Snapshot of Science for December 2022

Welcome to our Snapshot of Science for December 2022.

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:

22 new studies published in high-impact journals, along with 15 summaries submitted by the research teams
3 new research-related press releases
8 posts from the Mass General Research Institute blog

Publications

Spousal Fillings of Patient Opioid Prescriptions
Inappropriate Prescribing of Opioids for Patients Undergoing Surgery
Varady NH, Worsham CM, Chen AF, Smith EL, Woo J, Jena AB
Published in PNAS on November 28, 2022 | *Summary available

Organ Donation Opportunities Increase During Motorcycle Rallies
Organ Donation and Transplants During Major US Motorcycle Rallies
Cron DC, Worsham CM, Adler JT, Bray CF, Jena AB
Published in JAMA Internal Medicine on November 28, 2022 | *Summary available

New Interventions Needed to Support Patients Undergoing CAR-T Therapy
Perception of Prognosis, Quality of Life, and Distress in Patients Receiving Chimeric Antigen Receptor T-cell Therapy
Dhawale TM, Johnson PC, Gaballa MR, Nelson AM, Lavoie MW [et al.], El-Jawahri A
Published in Cancer on December 1, 2022 | *Summary available

The Impact of Selective Reduction on Down Syndrome Birth Rate and Population
Estimation of the Number of People with Down Syndrome in Australia and New Zealand
de Graaf G, Skladzien E, Buckley F, Skotko BG
Published in Genetics in Medicine on December 1, 2022 | Press Release

Human Antibodies that Bind DPRs with High Affinity and Specificity
Comprehensive Evaluation of Human-derived Anti-poly-ga Antibodies in Cellular and Animal Models of C9orf72 Disease
Jambeau M, Meyer KD, Hruska-Plochan M, Tabet R, Lee CZ [et al.], Lagier-Tourenne C
Published in PNAS on December 6, 2022 | *Summary available

Insights into the Actions of ARIP-4 in C. Elegans
The Caenorhabditis elegans ARIP-4 DNA Helicase Couples Mitochondrial Surveillance to Immune, Detoxification, and Antiviral Pathways
Mao K, Breen P, Ruvkun G
Published in PNAS on December 6, 2022 | *Summary available

250+ Risk Loci for Coronary Artery Disease
Discovery and Systematic Characterization of Risk Variants and Genes for Coronary Artery Disease in over a Million Participants
Aragam KG, Jiang T, Goel A, Kanoni S, Wolford BN [et al.], Butterworth AS; CARDIoGRAMplusC4D Consortium
Published in Nature Genetics on December 6, 2022

Changes in Insulin Receptor Clusters Contribute to Insulin Resistance
The Dynamic Clustering of Insulin Receptor Underlies Its Signaling and Is Disrupted in Insulin Resistance
Dall'Agnese A, Platt JM, Zheng MM, Friesen M, Dall'Agnese G [et al.], Young RA
Published in Nature Communications on December 6, 2022 | *Summary available

A Potential New Treatment for Osteoporosis
Structure-based Design of Selective, Orally Available Salt-inducible Kinase Inhibitors That Stimulate Bone Formation in Mice
Sato T, Andrade CDC, Yoon SH, Zhao Y, Greenlee WJ [et al.], Wein MN
Published in PNAS on December 6, 2022 | *Summary available | Press Release

AI System Predicts Oxygen Needs in COVID Patients Using Chest X-Rays
Prediction of Oxygen Requirement in Patients with COVID-19 Using a Pre-trained Chest Radiograph xAI Model: Efficient Development of Auditable Risk Prediction Models via a Fine-tuning Approach
Chung J, Kim D, Choi J, Yune S, Song K [et al], Do S
Published in Scientific Reports on December 7, 2022 | *Summary available

Metformin Might Reduce Risk of Dementia in Diabetes Patients
Causal Inference in Medical Records and Complementary Systems Pharmacology for Metformin Drug Repurposing Towards Dementia
Charpignon ML, Vakulenko-Lagun B, Zheng B, Magdamo C, Su B [et al.], Albers MW
Published in Nature Communications on December 10, 2022

Hippocampal Sparing Both Feasible and Safe in Pediatric Medulloblastoma Patients
Patterns of Failure in Pediatric Medulloblastoma and Implications for Hippocampal Sparing
Baliga S, Adams JA, Bajaj BVM, Van Benthuysen L, Daartz J [et al.], Yock TI
Published in Cancer on December 11, 2022 | *Summary available

