tbuckley/cabot-search huggingface dataset:
Pathogenic Autoimmunity in Atherosclerosis Evolves From Initially Protective Apolipoprotein B <sub>100</sub> –Reactive CD4 <sup>+</sup> T-Regulatory Cells
Authors: Dennis Wolf, Teresa Gerhardt, Holger Winkels, Nathaly Anto Michel, Akula Bala Pramod, Yanal Ghosheh, Simon Brunel, Konrad Buscher, Jacqueline Miller, Sara McArdle, Livia Baas, Kouji Kobiyama, Melanie Vassallo, Erik Ehinger, Thamotharampillai Dileepan, Amal Ali, Maximilian Schell, Zbigniew Mikulski, Daniel Sidler, Takayuki Kimura, Xia Sheng, Hauke Horstmann, Sophie Hansen, Lucia Sol Mitre, Peter Stachon, Ingo Hilgendorf, Dalia E. Gaddis, Catherine Hedrick, Chris A. Benedict, Bjoern Peters, Andreas Zirlik, Alessandro Sette, Klaus Ley
Journal: Circulation (2020)

Throughout the inflammatory response that accompanies atherosclerosis, autoreactive CD4+ T-helper cells accumulate in the atherosclerotic plaque. Apolipoprotein B100 (apoB), the core protein of low-density lipoprotein, is an autoantigen that drives the generation of pathogenic T-helper type 1 (TH1) cells with proinflammatory cytokine secretion. Clinical data suggest the existence of apoB-specific CD4+ T cells with an atheroprotective, regulatory T cell (Treg) phenotype in healthy individuals. Yet, the function of apoB-reactive Tregs and their relationship with pathogenic TH1 cells remain unknown.To interrogate the function of autoreactive CD4+ T cells in atherosclerosis, we used a novel tetramer of major histocompatibility complex II to track T cells reactive to the mouse self-peptide apo B978-993 (apoB+) at the single-cell level.We found that apoB+ T cells build an oligoclonal population in lymph nodes of healthy mice that exhibit a Treg-like transcriptome, although only 21% of all apoB+ T cells expressed the Treg transcription factor FoxP3 (Forkhead Box P3) protein as detected by flow cytometry. In single-cell RNA sequencing, apoB+ T cells formed several clusters with mixed TH signatures that suggested overlapping multilineage phenotypes with pro- and anti-inflammatory transcripts of TH1, T helper cell type 2 (TH2), and T helper cell type 17 (TH17), and of follicular-helper T cells. ApoB+ T cells were increased in mice and humans with atherosclerosis and progressively converted into pathogenic TH1/TH17-like cells with proinflammatory properties and only a residual Treg transcriptome. Plaque T cells that expanded during progression of atherosclerosis consistently showed a mixed TH1/TH17 phenotype in single-cell RNA sequencing. In addition, we observed a loss of FoxP3 in a fraction of apoB+ Tregs in lineage tracing of hyperlipidemic Apoe-/- mice. In adoptive transfer experiments, converting apoB+ Tregs failed to protect from atherosclerosis.Our results demonstrate an unexpected mixed phenotype of apoB-reactive autoimmune T cells in atherosclerosis and suggest an initially protective autoimmune response against apoB with a progressive derangement in clinical disease. These findings identify apoB autoreactive Tregs as a novel cellular target in atherosclerosis.
Gold Nanomaterial Engineering for Macrophage‐Mediated Inflammation and Tumor Treatment
Authors: Wanting Chen, Fenfen Zhang, Yanmin Ju, Jin Hong, Ya Ding
Journal: Advanced Healthcare Materials (2020)

