivates either of two genes (APOB or PCSK9). In studies of 209,537 multiracial participants, such protective variants were identified in approximately one in 250 participants. These individuals had substantially lower lifelong exposure to LDL-C, translating into a 49% reduction in CHD risk. Those with protective variants had below-average risk, even when they had other risk factors such as diabetes or smoking. These findings highlight the potential for sustained LDL-C lowering to markedly lower risk of CHD.

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

Lower body paralysis is a devastating complication that can occur hours or days after surgery to repair the aorta, the largest artery in the body. Post-surgical paraplegia is caused by reduced blood flow to the spinal cord during surgery. Previously, we found that breathing hydrogen sulfide prevents mice from experiencing delayed paraplegia after temporary blood flow restriction to the spinal cord. Because inhaled hydrogen sulfide increases the levels of polysulfides, we tested effects of polysulfides in a mouse model of aortic surgery. Intranasal administration of natural or synthetic polysulfides after transient occlusion of the aorta preserved spinal cord neurons and prevented delayed paraplegia in mice. If these polysulfides are found safe in patients, it may be possible to prevent delayed paraplegia in patients undergoing thoracoabdominal aortic surgery or suffering spinal cord injury.

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

Two types of melanin – black/brown eumelanin and red/yellow pheomelanin – color our hair and skin. In the skin, pheomelanin, which is high in those with red hair may be “bad” as it can cause oxidative damage and is associated with melanoma. In the brain, a group of cells that produce dopamine are also pigmented, and these pigmented cells die in Parkinson’s disease, resulting depigmentation of the black region in the brain. A new study from our group, together with international groups in Japan and Italy, reported that while eumelanin is reduced, red pigment is increased in Parkinson’s brain. Together with our discovery six years ago that redhead mice tend to develop Parkinson’s-like changes, this new study identified for the first time a link between red pigment and Parkinson’s in both periphery and the brain. More studies will be needed to understand if the skin/hair pigmentation pathway and the brain pigmentation pathway are interconnected at all and what causes the increase in red pigment in Parkinson’s brain. Regardless, this study is believed to open a new avenue for future investigations.

(Summary submitted by Xiqun Chen, MD, PhD, Department of Neurology)

Reading and understanding many life phenomena and life activities often require sustainable bioimaging to study the long-term, fast dynamics of fine subcellular activities up to days. We developed a novel, super-highly photostable and bright fluorescent probe, named graphene quantum dots (GQDs), which can be used as an excellent tool for in vivo fluorescent super-sustainable and multimodality tumor bioimaging in various scenarios with several days’ photostability. In addition, the protein-sized GQDs are believed to have great potential in broad applications, such as embryo development, stem cell differentiation trajectories, and imaging-based spatiotemporal single-cell omics.

(Summary submitted by Hao Yan, PhD, Wellman Center for Photomedicine & Tsinghua University)

Sepsis is a life-threatening medical emergency caused by the body’s overactive reaction to infection. A rapid diagnostic test that allows early intervention with appropriate treatments can significantly improve mortality. Here, we developed a new sensing technology that can detect sepsis in an hour. The technology harnesses chemical and optical signal amplification to analyze multiple cytokine biomarkers from patients’ blood samples. For rapid testing at a care site, we also developed a portable readout system. In a pilot clinical study, the system showed 100% accuracy for sepsis detection. We envision that the technology could be employed for rapid and sensitive testing of blood biomarkers for myriad clinical conditions.

(Summary submitted by Hyungsoon Im, PhD, Center for Systems Biology)

Researchers have used artificial intelligence (AI) and computational methods to identify 38 key molecules that play a crucial role in cancer metabolism and immune response. They found that targeting one of these molecules, ESRRA, can activate two mechanisms that suppress tumor growth and promote the body's natural immune response against cancer cells. Moreover, the study showed that combining the activity of these molecules can predict patient response to immunotherapy, which is a type of cancer treatment that harnesses the body's immune system to fight cancer. This research highlights the potential of AI to revolutionize cancer treatment and personalized medicine.

(Summary submitted by Avinash Sahu, PhD, Dana-Farber Cancer Institute)

Prostate cancer is common, so common in fact, that despite excellent therapies it remains one of the leading causes of cancer death. Our research set out to understand how prostate tumors avoid the immune system and to identify features that might predict a curable cancer as compared to a high-risk and potentially incurable cancer. We leveraged a coordinated team of Mass General surgeons, pathologists, oncologists, biologists and bioinformaticians to collect fresh patient samples straight from the operating room. Our paper highlights how prostate tumors trick immune cells – including T‑cells and macrophages – into supporting tumor growth. We hope that this paves the way for new therapies that might restore the ability of the immune system to target and to eradicate prostate tumors.

