tbuckley/cabot-search huggingface dataset:
Sustained Lower Incidence of Diabetes-Related End-Stage Kidney Disease Among American Indians and Alaska Natives, Blacks, and Hispanics in the U.S., 2000–2016
Authors: Nilka Ríos Burrows, Yan Zhang, Israel Hora, Meda E. Pavkov, Karen Sheff, Giuseppina Imperatore, Ann K. Bullock, Ann L. Albright
Journal: Diabetes Care (2020)

OBJECTIVE Diabetes-related end-stage kidney disease (ESKD-D) disproportionately affects U.S. racial/ethnic minority populations compared with whites. However, from 1996 to 2013, ESKD-D incidence among American Indians and Alaska Natives (AIANs) and blacks declined. We assessed recent ESKD-D incidence data to determine whether trends by race/ethnicity have changed since 2013. RESEARCH DESIGN AND METHODS United States Renal Data System data from 2000 to 2016 were used to determine the number of whites, blacks, AIANs, Asians, and Hispanics aged ≥18 years with newly treated ESKD-D (with diabetes listed as primary cause). Using census population estimates as denominators, annual ESKD-D incidence rates were calculated and age adjusted to the 2000 U.S. standard population. Joinpoint regression was used to analyze trends and estimate an average annual percent change (AAPC) in incidence rates. RESULTS For adults overall, from 2000 to 2016, age-adjusted ESKD-D incidence rates decreased by 53% for AIANs (66.7–31.2 per 100,000, AAPC −4.5%, P &amp;lt; 0.001), by 33% for Hispanics (50.0–33.3, −2.1%, P &amp;lt; 0.001), and by 20% for blacks (56.2–44.7, −1.6%, P &amp;lt; 0.001). However, during the study period, age-adjusted ESKD-D incidence rates did not change significantly for Asians and increased by 10% for whites (15.4–17.0, 0.6%, P = 0.01). In 2016, ESKD-D incidence rates in AIANs, Hispanics, and blacks were ∼2.0–2.5 times higher than whites. CONCLUSIONS ESKD-D incidence declined for AIANs, Hispanics, and blacks and increased for whites. Continued efforts might be considered to reverse the trend in whites and sustain and lower ESKD-D incidence in the other populations.
Everolimus improves the efficacy of dasatinib in PDGFRα-driven glioma
Authors: Zachary Miklja, Viveka Nand Yadav, Rodrigo T. Cartaxo, Ruby Siada, Chase C. Thomas, Jessica R. Cummings, Brendan Mullan, Stefanie Stallard, Alyssa Paul, Amy K. Bruzek, Kyle Wierzbicki, Tao Yang, Taylor Garcia, Ian Wolfe, Marcia Leonard, Patricia L. Robertson, Hugh J.L. Garton, Daniel R. Wahl, Hemant Parmar, Jann N. Sarkaria, Cassie Kline, Sabine Mueller, Theodore Nicolaides, Chana Glasser, Sarah E.S. Leary, Sriram Venneti, Chandan Kumar-Sinha, Arul M. Chinnaiyan, Rajen Mody, Manjunath P. Pai, Timothy N. Phoenix, Bernard L. Marini, Carl Koschmann
Journal: Journal of Clinical Investigation (2020)

