tbuckley/cabot-search huggingface dataset:
Single-cell Transcriptome Profiling reveals Dermal and Epithelial cell fate decisions during Embryonic Hair Follicle Development
Authors: Wei Ge, Shao-Jing Tan, Shan-He Wang, Lan Li, Xiao-Feng Sun, Wei Shen, Xin Wang
Journal: Theranostics (2020)

It is estimated that 50% of men and 25% of women worldwide suffer from hair loss, and therefore it is of great significance to investigate the molecular pathways driving hair follicle de novo morphogenesis. However, due to high cellular heterogeneity and the asynchronous development of hair follicles, our current understanding of the molecular mechanisms involved in follicle development remains limited. Methods: Single-cell suspensions from the dorsal skin of E13.5 (induction stage), E16.5 (organogenesis) fetal mice, and newborn mice (cytodifferentiation stage, postnatal day 0, P0) were prepared for unbiased single-cell RNA sequencing. To delineate the single-cell transcriptional landscape during hair follicle de novo morphogenesis, we performed t-distributed Stochastic Neighbor Embedding (tSNE), pseudotime cell trajectory inference, and regulon enrichment analysis to dissect cellular heterogeneity and reveal the molecular pathways underlying major cell type cell fate decisions. To validate our analysis, we further performed immunohistochemistry analysis of the key molecules involved during hair follicle morphogenesis. Meanwhile, intercellular communication between different cell populations was inferred based on a priori knowledge of ligand-receptor pairs. Results: Based on tSNE analysis, we identified 14 cell clusters from skin tissue and delineated their cellular identity from specific gene expression profiles. By using pseudotime ordering analysis, we successfully constructed the epithelium/dermal cell lineage differentiation trajectory. For dermal cell lineage, our analysis here recapitulated the dynamic gene expression profiles during dermal condensate (DC) cell fate commitment and delineated the heterogeneity of the different dermal papilla (DP) cell populations during in utero hair follicle development. For the epithelium cell lineage, our analysis revealed the dynamic gene expression profiles of the underappreciated matrix, interfollicular epidermis (IFE), hair shaft and inner root sheath (IRS) cell populations. Furthermore, single-cell regulatory network inference and clustering analysis revealed key regulons during cell fate decisions. Finally, intercellular communication analysis demonstrated that strong intercellular communication was involved during early hair follicle development. Conclusions: Our findings here provide a molecular landscape during hair follicle epithelium/dermal cell lineage fate decisions, and recapitulate the sequential activation of core regulatory transcriptional factors (TFs) in different cell populations during hair follicle morphogenesis. More importantly, our study here represents a valuable resource for understanding the molecular pathways involved during hair follicle de novo morphogenesis, which will have implications for future hair loss treatments.
Review of the Techniques Used for Investigating the Role Elastin and Collagen Play in Arterial Wall Mechanics
Authors: Alessandro Giudici, Ian B. Wilkinson, Ashraf W. Khir
Journal: IEEE Reviews in Biomedical Engineering (2020)

The arterial wall is characterised by a complex microstructure that impacts the mechanical properties of the vascular tissue. The main components consist of collagen and elastin fibres, proteoglycans, Vascular Smooth Muscle Cells (VSMCs) and ground matrix. While VSMCs play a key role in the active mechanical response of arteries, collagen and elastin determine the passive mechanics. Several experimental methods have been designed to investigate the role of these structural proteins in determining the passive mechanics of the arterial wall. Microscopy imaging of load-free or fixed samples provides useful information on the structure-function coupling of the vascular tissue, and mechanical testing provides information on the mechanical role of collagen and elastin networks. However, when these techniques are used separately, they fail to provide a full picture of the arterial micromechanics. More recently, advances in imaging techniques have allowed combining both methods, thus dynamically imaging the sample while loaded in a pseudo-physiological way, and overcoming the limitation of using either of the two methods separately. The present review aims at describing the techniques currently available to researchers for the investigation of the arterial wall micromechanics. This review also aims to elucidate the current understanding of arterial mechanics and identify some research gaps.
Does NSAID Consumption Reduce the Risk of Acute Myeloid Leukemia? a National Population-Based Case-Control Study
Authors: Lene Sofie Granfeldt Østgård, Mette Nørgaard, Lars Pedersen, René Østgård, Marianne Tang Severinsen, Claudia Schöllkopf, Claus Werenberg Marcher, Lone Smidstrup Friis, Morten Krogh Jensen
Journal: Blood (2017)
Abstract B11: Collective extrusion initiates dissemination in organotypic model of high-grade serous carcinoma
Authors: Sarah Alshehri, Sadaf Farsinejad, Douglas Kung, Estefan Santi, Yali Zhai, Thomas Cattabiani, Hongjun Wang, Kathleen Cho, Marcin Iwanicki
Journal: Clinical Cancer Research (2020)

