Snapshot of Science for November 2021

Welcome to our Snapshot of Science for November 2021

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:

16 new studies published in high impact journals, along with 11 summaries submitted by the research teams
19 new research-related press releases from the Mass General Public Affairs office
3 posts from the Mass General Research Institute blog

Publications

MODELING THE HEALTH AND COST BENEFITS OF COVID-19 VACCINATION PROGRAM
Clinical Outcomes and Cost-effectiveness of COVID-19 Vaccination in South Africa
Reddy KP, Fitzmaurice KP, Scott JA, Harling G, Lessells RJ [et al.], Siedner MJ
Published in Nature Communications on Friday, October 29, 2021 | *Summary available

A KEY GENETIC NETWORK IN HUMAN EMBRYONIC STEM CELLS
Integrated Loss- and Gain-of-Function Screens Define a Core Network Governing Human Embryonic Stem Cell Behavior
Naxerova K, Di Stefano B, Makofske JL, Watson EV, de Kort MA [et al.], Elledge SJ
Published in Genes & Development on Monday, November 1, 2021 | *Summary available

A LOW-COST TREATMENT FOR NEUROINFLAMMATORY DISEASE?
D-Mannose Suppresses Oxidative Response and Blocks Phagocytosis in Experimental Neuroinflammation
Wang J, Jalali Motlagh N, Wang C, Wojtkiewicz GR, Schmidt S [et al.], Chen JW
Published in Proceedings of the National Academy of Sciences of the USA on Tuesday, November 2, 2021 | *Summary available

GENETIC RESISTANCE TESTING AND HIV SUPPRESSION
Resistance Testing for Management of HIV Virologic Failure in Sub-Saharan Africa : An Unblinded Randomized Controlled Trial
Siedner MJ, Moosa MS, McCluskey S, Gilbert RF, Pillay S [et al.], Marconi VC
Published in Annals of Internal Medicine on Tuesday, October 26, 2021 | *Summary available

SARS-COV-2 ANTIBODY TRANSFER INTO BREASTMILK
Selective Functional Antibody Transfer into the Breastmilk After SARS-CoV-2 Infection
Pullen KM, Atyeo C, Collier AY, Gray KJ, Belfort MB [et al.], Alter G
Published in Cell Reports on Friday, October 22, 2021

A NORMALIZATION AND STATISTICAL ASSOCIATION TESTING FRAMEWORK
Single-Cell Normalization and Association Testing Unifying CRISPR Screen and Gene Co-Expression Analyses with Normalisr
Wang L
Published in Nature Communications on Thursday, November 4, 2021

CELLULAR MECHANISMS DRIVING M2-TYPE MACROPHAGE POLARIZATION
Global Characterization of Macrophage Polarization Mechanisms and Identification of M2-type Polarization Inhibitors
He L, Jhong JH, Chen Q, Huang KY, Strittmatter K [et al.], Marneros AG
Published in Cell Reports on Tuesday, November 2, 2021 | *Summary available | Press Release

HOME-BASED OXYGEN THERAPY FOR LUNG DISEASE
Home Oxygen Therapy for Adults with Chronic Obstructive Pulmonary Disease or Interstitial Lung Disease
Wenger HC, Cifu AS, Lee CT
Published in JAMA on Tuesday, November 2, 2021

THE GENE NETWORK USED BY OSTEOCYTES TO DEVELOP DENDRITES
Control of Osteocyte Dendrite Formation by Sp7 and its Target Gene Osteocrin
Wang JS, Kamath T, Mazur CM, Mirzamohammadi F, Rotter D [et al.], Wein MN
Published in Nature Communications on Monday, November 1, 2021 | *Summary available | Press Release

OVERCOMING THERAPEUTIC RESISTANCE TO ICBs
Dendritic Cell Paucity in Mismatch Repair-proficient Colorectal Cancer Liver Metastases Limits Immune Checkpoint Blockade Efficacy
Ho WW, Gomes-Santos IL, Aoki S, Datta M, Kawaguchi K [et al.], Jain RK
Published in Proceedings of the National Academy of Sciences of the USA on Tuesday, November 9, 2021 | *Summary available