Macrophages play an important role in the body's immune defense process. Phenotype imbalance between M1 and M2 macrophages induced by inflammation-related disorders and tumor can also be reversibly converted to treat these diseases. As exogenous substances, a large part of gold-based nanomaterials interact with macrophages once they enter the body, which provides gold nanomaterials a huge advantage to act as imaging contrasts, active substance carriers, and therapeutic agents for macrophage modulation. By cutting off macrophage recruitment, inhibiting macrophage activities, and modulating M1/M2 polarization, gold nanomaterial engineering exerts therapeutic effects on inflammation-related diseases at target sites. In this review, biological functions of macrophages in inflammation-related diseases are introduced, the effect of physicochemical factors of gold nanomaterials including size, shape, and surface chemistry is focused on the interaction between macrophages and gold nanomaterials, and the applications of gold nanomaterials are elaborated for tracking and treating these diseases by macrophages. The rational and smart engineering of gold nanomaterials allows a promising platform for macrophage-mediated inflammation and tumor imaging and treatment.
State handgun purchase age minimums in the US and adolescent suicide rates: regression discontinuity and difference-in-differences analyses
Authors: Julia Raifman, Elysia Larson, Colleen L Barry, Michael Siegel, Michael Ulrich, Anita Knopov, Sandro Galea
Journal: BMJ (2020)

Abstract Objective To evaluate the association between US state policies that establish age 18 or 21 years as the minimum purchaser age for the sale of handguns and adolescent suicide rate. Design Regression discontinuity and difference-in-differences analyses. Setting 46 US states without policy changes between 2001 and 2017; Missouri and South Carolina, which lowered the age for handgun sales in 2007 and 2008, respectively; and West Virginia and Wyoming, which increased the age for handgun sales in 2010. Participants Adolescents aged 13 to 20 years (554 461 961 from 2001 to 2017) in the regression discontinuity analysis, and adolescents aged 18 to 20 years (168 934 041 from 2002 to 2014) in the main difference-in-differences analysis. Main outcome measure Suicide rate per 100 000 adolescents. Results In the regression discontinuity analysis, state policies that limited the sale of handguns to those aged 18 or older (relative to 21 or older) were associated with an increase in suicide rate among adolescents aged 18 to 20 years equivalent to 344 additional suicides in each state where they were in place between 2001 and 2017. In the difference-in-differences analysis, state policies that limited the sale of handguns to those aged 21 or older were associated with 1.91 fewer suicides per 100 000 adolescents aged 18 to 20 years (95% confidence interval −3.13 to −0.70, permutation adjusted P=0.025). In the difference-in-differences analysis, there were 1.83 fewer firearm related suicides per 100 000 adolescents (−2.66 to −1.00, permutation adjusted P=0.002), with no association between age 21 handgun sales policies and non-firearm related suicides. Separate event study estimates indicated increases in suicide rates in states that lowered the age of handgun sales, with no association in states that increased the age of handgun sales. Conclusions A clear discontinuity was shown in the suicide rate by age at age 18 in states that limited the sale of handguns to individuals aged 18 or older. State policies to limit the sale of handguns to individuals aged 21 or older were associated with a reduction in suicide rates among adolescents. Increases in suicide rates were observed after states lowered the age of handgun sales, but no effect was found in states that increased the age of handgun sales.
Immunological detection of serum antibodies in pediatric medical workers exposed to varying levels of SARS-CoV-2
Authors: Danna Tu, Junhua Shu, Xiaoli Wu, Heng Li, Zhi Xia, Yanfang Zhang, Yaohui Fang, Shu Shen, Wuxiang Guan, Hualin Wang, Zhaoxuan Huang, Guirong Wang, Xiaoqin Zhou, Fei Deng
Journal: Journal of Infection (2020)
Emerging role of exosomes in craniofacial and dental applications
Authors: Xin Xing, Shuang Han, Zhi Li, Zubing Li
Journal: Theranostics (2020)

Exosomes, a specific subgroup of extracellular vesicles that are secreted by cells, have been recognized as important mediators of intercellular communication. They participate in a diverse range of physiological and pathological processes. Given the capability of exosomes to carry molecular cargos and transfer bioactive components, exosome-based disease diagnosis and therapeutics have been extensively studied over the past few decades. Herein, we highlight the emerging applications of exosomes as biomarkers and therapeutic agents in the craniofacial and dental field. Moreover, we discuss the current challenges and future perspectives of exosomes in clinical applications.
Tumor Microenvironment-triggered Nanosystems as dual-relief Tumor Hypoxia Immunomodulators for enhanced Phototherapy
Authors: Zijun Shen, Junfei Xia, Qingming Ma, Wei Zhu, Zhen Gao, Shangcong Han, Yan Liang, Jie Cao, Yong Sun
Journal: Theranostics (2020)

