tbuckley/cabot-search huggingface dataset:
Biodistribution of surfactant-free poly(lactic-acid) nanoparticles and uptake by endothelial cells and phagocytes in zebrafish: Evidence for endothelium to macrophage transfer.
Authors: Julien Rességuier, Jean-Pierre Levraud, Nils K. Dal, Federico Fenaroli, Charlotte Primard, Jens Wohlmann, Gabrielle Carron, Gareth W. Griffiths, Dominique Le Guellec, Bernard Verrier
Journal: Journal of Controlled Release (2021)

In the development of therapeutic nanoparticles (NP), there is a large gap between in vitro testing and in vivo experimentation. Despite its prominence as a model, the mouse shows severe limitations for imaging NP and the cells with which they interact. Recently, the transparent zebrafish larva, which is well suited for high-resolution live-imaging, has emerged as a powerful alternative model to investigate the in vivo behavior of NP. Poly(D,L lactic acid) (PLA) is widely accepted as a safe polymer to prepare therapeutic NP. However, to prevent aggregation, many NP require surfactants, which may have undesirable biological effects. Here, we evaluate 'safe-by-design', surfactant-free PLA-NP that were injected intravenously into zebrafish larvae. Interaction of fluorescent NPs with different cell types labelled in reporter animals could be followed in real-time at high resolution; furthermore, by encapsulating colloidal gold into the matrix of PLA-NP we could follow their fate in more detail by electron microscopy, from uptake to degradation. The rapid clearance of fluorescent PLA-NP from the circulation coincided with internalization by endothelial cells lining the whole vasculature and macrophages. After 30 min, when no NP remained in circulation, we observed that macrophages continued to internalize significant amounts of NP. More detailed video-imaging revealed a new mechanism of NP transfer where NP are transmitted along with parts of the cytoplasm from endothelial cells to macrophages.
Dual Agonist of Farnesoid X Receptor and Takeda G Protein‐Coupled Receptor 5 Inhibits Hepatitis B Virus Infection In Vitro and In Vivo
Authors: Kiyoaki Ito, Akinori Okumura, Junko S. Takeuchi, Koichi Watashi, Rieko Inoue, Taeko Yamauchi, Kazumasa Sakamoto, Yukiko Yamashita, Yusuke Iguchi, Mizuho Une, Takaji Wakita, Kazuo Umezawa, Masashi Yoneda
Journal: Hepatology (2021)