Monoclonal Antibodies Demonstrate Antiviral Control in a Mouse Model of RSV
Antibody Effector Functions Are Associated with Protection from Respiratory Syncytial Virus
Bartsch YC, Cizmeci D, Kang J, Zohar T, Periasamy S [et al.], Alter G
Published in Cell on December 12, 2022

New Method to Identify Strength of New SARS-CoV-2 Variants
Inferring Selection Effects in SARS-CoV-2 with Bayesian Viral Allele Selection
Jankowiak M, Obermeyer FH, Lemieux JE
Published in PLoS Genetics on December 12, 2022

Genetic Variants Can Modify Gene Editing Outcomes
Human Genetic Diversity Alters Off-target Outcomes of Therapeutic Gene Editing
Cancellieri S, Zeng J, Lin LY, Tognon M, Nguyen MA [et al.], Pinello L
Published in Nature Genetics on December 15, 2022 | *Summary available

Children and Young Adults with NAFLD Have Increased Cardiovascular Risk
Cardiovascular Disease Risk in Paediatric and Young Adult Non-alcoholic Fatty Liver Disease
Simon TG, Roelstraete B, Alkhouri N, Hagström H, Sundström J, Ludvigsson JF
Published in Gut on December 15, 2022

AI Model Could Improve Early Detection of Collapsed Lungs
Evaluation of an Artificial Intelligence Model for Detection of Pneumothorax and Tension Pneumothorax in Chest Radiographs
Hillis JM, Bizzo BC, Mercaldo S, Chin JK, Newbury-Chaet I [et al.], Dreyer KJ
Published in JAMA Network Open on December 15, 2022

Opioid Antagonism a Potential Treatment for Radiation-Induced Fatigue
β-Endorphin Mediates Radiation Therapy Fatigue
Hermann AL, Fell GL, Kemény LV, Fung CY, Held KD [et al.], Fisher DE
Published in ScienceAdvances on December 16, 2022 | *Summary available | Press Release

An Unexpected Vascular-Regulated Mechanism of Neuroplasticity
Endothelial Cells Regulate Astrocyte to Neural Progenitor Cell Trans-differentiation in a Mouse Model of Stroke
Li W, Mandeville ET, Durán-Laforet V, Fukuda N, Yu Z [et al.], Lo EH
Published in Nature Communications on December 19, 2022 | *Summary available

Adagrasib as a Treatment for Colorectal Cancer
Adagrasib With or Without Cetuximab in Colorectal Cancer with Mutated KRAS G12C
Yaeger R, Weiss J, Pelster MS, Spira AI, Barve M [et al.], Klempner SJ
Published in New England Journal of Medicine on December 21, 2022 | *Summary available

Study Supports Use of Liso-Cel in Large B- Cell Lymphoma
Lisocabtagene Maraleucel as Second-line Therapy for Large B-cell Lymphoma: Primary Analysis of Phase 3 TRANSFORM Study
Abramson JS, Solomon SR, Arnason JE, Johnston PB, Glass B [et al.], Kamdar M
Published in Blood on December 21, 2022 | *Summary available

New Insights into the Development of the Maternal and Infant Microbiome and Metabolome
Mobile Genetic Elements from the Maternal Microbiome Shape Infant Gut Microbial Assembly and Metabolism
Vatanen T, Jabbar KS, Ruohtula T, Honkanen J, Avila-Pacheco J [et al.], Xavier RJ
Published in Cell on December 22, 2022 | *Summary available

Publication Summaries

In a study of about 450,000 married couples of which one underwent surgery, we found when the surgical patient didn’t fill a prescription themselves, their spouse was significantly more likely (5.5 times as likely compared to a normal day) to fill a prescription in their name on the same day; meanwhile, if the surgical patient filled an opioid prescription themself, spouses were not more likely to fill a prescription. This was highly suggestive that some surgeons are occasionally prescribing opioid pain medications to the spouse of the patient for whom it is intended—estimated to occur for thousands of patients each year. These inappropriate prescriptions bypass the safeguards of opioid monitoring programs and may represent barriers for patients with post-operative pain, highlighting the need for policies and regulations that allow surgeons to be confident their patients will receive necessary medications and be appropriately monitored.