Photodynamic therapy (PDT) is a promising strategy in cancer treatment that utilizes photosensitizers (PSs) to produce reactive oxygen species (ROS) and eliminate cancer cells under specific wavelength light irradiation. However, special tumor environments, such as those with overexpression of glutathione (GSH), which will consume PDT-mediated ROS, as well as hypoxia in the tumor microenvironment (TME) could lead to ineffective treatment. Moreover, PDT is highly light-dependent and therefore can be hindered in deep tumor cells where light cannot easily penetrate. To solve these problems, we designed oxygen-dual-generating nanosystems MnO
Comprehensive Genomic Analysis in NRG Oncology/RTOG 9802: A Phase III Trial of Radiation Versus Radiation Plus Procarbazine, Lomustine (CCNU), and Vincristine in High-Risk Low-Grade Glioma
Authors: Erica H. Bell, Peixin Zhang, Edward G. Shaw, Jan C. Buckner, Geoffrey R. Barger, Dennis E. Bullard, Minesh P. Mehta, Mark R. Gilbert, Paul D. Brown, Keith J. Stelzer, Joseph P. McElroy, Jessica l. Fleming, Cynthia D. Timmers, Aline P. Becker, Andrea L. Salavaggione, Ziyan Liu, Kenneth Aldape, David G. Brachman, Stanley Z. Gertler, Albert D. Murtha, Christopher J. Schultz, David Johnson, Nadia N. Laack, Grant K. Hunter, Ian R. Crocker, Minhee Won, Arnab Chakravarti
Journal: Journal of Clinical Oncology (2020)

NRG Oncology/RTOG 9802 (ClinicalTrials.gov Identifier: NCT00003375) is a practice-changing study for patients with WHO low-grade glioma (LGG, grade II), as it was the first to demonstrate a survival benefit of adjuvant chemoradiotherapy over radiotherapy. This post hoc study sought to determine the prognostic and predictive impact of the WHO-defined molecular subgroups and corresponding molecular alterations within NRG Oncology/RTOG 9802.IDH1/2 mutations were determined by immunohistochemistry and/or deep sequencing. A custom Ion AmpliSeq panel was used for mutation analysis. 1p/19q codeletion and MGMT promoter methylation were determined by copy-number arrays and/or Illumina 450K array, respectively. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Hazard ratios (HRs) were calculated using the Cox proportional hazard model and tested using the log-rank test. Multivariable analyses (MVAs) were performed incorporating treatment and common prognostic factors as covariates.Of the eligible patients successfully profiled for the WHO-defined molecular groups (n = 106/251), 26 (24%) were IDH-wild type, 43 (41%) were IDH-mutant/non-codeleted, and 37(35%) were IDH-mutant/codeleted. MVAs demonstrated that WHO subgroup was a significant predictor of PFS after adjustment for clinical variables and treatment. Notably, treatment with postradiation chemotherapy (PCV; procarbazine, lomustine (CCNU), and vincristine) was associated with longer PFS (HR, 0.32; P = .003; HR, 0.13; P < .001) and OS (HR, 0.38; P = .013; HR, 0.21; P = .029) in the IDH-mutant/non-codeleted and IDH-mutant/codeleted subgroups, respectively. In contrast, no significant difference in either PFS or OS was observed with the addition of PCV in the IDH-wild-type subgroup.This study is the first to report the predictive value of the WHO-defined diagnostic classification in a set of uniformly treated patients with LGG in a clinical trial. Importantly, this post hoc analysis supports the notion that patients with IDH-mutant high-risk LGG regardless of codeletion status receive benefit from the addition of PCV.
Effect of type and dosage of newly prescribed inhaled corticosteroids on obstructive lung disease and pneumonia hospitalisations in older individuals with asthma, COPD or both: a retrospective study of health administrative data
Authors: Tetyana Kendzerska, Shawn D. Aaron, Teresa To, Chris Licskai, Matthew B. Stanbrook, Mary-Ellen Hogan, Wan C. Tan, Jean Bourbeau, Andrea S. Gershon
Journal: European Respiratory Journal (2020)

<b>This study suggested a less favourable safety-effectiveness profile for fluticasone compared to budesonide and other ICS in elderly individuals with asthma, COPD or both. Higher ICS dose was not associated with improved effectiveness in these populations.</b>https://bit.ly/3iNdjkQ
Practice-Changing Interventions in the Systemic Management of Breast Cancer
Authors: William J. Gradishar
Journal: Journal of the National Comprehensive Cancer Network (2020)