Pediatric and adult high-grade gliomas (HGGs) frequently harbor PDGFRA alterations. We hypothesized that cotreatment with everolimus may improve the efficacy of dasatinib in PDGFRα-driven glioma through combinatorial synergism and increased tumor accumulation of dasatinib. We performed dose-response, synergism, P-glycoprotein inhibition, and pharmacokinetic studies in in vitro and in vivo human and mouse models of HGG. Six patients with recurrent PDGFRα-driven glioma were treated with dasatinib and everolimus. We found that dasatinib effectively inhibited the proliferation of mouse and human primary HGG cells with a variety of PDGFRA alterations. Dasatinib exhibited synergy with everolimus in the treatment of HGG cells at low nanomolar concentrations of both agents, with a reduction in mTOR signaling that persisted after dasatinib treatment alone. Prolonged exposure to everolimus significantly improved the CNS retention of dasatinib and extended the survival of PPK tumor–bearing mice (mutant TP53, mutant PDGFRA, H3K27M). Six pediatric patients with glioma tolerated this combination without significant adverse events, and 4 patients with recurrent disease (n = 4) had a median overall survival of 8.5 months. Our results show that the efficacy of dasatinib treatment of PDGFRα-driven HGG was enhanced with everolimus and suggest a promising route for improving targeted therapy for this patient population.
Bone Mineral Density and FRAX Score May Not Predict Fracture Risk in Patients With Cancer Undergoing Hormone Deprivation Therapies
Authors: Alberto Dalla Volta, Gherardo Mazziotti, Filippo Maffezzoni, Salvatore Grisanti, Carlotta Palumbo, Rebecca Pedersini, Roberto Maroldi, Alfredo Berruti
Journal: Journal of Clinical Oncology (2020)
Single-cell analysis of germinal-center B cells informs on lymphoma cell of origin and outcome
Authors: Antony B. Holmes, Clarissa Corinaldesi, Qiong Shen, Rahul Kumar, Nicolo Compagno, Zhong Wang, Mor Nitzan, Eli Grunstein, Laura Pasqualucci, Riccardo Dalla-Favera, Katia Basso
Journal: The Journal of Experimental Medicine (2020)

In response to T cell–dependent antigens, mature B cells are stimulated to form germinal centers (GCs), the sites of B cell affinity maturation and the cell of origin (COO) of most B cell lymphomas. To explore the dynamics of GC B cell development beyond the known dark zone and light zone compartments, we performed single-cell (sc) transcriptomic analysis on human GC B cells and identified multiple functionally linked subpopulations, including the distinct precursors of memory B cells and plasma cells. The gene expression signatures associated with these GC subpopulations were effective in providing a sc-COO for ∼80% of diffuse large B cell lymphomas (DLBCLs) and identified novel prognostic subgroups of DLBCL.
Phase I study of the <sup>177</sup>Lu-DOTA<sup>0</sup>-Tyr<sup>3</sup>-Octreotate (lutathera) in combination with nivolumab in patients with neuroendocrine tumors of the lung
Authors: Chul Kim, Stephen V Liu, Deepa S Subramaniam, Tisdrey Torres, Massimo Loda, Giuseppe Esposito, Giuseppe Giaccone
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Lutathera is a 177 Lutetium-labeled somatostatin analog approved for the treatment of gastroenteropancreatic neuroendocrine tumors (NETs). Somatostatin receptors are expressed in small cell lung cancer (SCLC). Nivolumab, an anti-PD-1 antibody, may act synergistically with lutathera to generate antitumor immunity. We conducted a phase I study of lutathera plus nivolumab in patients with advanced NETs of the lung. Methods Patients with relapsed/refractory extensive-stage SCLC (ES-SCLC), non-progressing ES-SCLC after first-line platinum-based chemotherapy, or advanced grade I-II pulmonary NETs were eligible. The primary objective was to determine the recommended phase 2 dose (RP2D). The phase I portion followed a standard 3+3 design, assessing two dose levels (dose level 1: lutathera 3.7 GBq every 8 weeks for four doses with nivolumab 240 mg every 2 weeks; dose level 2: lutathera 7.4 GBq every 8 weeks for four doses with nivolumab 240 mg every 2 weeks). Results Nine patients were enrolled (six ES-SCLC, two pulmonary atypical carcinoid, one high-grade pulmonary neuroendocrine carcinoma). No dose-limiting toxicities (DLTs) were observed at dose level 1. At dose level 2, one patient with refractory ES-SCLC developed a DLT (grade 3 rash). The most common treatment-related adverse events (TRAEs) were lymphopenia (n=7), thrombocytopenia (n=4), anemia (n=3), and nausea (n=3). The most common grade 3 TRAE was lymphopenia (n=4). Among the seven patients with measurable disease, one patient with ES-SCLC had a partial response. Two patients with pulmonary atypical carcinoid had stable disease lasting 6 months. The RP2D was dose level 2. Conclusions Lutathera plus nivolumab was well tolerated and showed signs of antitumor activity. This combination warrants further exploration. Trial registration number NCT03325816
Lgr4 Governs a Pro-Inflammatory Program in Macrophages to Antagonize Post-Infarction Cardiac Repair
Authors: Chun-Kai Huang, Daopeng Dai, Hongyang Xie, Zhengbin Zhu, Jian Hu, Min Su, Mingyao Liu, Lin Lu, Weifeng Shen, Guang Ning, Jiqiu Wang, Ruiyan Zhang, Xiaoxiang Yan
Journal: Circulation Research (2020)

