Snapshot of Science for October 2021

Personalizing Lung Cancer Treatments
Three Subtypes of Lung Cancer Fibroblasts Define Distinct Therapeutic Paradigms
Hu H, Piotrowska Z, Hare PJ, Chen H, Mulvey HE [et al.], Engelman JE
Published in Cancer Cell on September 28, 2021

Cortical Mean Diffusivity as a Predictor of Long-term Cognitive Decline
Association of Cortical Microstructure with Amyloid-B and Tau: Impact on Cognitive Decline, Neurodegeneration and Clinical Progression in Older Adults
Rodriguez-Vieitez E, Montal V, Sepulcre J, Lois C, Hanseeuw B [et al.], Vannini P
Published in Molecular Psychiatry on September 29, 2021

Expanding the Atlas of Genetic Associations in Non-European Populations
A Cross-Population Atlas of Genetic Associations for 220 Human Phenotypes
Sakaue S, Kanai M, Tanigawa Y, Karjalainen J, Kurki M [et al.], Okada Y
Published in Nature Genetics on September 30, 2021

A Central Aspect of Polycomb Group Function
A Polycomb Domain Found in Committed Cells Impairs Differentiation When Introduced into PRC1 in Pluripotent Cells
Jaensch ES, Zhu J, Cochrane JC, Marr SK, Oei TA [et al.], Kingston RE
Published in Molecular Cell on October 1, 2021

The Relationship Between Replication Timing and Histone Marks
Collective Regulation of Chromatin Modifications Predicts Replication Timing During Cell Cycle
Van Rechem C, Ji F, Chakraborty D, Black JC, Sadreyev RI, Whetstine JR
Published in Cell Reports on October 5, 2021

Targeting Hepatic SGK1 May Have Therapeutic Potential in Type 2 Diabetes
Serum- and Glucocorticoid-induced Kinase Drives Hepatic Insulin Resistance by Directly Inhibiting AMP-activated Protein Kinase
Zhou B, Zhang Y, Li S, Wu L, Fejes-Toth G, Naray-Fejes-Toth A, Soukas AA
Published in Cell Reports on October 5, 2021

Molecularly Defining Cell Types Across the Cerebellum
A Transcriptomic Atlas of Mouse Cerebellar Cortex Comprehensively Defines Cell Types
Kozareva V, Martin C, Osorno T, Rudolph S, Guo C [et al.], Macosko E
Published in Nature on October 6, 2021

A Novel IEG Regulatory Pathway with Therapeutic Implications
NR4A1 Regulates Expression of Immediate Early Genes, Suppressing Replication Stress in Cancer
Guo H, Golczer G, Wittner BS, Langenbucher A, Zachariah M [et al.], Haber DA
Published in Molecular Cell on October 7, 2021

The Role of Tissue Morphology in Dermal Remodeling Outcomes
MagneTEskin-Reconstructing Skin by Magnetically Induced Assembly of Autologous Microtissue Cores
Fuchs C, Pham L, Wang Y, Farinelli WA, Anderson RR, Tam J
Published in Science Advances on October 8, 2021 | *Summary available

Oncologist Perceptions of Patient Requests to Record Visits
Do You Mind If I Record?: Perceptions and Practice Regarding Patient Requests to Record Clinic Visits in Oncology
Jimenez RB, Johnson AE, Horick NK, Hlubocky FJ, Lei Y [et al.], Peppercorn JM
Published in Cancer on October 11, 2021

Combined Ipilimumab and Nivolumab Therapy Holds Promise for Leptomeningeal Disease Patients
Phase II Study of Ipilimumab and Nivolumab in Leptomeningeal Carcinomatosis
Brastianos PK, Strickland MR, Lee EQ, Wang N, Cohen JV [et al.], Sullivan RJ
Published in Nature Communications on October 12, 2021 | *Summary available