(Summary submitted by David Sykes, MD, PhD, Center for Regenerative Medicine)

For patients with pancreatic cancer, the only available curative treatment is complete surgical resection, which is feasible in a minority of cases. We previously showed that adding the anti-hypertensive agent losartan to cytotoxic treatment can convert many locally advanced pancreatic cancers to resectable diseases. Analysis of the resected specimens revealed that adding losartan to cytotoxics reduced the expression of genes involved in immunosuppression and invasion, which associated with improved patient survival. In responding lesions, we found less immunosuppressive cells while the number of effector lymphocytes was increased. These results indicate that losartan may overcome resistance to cytotoxic regimens and promote anti-tumor immunity in pancreatic cancer.

(Summary submitted by Rakesh Jain, PhD, Department of Radiation Oncology)

Although the impact of social factors is well-known, most prediction models only draw on medical comorbidities. In this study, we developed a Social Frailty Index, which includes age, gender, and 8 social attributes, such as isolation, everyday discrimination, and financial control, to predict longevity in older adults. The index was created using a comprehensive inventory of 183 social characteristics in 8,250 older adults. The index predicts longevity and improves traditional models. The tool aims to identify at-risk individuals to improve their access to high-quality care. You can see the index here.

(Summary submitted by Sachin Shah, MD, MPH, Department of Medicine)

Ischemic cardiomyopathy (ICM) is a leading cause of heart failure with an unclear molecular signature. To understand how cellular composition and gene expression change in the hearts of ICM patients, we performed single-nucleus RNA sequencing of over 99,000 nuclei from seven ICM patients and eight healthy controls. In ICM, we observed a reduction in the muscle cells of the heart, cardiomyocytes, and an increase in certain sub-types of endothelial cells (ECs) including lymphatic, angiogenic, and arterial ECs. By comparing gene expression in ICM to other cardiomyopathies, we define a shared transcriptional signature and identify druggable gene candidates for end-stage heart failure.

(Summary submitted by Mark Chaffin, MS, Broad Institute)

Hydrocephalus is a swelling of the brain’s ventricles, which are brain cavities that are filled with cerebrospinal fluid (CSF) produced by the choroid plexus. In the new study, we studied rat models of hydrocephalus using multi-omic approaches and measurements of CSF flow to understand how brain infections and brain bleeds cause hydrocephalus. We found that bacterial or blood products cause the choroid plexus to be inflamed, leading to increased fluid secretion. Blocking inflammation using an anti-inflammatory drug prevented the development of hydrocephalus, suggesting the possibility of treating hydrocephalus non-invasively with a drug rather than brain surgery.

(Summary submitted by Duy Phan, PhD, Yale School of Medicine)

Squamous cell carcinoma (SCCs) is among the most frequent types of cancer. Identifying druggable mechanisms controlling squamous cell proliferation has direct therapeutic implications. We show that ULK3 is a nuclear kinase highly expressed in SCCs, and in pre-cancerous skin SCCs lesions (actinic keratosis). ULK3 loss reduces the growth of keratinocytes and SCC-derived cells, affecting the transcription of stem-cell and metabolic programs. Mechanistically, ULK3 recruits to specific promoters the activity of PRMT1 and 5, two enzymes that methylate arginines on histones. In vivo, decreasing ULK3 levels blunts the growth of SCC cells, and can represent a strategy for skin cancer treatment.

(Summary submitted by Sandro Goruppi, PhD, Department of Dermatology)

Distinguishing parathyroid hormone (PTH) deficiency from PTH-resistance requires measuring circulating parathyroid hormone (PTH) levels. Three patients who had symptomatic hypocalcemia with elevated or low/undetectable PTH levels, depending on the clinical assay, were shown to have a homozygous mutation replacing serine at position 1 (S1) of mature PTH with proline (P1). Surprisingly, synthetic PTH(1-34) analogs with either S1 or P1 were equally active in vitro. However, cells transfected with plasmids encoding the PTH precursor showed that the P1 mutation leads to secretion of biologically inactive pro[P1]PTH. Similar mutations in other hormone precursors may allow secretion of inactive peptides that are nonetheless detected by diagnostic assays.