Systemic treatment for metastatic breast cancer now incorporates many targeted agents and a plethora of combinations specific to the breast cancer subtype. New to the treatment paradigm are fam-trastuzumab deruxtecan-nxki, and tucatinib for HER2-positive disease; the PI3K inhibitor alpelisib in combination with fulvestrant for estrogen receptor–positive and PIK3CA -mutated tumors; PARP inhibitors for patients with germline BRCA1/2 mutations; and the anti–PD-L1 agent atezolizumab in combination with albumin-bound paclitaxel for triple-negative disease with PD-L1 mutations in tumors. In addition, for estrogen receptor–positive disease, the role of CDK4/6 inhibitors increased substantially during the past year, as overall survival results have emerged. These targeted agents are greatly improving patient outcomes, and thus have all been incorporated into the NCCN Guidelines for Breast Cancer.
A general-purpose Nanohybrid fabricated by Polymeric Au(I)-peptide precursor to wake the function of Peptide Therapeutics
Authors: Jin Yan, Fanpu Ji, Siqi Yan, Weiming You, Fang Ma, Fanni Li, Yinong Huang, Wenjia Liu, Wangxiao He
Journal: Theranostics (2020)

Peptide-derived nanocomposites have been exhibiting fascinating biological advantages, including but not limited to excellent biocompatibility, biological degradation, high targetability and subsequent potent therapeutic efficacy. While some successes have been achieved in the nanoengineering of peptide-based architectures with defined dimensions and medical functions, enormous challenges remain about clinical nano-pharmaceutics of peptides, especially those modulating intracellular protein-protein interactions (PPIs).
Prevention of heart failure events with intensive versus standard blood pressure lowering across the spectrum of kidney function and albuminuria: a <scp>SPRINT</scp> substudy
Authors: Muthiah Vaduganathan, Manan Pareek, Anna M.D. Kristensen, Tor Biering‐Sørensen, Christina Byrne, Zaid Almarzooq, Thomas Bastholm Olesen, Michael H. Olsen, Deepak L. Bhatt
Journal: European Journal of Heart Failure (2020)
Circadian rhythm influences induction of trained immunity by BCG vaccination
Authors: L. Charlotte J. de Bree, Vera P. Mourits, Valerie A.C.M. Koeken, Simone J.C.F.M. Moorlag, Robine Janssen, Lukas Folkman, Daniele Barreca, Thomas Krausgruber, Victoria Fife-Gernedl, Boris Novakovic, Rob J.W. Arts, Helga Dijkstra, Heidi Lemmers, Christoph Bock, Leo A.B. Joosten, Reinout van Crevel, Christine S. Benn, Mihai G. Netea
Journal: Journal of Clinical Investigation (2020)

BACKGROUND. The antituberculosis vaccine bacillus Calmette-Guérin (BCG) reduces overall infant mortality. Induction of innate immune memory, also termed trained immunity, contributes toward protection against heterologous infections. Since immune cells display oscillations in numbers and function throughout the day, we investigated the effect of BCG administration time on the induction of trained immunity.
X chromosome dosage of histone demethylase KDM5C determines sex differences in adiposity
Authors: Jenny C. Link, Carrie B. Wiese, Xuqi Chen, Rozeta Avetisyan, Emilio Ronquillo, Feiyang Ma, Xiuqing Guo, Jie Yao, Matthew Allison, Yii-Der Ida Chen, Jerome I. Rotter, Julia S. El -Sayed Moustafa, Kerrin S. Small, Shigeki Iwase, Matteo Pellegrini, Laurent Vergnes, Arthur P. Arnold, Karen Reue
Journal: Journal of Clinical Investigation (2020)