Background and Aims Chronic HBV infection is a major health problem worldwide. Currently, the first‐line treatment for HBV is nucleos(t)ide analogs or interferons; however, efficient therapeutic approaches that enable cure are lacking. Therefore, anti‐HBV agents with mechanisms distinct from those of current drugs are needed. Sodium taurocholate cotransporting polypeptide (NTCP) was previously identified as an HBV receptor that is inhibited by several compounds. Farnesoid X receptor (FXR) activation also inhibits NTCP function. Approach and Results In this study, we investigated the inhibitory effect of bile acid (BA) derivatives—namely obeticholic acid (OCA), 6α‐ethyl‐24‐nor‐5β‐cholane‐3α,7α,23‐triol‐23 sulfate sodium salt (INT‐767; a dual agonist of FXR and Takeda G protein‐coupled receptor [TGR5]), and 6α‐ethyl‐23(S)‐methyl‐cholic acid (INT‐777; a TGR5 agonist)—3‐(2,6‐dichlorophenyl)‐4‐(3′‐carboxy‐2‐chlorostilben‐4‐yl)oxymethyl‐5‐isopropylisoxazole (GW4064; a FXR agonist), cyclosporin A, and irbesartan. OCA and INT‐777 suppressed HBV infection in HepG2‐human NTCP‐C4 cells. Interestingly, INT‐767 showed potent inhibition by attaching to HBV particles rather than binding to NTCP. As an entry inhibitor, INT‐767 was stronger than various natural BAs. Furthermore, in chimeric mice with humanized liver, INT‐767 markedly delayed the initial rise of HBsAg, HBeAg, and HBV DNA and reduced covalently closed circular DNA. The strong inhibitory effect of INT‐767 may be due to the cumulative effect of its ability to inhibit the entry of HBV and to stimulate FXR downstream signaling, which affects the postentry step. Conclusions Our results suggest that BA derivatives, particularly INT‐767, are prospective candidate anti‐HBV agents. Clarifying the underlying mechanisms of BA derivatives would facilitate the development of anti‐HBV agents.
Up-Regulation of iNOS in AML Blasts Creates an Immunosuppressive Microenvironment, Inhibits T-Cell Proliferation and Transforms T-Cells Towards a Tumor-Tolerating Phenotype
Authors: Rodrigo Jacamo, Nguyet-Minh Hoang, Ahmed Al Rawi, Charlie Ly, Robin Parihar, Teresa McQueen, Peter P. Ruvolo, Patrick Williams, Gheath Alatrash, Marina Konopleva, Michael Andreeff
Journal: Blood (2017)
Response to Drug-Eluting Stents: Do We Need Drugs to Recompense Drug Elution?⁎⁎Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
Authors: Georg Nickenig, Jan-Malte Sinning
Journal: Journal of the American College of Cardiology (2009)
FAILURE TO USE SEAT BELTS IN THE UNITED STATES: THE 1981-1983 BEHAVIORAL RISK FACTOR STUDIES
Authors: G M Goldbaum, P L Remington, K E Powell, G C Hogelin, E M Gentry
Journal: JAMA (1986)

Although seat belt use could prevent thousands of highway deaths and save billions of dollars annually, most Americans do not routinely buckle up. To understand better this phenomenon and other health-related behaviors, 28 states, the District of Columbia, and the Centers for Disease Control, Atlanta, surveyed over 22,000 US adults from 1981 through 1983. Overall, 76% of US adults reported not using seat belts. Blacks, 18- to 24-years-olds, persons with no more than a high school school education, and persons with other risk behaviors (especially drunk drivers) were least likely to use seat belts. Legislation by the states and education by physicians can increase seat belt use and reduce morbidity and mortality due to motor vehicle collisions.
Caloric Restriction Promotes Immunometabolic Reprogramming Leading to Protection from Tuberculosis
Authors: Carla Palma, Claudia La Rocca, Vincenzo Gigantino, Gabriella Aquino, Giovanni Piccaro, Dario Di Silvestre, Francesca Brambilla, Rossana Rossi, Fabrizia Bonacina, Maria Teresa Lepore, Matteo Audano, Nico Mitro, Gerardo Botti, Sara Bruzzaniti, Clorinda Fusco, Claudio Procaccini, Veronica De Rosa, Mario Galgani, Carlo Alviggi, Annibale Puca, Fabio Grassi, Tanja Rezzonico-Jost, Giuseppe Danilo Norata, Pierluigi Mauri, Mihai G. Netea, Paola de Candia, Giuseppe Matarese
Journal: Cell Metabolism (2021)
Evolution of regulatory networks associated with traits under selection in cichlids
Authors: Tarang K. Mehta, Christopher Koch, Will Nash, Sara A. Knaack, Padhmanand Sudhakar, Marton Olbei, Sarah Bastkowski, Luca Penso-Dolfin, Tamas Korcsmaros, Wilfried Haerty, Sushmita Roy, Federica Di-Palma
Journal: Genome biology (2021)

