Snapshot of Science for January 2023

Welcome to our Snapshot of Science for January 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:

34 new studies published in high-impact journals, along with 27 summaries submitted by the research teams
12 new research-related press releases
10 posts from the Mass General Research Institute blog
3 research spotlights

Publications

New Way to Identify Those at Greatest Risk of Lung Cancer
Validation of a Deep Learning-based Model to Predict Lung Cancer Risk Using Chest Radiographs and Electronic Medical Record Data
Raghu VK, Walia AS, Zinzuwadia AN, Goiffon RJ, Shepard JO, Aerts HJWL, Lennes IT, Lu MT
Published in JAMA Network Open on December 28, 2022 | *Summary available

Modified CRISPR-based Enzymes Improve the Prospect of Inserting Entire Genes Into the Genome to Overcome Diverse Disease-causing Mutations
Precise Cut-and-Paste DNA Insertion Using Engineered Type V-K CRISPR-associated Transposases
Tou CJ, Orr B, Kleinstiver BP
Published in Nature Biotechnology on January 2, 2023 | *Summary available | Press Release

New Potential Diagnostic Approaches for Personalized Immunotherapy in Recurrent HCCs
Distinct Single-Cell Immune Ecosystems Distinguish True and De Novo HBV-related Hepatocellular Carcinoma Recurrences
Chen S, Huang C, Liao G, Sun H, Xie Y [et al.], Kuang M
Published in Gut on January 3, 2023 | *Summary available

Free Spike Antigen Potential Underlying Cause in Adolescents and Young Adults With Post-mRNA Vaccine Myocarditis
Circulating Spike Protein Detected in Post-COVID-19 mRNA Vaccine Myocarditis
Yonker LM, Swank Z, Bartsch YC, Burns MD, Kane A [et al.], Walt DR
Published in Circulation on January 4, 2023

New Framework for Best Practice Use of Polygenic Risk Scores
Global Biobank Analyses Provide Lessons for Developing Polygenic Risk Scores Across Diverse Cohorts
Wang Y, Namba S, Lopera E, Kerminen S, Tsuo K [et al.], Hirbo J
Published in Cell Genomics on January 4, 2023 | *Summary available

AI Model Identifies Potential Candidates for Stroke Thrombectomy Treatment
Head CT Deep Learning Model Is Highly Accurate for Early Infarct Estimation
Gauriau R, Bizzo BC, Comeau DS, Hillis JM, Bridge CP [et al.], Lev MH
Published in Science Reports on January 5, 2023 | *Summary available

Cilia as Organizer Function of Left-Right Body Plan of Developing Embryo
Cilia Function as Calcium-mediated Mechanosensors That Instruct Left-Right Asymmetry
Djenoune L, Mahamdeh M, Truong TV, Nguyen CT, Fraser SE [et al.], Yuan S
Published in Science on January 5, 2023 | *Summary available | Press Release

Disabling Neuron Synchronization Alleviated Pain in Mouse Model
Highly Synchronized Cortical Circuit Dynamics Mediate Spontaneous Pain in Mice
Ding W, Fischer L, Chen Q, Li Z, Yang L [et al.], Shen S
Published in Journal of Clinical Investigation on January 5, 2023 | *Summary available

Challenging the Viewpoint That Surgical Interventions for Patients Receiving Palliative Care Are Futile
Surgical Intervention in Patients Receiving Pediatric Palliative Care Services
Ellis DI, Nye RT, Wolfe J, Feudtner C
Published in Pediatrics on January 6, 2023 | *Summary available

Mathematical Model Predicts Long-Term Effectiveness of COVID-19 Vaccine Booster Doses in Different Patient Populations
Mechanistic Model for Booster Doses Effectiveness in Healthy, Cancer, and Immunosuppressed Patients Infected With SARS-CoV-2
Voutouri C, Hardin CC, Naranbhai V, Nikmaneshi MR, Khandekar MJ [et al.], Jain RK
Published in PNAS on January 9, 2023 | *Summary available | Press Release

Address Epithelial Defects and Immune Cell Defects to Alleviate Chronic Infections in Job Syndrome Patients
STAT3 Mutation-associated Airway Epithelial Defects in Job Syndrome
Zhang Y, Lin T, Leung HM, Zhang C, Wilson-Mifsud B [et al.], Mou H
Published in Journal of Allergy and Clinical Immunology on January 9, 2023

Scientists Identify Gene Target to Boost Effectiveness of Cancer Immunotherapy
Targeting TBK1 to Overcome Resistance to Cancer Immunotherapy
Sun Y, Revach OY, Anderson S, Kessler EA, Wolfe CH [et al.], Jenkins RW
Published in Nature on January 12, 2023 | Press Release

Patients Undergoing Surgery For Cancer Face Higher Risk of Suicide
Incidence, Timing, and Factors Associated With Suicide Among Patients Undergoing Surgery for Cancer in the U.S.
Potter AL, Haridas C, Neumann K, Kiang MV, Fong ZV [et al.], Yang CJ
Published in JAMA Oncology on January 12, 2023 | Press Release

Clinical Trial Results Indicate Low Rate of Adverse Events Associated With Implanted Brain Computer Interface
Interim Safety Profile From the Feasibility Study of the BrainGate Neural Interface System
Rubin DB, Ajiboye AB, Barefoot L, Bowker M, Cash SS [et al.], Hochberg LR
Published in Neurology on January 13, 2023 | *Summary available | Press Release