ENROLLMENT DIVERSITY IN PRECISION ONCOLOGY TRIALS
Racial and Ethnic Disparities Among Participants in Precision Oncology Clinical Studies
Aldrighetti CM, Niemierko A, Van Allen E, Willers H, Kamran SC
Published in JAMA on Monday, November 1, 2021 | *Summary available

CONSEQUENCES OF PHAGOSOMAL MEMBRANE DAMAGE
Mycobacterium Tuberculosis Canonical Virulence Factors Interfere with a Late Component of the TLR2 Response
Hinman AE, Jani C, Pringle SC, Zhang WR, Jain N [et al.], Barczak AK
Published in eLife on Wednesday, November 10, 2021

A NEW SUITE OF LUMINESCENT MOLECULES
Bright and Stable Luminescent Probes for Target Engagement Profiling in Live Cells
Payne NC, Kalyakina AS, Singh K, Tye MA, Mazitschek R
Published in Nature Chemical Biology on Monday, November 1, 2021 | *Summary available

MECHANISMS OF TRAINED IMMUNITY INDUCED BY BCG VACCINE
Single-Cell Transcriptomic Profiles Reveal Changes Associated with BCG-induced Trained Immunity and Protective Effects in Circulating Monocytes
Kong L, Moorlag SJCFM, Lefkovith A, Li B, Matzaraki V [et al.], Xavier RJ
Published in Cell Reports on Tuesday, November 16, 2021 | *Summary available

VACCINE IMMUNOGENS AND ANTI-MALARIAL ANTIBODIES
Vaccination in a Humanized Mouse Model Elicits Highly Protective PfCSP-targeting Anti-Malarial Antibodies
Kratochvil S, Shen CH, Lin YC, Xu K, Nair U [et al.], Batista FD
Published in Immunity on Wednesday, November 10, 2021

A NEWLY IDENTIFIED PATIENT WITH STERILIZING CURE FOR HIV
A Possible Sterilizing Cure of HIV-1 Infection Without Stem Cell Transplantation
Turk G, Seiger K, Lian X, Sun W, Parsons EM [et al.], Yu XG
Published in Annals of Internal Medicine on Tuesday, November 16, 2021

Publication Summaries

Cost, supply, and logistics present challenges to COVID-19 vaccine rollout in low- and middle-income countries. We use a validated computer simulation model to demonstrate that expanding a COVID-19 vaccination program in South Africa would save lives and potentially decrease health care costs by reducing hospitalizations. Importantly, we show that the pace of vaccine rollout (doses administered per day) is likely more important than relatively small differences in vaccine efficacy to maximizing public health benefits and cost-effectiveness. These results provide clinical and economic evidence for the prompt funding and rapid distribution of COVID-19 vaccines by global policymakers to resource-limited settings.

(Summary submitted by Krishna Reddy, MD, MS, Division of Pulmonary & Critical Care Medicine, Department of Medicine)

At the earliest stages of human embryonic development, a small collection of cells known as human embryonic stem cells (hESCs) orchestrates growth and differentiation, eventually giving rise to highly specialized human tissues. As pluripotent cells—progenitors of every type of cell type in the body—hESCs are of central interest to developmental and regenerative biologists. Many genes driving hESC functioning have previously been identified, but powerful tools that shed light on the interrelated activities of these genes have only emerged more recently. We used genome-wide genetic screening to both over-express and inactivate ("knock out") tens of thousands of genes in hESCs. We uncovered key networks that simultaneously control pluripotency and readiness for cell death (apoptosis), helping to ensure optimal conditions for embryonic development. Our findings offer new insights into cancer genetics and a novel approach for regenerative medicine research.

Inflammatory cells called macrophages and microglia play key roles in neuroinflammatory diseases such as multiple sclerosis (MS). Current drugs for MS do not directly target these cells. We found that D-mannose, a simple sugar, decreased oxidative stress and blocked phagocytosis from these cells, resulting in less damage and boosting the reparative response from these cells. Our findings suggest that D-mannose, an over-the-counter supplement, may be an effective, low-cost treatment option for MS and other neuroinflammatory diseases. The availability of such a drug could significantly improve patient access to needed drugs and improve outcome for patients suffering from neuroinflammatory diseases.