A New Technique for Enabling OCT Molecular Imaging
Spectral- and Polarization-dependent Scattering of Gold Nanobipyramids for Exogenous Contrast in Optical Coherence Tomography
Keahey P, Si P, Razavi M, Yu S, Lippok N, [et al.], Bouma B
Published in Nano Letters on October 13, 2021 | *Summary available

Stimulus Gestalt Representation Within the Human Primary Visual Cortex
The Global Configuration of Visual Stimuli Alters Co-Fluctuations of Cross-Hemispheric Human Brain Activity
Nasr S, Kleinfeld D, Polimeni JR
Published in Journal of Neuroscience on October 15, 2021 | *Summary available

Insights From 4D Chromosome Modeling
Four-Dimensional Chromosome Reconstruction Elucidates the Spatiotemporal Reorganization of the Mammalian X Chromosome
Lappala A, Wang CY, Kriz A, Michalk H, Tan K, Lee JT, Sanbonmatsu KY
Published in PNAS on October 19, 2021 | *Summary available

Sex Differences in Placental Immune Response to SARS-CoV-2
Maternal SARS-CoV-2 Infection Elicits Sexually Dimorphic Placental Immune Responses
Bordt EA, Shook LL, Atyeo C, Pullen KM, De Guzman RM [et al.], Edlow AG
Published in Science Translational Medicine on October 19, 2021 | *Summary available

Pregnancy, Lactation and COVID-19 mRNA Vaccine Response
COVID-19 mRNA Vaccines Drive Differential Antibody Fc-Functional Profiles in Pregnant, Lactating and Non-Pregnant Women
Atyeo C, DeRiso EA, Davis C, Bordt EA, De Guzman RM [et al.], Alter G
Published in Science Translational Medicine on October 19, 2021 | *Summary available

How Tumor Cells Escape the Prostate and Evade the Immune System
Human Prostate Cancer Bone Metastases Have an Actionable Immunosuppressive Microenvironment
Kfoury Y, Baryawno N, Severe N, Mei S, Gustafsson K [et al.], Kharchenko PV
Published in Cancer Cell on October 19, 2021 | *Summary available

Expanding Our Understanding of Tuberculosis Lineages
Population Structure, Biogeography and Transmissibility of Mycobacterium Tuberculosis
Freschi L, Vargas R Jr, Husain A, Kamal SMM, Skrahina A [et al.], Farhat MR
Published in Nature Communications on October 20, 2021 | *Summary available

Enabling Onsite THC Detection in Oral Fluids Within Minutes
A Rapid Assay Provides On-Site Quantification of Tetrahydrocannabinol in Oral Fluid
Yu H, Lee H, Cheong J, Woo SW, Oh J [et al.], Lee H
Published in Science Translational Medicine on October 20, 2021 | *Summary available

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 November 2, 2021 | *Summary available

The Role of Tissue Morphology in Determining Dermal Remodeling Outcomes
MagneTEskin-Reconstructing Skin by Magnetically Induced Assembly of Autologous Microtissue Cores
Fuchs C, Pham L, Wang Y, Farinelli WA, Anderson RR, Tam J
Published in Science Advances on October 8, 2021

Skin wounds are an immense medical and socioeconomic burden that has bedeviled the regenerative medicine field for decades. Our group previously invented a method to improve wound healing using autologous micro skin tissue cores (MSTCs) that can be harvested without the donor site morbidity of traditional skin grafts. Here, we developed a new technology to magnetically assemble MSTCs while maintaining their natural epidermal-dermal orientation to produce constructs that highly resemble natural skin structure. This method resulted in faster and more orderly wound healing and revealed a previously unknown role for tissue morphology in determining the fate of wound tissue remodeling.