Higher Levels of Pre-Pandemic Physical Activity Associated With Lower Risk of COVID-19 Infection and Severity
Physical Activity, Sedentary Behavior, and Risk of Coronavirus Disease 2019
Ma W, Murray E, Nguyen LH, Drew DA, Ding M [et al.], Martinez ME
Published in American Journal of Medicine on January 16, 2023 | *Summary available

Researchers Discover Why Only Some People Experience Long-Term Benefits from Peanut Allergy Treatments
Immunotherapy-induced Neutralizing Antibodies Disrupt Allergen Binding and Sustain Allergen Tolerance in Peanut Allergy
LaHood NA, Min J, Keswani T, Richardson CM, Amoako K [et al.], Patil SU
Published in Journal of Clinical Investigation on January 17, 2023 | *Summary available | Press Release

Fat Location Associated With Different Ricks of Diabetes and Heart Disease
BMI-adjusted Adipose Tissue Volumes Exhibit Depot-specific and Divergent Associations With Cardiometabolic Diseases
Agrawal S, Klarqvist MDR, Diamant N, Stanley TL, Ellinor PT [et al.], Khera AV
Published in Nature Communications on January 17, 2023 | *Summary available

Deep Learning Model to Help Triage Chest Pains in ED
Deep Learning Analysis of Chest Radiographs to Triage Patients With Acute Chest Pain Syndrome
Kolossváry M, Raghu VK, Nagurney JT, Hoffmann U, Lu MT
Published in Radiology on January 17, 2023 | *Summary available

Risk of Retinopathy Increases With Higher Hydroxychloroquine Dose
Hydroxychloroquine Dose and Risk For Incident Retinopathy: A Cohort Study
Melles RB, Jorge AM, Marmor MF, Zhou B, Conell C [et al.], Choi HK
Published in Annals of Internal Medicine on January 17, 2023 | *Summary available

Investigational Drug May Combat Brain Tumors By Targeting Cancer Cells' Fat Production
Targeting De Novo Lipid Synthesis Induces Lipotoxicity and Impairs DNA Damage Repair in Glioblastoma Mouse Models
Eyme KM, Sammarco A, Jha R, Mnatsakanyan H, Pechdimaljian C [et al.], Badr CE
Published in Science Translational Medicine on January 18, 2023 | *Summary available | Press Release

Reward Insensitivity Arises from Memory Limitations
Undermatching Is a Consequence of Policy Compression
Bari BA, Gershman SJ
Published in Journal of Neuroscience on January 18, 2023 | *Summary available

App for AML Patients Can Help With Quality of Life
Psychological Mobile App for Patients With Acute Myeloid Leukemia (AML): A Pilot Randomized Clinical Trial
El-Jawahri A, Luskin MR, Greer JA, Traeger L, Lavoie M [et al.], Temel JS
Published in Cancer on January 18, 2023

New Biobank-based Genomic Project
FinnGen Provides Genetic Insights From a Well-phenotyped Isolated Population
Kurki MI, Karjalainen J, Palta P, Sipilä TP, Kristiansson K [et al.], Palotie A
Published in Nature on January 18, 2023 | *Summary available

FinnGen Resource Uncovers Unexpectedly Diverse Patterns of Inheritance In Which DNA Variation Influences Rare and Common Disease
Mono- and Biallelic Variant Effects on Disease at Biobank Scale
Heyne HO, Karjalainen J, Karczewski KJ, Lemmelä SM, Zhou W; FinnGen, [et al.], Daly MJ
Published in Nature on January 18, 2023 | *Summary available

Genetic Links Between Allergic Sinonasal Diseases, Asthma as Well as Ear Infections and Appendicitis
Inflammatory and Infectious Upper Respiratory Diseases Associate With 41 Genomic Loci and Type 2 Inflammation
Saarentaus EC, Karjalainen J, Rämö JT, Kiiskinen T, Havulinna AS [et al.], Palotie A
Published in Nature Communications on January 18, 2023 | *Summary available

27 Different Genetic Regions Found Regulate Otosclerosis Risk
Genome-wide Screen of Otosclerosis in Population Biobanks: 27 Loci and Shared Associations With Skeletal Structure
Rämö JT, Kiiskinen T, Seist R, Krebs K, Kanai M [et al.], Palotie A
Published in Nature Communications on January 18, 2023 | *Summary available

Insufficient Representation of Racial/Ethnic Minorities in Cancer Biorepositories
Racial and Ethnic Disparities in a Real-world Precision Oncology Data Registry
Cheung ATM, Palapattu EL, Pompa IR, Aldrighetti CM, Niemierko A [et al.], Kamran SC
Published in NPJ Precision Oncology on January 19, 2023 | *Summary available

New Treatment of Adult Patients With Intrahepatic Cholangiocarcinoma
Futibatinib for FGFR2-rearranged Intrahepatic Cholangiocarcinoma
Goyal L, Meric-Bernstam F, Hollebecque A, Valle JW [et al.], Bridgewater JA; FOENIX-CCA2 Study Investigators
Published in New England Journal of Medicine on January 19, 2023 | *Summary available