Abstract Background Seminal studies of vertebrate protein evolution speculated that gene regulatory changes can drive anatomical innovations. However, very little is known about gene regulatory network (GRN) evolution associated with phenotypic effect across ecologically diverse species. Here we use a novel approach for comparative GRN analysis in vertebrate species to study GRN evolution in representative species of the most striking examples of adaptive radiations, the East African cichlids. We previously demonstrated how the explosive phenotypic diversification of East African cichlids can be attributed to diverse molecular mechanisms, including accelerated regulatory sequence evolution and gene expression divergence. Results To investigate these mechanisms across species at a genome-wide scale, we develop a novel computational pipeline that predicts regulators for co-extant and ancestral co-expression modules along a phylogeny, and candidate regulatory regions associated with traits under selection in cichlids. As a case study, we apply our approach to a well-studied adaptive trait—the visual system—for which we report striking cases of network rewiring for visual opsin genes, identify discrete regulatory variants, and investigate their association with cichlid visual system evolution. In regulatory regions of visual opsin genes, in vitro assays confirm that transcription factor binding site mutations disrupt regulatory edges across species and segregate according to lake species phylogeny and ecology, suggesting GRN rewiring in radiating cichlids. Conclusions Our approach reveals numerous novel potential candidate regulators and regulatory regions across cichlid genomes, including some novel and some previously reported associations to known adaptive evolutionary traits.
Cognitive Trajectories and Resilience in Centenarians—Findings From the 100-Plus Study
Authors: Thomas T. Perls
Journal: JAMA Network Open (2021)

Nina Beker, PhD; Andrea Ganz, MSc; Marc Hulsman, PhD; Thomas Klausch, PhD; Ben A. Schmand, PhD; Philip Scheltens, MD, PhD; Sietske A. M. Sikkes, PhD; Henne Holstege, PhD
Doubling up on function: dual-specificity tyrosine-regulated kinase 1A (DYRK1A) in B cell acute lymphoblastic leukemia
Authors: Jung-Hyun Kim, Liping Li, Linda M.S. Resar
Journal: Journal of Clinical Investigation (2021)

DYRK1A, the dual-specificity kinase, is again doubling up on function, as reported by Bhansali, Rammohan, and colleagues in this issue of the JCI. DYRK1A is an evolutionarily conserved protein kinase with dual specificity; it adds phosphates to serine/threonine residues of diverse regulatory proteins and activates its own function by autophosphorylating a critical tyrosine at position 321 in the activation loop. Bhansali, Rammohan, and colleagues investigated B cell acute lymphoblastic leukemia (B-ALL) in individuals with Down syndrome (DS) and in children with leukemia characterized by aneuploidy. The study revealed a DYRK1A/FOXO1 and STAT3 signaling pathway in B-ALL that could be targeted pharmacologically, thus opening the door to therapeutic strategies for patients with leukemia with or without DS.
A CRISPR/Cas9-Engineered <i>ARID1A</i>-Deficient Human Gastric Cancer Organoid Model Reveals Essential and Nonessential Modes of Oncogenic Transformation
Authors: Yuan-Hung Lo, Kevin S. Kolahi, Yuhong Du, Chiung-Ying Chang, Andrey Krokhotin, Ajay Nair, Walter D. Sobba, Kasper Karlsson, Sunny J. Jones, Teri A. Longacre, Amanda T. Mah, Bahar Tercan, Alexandra Sockell, Hang Xu, Jose A. Seoane, Jin Chen, Ilya Shmulevich, Jonathan S. Weissman, Christina Curtis, Andrea Califano, Haian Fu, Gerald R. Crabtree, Calvin J. Kuo
Journal: Cancer Discovery (2021)