(Summary submitted by Harald Jueppner, MD, Division of Pediatric Nephrology, Mass General Hospital for Children)

Familial dysautonomia (FD) is a rare neurodegenerative disease caused by a mutation in the gene encoding for the Elongator complex protein 1 (ELP1). This mutation leads to a reduction of ELP1 protein, mainly in the nervous system. Due to the crucial function of ELP1 in neuronal development and survival, FD patients exhibit many neurological symptoms, including retinal degeneration and inability to coordinate movements. In our recently published study, we describe the optimization of an oral treatment for FD that restores the expression of functional ELP1 protein in every tissue, including brain, and rescues retinal degeneration and motor coordination in a mouse model of FD.

(Summary submitted by Elisabetta Morini, PhD, Center for Genomic Medicine)

The Genomic Architecture of the Cerebral Cortex
Multivariate Genomic Architecture of Cortical Thickness and Surface Area at Multiple Levels of Analysis
Grotzinger AD, Mallard TT, Liu Z, Seidlitz J, Ge T, Smoller JW
Published in Nature Communications on February 20, 2023

We used large-scale neuroimaging and genetic datasets to understand the organization of the brain, characterizing how genetic factors shape the thickness and surface area of the cortex. We found that genetic factors play a significant role in shaping brain structure, where physically proximal regions are often influenced by the same genes. Moreover, our results suggest that certain categories of genes, such as those related to specific types of brain cells, play a disproportionately large role in shaping different parts of the brain. The team also found that the genetic bases of brain structure were broadly associated with cognitive function, but not necessarily with psychiatric disorders. These findings help advance knowledge of brain structure and function, neurodevelopment, and related processes in health and disease.

(Summary submitted by Travis Mallard, PhD, Center for Genomic Medicine)

Intraductal papillary mucinous neoplasms (IPMNs) are premalignant cystic lesions that broadly include higher-risk main duct lesions and lower-risk branch-duct lesions. Though classified as a branch duct, the uncinate duct is the primary duct of the pancreatic ventral anlage. Understanding which IPMNs are at highest risk for progression to cancer can aid in surgical decision-making. Uncinate ductal dilatation is a radiographic feature that has not been rigorously evaluated as a risk factor. In a study of 467 patients with resected IPMNs, this large study demonstrated that uncinate duct dilatation was independently associated with a nearly three-fold increased risk of malignancy and performed similarly to high-risk IPMN stigmata and main-duct disease.

(Summary submitted by Motaz Qadan, MD, PhD)

People with HIV (PWH) appear at higher risk for worse responses to COVID-19, but the underlying mechanisms remain unclear. The Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE), a global cardiovascular primary prevention trial, provided a comprehensive assessment of antibody responses to numerous pathogens using a specialized Luminex platform. Among those with COVID-19, 1) higher BMI was associated with exaggerated antibody responses, suggesting a potentially damaging inflammatory response, and 2) lower nadir CD4+ T-cell counts (a surrogate for persistent immune dysfunction) was associated with poor functional responses. These new data help to explain why certain subgroups of PWH have worse outcomes to COVID-19.

(Summary submitted by Steven K. Grinspoon, MD, Metabolism Unit, Department of Medicine)

Over the last two to threedecades, plenty of computer software tools have been developed to study the human brain from magnetic resonance imaging (MRI) scans of living people. These are designed for high-resolution scans like the ones acquired in research studies but are incompatible with the types of scans used in clinical practice. This article presents a computer tool that can, for the first time, analyze heterogeneous brain MRI scans acquired with different machines and protocols, and study the human brain with millions and millions of scans that already exist at hospitals worldwide – compared with typical research studies relying on a few hundred volunteers.

(Summary submitted by Juan Eugenio Iglesias, PhD, Martinos Center for Biomedical Imaging)

Congenital Diaphragmatic Hernia (CDH) is a common birth defect that accounts for 1-2% of total infant deaths. CDH is characterized by a hole in the diaphragm and a smaller lung. Historically, CDH research has been limited by a lack of access to the infant lung. Thus, we have developed an innovative patient-derived airway epithelial stem cell model to study lung phenotypes in human CDH for the first time. We discovered that CDH airway stem cells display defective differentiation and a proinflammatory signature. This model leads to the application of anti-inflammatory drugs, such as steroids, to alleviate lung defects in CDH.