Clinical Trial Shows Better Results With First-line Immune Checkpoint Inhibitors for Colorectal Cancer Patients
Comparative Effectiveness of Immune Checkpoint Inhibitors vs. Chemotherapy in Patients With Metastatic Colorectal Cancer With Measures of Microsatellite Instability, Mismatch Repair, or Tumor Mutational Burden
Quintanilha JCF, Graf RP, Fisher VA, Oxnard GR, Ellis H [et al.], Klempner SJ
Published in JAMA Network Open on January 23, 2023

Highly Sensitive Liquid Biopsy Method to Detect Cholangiocarcinoma
Plasmon-enhanced Single Extracellular Vesicle Analysis for Cholangiocarcinoma Diagnosis
Jeong MH, Son T, Tae YK, Park CH, Lee HS [et al.], Im H
Published in Advanced Science on January 25, 2023 | *Summary available

Targeted Therapy Use for Lung Cancer Lower Than Expected for Medicaid Patients
Variation in Use of Lung Cancer Targeted Therapies Across State Medicaid Programs, 2020-2021
Roberts TJ, Kesselheim AS, Avorn J
Published in JAMA Network Open on January 25, 2023 | *Summary available

Immunotherapy Combined With Targeted Therapy for Colorectal Cancer Yields Promising Outcomes for Patients
Combined PD-1, BRAF and MEK Inhibition in BRAFV600E Colorectal Cancer: A Phase 2 Trial
Tian J, Chen JH, Chao SX, Pelka K, Giannakis M [et al.], Corcoran RB
Published in Nature Medicine on January 26, 2023 | Press Release

BacDrop, A Highly Scalable Technology for Bacterial Single-Cell RNA Sequencing
Bacterial Droplet-based Single-Cell RNA-seq Reveals Antibiotic-associated Heterogeneous Cellular States
Ma P, Amemiya HM, He LL, Gandhi SJ, Nicol R [et al.], Hung DT
Published in Cell on January 27, 2023 | *Summary available

Peer Review Process Continued to Function During COVID-19 Pandemic
Peer Review in a General Medical Research Journal Before and During the COVID-19 Pandemic
Perlis RH, Kendall-Taylor J, Hart K, Ganguli I, Berlin JA [et al.], Flanagin A
Published in JAMA Network Open on January 27, 2023 | *Summary available

Publication Summaries

Lung cancer is the leading cause of cancer death, responsible for more deaths than the next three cancers combined. Lung cancer screening with chest CT is an effective way to catch lung cancer early, yet the vast majority of eligible people are not screened. This study validates a new way to identify those at greatest risk of lung cancer, using an open-source Artificial Intelligence (AI) tool and existing chest x-rays from 14,737 people. This study paves the way for a clinical trial to improve lung cancer screening participation using electronic medical record data.

(Summary submitted by Michael T. Lu, MD, MPH, Cardiovascular Imaging Research Center, Department of Radiology)

The programmable integration of gene-sized DNA segments into mammalian genomes would be transformational for a variety of scientific fields. This capability would enable genetic medicines that can be generalized to a range of patients afflicted by a common disease, irrespective of their genetic mutation(s). One promising class of technologies capable of large genetic edits are CRISPR-associated transposases (CASTs), which can be programmed by a guide RNA to direct kilobase-sized DNA insertions into target sites. However, naturally occurring CASTs have undesirable properties for genome editing applications — including high unwanted integration at unintended "off-target" sites and suboptimal insertion product purity. In this study, we develop engineered CASTs (which we coin "HELIX") to address these shortcomings, leading to efficient and safe HELIX enzymes capable of kilobase-scale insertions in both bacterial and human cellular contexts.

(Summary submitted by Connor Tou, Center for Genomic Medicine)

Hepatocellular carcinoma (HCC) incidence is increasing worldwide. Patients diagnosed with HCC have poor prognoses due to frequent recurrences after surgical resection. HCC recurrences may be intrahepatic metastases or de novo cancers, which differ in known oncogenic drivers. This report defined the distinct single-cell immune ecosystems of these two types of HCC recurrence. It also showed that truly recurrent (metastatic) lesions could be seeded before primary tumor diagnosis and that de novo cancers can occur earlier than the clinically used two-year limit. These findings provide new potential diagnostic approaches and therapeutic avenues for personalized immunotherapy in recurrent HCCs.

(Summary submitted by Dan G. Duda, DMD, PhD, FAIMBE, FAAAS, Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology)

Polygenic risk scores (PRS), which are being widely explored in precision medicine, predict the genetic component of disease risk. To thoroughly investigate best practices for PRS in global populations across different diseases, we here used the unique resource from Global-Biobank Meta-analysis Initiative to develop and evaluate PRS for 14 disease endpoints with varying genetic architectures and prevalences. We developed guidelines regarding the effects of multi-ancestry and heterogeneous genome-wide association studies, trait-specific genetic architecture, and PRS methods on prediction performance across diverse populations. Our framework applies to biobank-scale resources with both homogenous and diverse ancestries.