Males and females differ in body composition and fat distribution. Using a mouse model that segregates gonadal sex (ovaries and testes) from chromosomal sex (XX and XY), we showed that XX chromosome complement in combination with a high-fat diet led to enhanced weight gain in the presence of male or female gonads. We identified the genomic dosage of Kdm5c, an X chromosome gene that escapes X chromosome inactivation, as a determinant of the X chromosome effect on adiposity. Modulating Kdm5c gene dosage in XX female mice to levels that are normally present in males resulted in reduced body weight, fat content, and food intake to a degree similar to that seen with altering the entire X chromosome dosage. In cultured preadipocytes, the levels of KDM5C histone demethylase influenced chromatin accessibility (ATAC-Seq), gene expression (RNA-Seq), and adipocyte differentiation. Both in vitro and in vivo, Kdm5c dosage influenced gene expression involved in extracellular matrix remodeling, which is critical for adipocyte differentiation and adipose tissue expansion. In humans, adipose tissue KDM5C mRNA levels and KDM5C genetic variants were associated with body mass. These studies demonstrate that the sex-dependent dosage of Kdm5c contributes to male/female differences in adipocyte biology and highlight X-escape genes as a critical component of female physiology.
Too much medicine?
Authors: R. Moynihan
Journal: BMJ (2002)

Most doctors believe medicine to be a force for good. Why else would they have become doctors? Yet while all know medicine's power to harm individual patients and whole populations, presumably few would agree with Ivan Illich that “The medical establishment has become a major threat to health.”1 Many might, however, accept the concept of the health economist Alain Enthoven that increasing medical inputs will at some point become counterproductive and produce more harm than good. So where is that point, and might we have reached it already?

Readers of the BMJ voted in a poll for us to explore these questions in a theme issue of the BMJ , and this is that issue. Unsurprisingly, we reach no clear answers, but the questions deserve far more intense debate in a world where many countries are steadily increasing their investment in health care. Presumably no one wants to keep cutting back on education, the arts, scientific research, good food, travel, and much else as we spend more and more of our resources on an unwinnable battle against death, pain, and sickness—particularly if Illich is right that in doing so we destroy our humanity. And do we in the rich world want to keep developing increasingly expensive treatments that achieve marginal benefits when most in the developing world do not have the undoubted benefits that come with simple measures like …
Sampling the host response to SARS-CoV-2 in hospitals under siege
Authors: Alexander W. Charney, Nicole W. Simons, Konstantinos Mouskas, Lauren Lepow, Esther Cheng, Jessica Le Berichel, Christie Chang, Robert Marvin, Diane Marie Del Valle, Sharlene Calorossi, Alona Lansky, Laura Walker, Manishkumar Patel, Hui Xie, Nancy Yi, Alex Yu, Gurpawan Kang, Anthony Mendoza, Lora E. Liharska, Emily Moya, Matthew Hartnett, Sandra Hatem, Lillian Wilkins, Melody Eaton, Hajra Jamal, Kevin Tuballes, Steven T. Chen, Alexandra Tabachnikova, Jonathan Chung, Jocelyn Harris, Craig Batchelor, Jose Lacunza, Mahlet Yishak, Kimberly Argueta, Neha Karekar, Brian Lee, Geoffrey Kelly, Daniel Geanon, Diana Handler, John Leech, Hiyab Stefanos, Travis Dawson, Ieisha Scott, Nancy Francoeur, Jessica S. Johnson, Akhil Vaid, Benjamin S. Glicksberg, Girish N. Nadkarni, Eric E. Schadt, Bruce D. Gelb, Adeeb Rahman, Robert Sebra, Glenn Martin, Charuta Agashe, Priyal Agrawal, Alara Akyatan, Kasey Alesso-Carra, Eziwoma Alibo, Kelvin Alvarez, Angelo Amabile, Steven Ascolillo, Rasheed Bailey, Priya Begani, Paloma Bravo Correra, Stacey-Ann Brown, Mark Buckup, Larissa Burka, Lena Cambron, Gina Carrara, Serena Chang, Jonathan Chien, Mashkura Chowdhury, Cansu Cimen Bozkus, Phillip Comella, Dana Cosgrove, Francesca Cossarini, Liam Cotter, Arpit Dave, Bheesham Dayal, Maxime Dhainaut, Rebecca Dornfeld, Katie Dul, Nissan Eber, Cordelia Elaiho, Frank Fabris, Jeremiah Faith, Dominique Falci, Susie Feng, Brian Fennessy, Marie Fernandes, Sandeep Gangadharan, Joanna Grabowska, Gavin Gyimesi, Maha Hamdani, Manon Herbinet, Elva Herrera, Arielle Hochman, Gabriel E. Hoffman, Jaime Hook, Laila Horta, Etienne Humblin, Subha Karim, Jessica Kim, Dannielle Lebovitch, Grace Lee, Gyu Ho Lee, Jacky Lee, Mike Leventhal, Katherine Lindblad, Alexandra Livanos, Rosalie Machado, Zafar Mahmood, Kelcey Mar, Shrisha Maskey, Paul Matthews, Katherine Meckel, Saurabh Mehandru, Cynthia Mercedes, Dara Meyer, Gurkan Mollaoglu, Sarah Morris, Kai Nie, Marjorie Nisenholtz, George Ofori-Amanfo, Kenan Onel, Merouane Ounadjela, Vishwendra Patel, Cassandra Pruitt, Shivani Rathi, Jamie Redes, Ivan Reyes-Torres, Alcina Rodrigues, Alfonso Rodriguez, Vladimir Roudko, Evelyn Ruiz, Pearl Scalzo, Pedro Silva, Alessandra Soares Schanoski, Meghan Straw, Sasha Tabachnikova, Collin Teague, Bhaskar Upadhyaya, Verena Van Der Heide, Natalie Vaninov, Daniel Wacker, Hadley Walsh, C. Matthias Wilk, Jessica Wilson, Karen M. Wilson, Li Xue, Naa-akomaah Yeboah, Sabina Young, Nina Zaks, Renyuan Zha, Thomas Marron, Noam Beckmann, Seunghee Kim-Schulze, Sacha Gnjatic, Miriam Merad
Journal: Nature Medicine (2020)
Suicidality, self-harm, and their correlates among transgender and cisgender people living in Aotearoa/New Zealand or Australia
Authors: Gareth J. Treharne, Damien W. Riggs, Sonja J. Ellis, Jayde A. M. Flett, Clare Bartholomaeus
Journal: International Journal of Transgender Health (2020)