(Summary submitted by Gaurang Amonkar, Mass General Hospital for Children)

Treatment failure in inflammatory bowel disease (IBD) is common, especially for 5-ASA, one most common IBD medicines. Prior to our work, we knew that when 5-ASA is added to stool, it gets turned into a compound that has no anti-inflammatory effect. We didn't know which gut bacterial enzymes were responsible for this, though. We used a novel computational workflow leveraging metatranscriptomics, metagenomics, and metabolomics from the Human Microbiome Project 2 to identify 12 candidate enzymes from two protein families that could perform this conversion. Neither had previously been implicated in drug metabolism. In vitro, we confirmed 5-ASA inactivation using purified proteins from each family. To understand how these bacterial enzymes inactivate 5-ASA, we crystallized one of the proteins, showing that its active site could promiscuously donate an acetyl group to 5-ASA. Excitingly, we then found that metagenomic carriage of a subset of these acetyltransferases could predict treatment failure in the discovery cohort, as well as a prospective validation cohort. We hope these data help our patients with IBD, through precision medicine approaches or even inhibitors to boost 5-ASA efficacy.

(Summary submitted by Raaj S. Mehta, MD, Division of Gastroenterology, Department of Medicine)

TGFß in the hypoxic cancer microenvironment induces a senescent state which leads to the production of 14 specific bioactive molecules that influence the immune cell infiltration into cancers. This immune infiltrate is biased towards immune suppression. Consistent with these findings, non-small cell lung cancers expressing higher 14-gene gene signatures exhibit adverse clinical outcomes upon receiving immune checkpoint therapy. Therefore, microenvironmental hypoxia-TGFß-induced senescence may represent a naturally occurring cell state in cancers whose secretory activity is exploited to remodel the immune microenvironment to mount innate resistance to immune checkpoint inhibitors.

(Summary submitted by Shyamala Maheswaran, PhD, Center for Cancer Research, Department of Surgery)

Phosphate is an essential electrolyte that is required to make many molecules such as DNA, make energy, and form bones and teeth. How our body detects circulating phosphate levels was previously not understood. The current study finds that phosphate is detected by the kidney, where it activates an energetic pathway called glycolysis. Activation of this pathway in the kidney then controls a hormone that causes the body to excrete more phosphate in urine. These findings resolve a long-standing mystery in how phosphate levels are detected and controlled, and open new opportunities to treat disorders of the kidneys and bones.

(Summary submitted by Eugene P. Rhee, MD, Nephrology Division, Department of Medicine)

The Clinical Competency Committee (CCC) is a key mechanism for ensuring that residency programs meet or exceed competency standards for each resident. In our paper, we highlight the current learning analytics landscape and key data integration failures across existing residency education systems. Improved integration of clinical data from electronic health records, residency management systems, and clinical education data including resident work-place based assessments, evaluations, and Accreditation Council for Graduate Medical Education (ACGME) Milestones could begin to realize the potential of learning analytics to support competency-based medical education. We make recommendations to enhance data quality, decision making and faculty development. Co-authors on this paper represent the American Medical Association (AMA) Re-imagining Residency Initiative Working Group on Learning Analytics and CCCs.

(Summary submitted by Mary Ellen J. Goldhamer, MD MPH, Division of General Internal Medicine Research, Department of Medicine)

Scientists have been studying the effect of redox balance on cancer cells for several decades. One major focus is the role of the antioxidant regulator NRF2 in cancer growth. While NRF2 is activated in about 30% of non-small cell lung cancer (NSCLC), its role in other subtypes remains unclear. Our study revealed that >13% of NSCLC cell lines are dependent on KEAP1, the negative regulator of NRF2. Activation of NRF2 can cause reductive stress by upregulating a detoxification enzyme, leading to mitochondrial dysfunction. Leveraging these findings, we discovered a way to target NRF2 activated lung cancers using clinical grade mitochondrial inhibitors. This study highlights the importance of looking at the metabolic states of cancer from multiple angles to uncover new dependencies and potential therapies.

(Summary submitted by Maolin Ge, PhD, Center for Cancer Research, Department of Medicine)

Press Releases

Blood Pressure Drug May Prevent Immunotherapy-Induced Brain Swelling in Patients with Glioblastoma
Featuring Rakesh K. Jain, PhD

Immune checkpoint inhibitors that have revolutionized the treatment of multiple cancers, have failed in all randomized clinical trials in glioblastoma patients. One reason for this failure is that these inhibitors increase brain swelling, or edema. The widely prescribed, safe, and inexpensive blood pressure drug losartan can prevent immunotherapy-related edema by reducing the expression of certain enzymes in cells that line tumor-associated blood vessels and induce blood vessel leakage to cause edema.