Abstract Development of serous tubal intraepithelial carcinoma (STIC) from transformed fallopian tube secretory epithelial cells (FTSEC) is considered to be an initiating event for a significant proportion of high-grade serous carcinomas (HGSCs). Some regions of STIC lesions can form multicellular loosely cohesive outgrowths that apically extend out of the tubal epithelium. These outgrowths can detach and disseminate within the peritoneal cavity, causing organ obstruction. Immunohistochemical analysis of STICs suggests the possibility that molecular pathways associated with proliferation, DNA repair, cytoskeletal dynamics, and extracellular matrix adhesion contribute to outgrowth formation. Due to limited availability of transformed FTSEC in vitro culture models that faithfully capture outgrowth dynamics, the role of these pathways in STIC/HGSC outgrowth formation remains unknown. Here we present the development of an organotypic model of outgrowth formation. Long-term live-cell imaging of transformed human, and mouse FTSEC and STIC-like multicellular organotypic assemblies, have shown that outgrowths are initiated by collective apical extrusion of less-cohesive, loosely attached cell populations that can proliferate outside of the organotypic assembly. mRNA and immunofluorescence analysis of loosely attached cell populations revealed: (i) activation of Rho pathway, (ii) increased expression of several alpha integrin subunits that form heterodimers with beta 1 integrin, and (iii) nonpolarized apical and junctional localization of activated integrin beta 1. Pharmacologic or genetic inhibition of Rho-associated kinase (ROCK) blocked outgrowth formation without affecting cell proliferation. Conversely, activation of Rho significantly accelerated outgrowths, indicating that Rho-ROCK is a critical regulator of early steps of HGSC dissemination. Quantitative image-based evaluation of ROCK target phosphorylated myosin light chain expression in patient-derived xenograft cells revealed the presence of cell populations with high ROCK activation. Blocking integrin beta 1 activity resulted in the disintegration of already formed outgrowths. Our data indicate that cell populations with high Rho/ROCK activity remodel integrin beta 1-dependent adhesion to initiate apical extrusion and peritoneal dissemination. Citation Format: Sarah Alshehri, Sadaf Farsinejad, Douglas Kung, Estefan Santi, Yali Zhai, Thomas Cattabiani, Hongjun Wang, Kathleen Cho, Marcin Iwanicki. Collective extrusion initiates dissemination in organotypic model of high-grade serous carcinoma [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B11.
A re-analysis in exploring the association between temperature and COVID-19 transmissibility: an ecological study with 154 Chinese cities
Authors: Jinjun Ran, Shi Zhao, Lefei Han, Gengze Liao, Kai Wang, Maggie H. Wang, Daihai He
Journal: European Respiratory Journal (2020)

<b>In this national ecological study across 154 Chinese cities, the ambient temperature was found to have a nonlinear negative association with COVID-19 transmissibility</b>https://bit.ly/3esw8rc
Impacts and Echoes: The Lasting Influence of the White House Conference on Food, Nutrition, and Health
Authors: Catherine E. Woteki, Brandon L. Kramer, Samantha Cohen, Vicki A. Lancaster
Journal: Annual Review of Nutrition (2020)

The 1969 White House Conference on Food, Nutrition, and Health had a significant influence on the direction of food and nutrition policy in the United States. The conference produced recommendations leading to federal legislation and programs to alleviate hunger and malnutrition, improve consumers’ nutrition knowledge through education and labeling, and monitor the nutritional status of the population. Fifty years later, its legacy was revisited at a conference convened by Harvard University and Tufts University. This article reviews the literature contributing to the first author's keynote speech at the conference, its influencers, and its influences. We focus on the highlights of five domains that set the stage for the conference: the social environment, the food environment, nutrition science, public health data, and policy events. We briefly describe the conference, its proposed directions, and its lasting legacy in these five domains.
BCG vaccine and COVID-19: implications for infection prophylaxis and cancer immunotherapy
Authors: Madhuri Koti, Alvaro Morales, Charles H Graham, David Robert Siemens
Journal: Journal for ImmunoTherapy of Cancer (2020)