(Summary submitted by John Chen, MD, PhD, Division of Neuroradiology, Department of Radiology)

GENETIC RESISTANCE TESTING AND HIV SUPPRESSION
Resistance Testing for Management of HIV Virologic Failure in Sub-Saharan Africa: An Unblinded Randomized Controlled Trial
Siedner MJ, Moosa MS, McCluskey S, Gilbert RF, Pillay S [et al.], Marconi VC
Published in Annals of Internal Medicine on Tuesday, October 26, 2021

In this randomized clinical trial, led by investigators at Mass General in partnership with colleagues in Uganda and South Africa, we attempted to understand how to best manage patients with HIV who are struggling with treatment. To do so, study participants with HIV and treatment failure in Uganda and South Africa were randomized to usual care or the additional of a laboratory test to determine if they harbor a virus that is resistant to the medicines they were taking. These so-called "resistance tests" are commonly used worldwide but have not been tested in Africa due to concerns about cost and logistics. We found no difference nine months later in how many participants in each arm had achieved disease control, which were relatively low in both groups (60%). We concluded that patients with treatment failure require additional support to help them overcome the many barriers to successful treatment—and that a single blood test was no magic bullet.

(Summary submitted by Mark Seidner, MD, MPH, Division of Infectious Diseases, Department of Medicine)

Activation of macrophages can lead to a population of macrophages, called M2-type polarized macrophages, that can promote certain diseases, such as "wet" age-related macular degeneration, organ fibrosis, or cancer. In our new paper we describe the results of a detailed global characterization of the cellular mechanisms that drive M2-type polarization of macrophages. Moreover, we performed drug screens that identified drugs that are able to inhibit this process. These drugs that are currently used for other indications can now be repurposed to ameliorate diseases that are promoted by M2-type macrophages.

(Summary submitted by Alexander Marneros, MD, PhD, Cutaneous Biology Research Center, Department of Dermatology)

Buried deep within mineralized bone tissue, osteocytes use a network of projections called dendrites to communicate with other important cells in bone. During aging, osteocytes lose these dendrites, and this loss contributes to the common disease osteoporosis. However, exactly how osteocytes develop and maintain their dendrites has remained unknown until now. In this study, we describe a gene network used by osteocytes to develop dendrites. In doing so, we uncovered a key role for a protein called osteocrin in promoting healthy dendrite growth. These findings suggest novel ways to maintain and improve bone strength for patients with osteoporosis.

(Summary submitted by Marc Wein, MD, PhD, Division of Endocrinology, Department of Medicine)

Our study highlights the critical importance of investigating tumors in their natural microenvironment in oncology research and demonstrates a novel therapeutic approach to overcome resistance to immune-checkpoint blockers (ICBs) in colorectal cancer liver metastasis (CRC-Lim). We found that CRC-Lims in mice are highly resistant to ICBs, recapitulating the paucity of dendritic cells and poor response to ICBs seen in CRC-Lim in patients. By contrast, subcutaneously grown CRCs are responsive to the same ICBs, and fail to mimic the clinical features of CRC-Lim. The study also shows that CRC-Lims become responsive to ICBs by boosting dendritic cells with Flt3L.

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

This cross-sectional analysis evaluated breast, prostate, lung, and colorectal cancer studies in the Clinicaltrials.gov registry with precision medicine objectives and reporting race and ethnicity. We found that most studies (>50%) do not report race or ethnicity, but reporting did increase over time. In addition, minority racial groups (Black, Hispanic, American Indian/Alaskan Native) were significantly underrepresented, while non-Hispanic White participants were overrepresented relative to their incidence in the U.S. cancer population. Our findings demonstrate an urgent need to increase enrollment of diverse participants onto precision oncology studies so that all individuals and communities may benefit from cancer research breakthroughs and personalized treatments.

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

A NEW SUITE OF LUMINESCENT MOLECULES
Bright and Stable Luminescent Probes for Target Engagement Profiling in Live Cells
Payne NC, Kalyakina AS, Singh K, Tye MA, Mazitschek R
Published in Nature Chemical Biology on Monday, November 1, 2021

The pioneering biologist Sydney Brenner once said, "Progress in science depends on new techniques, new discoveries and new ideas, probably in that order." In our manuscript, we report the development of CoraFluors, a suite of novel luminescent molecules optimized for biological applications, including measuring protein-protein interactions, binding of drugs to their targets, and sensitive fluorescence imaging studies. CoraFluors enable the quantitative profiling of biomolecular interactions in cell-free systems—and even inside living cells. Our technology promises to accelerate biomedical research, offering scientists unparalleled flexibility and assay performance for both studying fundamental biological processes, as well as developing new therapeutics.