Abstract Mutations in ARID1A rank among the most common molecular aberrations in human cancer. However, oncogenic consequences of ARID1A mutation in human cells remain poorly defined due to lack of forward genetic models. Here, CRISPR/Cas9-mediated ARID1A knockout (KO) in primary TP53−/− human gastric organoids induced morphologic dysplasia, tumorigenicity, and mucinous differentiation. Genetic WNT/β-catenin activation rescued mucinous differentiation, but not hyperproliferation, suggesting alternative pathways of ARID1A KO-mediated transformation. ARID1A mutation induced transcriptional regulatory modules characteristic of microsatellite instability and Epstein–Barr virus–associated subtype human gastric cancer, including FOXM1-associated mitotic genes and BIRC5/survivin. Convergently, high-throughput compound screening indicated selective vulnerability of ARID1A-deficient organoids to inhibition of BIRC5/survivin, functionally implicating this pathway as an essential mediator of ARID1A KO-dependent early-stage gastric tumorigenesis. Overall, we define distinct pathways downstream of oncogenic ARID1A mutation, with nonessential WNT-inhibited mucinous differentiation in parallel with essential transcriptional FOXM1/BIRC5-stimulated proliferation, illustrating the general utility of organoid-based forward genetic cancer analysis in human cells. Significance: We establish the first human forward genetic modeling of a commonly mutated tumor suppressor gene, ARID1A. Our study integrates diverse modalities including CRISPR/Cas9 genome editing, organoid culture, systems biology, and small-molecule screening to derive novel insights into early transformation mechanisms of ARID1A-deficient gastric cancers. See related commentary by Zafra and Dow, p. 1327. This article is highlighted in the In This Issue feature, p. 1307
Has the mortality from pulmonary mucormycosis changed over time? A systematic review and meta-analysis
Authors: Valliappan Muthu, Ritesh Agarwal, Sahajal Dhooria, Inderpaul Singh Sehgal, Kuruswamy Thurai Prasad, Ashutosh N. Aggarwal, Arunaloke Chakrabarti
Journal: Clinical Microbiology and Infection (2021)
PI3K-driven HER2 expression is a potential therapeutic target in colorectal cancer stem cells
Authors: Laura Rosa Mangiapane, Annalisa Nicotra, Alice Turdo, Miriam Gaggianesi, Paola Bianca, Simone Di Franco, Davide Stefano Sardina, Veronica Veschi, Michele Signore, Sven Beyes, Luca Fagnocchi, Micol Eleonora Fiori, Maria Rita Bongiorno, Melania Lo Iacono, Irene Pillitteri, Gloria Ganduscio, Gaspare Gulotta, Jan Paul Medema, Alessio Zippo, Matilde Todaro, Ruggero De Maria, Giorgio Stassi
Journal: Gut (2021)

Cancer stem cells are responsible for tumour spreading and relapse. Human epidermal growth factor receptor 2 (HER2) expression is a negative prognostic factor in colorectal cancer (CRC) and a potential target in tumours carrying the gene amplification. Our aim was to define the expression of HER2 in colorectal cancer stem cells (CR-CSCs) and its possible role as therapeutic target in CRC resistant to anti- epidermal growth factor receptor (EGFR) therapy.A collection of primary sphere cell cultures obtained from 60 CRC specimens was used to generate CR-CSC mouse avatars to preclinically validate therapeutic options. We also made use of the ChIP-seq analysis for transcriptional evaluation of HER2 activation and global RNA-seq to identify the mechanisms underlying therapy resistance.Here we show that in CD44v6-positive CR-CSCs, high HER2 expression levels are associated with an activation of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway, which promotes the acetylation at the regulatory elements of the Erbb2 gene. HER2 targeting in combination with phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase kinase (MEK) inhibitors induces CR-CSC death and regression of tumour xenografts, including those carrying Kras and Pik3ca mutation. Requirement for the triple targeting is due to the presence of cancer-associated fibroblasts, which release cytokines able to confer CR-CSC resistance to PI3K/AKT inhibitors. In contrast, targeting of PI3K/AKT as monotherapy is sufficient to kill liver-disseminating CR-CSCs in a model of adjuvant therapy.While PI3K targeting kills liver-colonising CR-CSCs, the concomitant inhibition of PI3K, HER2 and MEK is required to induce regression of tumours resistant to anti-EGFR therapies. These data may provide a rationale for designing clinical trials in the adjuvant and metastatic setting.
The Antisocial Network: Cross Talk Between Cell Death Programs in Host Defense
Authors: Annelise G. Snyder, Andrew Oberst
Journal: Annual Review of Immunology (2021)