The COVID-19 pandemic has killed over 400 000 people globally. Ecological evidence indicates that countries with national universal BCG vaccination programs for tuberculosis (TB) prevention have a much lower incidence of severe COVID-19 and mortality compared with those that do not have such programs. BCG is a century old vaccine used for TB prevention via infant/childhood vaccination in lowto middle-income countries with high infection prevalence rate and is known to reduce all-cause neonatal mortality. BCG remains the standard immunotherapy treatment for patients with high-risk non-muscle invasive bladder cancer globally for more than 44 years. Several trials are, therefore, investigating BCG as a prophylactic against COVID-19 in healthcare workers and the elderly. In this commentary, we discuss the potential mechanisms that may underlie BCG associated heterologous protection with a focus on tertiary lymphoid structure (TLS) organogenesis. Given the significance of TLSs in mucosal immunity, their association with positive prognosis and response to immune checkpoint blockade with a critical role of Type I interferon (IFN-1) in inducing these, we also discuss potentiating TLS formation as a promising approach to enhance anti-tumor immunity. We propose that lessons learned from BCG immunotherapy success could be applied to not only augment such microbe-based therapeutics but also lead to similar adjunctive IFN-1 activating approaches to improve response to immune checkpoint blockade therapy in cancer.
US Hydroxychloroquine, Chloroquine, and Azithromycin Outpatient Prescription Trends, October 2019 Through March 2020
Authors: Nadine Shehab, Maribeth Lovegrove, Daniel S. Budnitz
Journal: JAMA Internal Medicine (2020)

The voices of women in cardiovascular clinical research are not being heard, and the losses are tangible.Women lose rewarding careers, trainees lose valuable role models, patients lose inclusiveness in clinical trials, and research loses crucial perspectives.Career advancement benefits associated with clinical trial leadership extend well beyond manuscript authorship; these include research funding support, presentations at prestigious and highly visible late-breaking clinical trial sessions at the large annual scientific sessions, institutional and media recognition, and thought leadership reputation that leads to future, higher-effect opportunities.Advances in women's leadership in academic medicine have historically preceded advances in women's health, and there remains room for improvement on both. 5Disease manifestation, risk factors, and treatments of cardiovascular conditions in women remain understudied.Enrollment of women in clinical trials of heart failure and acute coronary syndrome still lag behind disease prevalence in the general population, which likely reflects the paucity of female leadership in these trials. 6 In contrast, the Women's Health Initiative, with strong female study leadership, successfully enrolled almost a half million women.This study underscores the need for immediate action.The authors point out implicit bias and a lack of mentorship as contributors to observed gender disparities in academic cardiology.However, other targets more readily amenable to change are prevalent.Lessons learned from how to banish "manels" at conferences can be applied to clinical trial leadership selection: studies without any female representation should be called out, the talent pool from which qualified leaders can be chosen should be readily available and searchable, and women need to be actively promoted from behind-the-scenes or local study roles to more visible and national leadership roles.Research funding bodies, such as the National Institutes of Health (NIH), can expand existing policies guiding diversity and inclusion in clinical trial subjects to trial leadership roles.Francis Collins, MD, PhD, director of the NIH, announced last year: "I want to send a clear message of concern: It is time to end the tradition in science of all-male speaking panels….Starting now, when I consider speaking invitations, I will expect a level playing field, where scientists of all backgrounds are evaluated fairly for speaking opportunities." 7(p295) This guiding principle and the results of this study should prompt all research sponsors, including the NIH and industry, to commit to study leadership diversity as a core criterion in funding decisions.If we are to capitalize on the benefits of a diverse workforce, it must start at the top.The design, conduct, and interpretation of clinical trials research can and should maximally benefit from the experience and expertise of both male and female investigators.
Response to Lehrer and Rheinstein
Authors: Stacey A Fedewa, Jiemin Ma, Ahmedin Jemal
Journal: JNCI Journal of the National Cancer Institute (2020)