Rationale: Macrophages are critically involved in wound healing following myocardial infarction (MI). Lgr4, a member of LGR (leucine-rich repeat-containing G protein-coupled receptor) family, is emerging as a regulator of macrophage-associated immune responses. However, the contribution of Lgr4 to macrophage phenotype and function in the context of MI remains unclear. Objective: To determine the role of macrophage Lgr4 in MI and to dissect the underlying mechanisms. Methods and Results: During early inflammatory phase of MI, infarct macrophages rather than neutrophils expressed high level of Lgr4. Macrophage-specific Lgr4 knockout mice had no baseline cardiovascular defects but manifested improved heart function, modestly reduced infarct size, decreased early mortality due to cardiac rupture, and ameliorated adverse remodeling after MI. Improved outcomes in macrophage-specific Lgr4 knockout mice subjected to MI were associated with mitigated ischemic injury and optimal infarct healing, as determined by reduction of cardiac apoptosis in the peri-infarct zone, attenuation of local myocardial inflammatory response, decrease of matrix metalloproteinase expression in the infarct, enhancement of angiogenesis, myofibroblast proliferation, and collagen I deposition in reparative granulation tissue as well as formation of collagen-rich scar. More importantly, macrophage-specific Lgr4 knockout infarcts had reduced numbers of infiltrating leukocytes and inflammatory macrophages but harbored abundant reparative macrophage subsets. Lgr4-null infarct macrophages exhibited a less inflammatory transcriptional signature. These findings were further supported by transcriptomic profiling data showing repression of multiple pathways and broad-spectrum genes associated with proinflammatory responses in macrophage-specific Lgr4 knockout infarcts. Notably, we discovered that Lgr4-mediated functional phenotype programing in infarct macrophages was at least partly attributed to regulation of AP (activator protein)-1 activity. We further demonstrated that the synergistic effects of Lgr4 on AP-1 activation in inflammatory macrophages occurred via enhancing CREB (cAMP response element-binding protein)-mediated c-Fos , Fosl1 , and Fosb transactivation. Conclusions: Together, our data highlight the significance of Lgr4 in governing proinflammatory phenotype of infarct macrophages and postinfarction repair.
Broccoli: Combining Phylogenetic and Network Analyses for Orthology Assignment
Authors: Romain Derelle, Hervé Philippe, John K Colbourne
Journal: Molecular Biology and Evolution (2020)

Orthology assignment is a key step of comparative genomic studies, for which many bioinformatic tools have been developed. However, all gene clustering pipelines are based on the analysis of protein distances, which are subject to many artifacts. In this article, we introduce Broccoli, a user-friendly pipeline designed to infer, with high precision, orthologous groups, and pairs of proteins using a phylogeny-based approach. Briefly, Broccoli performs ultrafast phylogenetic analyses on most proteins and builds a network of orthologous relationships. Orthologous groups are then identified from the network using a parameter-free machine learning algorithm. Broccoli is also able to detect chimeric proteins resulting from gene-fusion events and to assign these proteins to the corresponding orthologous groups. Tested on two benchmark data sets, Broccoli outperforms current orthology pipelines. In addition, Broccoli is scalable, with runtimes similar to those of recent distance-based pipelines. Given its high level of performance and efficiency, this new pipeline represents a suitable choice for comparative genomic studies. Broccoli is freely available at https://github.com/rderelle/Broccoli.
Preventive Health Care Utilization Among Youths Who Have Run Away, Experienced Homelessness, or Been Stably Housed
Authors: Janna R. Gewirtz O’Brien, Andrew J. Barnes, Peter B. Scal, Annie-Laurie McRee
Journal: JAMA Pediatrics (2020)