(Summary submitted by Ying Wang, MD, Analytic and Translational Genetics Unit, Department of Medicine)

Non-contrast enhanced head CT scans (NCCT) are the standard of care for the initial evaluation of patients with acute stroke, but are extremely insensitive for early infarct identification. We developed an artificial intelligence model that detects and delineates suspected early acute infarcts on NCCT, using diffusion-weighted MRI as the "ground truth" reference standard for model training. The model substantially outperformed 3 expert neuroradiologists on a test set of scans from patients who were potential candidates for stroke thrombectomy treatment, with sensitivity 96% for the model versus 61–66% for the experts; model infarct volume estimates also strongly correlated with those of diffusion MRI. Moreover, at the infarct volume thresholds that are clinically important for selecting patients for thrombectomy—an assessment which currently requires more advanced, CT angiographic, CT perfusion, and/or MR imaging techniques—sensitivity was 97% for the model and ranged from 23-47% for the expert readers, for equal specificities of 99%–100%.

(Summary submitted by Michael H Lev, MD FAHA FACR, Department of Radiology)

Cilia as Organizer Function of Left-right Body Plan of Developing Embryo
Cilia Function as Calcium-mediated Mechanosensors That Instruct Left-Right Asymmetry
Djenoune L, Mahamdeh M, Truong TV, Nguyen CT, Fraser SE [et al.], Yuan S
Published in Science on January 5, 2023

There are remarkable left-right differences in the shape and positioning of most internal organs including the heart, lungs, and liver. Left-right differences are specified during early embryogenesis by a small cluster of cells termed the left-right organizer. Within this organizer, motile cilia move rapidly to create a leftward directional flow of extracellular fluid which is the first sign of a left-right difference, but how this flow is translated into left-right asymmetry was unknown. In this study, we demonstrated that immotile cilia in the organizer function as mechanosensors that translate biomechanical forces into calcium signals to sculpt the left-right body plan of the developing embryo.

(Summary submitted by Shiaulou Yuan, PhD, Cardiovascular Research Center, Cardiology Division, Department of Medicine)

Disabling Neuron Synchronization Alleviated Pain
Highly Synchronized Cortical Circuit Dynamics Mediate Spontaneous Pain in Mice
Ding W, Fischer L, Chen Q, Li Z, Yang L [et al.], Shen S
Published in Journal of Clinical Investigation on January 5, 2023

Pain is one of the most unpleasant feelings. Trigeminal neuralgia is one of the most painful conditions known to the humanity. Despite many years of research, how pain is processed in the cerebral cortex- the highest center for information integration in the brain, is largely unknown. We created an animal model that recapitulates key clinical features of trigeminal neuralgia. Based on this model, we leveraged a technique through which neuronal activities could be tracked in live animals under direct visualization for about 1 month, at single cell resolution. We found that pain pushes cortical neurons into an aberrant state, characterized by dramatic firing at the same time, called synchronization. This particular synchronization was crucial for processing pain; disabling the synchronization alleviated pain. These findings unravel a previously unknown cortical activity pattern mediates 'pain in the head'.

(Summary submitted by Weihua Ding, MD, Department of Anesthesia, Critical Care and Pain Medicine)

Palliative care is an essential and increasingly standard component of caring for seriously ill children. Pediatric surgeons are involved in counseling and treating children receiving palliative care, but there is a lack of data telling us what kinds of surgical interventions they undergo. We did a cohort analysis to assess the incidence, type, and likely purpose of surgical interventions performed in children after the initiation of palliative care services. Of the 602 children receiving palliative care, 81% had undergone at least one surgical intervention with a median of 4. Having more chronic, complex conditions was associated with an increased rate of intervention, whereas girls, Latino patients, and older children were less likely to undergo intervention. Children who underwent any surgical intervention were less likely to die, challenging the viewpoint that surgical interventions for patients receiving palliative care are futile, harmful, or hasten mortality.

(Summary submitted by Danielle Ellis, MD, MT, Department of Surgery)

We have developed a mathematical model that can predict COVID-19 vaccines' effectiveness over the long term in healthy individuals and those who have cancer or suppressed immune responses. Our model also analyzes the potential of different vaccines—including new bivalent vaccines—for protecting against hypothetical future viral variants. The model suggests possible strategies for future vaccinations, including high-risk groups. For healthy people, booster shots may be necessary every 8-12 months, whereas for patients with cancer or immunosuppression sooner, 4-6 months, to maintain protection.

(Summary submitted by Rakesh K. Jain, PhD, E.L. Steele Laboratories, Department of Radiation Oncology)

For people with paralysis caused by neurologic injury or disease, brain computer interfaces (BCIs) can provide an effective means to restore communication, mobility, and functional independence. The BrainGate trial was initiated in 2004 to obtain safety information and to demonstrate the feasibility of people with paralysis using an implanted BCI to control a computer cursor and other assistive devices. In this study, we report on all safety data acquired during the BrainGate trial, which includes 14 participants and over 12,000 participant-days between 2004 and 2021. During this time period, there were no safety events that required device removal, permanently increased disability, or death. Overall, we find that the implanted BrainGate Neural Interface System has a safety profile comparable to other approved implanted neurotechnologies.

(Summary submitted by Daniel Rubin, MD, PhD, Department of Neurology)

Physical inactivity is a well-established risk factor for chronic comorbidities associated with severe COVID-19. However, data on the association of pre-pandemic physical activity with SARS-CoV-2 infection and COVID-19 severity, particularly milder illness, have been limited. We used data from 43,913 participants of the two large prospective cohorts in the U.S. who responded to periodic COVID-related surveys. Higher levels of pre-pandemic physical activity were associated with a lower risk of SAR-CoV-2 infection and COVID-19 severity. These data solidify the need for public health agencies to consider adding physical inactivity as a modifiable risk factor for COVID-19.