(Summary submitted by Christiane Fuchs, PhD, of the ‪Wellman Center for Photomedicine and Department of Dermatology)

Combined Ipilimumab and Nivolumab Therapy Holds Promise for Leptomeningeal Disease
Phase II Study of Ipilimumab and Nivolumab in Leptomeningeal Carcinomatosis
Brastianos PK, Strickland MR, Lee EQ, Wang N, Cohen JV [et al.], Sullivan RJ
Published in Nature Communications on October 12, 2021

Leptomeningeal carcinomatosis (LMD)—the spread of cancer to the lining of the brain and/or spinal cord—is a devastating complication of cancer. The vast majority of patients with LMD are excluded from clinical trials. Immune checkpoint blockade, which stimulates a patient's immune system to fight cancer, has revolutionized the management of many types of cancers including melanoma and lung cancer. However, patients with LMD have largely not been enrolled in trials with immunotherapy. In these two published studies, we demonstrated in patients—and microscopically in the laboratory—that immune checkpoint blockade has promising activity for patients with LMD.

(Summary submitted by Priscilla Brastianos, MD, of the Division of Hematology/Oncology and Mass General Cancer Center)

A New Technique for Enabling OCT Molecular Imaging
Spectral- and Polarization-dependent Scattering of Gold Nanobipyramids for Exogenous Contrast in Optical Coherence Tomography
Keahey P, Si P, Razavi M, Yu S, Lippok N [et al.], Bouma B
Published in Nano Letters on October 13, 2021

The lymphatic system plays a critical role in maintaining tissue fluid balance, regulating the immune system and transport of nutrients. Developing new imaging techniques to visualize the lymphatic network is key to improving our understanding of lymphatic anatomy and function as it relates to disease progression and cancer. Here we demonstrate a new in vivo molecular imaging technique utilizing nanoparticles and optical coherence tomography to visualize lymphatic networks and track lymph fluid flow. This new technique can visualize multiple exogenous contrast agents at micron-scale resolutions and up to several millimeter in depth.

(Summary submitted by Pelham Keahey, PhD, of the ‪Wellman Center for Photomedicine)

Stimulus Gestalt Representation Within the Human Primary Visual Cortex
The Global Configuration of Visual Stimuli Alters Co-Fluctuations of Cross-Hemispheric Human Brain Activity
Nasr S, Kleinfeld D, Polimeni JR
Published in Journal of Neuroscience on October 15, 2021

Classic neuroscience studies in animal models demonstrated that electrophysiological neural activity within distinct locations in the brain becomes synchronized when the locations represent the same "object," such as a figure in the visual field. In this study, using functional MRI (fMRI), neural activity was measured simultaneously in multiple locations of the human visual cortex while subjects viewed various visual stimuli. When these locations represented a single object, changes in the correlations of the functional MRI data were detected, in agreement with the prior electrophysiological studies. This finding suggests that rapid dynamics of synchronous neuronal activity can be detected in humans using fMRI.

(Summary submitted by Shahin Nasr, PhD, of the ‪Martinos Center and Department of Radiology)

Insights From 4D Chromosome Modeling
Four-Dimensional Chromosome Reconstruction Elucidates the Spatiotemporal Reorganization of the Mammalian X Chromosome
Lappala A, Wang CY, Kriz A, Michalk H, Tan K, Lee JT, Sanbonmatsu KY
Published in PNAS on October 19, 2021

Chromosomes are long and stringy like spaghetti. If stretched out, the total length of DNA in just one cell in our body would extend almost two miles. Thus, in order to fit into our cell, our chromosomes have to be folded, but the folding has to be organized in a dynamic way throughout development and life so that our cells can access the right information at the right time. A multidisciplinary team has now developed a computational algorithm, 4DHiC, to extract 3D folding patterns across time using the female inactive X-chromosome as a model. The novel computational method unveiled principles behind the origami-like structures of the X-chromosome and enabled visualizing how gene silencing spreads in 4D (space + time) during this female-unique process.