sitivity analysis and observed a similar statistical difference between groups when including those with unknown symptom duration.Additionally, we identified only a very weak correlation between symptom duration and CT in the overall cohort (Spearman ρ = 0.22) and in each subgroup (young children, Spearman ρ = 0.20; older children, Spearman ρ = 0.19; and adults, Spearman ρ = 0.10).Discussion | Our analyses suggest children younger than 5 years with mild to moderate COVID-19 have high amounts of SARS-CoV-2 viral RNA in their nasopharynx compared with older children and adults.Our study is limited to detection of viral nucleic acid, rather than infectious virus, although SARS-CoV-2 pediatric studies reported a correlation between higher nucleic acid levels and the ability to culture infectious virus. 5Thus, young children can potentially be important drivers of SARS-CoV-2 spread in the general population, as has been demonstrated with respiratory syncytial virus, where children with high viral loads are more likely to transmit. 6 Behavioral habits of young children and close quarters in school and day care settings raise concern for SARS-CoV-2 amplification in this population as public health restrictions are eased.In addition to public health implications, this population will be important for targeting immunization efforts as SARS-CoV-2 vaccines become available.
SARS-CoV-2 viral load and antibody responses: the case for convalescent plasma therapy
Authors: Arturo Casadevall, Michael J. Joyner, Liise-anne Pirofski
Journal: Journal of Clinical Investigation (2020)

Most patients with COVID-19 lack antibody to SARS-CoV-2 in the first 10 days of illness while the virus drives disease pathogenesis. SARS-CoV-2 antibody deficiency in the setting of a tissue viral burden suggests that using an antibody as a therapeutic agent would augment the antiviral immune response. In this issue of the JCI, Wang and collaborators describe the kinetics of viral load and the antibody responses of 23 individuals with COVID-19 experiencing mild and severe disease. The researchers found that (a) individuals with mild and severe disease produced neutralizing IgG to SARS-CoV-2 10 days after disease onset, (b) SARS-CoV-2 persisted longer in those with severe disease, and (c) there was cross-reactivity between antibodies to SARS-CoV-1 and SARS-CoV-2, but only antibodies from patients with COVID-19 neutralized SARS-CoV-2. These observations provide important information on the serological response to SARS-CoV-2 of hospitalized patients with COVID-19 that can inform the use of convalescent plasma therapy.
The EPR effect and beyond: Strategies to improve tumor targeting and cancer nanomedicine treatment efficacy
Authors: Yang Shi, Roy van der Meel, Xiaoyuan Chen, Twan Lammers
Journal: Theranostics (2020)

Following its discovery more than 30 years ago, the enhanced permeability and retention (EPR) effect has become the guiding principle for cancer nanomedicine development. Over the years, the tumor-targeted drug delivery field has made significant progress, as evidenced by the approval of several nanomedicinal anticancer drugs. Recently, however, the existence and the extent of the EPR effect - particularly in patients - have become the focus of intense debate. This is partially due to the disbalance between the huge number of preclinical cancer nanomedicine papers and relatively small number of cancer nanomedicine drug products reaching the market. To move the field forward, we have to improve our understanding of the EPR effect, of its cancer type-specific pathophysiology, of nanomedicine interactions with the heterogeneous tumor microenvironment, of nanomedicine behavior in the body, and of translational aspects that specifically complicate nanomedicinal drug development. In this virtual special issue, 24 research articles and reviews discussing different aspects of the EPR effect and cancer nanomedicine are collected, together providing a comprehensive and complete overview of the current state-of-the-art and future directions in tumor-targeted drug delivery.
LIN28B promotes the development of neuroendocrine prostate cancer
Authors: Jessica Lovnicki, Yu Gan, Tingting Feng, Yinan Li, Ning Xie, Chia-Hao Ho, Ahn R. Lee, Xufeng Chen, Lucia Nappi, Bo Han, Ladan Fazli, Jiaoti Huang, Martin E. Gleave, Xuesen Dong
Journal: Journal of Clinical Investigation (2020)