(Summary submitted by Wenjie Ma, DSc, Division of Gastroenterology, Department of Medicine)

Peanut allergy is persistent and severe. Minute amounts can cause reactions in individuals with IgE allergy antibodies that bind to peanut. Oral immunotherapy (OIT), with incremental peanut exposure, results in a long-lived tolerance in few individuals. To identify how non-IgE antibodies contribute to long-lived tolerance, we re-created antibodies from treated individuals and characterized where they bound to peanut allergen. Antibodies found only in individuals with durable tolerance bound the allergen in unique regions. These neutralizing antibodies effectively inhibit binding of multiple IgE antibodies to allergen, preventing activation of allergy cells. We hope this work will lead to new treatments.

(Summary submitted by Sarita U. Patil, MD, Center for Immunology and Inflammatory Diseases, Department of Medicine)

Doctors use body mass index (BMI) to help understand how an individual's body size might affect disease risk. At any given BMI, individuals can vary substantially in body fat distribution. We set out to investigate the association of body fat distribution with diabetes and heart disease by measuring specific adipose tissue volumes from body MRI in 40,000 individuals. After accounting for BMI, we found that having increased visceral fat (fat in the deep belly) is associated with higher risk of diabetes and heart disease, while having increased gluteofemoral fat (fat in the hips and thighs) is associated with reduced risk.

(Summary submitted by Saaket Agrawal, Broad Institute)

Rapid triage of patients presenting to the emergency department (ED) with chest pain is critical to ensure timely treatment. Using 23,005 patients' chest radiograph (x-ray) images, we trained a deep learning model to identify those at highest risk of myocardial infarction, pulmonary embolism, or aortic dissection. Testing our model on 22,764 patients from a second hospital, our automated deep learning model identified those most likely to suffer these adverse events. A chest radiograph is often the first test in the evaluation of chest pain, and this automated tool could help triage those needing immediate attention versus those who may be safely discharged.

(Summary submitted by Michael T. Lu, MD, MPH, Cardiovascular Imaging Research Center, Department of Radiology)

Risk of Retinopathy Increases With Higher Hydroxychloroquine Dose
Hydroxychloroquine Dose and Risk for Incident Retinopathy: A Cohort Study
Melles RB, Jorge AM, Marmor MF, Zhou B, Conell C [et al.], Choi HK
Published in Annals of Internal Medicine on January 17, 2023

Hydroxychloroquine is an important medication for treating rheumatic diseases, but it can cause a long-term side effect of retinopathy, a type of eye toxicity. This study examined the risk of retinopathy according to the hydroxychloroquine dose. A cohort of over 3,000 patients were followed through 15 years of hydroxychloroquine use. Yearly retinopathy screening studies were reviewed by experts. The overall risk of retinopathy was 8.6% after 15 years, and most cases were mild. Hydroxychloroquine doses over 6 mg/kg/day had the highest risk of retinopathy, followed by 5-6 mg/kg/day, and doses under 5 mg/kg/day had the lowest risk of retinopathy.

(Summary submitted by April Jorge, MD, Division of Rheumatology, Allergy, and Immunology, Department of Medicine)

Glioblastoma is a highly aggressive and lethal brain cancer. Glioblastoma cells require lipids to support the cells' energy demands. An investigational drug called YTX-7739, currently being evaluated in phase I clinical trials for Parkinson's disease, interferes with this process. In this study, we showed that YTX-7739 delayed tumor growth and increased sensitivity to anticancer therapies when administered in mice with glioblastoma. We also identified the molecular mechanisms that make glioblastoma cells either vulnerable or resistant to YTX-7739 and other therapeutics targeting lipid synthesis. Based on this knowledge, we might be able to predict which patients are most likely to benefit from such therapies. Overall, our findings may lead to new treatment options for patients.

(Summary submitted by Christian E. Badr, PhD, Department of Neurology)

Reward Insensitivity Arises From Memory Limitations
Undermatching Is a Consequence of Policy Compression
Bari BA, Gershman SJ
Published in Journal of Neuroscience on January 18, 2023

Reward insensitivity is common across neuropsychiatric conditions. Despite its prevalence, we do not understand how it arises. We recently developed a broad theory of decision making that explains how we act when the brain's memory is limited. In this study, we applied this theory to explain reward insensitivity in "matching" behavior, a form of decision making studied for over 50 years. We found that patients with Parkinson's disease are highly reward insensitive and become more sensitive when treated with dopamine-boosting medications, consistent with our theory's predictions. In summary, we find that reward insensitivity arises from memory limitations.

(Summary submitted by Bilal A. Bari, MD, PhD, Department of Psychiatry)

FinnGen is a biobank-based genomic project, building a resource that integrates genomic information from 500,000 Finns with extensive national health registry data. Here our FinnGen team describes results based on 224,737 Finnish biobank participants. After performing comprehensive genetic analyses for more than 1,900 diseases, the researchers identify almost 2,500 genomic regions that are linked with at least one of these diseases. Among these discoveries are many previously unknown risk and protective variants for both common and rare diseases — delivering new entry points into the biology of many debilitating diseases which yield novel hypotheses for therapeutic development.