We thank Drs Lehrer and Rheinstein for their interest in our recent article published in the Journal.In this article, we reported that prostate cancer incidence rates continued to decline for early staged disease, whereas rates increased for regional-and distant-stage diseases following the US Preventive Services Task Force recommendations against routine prostate-specific antigen (PSA) testing for men aged 75 years and older in 2008 and for all men in 2012 (1).For example, among men who were 50 years and older, local-staged prostate cancer incidence decreased by 6.9% per year from 2007 to 2016.In contrast, regional-staged incidence statistically significantly increased by 11.1% per year from 2012 to 2016, and distant-staged prostate cancer incidence increased by 5.0% per year from 2010 to 2016.In our discussion, we state that these findings, along with previously reported stabilization of prostate cancer death rates, can inform the population of the benefits and harms of PSA testing.Lehrer and Rheinstein examined stage-specific prostate cancer survival trends.They report that 12-month relative survival for patients diagnosed between 1998 and 2016 remained 100% for localized prostate cancer and increased from 72% to 81.4% for distant-stage disease (2).The authors state, "Our analysis confirms the recent stabilization of prostate cancer death rates after a steady decline since the early 1990s."Further, the authors conclude, "Given the complications associated with Figure 1.Stage-specific prostate cancer death rates by stage, age group, and year of diagnosis, SEER 18 (2010-2017).
Shree Vishna Rasiah
Authors: Raman Lakshman, Anuja Natarajan, Anju Singh, Andrew Ewer
Journal: BMJ (2020)

Shree Vishna Rasiah (known as Vish to friends, family, and colleagues) was a well respected and much loved consultant neonatologist at Birmingham Women’s Hospital. Born in Kuala Lumpur, Malaysia, Vish spoke Tamil, Mandarin, and Malay in addition to English. After completing his undergraduate medicine in Adelaide, he came to south Yorkshire, training in Bradford and Sheffield before joining Professor Andrew Ewer’s research group in Birmingham. He joined the Birmingham Women’s Hospital (BWH) as consultant neonatologist in 2007. He contributed to neonatal care at local, national, and international levels. He encouraged and mentored innumerable junior doctors and medical students, supporting original …
Too much information, too little evidence: is waste in research fuelling the covid-19 infodemic?
Authors: Virginia Casigliani, Francesca De Nard, Erica De Vita, Guglielmo Arzilli, Francesca Maria Grosso, Filippo Quattrone, Lara Tavoschi, Pierluigi Lopalco
Journal: BMJ (2020)

Thank you for your interest in spreading the word about The BMJ.NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address. Username * Your Email * Send To * You are going to email the following Too much information, too little evidence: is waste in research fuelling the covid-19 infodemic? Your Personal Message CAPTCHA This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
COVID-19: Progress in diagnostics, therapy and vaccination
Authors: Xue Liu, Chao Liu, Gang Liu, Wenxin Luo, Ningshao Xia
Journal: Theranostics (2020)

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has recently become a pandemic.As the sudden emergence and rapid spread of SARS-CoV-2 is endangering global health and the economy, the development of strategies to contain the virus's spread are urgently needed.At present, various diagnostic kits to test for SARS-CoV-2 are available for use to initiate appropriate treatment faster and to limit further spread of the virus.Several drugs have demonstrated in vitro activity against SARS-CoV-2 or potential clinical benefits.In addition, institutions and companies worldwide are working tirelessly to develop treatments and vaccines against COVID-19.However, no drug or vaccine has yet been specifically approved for COVID-19.Given the urgency of the outbreak, we focus here on recent advances in the diagnostics, treatment, and vaccine development for SARS-CoV-2 infection, helping to guide strategies to address the current COVID-19 pandemic.
Abstract 13271: Validation of a Novel Low-Density Lipoprotein Cholesterol Equation in the ELSA-Brasil Cohort Study
Authors: Vincent A Pallazola, Vasanth Sathiyakumar, Oluwaseun E Fashanu, Steven R Jones, Raul D Santos, Peter P Toth, Marcio S Bittencourt, Bruce B Duncan, Paulo A Lotufo, Isabela M Benseñor, Michael J Blaha, Seth S Martin
Journal: Circulation (2018)