(Summary submitted by Ralph Mazitschek, PhD, Center for Systems Biology, Department of Radiology)

Bacillus Calmette-Guérin (BCG) vaccine, widely used to protect against tuberculosis, confers non-specific protection against other infections by boosting innate immune responses. To better understand this immune reprogramming, termed "trained immunity," we performed single-cell transcriptomic profiling in monocytes before and after BCG vaccination. We find that BCG reduces systemic inflammation and identify 75 genes with altered response to secondary stimulation by bacterial lipopolysaccharide. BCG alters gene co-expression, increasing coordination of a module containing isoforms encoding cytoprotective humanin, which we confirm induces trained immunity in vitro. Our findings uncover mechanisms of trained immunity that could be leveraged to improve vaccine development.

(Summary submitted by Heather Kang, Broad Institute)

Our research team at the Ragon Institute of Mass General, MIT and Harvard along with Natalia Laufer's team at INBIRS have identified the second person living with HIV who seems to have rid herself completely of the virus. This patient has been asked to be referred to as the Esperanza (Hope) Patient. Our group assayed over 1.5 billion cells and did not identify a single intact, replication-competent HIV. Two other individuals were able to achieve this "sterilizing cure" through a stem cell transplant. The finding of the Esperanza Patient is extraordinary because her own immune system was able to eradicate HIV without stem cell transplant. This research gives hope for a path to a cure for other people living with HIV.

(Summary submitted by Kyra Seiger, Ragon Institute of Mass General, MIT and Harvard)

Press Releases

In Children with Multiple Sclerosis, Teriflunomide Tempers Lesion Growth
Featuring Tanuja Chitnis, MD

The drug's ability to reduce the number of new or enlarged lesions that are detected through MRI suggests that it might have beneficial effects in children with relapsing forms of multiple sclerosis.

New Details Behind How the Shigella Pathogen Delivers Bacterial Proteins Into Our Cells
Featuring Poyin Chen, PhD

In a study published in mBio, a team at Mass General has uncovered important details about Shigella that may help researchers devise new ways to block infection.

Strategy to Overcome Tumors' Resistance to Immunotherapy Generates Promising Clinical Trial Results
Featuring David Ting, MD

A new clinical trial led by investigators at Mass General indicates that combining radiation with immune checkpoint inhibitors may be an effective strategy to combat treatmement-resistant colorectal and pancreatic cancers.

B Cells Do More than Just Fight Infection: A New Study Shows They Can Support Tissue Repair and Regeneration After Injury
Featuring Mark Poznansky, MD, PhD, and Ruxandra Sîrbulescu, PhD

A research team at the Vaccine and Immunotherapy Center is exploring the novel protective roles that B cells may play in the context of injury.

Scientists Create New Best-in-Class Malarial Antibody
Featuring Facundo D. Batista, PhD

Researchers have created a new best-in-class anti-malarial antibody using an approach that may allow them to create even more protective variants of anti-malarial monoclonal antibodies.

Commonly Prescribed Treatment Regimen After Stent Procedures May Be Outdated
Featuring Neel M. Butala, MD, MBA

A recent analysis indicates that the prolonged antiplatelet drug regimen may be outdated and should not be followed for most patients today.

The HEALEY ALS Platform Trial Completes Enrollment for First Three Investigational Treatments
Featuring Merit Cudkowicz, MD

The HEALEY ALS Platform Trial, the first platform trial for this disease, is designed to evaluate multiple investigational treatments simultaneously, thus accelerating the development of effective and breakthrough treatments for people living with ALS.

Scientists Identify Second HIV Patient Whose Body Appears to Have Rid Itself of the Virus
Featuring Xu Yu, MD

These findings, especially with the identification of a second case, indicate there may be an actionable path to a sterilizing cure for people who are not able to do this on their own.