(Summary submitted by Mari Kaunisto, PhD, University of Helsinki)

In this paper, the FinnGen resource was used to uncover unexpectedly diverse patterns of inheritance with which DNA variation influences rare and common disease. We searched first for recessive causes of common and rare disease (those that develop only when both copies of a gene are mutated) and found numerous connections to disease missed by standard GWAS analysis. In addition, we examined hundreds of variants reported as causally linked to rare disease with a specific mode of inheritance (generally dominant or recessive) and describe many instances where inheritance is more complex than those conventional definitions, and many recessive variants where carriers demonstrate significant clinical phenotype.

(Summary submitted by Mark Daly, PhD, Analytic and Translational Genetics Unit, Department of Medicine)

Frequent infections are common manifestations of several chronic conditions of the upper respiratory tract, such as chronic sinus infection. In a biobank study of 260,000 Finnish participants, we detected and validated 41 locations in the human genome linking to these conditions. The results showed a highly shared genetic risk for allergic sinonasal diseases such as hay fever, sinus infections and nasal polyps, with genes relevant to type 2 innate immunity and relevant to asthma as well. Chronic tonsillar infections shared genes with acute peritonsillar abscess (quinsy), ear infections and acute appendicitis. Studying these mechanisms further may uncover mechanisms and drug targets relevant to multiple conditions.

(Summary submitted by Elmo Saarentaus, MD, PhD, University of Helsinki)

Otosclerosis is rare disease that can cause hearing loss starting in early adulthood due to impaired sound conduction in the middle ear. Otosclerosis is highly heritable, but its genetic causes have not been known. A new multi-center study led by researchers from Mass General Hospital studied genetic data from 3500 otosclerosis patients and more than 860 000 controls. In a breakthrough for the disease, the study identified 27 different genetic regions that regulate otosclerosis risk. Many identified genes are also associated with bone structure or skeletal disorders. The study highlights biological pathways that could represent new targets for therapeutic development for otosclerosis.

(Summary submitted by Joel Rämö, MD, PhD, Cardiovascular Research Center, Department of Medicine)

Insufficient Representation of Racial/Ethnic Minorities in Cancer Biorepositories
Racial and Ethnic Disparities in a Real-World Precision Oncology Data Registry
Cheung ATM, Palapattu EL, Pompa IR, Aldrighetti CM, Niemierko A [et al.], Kamran SC
Published in NPJ Precision Oncology on January 19, 2023

Large biorepositories — or databases that contain biological samples and genomic sequencing — have been critical to enabling cancer research, but they have historically consisted of mostly white patients. It remains unknown whether these data registries reflect the true distribution of cancers in racial and ethnic minorities. Our analysis of Project Genomics Evidence Neoplasia Information Exchange (GENIE), a real-world cancer data registry designed to accelerate precision oncology discovery, indicates that racial/ethnic minorities do not have sufficient representation by cancer type, which may impact the validity of studies directly comparing mutational profiles between racial/ethnic groups and limit the generalizability of biomarker discoveries to all cancer populations.

(Summary submitted by Sophia C. Kamran, MD, Department of Radiation Oncology)

Intrahepatic cholangiocarcinoma (iCCA) is a rare but increasingly common malignancy with a historically poor prognosis. FGFR2 fusions and rearrangements, present in 9–14% of iCCA tumors, predict response to FGFR inhibitors. FOENIX-CCA2, a single-arm, global, multicenter phase 2 study, demonstrated that treatment with futibatinib, a highly selective, covalently-binding, pan-FGFR inhibitor, resulted in durable responses and survival that surpassed historical outcomes with chemotherapy in patients with refractory iCCA, while maintaining quality of life. These data also demonstrate that the paradigm of molecularly targeting genomic drivers, such as FGFR2 alterations in iCCA, has the potential to substantially improve outcomes of cancer. Based on the results of the FOENIX-CCA2 study, futibatinib is now FDA-approved for the treatment of adult patients with previously treated, unresectable, locally advanced or metastatic intrahepatic cholangiocarcinoma harboring FGFR2 gene fusions or other rearrangements.

(Summary submitted by Lipika Goyal, MD, Mass General Cancer Center, Department of Medicine)

Cholangiocarcinoma (CCA) is often hard to detect until the late stages, causing high mortality rates. One of the reasons is that there are no good easily accessible biomarkers. To facilitate the diagnosis, we developed a highly sensitive liquid biopsy method to detect and analyze nanosized vesicles, named extracellular vesicles (EVs), shed by tumors. We used a nanosensor chip, enabling robust signal amplification for single tumor-derived EV analysis. Using the technology, we could detect small tumor-derived EVs undetectable by conventional methods and demonstrate high detection accuracy for CCA. The sensitive and accurate EV sensing technology can potentially transform cancer research and clinical practice for early CCA detection.

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

Targeted therapies can improve survival for patients with lung cancer by several years. However, many patients who could benefit from these medications do not receive them. In this study we found that use of targeted therapies for lung cancer was 34% lower than expected in state Medicaid programs. In more than half of the states, use of targeted therapies was more than 50% below expected levels. Variations in use of targeted therapies were associated with Medicaid policies that could affect access to these drugs, suggesting that policy reforms could increase access to targeted therapies and improve survival among Medicaid patients with lung cancer.