(Summary submitted by Anna Lappala, PhD, of the Department of Molecular Biology)

Sex Differences in the Placental Immune Response to SARS-CoV-2
Maternal SARS-CoV-2 Infection Elicits Sexually Dimorphic Placental Immune Responses
Bordt EA, Shook LL, Atyeo C, Pullen KM, De Guzman RM [et al.], Edlow AG
Published in Science Translational Medicine on October 19, 2021

Males fare worse against SARS-CoV-2 infection than do females. Given that maternal infection can impact both the mother and the fetus, we wondered whether this vulnerability may even start in utero. This study found that mothers infected with SARS-CoV-2 and pregnant with a male fetus generated fewer antibodies against SARS-CoV-2 and transferred fewer of these antibodies to the fetus compared to mothers pregnant with a female fetus. We found that maternal SARS-CoV-2 infection increased levels of antiviral proteins in the placenta, only when the mother was pregnant with a male fetus. This study highlights the need to study sex differences in fetal responses to maternal infections.

(Summary submitted by Evan Bordt, PhD, of the Department of Pediatrics)

Pregnancy, Lactation and COVID-19 Vaccine Response
COVID-19 mRNA Vaccines Drive Differential Antibody Fc-Functional Profiles in Pregnant, Lactating and Non-Pregnant Women
Atyeo C, DeRiso EA, Davis C, Bordt EA, De Guzman RM [et al.], Alter G
Published in Science Translational Medicine on October 19, 2021

Pregnancy represents an immunological marvel, whereby the maternal immune system learns to tolerate the growth of a foreign graft for 10 months. From the time of implantation of the embryo, the maternal immune system experiences waves of tissue repair, immune suppression and bursts of immune transfer, aimed at supporting the survival of the maternal:fetal dyad. While traditionally pregnancy was regarded as an immune-tolerant state, rendering women more vulnerable to infections and disease during pregnancy, emerging data point to pregnancy as a dynamic immunologically unique state, not a compromised one. In this paper, we dug deeply into this biology, characterizing the immune response to COVID-19 mRNA vaccination for the first time. We demonstrated that while pregnant and lactating women respond more slowly to vaccination, two doses of mRNA vaccines induced robust immune responses that differed slightly across the Moderna and Pfizer/BioNTech vaccines.

(Summary submitted by Elizabeth DeRiso, PhD, of the Ragon Institute)

How Tumor Cells Escape the Prostate and Evade the Immune System
Human Prostate Cancer Bone Metastases Have an Actionable Immunosuppressive Microenvironment
Kfoury Y, Baryawno N, Severe N, Mei S, Gustafsson K [et al.], Kharchenko PV
Published in Cancer Cell on October 19, 2021

Prostate cancer is the most common type of cancer in men. If the cancer becomes metastatic—spreading outside of the prostate—it is an incurable disease. Metastatic prostate cancer kills more than 30,000 Americans every year. Our project focused on patients whose prostate cancer had spread to the bone marrow of the spine. Taking these tumor samples from the operating room to the laboratory, we analyzed the cancer cells and the cells of the immune system. Our research focused on how the tumor cells managed to escape the prostate and evade the normal immune system. Our goal is to use this information to develop new therapies that specifically target metastatic prostate cancer.

(Summary submitted by David Sykes, MD, PhD, of the Division of Hematology/Oncology and Mass General Cancer Center)

Expanding Our Understanding of Mycobacterium Tuberculosis Lineages
Population Structure, Biogeography and Transmissibility of Mycobacterium Tuberculosis
Freschi L, Vargas R Jr, Husain A, Kamal SMM, Skrahina A [et al.], Farhat MR
Published in Nature Communications on October 20, 2021

M. tuberculosis bacterium, the cause of the widely prevalent Tuberculosis infection, is classified into nine different global genotypes, a.k.a. lineages, that each have a distinct geographic distribution. In this study, we reexamined the genetic diversity of the M. tuberculosis lineages using the most comprehensive whole genome sequencing dataset to date. This spans samples collected by the World Health Organization for surveying resistance in five countries. We discovered new sublineages within M. tuberculosis lineages 1 and 3 and provided evidence that M. tuberculosis lineages have different abilities to transmit disease across and within certain human populations.