(Summary submitted by Christopher Worsham, MD, MPH, Pulmonary & Critical Care Unit, Department of Medicine)

Organ Donation Opportunities Increase During Motorcycle Rallies
Organ Donation and Transplants During Major U.S. Motorcycle Rallies
Cron DC, Worsham CM, Adler JT, Bray CF, Jena AB
Published in JAMA Internal Medicine on November 28, 2022

Motor vehicle crash-related injuries and fatalities increase during the number of large-scale motorcycle rallies that occur annually in the United States. In the regions containing these motorcycle rallies, there was a 21% increase in organ donation and a 26% increase in transplant recipients during rally weeks compared to the four weeks before or after the rallies. This amounted to about one additional organ donor or three additional transplant recipients per event. These findings emphasize a need to improve the safety of these events. Second, local transplant teams can prepare for these events to maximize the ability to identify organ donors and to be able to turn these unfortunate tragedies into a gift of life. Additionally, there may be opportunities to improve education and outreach around these events to enhance public awareness and perception of organ donation.

(Summary submitted by David Cron, MD, MS, Department of Surgery)

In our study, we showed that patients undergoing chimeric antigen receptor (CAR) T-cell therapy for hematologic malignancies experience high psychological distress and are overly optimistic about their prognosis. Most importantly, we found that high emotional coping with prognosis and adaptive response (i.e., the capacity to use one’s understanding of prognosis to inform life decisions) were associated with better quality of life and less psychological distress in these patients.

(Summary submitted by Tejaswini M. Dhawale, MD, Division of Hematology, Department of Medicine)

Human Antibodies That Bind DPRs With High Affinity and Specificity
Comprehensive Evaluation of Human-derived Anti-poly-ga Antibodies in Cellular and Animal Models of C9orf72 Disease
Jambeau M, Meyer KD, Hruska-Plochan M, Tabet R, Lee CZ [et al.], Lagier-Tourenne C
Published in PNAS on December 6, 2022

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia are two devastating neurodegenerative disease with clinical, pathologic and genetic overlap. The most common inherited cause of ALS and FTD is an hexanucleotide G₄C₂ repeat expansion in the C9ORF72 gene that leads to the accumulation of abnormal proteins called dipeptide repeat proteins (DPRs). In this collaboration between academic and industry partners, we have systematically characterized human antibodies against multiple DPR species and tested the biological effects of antibodies targeting poly-GA in different cellular and mouse models. Treatment with antibodies was shown to alter the morphological and biochemical properties of poly-GA with a significant increase in poly-GA insolubility. Chronic administration of anti-GA antibodies in ALS mice was associated with increased levels of poly-GA and did not significantly reduce poly-GA aggregates or alleviate disease progression.

(Submitted by Clotilde Lagier-Tourenne, MD, PhD, Department of Neurology)

Insights into the Actions of ARIP-4 in C. Elegans
The Caenorhabditis elegans ARIP-4 DNA Helicase Couples Mitochondrial Surveillance to Immune, Detoxification, and Antiviral Pathways
Mao K, Breen P, Ruvkun G
Published in PNAS on December 6, 2022

One of the largest class of mutations that increase the lifespan the nematode are mutations that reduce mitochondrial function. Mitochondria also serve as a key signaling hub for immune responses to viruses across the animal kingdom. This paper identifies the DNA helicase gene arip-4 that is required for the antiviral RNAi response to mitochondrial dysfunction. The enhanced RNAi caused by a mitochondrial mutant is suppressed by arip-4 mutations, which also extends the lifespan and healthspan of both wild type and a mitochondrial mutant, suggesting that the antiviral response is deleterious in a mitochondrial mutant.

(Summary submitted by Gary Ruvkun, PhD, Center for Computational and Integrative Biology)

Insulin receptor signaling is central to normal metabolic control and is dysregulated in metabolic diseases such as type 2 diabetes. In this article, we show that insulin receptor functions by forming dynamic clusters, called condensates, in cells. These condensates become dysfunctional in insulin resistance and are partially rescued by metformin, a first-line drug used to treat type 2 diabetes. This research improves our understanding of diabetes at a molecular level and may lead to new therapies.

(Summary submitted by Jesse Platt, MD, PhD, Division of Gastroenterology, Department of Medicine)

Novel orally available therapies are desperately needed to stimulate bone formation for patients with osteoporosis. Parathyroid hormone injections increase bone formation. A key step in the intracellular action of PTH is to inhibit salt-inducible kinases. Here, we used structure-based drug design followed by iterative medicinal chemistry to identify selective, orally available SIK2/SIK3 inhibitors. A lead compound, SK-124, increases bone formation and bone mass when given to mice by once daily oral treatment. These findings support the further development of specific SIK2/SIK3 inhibitors as a novel class of bone anabolic osteoporosis therapies.