(Summary submitted by Thomas J. Roberts, MD, MBA, Center for Hematology/Oncology, Department of Medicine)

The ability to transcriptionally profile individual eukaryotic cells has led to important advances in our understanding of the heterogeneity between different cell types and cell states. However, technical limitations have heretofore hindered the ability to carry out such studies in large numbers of individual bacterial cells. Here we show a droplet-based technology for transcriptionally profiling individual bacterial cells (BacDrop) that can be scaled to millions of cells or hundreds of samples. BacDrop revealed heterogeneity within a previously presumed homogeneous population of Klebsiella pneumoniae, an important human pathogen and leading threat in the antibiotic resistance crisis. In the absence of antibiotic treatment, we identified a rare population of K. pneumoniae characterized by the expression of mobile genetic elements that can promote the evolution of antibiotic resistance. After antibiotic treatment, BacDrop revealed distinct subpopulations associated with decreased antibiotic efficacy. This technology may be used to reveal new insights into how individual bacteria within a population of the same species or a mixed species, such as the microbiome, respond to perturbations such as antibiotic treatment.

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

The peer review process is a key component of disseminating medical research, but requires substantial effort from the research community to review each others' work. We analyzed peer review data from more than 5,000 manuscripts submitted to a large, open-access general medicine journal before and during the COVID-19 pandemic. We found that, during the pandemic, the quality of peer reviews was modestly improved, while the time to return them decreased slightly. The paper suggests that, despite the added stress of the pandemic, the peer review process in medicine continued to function well.

(Summary submitted by Roy Perlis, MD, Center for Genomic Medicine, Department of Psychiatry)

Press Releases

Telling Left From Right: Cilia as Cellular Force Sensors During Embryogenesis
Featuring Shiaulou Yuan, PhD

Left-right asymmetry is known to be established during early embryogenesis by a small cluster of cells termed the left-right organizer. Within this organizer, motile cilia, hair-like structures on the cell surfaces, beat rapidly to create a leftward directional flow of extracellular fluid, which is the first outward sign of a left-right difference. This early flow has been shown to be critical to the distinction of right from left; however, how this flow is sensed and translated into left-right asymmetry has been unknown. A new study shows that cilia in the organizer also act as sensors for the biomechanical forces exerted by the flow to shape the left-right body plan of the developing embryo.

Mathematical Model Predicts Long-Term Effectiveness of COVID-19 Vaccine Booster Doses in Different Patient Populations
Featuring Rakesh K. Jain, PhD

Scientists have designed a mathematical model that can predict COVID-19 vaccines' effectiveness over the long term in healthy individuals and those who have cancer or suppressed immune responses. The model also considers the potential of the vaccines—including new bivalent vaccines—for protecting against hypothetical future viral variants.

Scientists Identify Gene Target to Boost Effectiveness of Cancer Immunotherapy
Featuring Russell W. Jenkins, MD, PhD, and Robert T. Manguso, PhD

Investigators have discovered that cancer cells' expression of an immune evasion gene may allow the cells to be unaffected by immunotherapy or develop resistance during treatment. Silencing the gene or blocking its expressed protein enhanced cancer cells' susceptibility to immunotherapy in multiple preclinical models.

Clinical Trial Results Indicate Low Rate of Adverse Events Associated With Implanted Brain Computer Interface
Featuring Daniel Rubin, MD, PhD

Brain-computer interfaces, which provide a direct communication link between the brain and a computer or other external device, may help people with difficulty communicating due to paralysis caused by ALS, brainstem stroke, spinal cord injury, and other neurologic conditions. The most sophisticated of these devices use sensors that are surgically placed into parts of the brain that control movement; however, the safety of these chronic brain implants is unknown. Results from the largest and longest-running clinical trial of an implanted brain computer interface suggests that the investigational BrainGate Neural Interface system safety is comparable to other chronically implanted devices used to manage neurologic disease.

Modified CRISPR-based Enzymes Improve the Prospect of Inserting Entire Genes Into the Genome to Overcome Diverse Disease-causing Mutations
Featuring Ben Kleinstiver, PhD

Investigators have developed an improved method to more accurately insert large DNA sequences—such as an entire normal replacement gene—in cells. The advance may lead to the development of techniques that have wide-ranging clinical applications to fix diverse disease-causing mutations.

Simple Laser Treatments May Help Prevent Nonmelanoma Skin Cancer
Featuring Mathew Avram, MD, JD

In a study of patients with a history of facial keratinocyte carcinoma, 20.9% of those treated with nonablative fractional lasers experienced a subsequent keratinocyte carcinoma, compared with 40.4% of patients who did not receive laser treatment. Among patients who developed a facial keratinocyte carcinoma, the time to development was longer in patients treated with NAFL compared with untreated patients

Investigational Drug May Combat Brain Tumors By Targeting Cancer Cells' Fat Production
Featuring Christian Badr, PhD

Glioblastoma cells rely on the conversion of carbohydrates to fats to support the cells' energy demands. An investigational drug called YTX-7739 interferes with this process. When given to mice with glioblastoma, YTX-7739 delayed tumor growth and increased glioblastoma cells' sensitivity to anticancer therapies.