Nearly all animal cells contain proteins evolved to trigger the destruction of the cell in which they reside. The activation of these proteins occurs via sequential programs, and much effort has been expended in delineating the molecular mechanisms underlying the resulting processes of programmed cell death (PCD). These efforts have led to the definition of apoptosis as a form of nonimmunogenic PCD that is required for normal development and tissue homeostasis, and of pyroptosis and necroptosis as forms of PCD initiated by pathogen infection that are associated with inflammation and immune activation. While this paradigm has served the field well, numerous recent studies have highlighted cross talk between these programs, challenging the idea that apoptosis, pyroptosis, and necroptosis are linear pathways with defined immunological outputs. Here, we discuss the emerging idea of cell death as a signaling network, considering connections between cell death pathways both as we observe them now and in their evolutionary origins. We also discuss the engagement and subversion of cell death pathways by pathogens, as well as the key immunological outcomes of these processes.
Abstract 11339: Socioeconomic Status Influences the Choice of Pacemaker Type in Atrial Fibrillation - Insights From Danish Nationwide Registries
Authors: Frederik Dalgaard, Jannik Pallisgaard, Gunnar Gislason, Tommi Lindhardt, Martin Ruwald
Journal: Circulation (2018)

Introduction and Hypothesis: Patients with low socioeconomic status (SES) experience more procedure complications. We hypothesized that atrial fibrillation (AF) patients with low SES are more likel...
Image‐guided lymph node core‐needle biopsy predicts survival in mycosis fungoides and Sézary syndrome*
Authors: J. Calvani, A. de Masson, C. de Margerie‐Mellon, É. de Kerviler, C. Ram‐Wolff, A. Gruber, V. Meignin, P. Brice, A. Sadoux, S. Mourah, M. Bagot, M. Battistella
Journal: British Journal of Dermatology (2021)

The prognosis of Sézary syndrome (SS) and mycosis fungoides (MF) depends on lymph node (LN) involvement. The usefulness of LN image-guided core-needle biopsies (CNBs), instead of surgical sampling, has been poorly evaluated.To determine the prognostic value of LN CNB in MF/SS.A retrospective search was conducted to identify all LN biopsy specimens of MF/SS between 2008 and 2019. Biopsies were staged according to the International Society for Cutaneous Lymphomas/European Organisation for Research and Treatment of Cancer (ISCL/EORTC) criteria. We performed immunolabelling and determined the tumour clone frequency (TCF) by high-throughput sequencing of the T-cell receptor beta locus.We included 119 consecutive biopsies from 100 patients, 45 with MF and 55 with SS. N1, N2 and N3 stages were diagnosed in 34 (29%), 26 (22%) and 59 (49%) cases, respectively. The TCF, Ki67 index, and percentage of cells positive for thymocyte selection-associated high mobility group box protein (TOX), programmed cell death protein 1 (PD1), killer cell immunoglobulin-like receptor 3DL2 (KIR3DL2) and cluster of differentiation (CD)30 were all positively correlated with the N stage. Median overall survival (OS) for N1/N2 vs. N3 patients was 42 months (range 26-not reached) vs. 14 months (range 5-30), respectively (P < 0·001). In univariate analyses, an age > 75 years, LN short-axis diameter > 15 mm, N3 stage, presence of large-cell transformation, TOX > 60%, PD1 > 25%, Ki67 > 30%, KIR3DL2 > 15%, CD30 > 10% and TCF > 25% were identified as adverse prognostic factors. In multivariate analyses, only an age > 75 years and Ki67 index > 30% were associated with reduced OS. We developed a new prognostic index associating the N stage and the Ki67 index, which better discriminates N3 patients with poor prognosis.CNB allows an objective assessment of the LN involvement in MF/SS, relevant for staging and prognosis.
Effectiveness of Sequential Chemoradiation vs Concurrent Chemoradiation or Radiation Alone in Adjuvant Treatment After Hysterectomy for Cervical Cancer
Authors: He Huang, Yan-Ling Feng, Ting Wan, Yan-Na Zhang, Xin-Ping Cao, Yong-Wen Huang, Ying Xiong, Xin Huang, Min Zheng, Yan-Fang Li, Jun-Dong Li, Guan-Di Chen, Hu Li, Yi-Le Chen, Li-Guo Ma, Hong-Ying Yang, Li Li, Shu-Zhong Yao, Wei-Jun Ye, Hua Tu, Qi-Dan Huang, Li-Zhi Liang, Fu-Yuan Liu, Qing Liu, Ji-Hong Liu
Journal: JAMA Oncology (2021)