Nasal Drops of Polysulfides May Prevent a Serious Side Effect—Paralysis of the Lower Body—After Surgery to Repair the Aorta
Featuring Fumito Ichinose, MD, PhD

Paraplegia represents a potential delayed complication after aortic surgery. In a mouse model of paraplegia after aortic surgery, intra-nasal administration of chemical compounds known as polysulfides inhibited damage to spinal cord motor neurons and prevented paraplegia.

Researchers Find that Certain Social Factors Can Predict Early Death in Older Adults
Featuring Sachin J. Shah, MD, MPH

Researchers have identified eight social characteristics that can help to predict an older adult’s risk of premature death. A brief survey assessing these social factors may identify at-risk individuals who could benefit from measures that address the social issues affecting their health.

New Insights into How Blood Pressure Drug May Benefit Patients with Locally Advanced Pancreatic Cancer
Featuring Rakesh K. Jain, PhD

In patients with locally advanced pancreatic cancer, treatment with a combination therapy including the blood pressure drug losartan inhibited immunosuppression andreduced the expression of genes that promote the invasion of tumor cells into normal tissue. Losartan also induced changes in the blood levels of various molecules involved in blood vessel health and the immune response.

Scientists Identify Protein That's Crucial to Tumor Cells' Metabolism and Immune Evasion
Featuring Keith Flaherty, MD

By developing a new computational tool, researchers have identified a potential target for anti-cancer therapies that could simultaneously deplete tumors of energy and boost the body’s immune response against them. The target, called Estrogen Related Receptor Alpha, may also represent a marker to predict which patient will benefit from immunotherapy.

Nerve–immune cell interactions in the lungs drive the development of allergic asthma
Featuring Xingbin Ai, PhD

New research in mice indicates that interactions between the lungs’ nerves and immune cells contribute to the development of allergic asthma early in life. Targeting these interactions may help prevent allergic asthma in childhood or block its progression into adulthood.

A Mass General Team is the First to Trace a Rare Smooth Muscle Disorder to a Single Mutation in a Non-Coding Gene
Featuring Mark Lindsay, MD, PhD, Patricia Musolino, MD, PhD, and David Sweetser, MD, PhD

Using whole genome sequencing, researchers identified a single variant in a microRNA gene, MIR145-5p, as the source of multisystemic smooth muscle dysfunction syndrome, which had gone undiagnosed in a child for years. The discovery originated from the Undiagnosed Diseases Network study at Mass General, part of an NIH-funded research program to focus the nation’s leading scientific talent and technologies on solving the most challenging medical mysteries. The findings will enable pediatricians to offer treatment to the patient for the first time.

Blog Posts

Meet Our Newest MGRI Intern, Siddharth!
Featuring Siddharth Valecha

My primary responsibilities will be taking complex research and presenting it in the most understandable way.

Humans of MGRI: Arvina Grahl, PhD
Featuring Arvina Grahl, PhD

Arvina Grahl, PhD is studying the brain mechanisms of the patient-clinician relationship using simultaneous synchronized fMRI.

Benchmarks for February 3, 2023

Mindfulness vs. medication as a treatment for anxiety, what "goblin mode" means from a psychiatric perspective, the tweets of the week & more.

Heart Health Month: How Cardiovascular Exercise Can Improve Your Overall Health More Than You Think
Featuring Christiane Wrann, PhD, DVM

For our first heart health month blog, Christiane Wrann, PhD, DVM, from the Wrann Lab investigates how aerobic exercise and heart health contribute to our cognition.

Ciencia En Tu Idioma [Science in Your Language]
Featuring Efren Flores, MD

"Ciencia en tu idioma" is a new podcast by the Mass General Research Institute for conversations about science and medicine in Spanish!

Benchmarks for February 10, 2023

Learning more about sensory issues in individuals with autism, identifying disparities in cancer care, the tweets of the week and more.

Footnotes in Science: Q&A with Jarone Lee, MD, MPH and Shuhan He, MD
Featuring Jarone Lee, MD, MPH and Shuhan He, MD

Footnotes in Science is a space where investigators bring you the behind-the-scenes details of their recently published work.