Researchers Discover Why Only Some People Experience Long-Term Benefits From Peanut Allergy Treatments
Featuring Sarita U. Patil, MD

New research reveals why oral immunotherapy for peanut allergy can lead to sustained tolerance in some individuals but only transient tolerance in others. In patients with sustained tolerance, neutralizing antibodies block specific regions of the peanut allergen, which prevents the binding of other antibodies that trigger allergic reactions.

Patients Undergoing Surgery for Cancer Face Higher Risk of Suicide
Featuring Chi-Fu Jeffrey Yang, MD

In a study of United States patients who underwent major cancer operations, the incidence of suicide was significantly higher than that observed in the general population. Approximately 50% of suicides were committed during the first three years after cancer surgery. Patients who were male, white, and divorced or single faced the greatest risk of suicide.

Immunotherapy Combined With Targeted Therapy for Colorectal Cancer Yields Promising Outcomes for Patients
Featuring Ryan Corcoran, MD, PhD, and Nir Hacohen, PhD

Bench-to-bedside research led from preclinical experiments to a durable response among patients with a difficult-to-treat form of colorectal cancer. Insights from single-cell sequencing of participant samples revealed why the combination approach may work, with broad implications for future treatment.

Researchers Uncover a Novel Preference Structure to Explain the Aesthetics Behind Our Everyday Choice of Clothing
Featuring Nancy Etcoff, PhD

Individual preferences across four types of everyday clothing (essential, comfortable, feminine and trendy) are heavily influenced by color characteristics and the personality of the wearer. The study of fashion as an object of aesthetics and empirical science can yield valuable insights to guide the fashion industry as well as consumers on the factors that motivate people to purchase and wear clothing.

Researchers Uncover Racial and Ethnic Disparities in a Widely Used Precision Oncology Data Registry
Featuring Sophia Kamran, MD

Biorepositories created to support precision cancer research through their vast stores of genomic data may lack sufficient representation of cancer distribution among racial and ethnic minorities.

Blog Posts

Benchmarks: Mass General Research News and Notes for Jan 6, 2022

New insights into the role of cilia in left-right asymmetry; sedatives could prevent delirium in heart patients, plus the tweets of the week and more.

Benchmarks: Mass General Research News and Notes for Jan 13, 2023

Machine learning tool to predict melanoma recurrence, insights into myocarditis after COVID vaccination plus the tweets of the week and more.

Benchmarks: Mass General Research News and Notes for Jan 20, 2023

The world's longest running study on aging finds a connection between relationships and happiness, AI to help patients with chest pains, and lots more.

How Traffic and Tragedy Combined to Launch Telemedicine at Massachusetts General Hospital

Traffic tie-ups that delayed patient care in the mid 1960s led to the establishment of telemedicine at Mass General.

Through the Magnifying Glass: The Chetty Lab at the Center for Regenerative Medicine
Featuring Sundari Chetty, PhD

A close up look at the Mass General Metabolism Unit, which is working to understand more about metabolism-related medical disorders.

Benchmarks: Mass General Research News and Notes for January 27, 2023

A laser treatment reduces the risk of skin cancer recurrence, a new program to promote healthy sleep in youth affected by gun violence and more.

Meet Our Newest MGRI Intern, Kyle!

Kyle Banker is a senior at the University of Miami majoring in Biology with minors in Marketing and Computer Science. He is one of our Spring Science Communications Interns at the Mass General Research Institute. Please join us in welcoming him to the MGRI team!

And the 2022 MGRI Image Awards Winners Are:

Congratulations to the winners of the 2022 Mass General Research Institute Image Awards in the categories of People's Choice, Humans of MGRI, A Closer Look, Science as Art and Mixed Media.

Kingston Ready for New Challenges as Mass General's First Chief Academic Officer
Featuring Robert Kingston, PhD

After 37 years at Mass General, Kingston looks forward to the new challenges that the role will bring.

Footnotes in Science: Q&A With Jessica Haberer, MD

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

Research Spotlights

Research Spotlight: Identifying a Promising New Target for Immune Oncology
Featuring Bin Zheng, PhD

Bin Zheng, PhD, an investigator in the Department of Dermatology, is the Senior author of a recent letter published in Nature Metabolism, Myeloid-derived Itaconate Suppresses Cytotoxic CD8+ T Cells and Promotes Tumour Growth.

Research Spotlight: Tackling Prediction Uncertainty in Machine Learning for Healthcare
Featuring Michelle Chua, MD, and Synho Do, PhD

Michelle Chua, MD, and Synho Do, PhD, from the Department of Radiology at Massachusetts General Hospital, are the first and corresponding authors of a new perspective in Nature Biomedical Engineering, Tackling Prediction Uncertainty in Machine Learning for Healthcare.

Research Spotlight: Predicting Health Crises From Early Warning Signs in Patient Medical Records
Featuring Sebastián Gallo Bernal, MD, and Oleg S. Pianykh, PhD

Sebastián Gallo Bernal, MD, a postdoctoral fellow in the Department of Radiology, is co-lead author of a recent study in Nature Scientific Reports, “Predicting Health Crises From Early Warning Signs in Patient Medical Records.” Oleg S. Pianykh, PhD, an investigator in the Department of Radiology and Assistant Professor of Radiology at Harvard Medical School is the senior author.

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Snapshot of Science for January 2023