There is no current consensus on the role of chemotherapy in addition to radiation for postoperative adjuvant treatment of patients with early-stage cervical cancer with adverse pathological factors.To evaluate the clinical benefits of sequential chemoradiation (SCRT) and concurrent chemoradiation (CCRT) compared with radiation alone (RT) as a postoperative adjuvant treatment in early-stage cervical cancer.After radical hysterectomy at 1 of 8 participating hospitals in China, patients with FIGO (International Federation of Gynecology and Obstetrics) stage IB to IIA cervical cancer with adverse pathological factors were randomized 1:1:1 to receive adjuvant RT, CCRT, or SCRT. Data were collected from February 2008 to December 2018.Patients received adjuvant RT (total dose, 45-50 Gy), CCRT (weekly cisplatin, 30-40 mg/m2), or SCRT (cisplatin, 60-75 mg/m2, plus paclitaxel, 135-175 mg/m2) in a 21-day cycle, given 2 cycles before and 2 cycles after radiotherapy, respectively.The primary end point was the rate of disease-free survival (DFS) at 3 years.A total of 1048 women (median [range] age, 48 [23-65] years) were included in the analysis (350 in the RT group, 345 in the CCRT group, and 353 in the SCRT group). Baseline demographic and disease characteristics were balanced among the treatment groups except that the rate of lymph node involvement was lowest in the RT group (18.3%). In the intention-to-treat population, SCRT was associated with a higher rate of DFS than RT (3-year rate, 90.0% vs 82.0%; hazard ratio [HR], 0.52; 95% CI, 0.35-0.76) and CCRT (90.0% vs 85.0%; HR, 0.65; 95% CI, 0.44-0.96). Treatment with SCRT also decreased cancer death risk compared with RT (5-year rate, 92.0% vs 88.0%; HR, 0.58; 95% CI, 0.35-0.95) after adjustment for lymph node involvement. However, neither DFS nor cancer death risk was different among patients treated with CCRT or RT.In this randomized clinical trial, conducted in a postoperative adjuvant treatment setting, SCRT, rather than CCRT, resulted in a higher DFS and lower risk of cancer death than RT among women with early-stage cervical cancer.ClinicalTrials.gov Identifier: NCT00806117.
Abstract 20812: Relationship Between Discharge Heart Rate and Mortality in Japanese Patients With Acute Heart Failure
Authors: Hiroki Mochizuki, Atsushi Mizuno, Keitaro Mahara, Ayumi Goda, Yasumori Sujino, Takashi Kohno, Shun Kohsaka, Tsutomu Yoshikawa
Journal: Circulation (2017)

Introduction: The impact of discharge heart rate on the prognosis of heart failure with reduced left ventricular ejection fraction (LVEF) had been described. On the other hand, the association of d...
Audio Interview: Covid-19 in South Africa and a New SARS-CoV-2 Variant
Authors: Eric J. Rubin, Lindsey R. Baden, Salim S. Abdool Karim, Stephen Morrissey
Journal: New England Journal of Medicine (2021)

Covid-19 in South Africa and a New SARS-CoV-2 Variant In this audio interview conducted on January 13, 2021, the editors are joined by South African infectious disease physician Salim Abdool Karim ...