(Summary submitted by Maha Farhat, MD, MSc, of the Division of Pulmonary and Critical Care Medicine)

Enabling Onsite THC Detection in Oral Fluids Within Minutes
A Rapid Assay Provides On-Site Quantification of Tetrahydrocannabinol in Oral Fluid
Yu H, Lee H, Cheong J, Woo SW, Oh J [et al.], Lee H
Published in Science Translational Medicine on October 20, 2021

Smoking marijuana can impair cognitive functions and increases the risk of vehicular accidents. Detecting recent use of marijuana, however, is challenging; commercial kits have low sensitivity, while laboratory-based tests have long turnaround time. We devised a new sensing platform, EPOCH (express probe for on-site cannabis inhalation), for on-site quantification of oral tetrahydrocannabinol within 5 minutes. EPOCH integrates novel engineering features like a radial flow assay and transmission optics-based signal processing. In a pilot field testing, EPOCH not only identified recent (<12 hours) marijuana users but also distinguished marijuana users from non-users with 100% accuracy.

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

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 November 2, 2021

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 in Cell Reports, 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, of the Cutaneous Biology Research Center and Department of Dermatology)

Fibroblasts Could Serve as New Key to Enhancing Personalized Treatment for Lung Cancer Patients
Featuring Haichuan Hu, MD, PhD

Three subtypes of cancer-associated fibroblasts could guide the design of personalized treatment for lung cancer patients, according to a new study in Cancer Cell led by researchers at Mass General.

Immunotherapy May Benefit Patients with Cancer That Has Spread to Tissues Around the Brain
Featuring Priscilla K. Brastianos, MD

Two new studies indicate that immunotherapy may benefit people with leptomeningeal carcinomatosis, a rare but serious complication of cancer that has spread to the brain and/or spinal cord.

Pregnant and Lactating Women Should Adhere Closely to Recommended COVID-19 Vaccine Schedules to Attain Full Antibody Protection
Featuring Andrea Edlow, MD, MSc

A new study indicates that the two-dose immunization schedule for COVID-19 mRNA vaccines ultimately stimulates comparable antibody responses in pregnant, lactating, and nonpregnant women of reproductive age, but key antibody functions kick in more slowly in pregnant and lactating women following the first dose.

In Pregnant Women with COVID-19, Sex of Fetus May Influence Maternal and Placental Immune Response and Neonatal Immune Protection
Featuring Andrea Edlow, MD, MSc

In pregnant women who tested positive for SARS-CoV-2, the virus that causes COVID-19, male placentas demonstrated significantly higher levels of certain genes and proteins associated with increased immune activation compared with female placentas.

"Superhuman, but Never Enough": Essay Details Inequities Experienced by Black Women Physicians in the United States
Featuring Fatima Cody Stanford, MD, MPH, MPA, MBA

Black women physicians in the United States face hurdles and inequities that contribute toward their underrepresentation in medicine, argues an essay in The Lancet by Mass General physician Fatima Cody Stanford, MD, MPH, MPA, MBA, and two colleagues.

New Insights on How Different Types of Physical Activity Affect Cardiorespiratory Fitness
Featuring Gregory Lewis, MD

We all know that exercise is good for us and that being fit can lower our risk of heart disease and possibly help us to live longer, but what amount and type of physical activity can change a person's fitness level?

The Poetry of Science and The Peoples' heART: Connecting Poetry and Science with Health Care and Social Justice
Featuring Joshua Sariñana, PhD, Linsey Covino-Deaso, MFA, and Daniel Chonde, MD, PhD

Two art projects have come together to confront health equity and under-representation through the combination of science and art.

Where Are They Now? A Virtual Magic Wand Alumni Panel Recap
Participants in the Virtual Magic Wand Program had a chance to hear about the business experiences of three previous participants.

An MGRI Milestone: Celebrating a New Permanent Fund for the Mass General Research Institute
Featuring Susan A. Slaugenhaupt, PhD

This new gift creates a permanent endowment to support the activities and programs overseen by the Office of the Scientific Director.