Researchers Discover New Insights About Tau Proteins in People Living with ALS
Featuring Ghazaleh Sadri-Vakili, PhD

A team led by investigators has shown that people living with ALS, or Lou Gehrig's disease, who carry a mutation in the C9orf72 gene exhibit elevated levels of tau and phosphorylated tau protein in the motor cortex region of the brain

Artificial Intelligence-Based Method Predicts Risk of Atrial Fibrillation
Featuring Steven A. Lubitz, MD, MPH, and Shaan Khurshid, MD, MPH

The AI-based method predicted atrial fibrillation risk on its own and was synergistic when combined with known clinical risk factors for predicting atrial fibrillation. The method was also highly predictive in subsets of individuals such as those with prior heart failure or stroke.

Augmented Reality Technology Paves the Way for Safer Spine Surgery
Featuring John H. Shin, MD

This novel technology can make complex surgery safer and more accurate by improving surgeons' visualization of anatomy and critical structures.

Research Uncovers New Insights on ALS and Points to a Potentially Promising Treatment Strategy
Featuring Ghazaleh Sadri-Vakili, PhD

Targeting tau with a new class of small molecules can reverse ALS-induced changes in mitochondria's shape and function.

Lingering COVID Symptoms in Young Competetive Athletes Rare, Study Finds
Featuring Aaron Baggish, MD

Persistent symptoms following COVID-19 infections in collegiate athletes appear to be rare. Experiencing chest pain upon returning to exercise is a rare but concerning finding that may warrant further clinical workup.

SARS-CoV-2 Vaccines Safe and Immunogenic in Most People With Cancer
Featuring Vivek Naranbhai, MBChB, PhD, DPhil

Collectively, cancer patients' responses to the three vaccines are modestly impaired relative to healthy people, but most patients have responses that are likely to be sufficient to protect against severe disease.

Baby Teeth May One Day Help Identify Kids at Risk for Mental Disorders Later in Life
Featuring Erin C. Dunn, ScD, MPH

New study links thickness of growth lines in the teeth with whether the mother experienced psychological distress or received social support in the neonatal period.

Novel Tool for Reporting Symptoms after Vaccination Helped Health Care Workers Discern Injection Side Effects From COVID-19 Symptoms
Featuring Erica S. Shenoy, MD, PhD

A decision-support tool helped health care workers distinguish symptoms associated with COVID-19 vaccinations from symptoms of the virus itself, found a study by a team of investigators at several hospitals in the Mass General Brigham system.

Study Identifies Specific Drugs That Can Prevent Disease-Causing Activity of Key Immune Cells
Featuring Alexander Marneros, MD, PhD

Researchers have uncovered the signaling mechanisms and changes in cell metabolism that occur during macrophage polarization in unprecedented detail.

Research Reveals How Osteoctyes Form Critical Structures That Maintain Bone Health
Featuring Marc Wein, MD, PhD

An international team led by investigators at Mass General has revealed how osteocytes form dendrites—a discovery that might lead to strategies to maintain these projections and therefore help protect individuals' bone health throughout life.

Noninvasive Imaging Strategy Detects Dangerous Blood Clots in the Body
Featuring David Sosnovik, MD, FACC

Investigators have developed and tested a targeted contrast agent that can detect blood clots in the hearts of patients with atrial fibrillation, or an irregular heartbeat.

Blog Posts

Could A Hormone Produced by Alzheimer's Disease Hold the Key to Treating Alzheimer's Disease?
Featuring Christiane Wrann, DVM, PhD

Researchers from Mass General and colleagues have learned more about how exercise benefits brain health—insights that open a promising new approach to treating Alzheimer's disease.

The Life and Science of Jack Belliveau

Remembering the larger-than-life Mass General researcher who played a key role in the introduction of fMRI imaging.

Excerpt from 20+20 Vision: 40 Years on the Cutting Edge of Science and Care (Book celebrating the 40th Anniversary of the Martinos Center)

Discovery of a Second Patient with Sterilizing Cure for HIV Sparks Hope for New Treatment Strategy
Featuring Xu Yu, MD

The findings could one day inform the development of a vaccine that eliminates the need for daily HIV medication.

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Snapshot of Science for November 2021