Therapy-induced neuroendocrine prostate cancer (t-NEPC) is a highly aggressive subtype of prostate cancer with poor patient survival. Emerging evidence indicates that t-NEPC can develop when prostate adenocarcinoma cells acquire cancer stem-like cell signaling in the presence of androgen receptor inhibition, followed by redifferentiation toward neuroendocrine lineage and subsequent t-NEPC progression. Whether the stem-like signaling is controlled by the core pluripotency stem cell genes (e.g., LIN28 and SOX2) remains unknown. Here, we report that the transcription of the LIN28B isoform and SOX2 were co-upregulated in t-NEPC patient tumors, patient-derived xenografts, transgenic mice, and cell models. Immunohistochemistry validated that LIN28B and SOX2 protein expression were elevated in t-NEPC patient biopsies. Using prostate adenocarcinoma and t-NEPC cell models, we demonstrated that LIN28B induced a stem-like gene network, neuroendocrine biomarkers, and neuroendocrine cell morphology. LIN28B depletion by CRISPR inhibited t-NEPC tumorigenesis and xenograft growth. These LIN28B functions were mediated mainly through the suppression of let-7 miRNA expression, resulting in de-repression of the transcription factor HMGA2 and HMGA2-mediated SOX2 expression. This study revealed a mechanism by which t-NEPC can develop through the LIN28B/let-7/SOX2 axis that regulates a cancer cell stem-like gene network, highlighting LIN28B as a potential therapeutic target in t-NEPC.
Radiation with STAT3 Blockade Triggers Dendritic Cell–T cell Interactions in the Glioma Microenvironment and Therapeutic Efficacy
Authors: Martina Ott, Cynthia Kassab, Anantha Marisetty, Yuuri Hashimoto, Jun Wei, Daniel Zamler, Jia-Shiun Leu, Karl-Heinz Tomaszowski, Aria Sabbagh, Dexing Fang, Pravesh Gupta, Waldemar Priebe, Rafal J. Zielinski, Jared K. Burks, James P. Long, Ling-Yuan Kong, Gregory N. Fuller, John DeGroot, Erik P. Sulman, Amy B. Heimberger
Journal: Clinical Cancer Research (2020)

Abstract Purpose: Patients with central nervous system (CNS) tumors are typically treated with radiotherapy, but this is not curative and results in the upregulation of phosphorylated STAT3 (p-STAT3), which drives invasion, angiogenesis, and immune suppression. Therefore, we investigated the combined effect of an inhibitor of STAT3 and whole-brain radiotherapy (WBRT) in a murine model of glioma. Experimental Design: C57BL/6 mice underwent intracerebral implantation of GL261 glioma cells, WBRT, and treatment with WP1066, a blood–brain barrier–penetrant inhibitor of the STAT3 pathway, or the two in combination. The role of the immune system was evaluated using tumor rechallenge strategies, immune-incompetent backgrounds, immunofluorescence, immune phenotyping of tumor-infiltrating immune cells (via flow cytometry), and NanoString gene expression analysis of 770 immune-related genes from immune cells, including those directly isolated from the tumor microenvironment. Results: The combination of WP1066 and WBRT resulted in long-term survivors and enhanced median survival time relative to monotherapy in the GL261 glioma model (combination vs. control P &amp;lt; 0.0001). Immunologic memory appeared to be induced, because mice were protected during subsequent tumor rechallenge. The therapeutic effect of the combination was completely lost in immune-incompetent animals. NanoString analysis and immunofluorescence revealed immunologic reprograming in the CNS tumor microenvironment specifically affecting dendritic cell antigen presentation and T-cell effector functions. Conclusions: This study indicates that the combination of STAT3 inhibition and WBRT enhances the therapeutic effect against gliomas in the CNS by inducing dendritic cell and T-cell interactions in the CNS tumor.
Designer Descemet Membranes Containing PDLLA and Functionalized Gelatins as Corneal Endothelial Scaffold
Authors: Jasper Van Hoorick, Jasper Delaey, Hendrik Vercammen, Jürgen Van Erps, Hugo Thienpont, Peter Dubruel, Nadia Zakaria, Carina Koppen, Sandra Van Vlierberghe, Bert Van den Bogerd
Journal: Advanced Healthcare Materials (2020)