Introduction: The Friedewald equation served as the gold standard for low-density lipoprotein cholesterol (LDL-C) estimation for over four decades, but tends to underestimate LDL-C in patients with...
The history and advances in cancer immunotherapy: understanding the characteristics of tumor-infiltrating immune cells and their therapeutic implications
Authors: Yuanyuan Zhang, Zemin Zhang
Journal: Cellular and Molecular Immunology (2020)

Abstract Immunotherapy has revolutionized cancer treatment and rejuvenated the field of tumor immunology. Several types of immunotherapy, including adoptive cell transfer (ACT) and immune checkpoint inhibitors (ICIs), have obtained durable clinical responses, but their efficacies vary, and only subsets of cancer patients can benefit from them. Immune infiltrates in the tumor microenvironment (TME) have been shown to play a key role in tumor development and will affect the clinical outcomes of cancer patients. Comprehensive profiling of tumor-infiltrating immune cells would shed light on the mechanisms of cancer–immune evasion, thus providing opportunities for the development of novel therapeutic strategies. However, the highly heterogeneous and dynamic nature of the TME impedes the precise dissection of intratumoral immune cells. With recent advances in single-cell technologies such as single-cell RNA sequencing (scRNA-seq) and mass cytometry, systematic interrogation of the TME is feasible and will provide insights into the functional diversities of tumor-infiltrating immune cells. In this review, we outline the recent progress in cancer immunotherapy, particularly by focusing on landmark studies and the recent single-cell characterization of tumor-associated immune cells, and we summarize the phenotypic diversities of intratumoral immune cells and their connections with cancer immunotherapy. We believe such a review could strengthen our understanding of the progress in cancer immunotherapy, facilitate the elucidation of immune cell modulation in tumor progression, and thus guide the development of novel immunotherapies for cancer treatment.
Poly(ADP-ribose) Glycohydrolase Inhibition Sequesters NAD+ to Potentiate the Metabolic Lethality of Alkylating Chemotherapy in IDH-Mutant Tumor Cells
Authors: Hiroaki Nagashima, Christine K. Lee, Kensuke Tateishi, Fumi Higuchi, Megha Subramanian, Seamus Rafferty, Lisa Melamed, Julie J. Miller, Hiroaki Wakimoto, Daniel P. Cahill
Journal: Cancer Discovery (2020)

Abstract NAD+ is an essential cofactor metabolite and is the currency of metabolic transactions critical for cell survival. Depending on tissue context and genotype, cancer cells have unique dependencies on NAD+ metabolic pathways. PARPs catalyze oligomerization of NAD+ monomers into PAR chains during cellular response to alkylating chemotherapeutics, including procarbazine or temozolomide. Here we find that, in endogenous IDH1-mutant tumor models, alkylator-induced cytotoxicity is markedly augmented by pharmacologic inhibition or genetic knockout of the PAR breakdown enzyme PAR glycohydrolase (PARG). Both in vitro and in vivo, we observe that concurrent alkylator and PARG inhibition depletes freely available NAD+ by preventing PAR breakdown, resulting in NAD+ sequestration and collapse of metabolic homeostasis. This effect reversed with NAD+ rescue supplementation, confirming the mechanistic basis of cytotoxicity. Thus, alkylating chemotherapy exposes a genotype-specific metabolic weakness in tumor cells that can be exploited by PARG inactivation. Significance: Oncogenic mutations in the isocitrate dehydrogenase genes IDH1 or IDH2 initiate diffuse gliomas of younger adulthood. Strategies to maximize the effectiveness of chemotherapy in these tumors are needed. We discover alkylating chemotherapy and concurrent PARG inhibition exploits an intrinsic metabolic weakness within these cancer cells to provide genotype-specific benefit. See related commentary by Pirozzi and Yan, p. 1629. This article is highlighted in the In This Issue feature, p. 1611
Changes in Bcl-2 members after ibrutinib or venetoclax uncover functional hierarchy in determining resistance to venetoclax in CLL
Authors: Marco V. Haselager, Karoline Kielbassa, Johanna ter Burg, Danique J. C. Bax, Stacey M. Fernandes, Jannie Borst, Constantine Tam, Francesco Forconi, Giorgia Chiodin, Jennifer R. Brown, Julie Dubois, Arnon P. Kater, Eric Eldering
Journal: Blood (2020)