How You Can Mend a Broken Heart: Emerging Imaging Technologies Advance Cardiovascular Care
Featuring Gary Boas

Mass General radiology researchers are developing innovative techniques to reduce the incidence of a broken heart (A.K.A keep a healthy heart).

Heart Health Month: Learn about the Life of a Cardiac Surgeon
Featuring Asishana Osho, MD, MPH

Asishana Osho, MD, MPH, and the team at the Mass General Heart Center work year-round to treat cardiac patients in all sorts of conditions with their needs, adding to the high number of annual cardiac procedures performed in the United States.

APPRAISE Study Team Seeks Feedback on New Clinical Trial for Trauma Patients
Featuring Andrew Reisner, MD

The APPRAISE software system was developed to make it easier for the trauma team to track the current state of the patient and appropriate clinical interventions.

Benchmarks for February 17, 2023

The science behind "butterflies" in your stomach, studying baby teeth for signs of childhood adversity, the tweets of the week and more.

The Vast Majority: The Journey Towards the Neuron
Featuring Manuel Rico Fernández

A guest blog post by Manuel Rico Fernández San Silvestre, a summer intern in the Sahay Lab at Massachusetts General Research Institute.

La Amplia Mayoría: El Viaje Hacia La Neurona
Featuring Manuel Rico Fernández

A guest blog post by Manuel Rico Fernández San Silvestre, a summer intern in the Sahay Lab at Massachusetts General Research Institute (Spanish version)

Heart Health Month: How Your Mental Health Impacts Your Heart Health
Featuring Christopher Celano, MD

For our third heart health month blog, Christopher Celano, MD, from the Cardiac Psychiatry Research Program (CPRP) talks about the connection between heart health and mental health.

Footnotes in Science: Q&A with Anne Thorndike, MD, MPH

Anne Thorndike, MD, MPH, discusses her recently published article on how to help food pantries improve healthy food choices.

These MGH Investigators Are at the Forefront of Rare Disease Research

At Massachusetts General Hospital, investigators are at the forefront of rare disease research. Here is what some of them said regarding their research, what motivates them and hope for a treatment or cure.

Research Spotlights

Research Opportunities in the Treatment of Mitral Valve Prolapse
Featuring Robert Levine, MD

Robert Levine, MD, a physician-investigator in the Cardiovascular Research Center at Mass General Hospital, is the senior author of an article in the Journal of the American College of Cardiology, “Research Opportunities in the Treatment of Mitral Valve Prolapse.”

Potential for AI-assisted Medical Education Using Large Language Models
Featuring Tiffany Kung, MD

Tiffany Kung, MD, a resident in the Department of Anesthesia, Critical Care and Pain Medicine at Mass General Hospital, is the lead author of a new research article in PLOS Digital Health, "Performance of ChatGPT on USMLE: Potential for AI-assisted Medical Education Using Large Language Models".

Trends in Oncological Imaging During the COVID-19 Pandemic Through the Vaccination Era
Featuring Marc Succi, MD

Marc Succi, MD, a physician-investigator in the Department of Radiology and Director of the MESH Incubator at Massachusetts General Hospital, is the senior author of an article in the journal Cancer Medicine, “Trends in oncological imaging during the COVID-19 pandemic through the vaccination era.”

Nicotine E-cigarettes as a Tool for Smoking Cessation
Featuring Nancy Rigotti, MD

Nancy Rigotti, MD, associate chief of the Division of General Internal Medicine and director of the Tobacco Research and Treatment Center at Mass General, is the co-author of a new commentary in Nature Medicine, Nicotine E-Cigarettes as a Tool for Smoking Cessation.

Health Status and Health Care Access among Lesbian, Gay, and Bisexual Adults in the US, 2013 to 2018
Featuring Alex Keuroghlian, MD, MPH

Alex Keuroghlian, MD, MPH, an Associate Chief of Public and Community Psychiatry at Massachusetts General Hospital and Associate Professor of Psychiatry at Harvard Medical School, is the senior author of an article in the journal JAMA Internal Medicine, "Health Status and Health Care Access among Lesbian, Gay, and Bisexual Adults in the US, 2013 to 2018" along with Harvard Medical School students Michael Liu and Sahil Sandhu.

The Mass General Difference

Conditions & Treatments

Patients & Visitors

Research & Innovation

Mass General
Research Institute

Snapshot of Science for February 2023