Abstract Corneal blindness is the fourth leading cause of visual impairment. Of specific interest is blindness due to a dysfunctional corneal endothelium which can only be treated by transplanting healthy tissue from a deceased donor. Unfortunately, corneal supply does not meet the demand with only one donor for every 70 patients. Therefore, there is a huge interest in tissue engineering of grafts consisting of an ultra‐thin scaffold seeded with cultured endothelial cells. The present research describes the fabrication of such artificial Descemet membranes based on the combination of a biodegradable amorphous polyester (poly ( d,l ‐lactic acid)) and crosslinkable gelatins. Four different crosslinkable gelatin derivatives are compared in terms of processing, membrane quality, and function, as well as biological performance in the presence of corneal endothelial cells. The membranes are fabricated through multi‐step spincoating, including a sacrificial layer to allow for straightforward membrane detachment after production. As a consequence, ultrathin (&lt;1 µm), highly transparent (&gt;90%), semi‐permeable membranes could be obtained with high biological potential. The membranes supported the characteristic morphology and correct phenotype of corneal endothelial cells while exhibiting similar proliferation rates as the positive control. As a consequence, the proposed membranes prove to be a promising synthetic alternative to donor tissue.
Abstract 12828: Minimally Invasive Surgical Mitral Valve Repair of Secondary Mitral Regurgitation Improves Outcome in Non-Ischemic Heart Failure With Preserved Ejection Fraction
Authors: Zsuzsanna Dorka Balogh, Carlos Collet, Guy Van Camp, Marc Vanderheyden, Jozef Bartunek, Monika Beles, Asim Katbeh, Marzia Albano, Evangelos Stefanidis, Martin Penicka
Journal: Circulation (2019)

Introduction: In patients with heart failure and preserved ejection fraction (HFPEF), even mild secondary mitral regurgitation (MR) has been associated with poor outcome Hypothesis: To test the hyp...
Using imaging to combat a pandemic: rationale for developing the UK National COVID-19 Chest Imaging Database
Authors: Joseph Jacob, Daniel Alexander, J. Kenneth Baillie, Rosalind Berka, Ottavia Bertolli, James Blackwood, Iain Buchan, Claire Bloomfield, Dominic Cushnan, Annemarie Docherty, Anthony Edey, Alberto Favaro, Fergus Gleeson, Mark Halling-Brown, Samanjit Hare, Emily Jefferson, Annette Johnstone, Myles Kirby, Ruth McStay, Arjun Nair, Peter J.M. Openshaw, Geoff Parker, Gerry Reilly, Graham Robinson, Giles Roditi, Jonathan C.L. Rodrigues, Neil Sebire, Malcolm G. Semple, Catherine Sudlow, Nick Woznitza, Indra Joshi
Journal: European Respiratory Journal (2020)

<b>The National COVID-19 Chest Imaging Database (NCCID) is a repository of chest radiographs, CT and MRI images and clinical data from COVID-19 patients across the UK, to support research and development of AI technology and give insight into COVID-19 disease</b>https://bit.ly/3eQeuha