(Summary submitted by Marc Wein, MD. PhD, Endocrine Unit, Department of Medicine)

Artificial intelligence (AI) algorithms must be trained by utilizing data from the past to produce meaningful results. However, there was a lack of past data with the unprecedented Covid-19, and the AI we had developed before was not targeted at this new problem. Yet, we have shown that AI can be reused for new problems by using explainable AI (xAI) to solve these problems. When Covid-19 patients, which have recently become a major problem worldwide, flocked to the emergency room, we developed a model to predict whether the patient needed high-flow oxygen (HFO) or mechanical ventilation (MV). Prediction accuracy for HFO and MV was 0.953 and 0.934 at 24 h and 0.932 and 0.836 at 72 h from the time of emergency department (ED) admission, respectively. These results are presented in new ways, such as an “interpretation table” and an “AI scoreboard”, so that AI can be easily interpreted. Clearly, these methods have been a great help for users to understand the impacts of AI.

(Summary submitted by Synho Do, PhD, Department of Radiology)

Pediatric medulloblastoma requires radiotherapy to the whole brain and spine because it can seed other parts of the brain. Most children (60-80%) are cured with this approach but develop memory and cognitive dysfunction that is worse in younger children. Studies in adults show that techniques that spare the hippocampi (brain structures associated with memory and cognitive function, can improve cognitive outcomes. In our study, we demonstrate that hippocampal sparing is both feasible and safe. We examined medulloblastoma patients who had recurred and found that most of the recurrences (92%) were outside of the hippocampal region. Therefore, hippocampal avoidance in children with medulloblastoma should improve cognitive function after treatment while maintaining high rates of cure. This study provides the necessary foundation to for a clinical trial of hippocampal avoidance in pediatric medulloblastoma patients.

(Summary submitted by Torunn I. Yock, MD, MCh, Department of Radiology Oncology)

We developed a tool called CRISPRme to help design guide RNA for CRISPR gene editing. The tool takes into account genetic variations that are not present in the reference genome in order to identify and prioritize off-target sites that could potentially be modified during CRISPR editing. When we applied CRISPRme to a guide RNA that is currently being tested in clinical trials, they found and validated an off-target site that had previously been overlooked due to a common alternative allele. The ability to predict off-target modifications is important for the safe development of therapeutic CRISPR editors.

(Summary submitted by Luca Pinello, PhD, Mass General Cancer Center, Department of Pathology)

Fatigue is a common toxicity of cancer radiation therapy. Prior evidence from our lab identified the opioid β-endorphin as a key factor produced by skin after ultraviolet radiation, contributing to “sun-seeking” behavior. We now used a series of preclinical models including gene knockouts that selectively lack β-endorphin in the skin, to show that fractionated ionizing radiation (as used for cancer) indeed elevates blood levels of β-endorphin produced in skin, which causes fatigue. We also demonstrated that the opiate antagonist naloxone prevented radiation fatigue in rats, offering a new therapeutic opportunity.

(Summary submitted by David E. Fisher MD, PhD, Cutaneous Biology Research Center, Department of Dermatology)

After cerebral ischemia, damaged brains try to repair themselves by converting parenchymal astrocytes into neurons in areas where neurogenesis does not normally occur. It is unclear how the damaged brain sends out signals to trigger parenchymal astrocyte conversion. In this study, we found that brain endothelial cells provide microvesicle-encased signals that convert parenchymal astrocytes into neural progenitors, thus improving outcomes after stroke. This brain vascular-regulated form of neuroplasticity may open up opportunities for pro-recovery therapies after stroke.

(Summary submitted by Wenlu Li, PhD, Department of Radiology)

Colon cancer is a major cause of global cancer-related deaths. Biomarkers such a BRAF V600E mutations and mismatch repair deficiency identify subgroups of patients who can benefit from targeted therapies and immunotherapies. Until recently KRAS mutations, including KRAS G12C, were considered undruggable. Here we demonstrate that an oral KRAS G12C inhibitor alone, or in combination with an anti-EGFR antibody, can lead to durable responses in heavily pre-treated colon cancers with KRAS G12C mutations. This is the first data to confirm the activity of these agents and is the basis for ongoing phase III trials and a recent FDA breakthrough designation.