Transgender people experience high rates of suicidality and self-harm. Past research has established a range of correlates of suicidality/self-harm among transgender people but little is known about whether these correlates are similar for transgender and cisgender people.
Advances in the Management of Pancreatic Adenocarcinoma
Authors: Eileen M. O’Reilly
Journal: Journal of the National Comprehensive Cancer Network (2020)

Outcomes in pancreatic cancer are improving. The beneficial effects being achieved with adjuvant and neoadjuvant therapies, and the recent application of molecular profiling, both germline and somatic, are collectively impacting survival. The NCCN Guidelines for Pancreatic Cancer urge clinicians to undertake “agnostic” germline testing for all persons with pancreatic cancer. Fit patients should also be considered for adjuvant therapy with modified FOLFIRINOX (leucovorin, 5-FU, irinotecan, oxaliplatin). Novel therapies that focus on DNA damage repair strategies are proving to be important, but notably several late-stage trials of several other approaches, reported in the last year, proved disappointing.
The Need to Expand Coverage and Enhance Access to Essential Services on a Predeductible Basis Following COVID-19
Authors: A. Mark Fendrick
Journal: JAMA Network Open (2020)

J. Frank Wharam, MD, MPH; Jamie Wallace, MPH; Fang Zhang, PhD; Xin Xu, MS; Christine Y. Lu, PhD, MSc; Adrian Hernandez, MD; Dennis Ross-Degnan, ScD; Joseph P. Newhouse, PhD
MPN patients with low mutant <i>JAK2</i> allele burden show late expansion restricted to erythroid and megakaryocytic lineages
Authors: Ronny Nienhold, Peter Ashcroft, Jakub Zmajkovic, Shivam Rai, Tata Nageswara Rao, Beatrice Drexler, Sara C. Meyer, Pontus Lundberg, Jakob R. Passweg, Danijela Leković, Vladan Čokić, Sebastian Bonhoeffer, Radek C. Skoda
Journal: Blood (2020)
Ethical Dilemmas in Covid-19 Medical Care: Is a Problematic Triage Protocol Better or Worse than No Protocol at All?
Authors: Sheri Fink
Journal: The American Journal of Bioethics (2020)

The anthrax mailings following the September 11, 2001 attacks in the United States led to fears that victims of bioterrorism could overwhelm hospitals. The federal government convened experts to de...