(Summary submitted by Samuel J. Klempner, MD, Department of Medicine)

Study Supports Use of Liso-Cel in Large B-Cell Lymphoma
Lisocabtagene Maraleucel as Second-line Therapy for Large B-cell Lymphoma: Primary Analysis of Phase 3 TRANSFORM Study
Abramson JS, Solomon SR, Arnason JE, Johnston PB, Glass B [et al.], Kamdar M
Published in Blood on December 21, 2022

The TRANSFORM trial is a randomized phase 3 trial comparing the anti-CD19 CAR T-cell lisocabtagene maraleucel (liso-cel) with the standard of care (SOC) of platinum based chemotherapy followed by high dose chemotherapy and autologous stem cell transplant in patients with large B-cell lymphoma progressing within 12 months of initial treatment. Liso-cel resulted in significant improvements in complete response, event-free survival and progression free survival over the SOC. The risk of progression or death was reduced by 60% for patients on the liso-cel arm. Toxicities were manageable with very low rates of immune-related toxicities. Based on these data, liso-cel is now FDA-approved as a 2nd line therapy for patients with large B-cell lymphomas that are primary refractory or relapsed within one year of initial therapy, and is now preferred over the historic SOC of autologous stem cell transplant.

(Summary submitted by Jeremy S Abramson, MD, Mass General Cancer Center, Department of Medicine)

The infant gut microbiome is seeded by the mother’s microbiome during and after birth, and plays important roles in health and development. We examined the dynamics of these microbial communities and their metabolites from late pregnancy through the first year of life in 70 mother–infant pairs. Our study uncovered large-scale horizontal gene transfer events between maternal and infant gut bacteria, in which hundreds of genes from maternal bacteria that fail to seed in the infant were transmitted to different species in the infant microbiome. Many genes were related to infant diet as well as immune and cognitive development. We also revealed distinct metabolite profiles that could impact both maternal and infant health. Together, our findings expand the understanding of factors that influence gut microbiome development throughout infancy, with implications for lifelong health.

(Summary submitted by Theresa Reimels, Division of Gastroenterology)

Press Releases

New Oral Compound Developed by Mass General Researchers May Help Prevent and Treat Osteoporosis
Featuring Marc Wein, MD, PhD

Parathyroid hormone–based medications can stimulate bone formation to treat osteoporosis but are only effective when administered by injection. Researchers have now identified an oral compound that influences components of the parathyroid hormone signaling pathway to increase bone formation and bone mass in mice.

Researchers Identify the Hormone that Drives Fatigue After Cancer Radiation Therapy
Featuring David E. Fisher, MD, PhD

New research indicates that cancer radiation therapy causes the skin to produce the hormone β-endorphin, and that elevated β-endorphin levels contribute to fatigue after treatment.

The Impact of Selective Terminations on the Birth Rate and Population Levels of Individuals with Down Syndrome in Australia and New Zealand
Featuring Brian Skotko, MD, MPP

Researchers from Mass General for Children and colleagues have learned more about the effect of selective terminations on birth prevalence and population prevalence of people with Down syndrome in Australia and New Zealand.

Blog Posts

Introducing: Break it Down for Me
Featuring David Izquierdo-Garcia, PhD

A new series that challenges Mass General researchers to break down the titles of their complex studies in ways the public can understand.

Benchmarks: Mass General Research News and Notes for Dec. 16, 2022
Mass General investigators discuss shared decision making, attitudes towards patients with disabilities and more.

Mass General Research Wrapped for 2022
A look back at the year in research for the Mass General Research Institute, including funding, awards, publications and lots more.

Mass General Research Bids Farewell to Dr. Orf (Plus 13 Things You Didn’t Know About Harry)
Featuring Harry Orf, PhD

We catch up with Harry Orf, PhD, SVP for research at Mass General, to talk about the growth of research at the hospital and what's next for him in retirement.

Holiday Jams Courtesy of the MGRI Community
Featuring Rudy Tanzi, PhD; Michael Datko, PhD; Ragon Institute Investigators

Hear unique versions of some of your favorite holiday songs from these Mass General researchers who moonlight as musicians.

Benchmarks: Mass General Research News and Notes for Dec. 23, 2022
A new endowed chair in reproductive biology, a spotlight on lifestyle medicine, the brain benefits of kindness during the holiday and more.

Our Top Five Research Blog Posts for 2022
2022 was another big year for research at Mass General, and to celebrate, we're looking back at our five most popular blog posts.

Benchmarks: Mass General Research News and Notes for Dec. 30, 2022
Improving cancer care for patients with serious mental illness, a potential new treatment for osteoporosis, and more.

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Snapshot of Science for December 2022