tbuckley/cabot-search huggingface dataset:
Everolimus Inhibits the Progression of Ductal Carcinoma <i>In Situ</i> to Invasive Breast Cancer Via Downregulation of MMP9 Expression
Authors: Guang Chen, Xiao-Fei Ding, Kyle Pressley, Hakim Bouamar, Bingzhi Wang, Guixi Zheng, Larry E. Broome, Alia Nazarullah, Andrew J. Brenner, Virginia Kaklamani, Ismail Jatoi, Lu-Zhe Sun
Journal: Clinical Cancer Research (2019)

Abstract Purpose: We evaluated the role of everolimus in the prevention of ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) progression. Experimental Design: The effects of everolimus on breast cancer cell invasion, DCIS formation, and DCIS progression to IDC were investigated in a 3D cell culturing model, intraductal DCIS xenograft model, and spontaneous MMTV-Her2/neu mouse model. The effect of everolimus on matrix metalloproteinase 9 (MMP9) expression was determined with Western blotting and IHC in these models and in patients with DCIS before and after a window trial with rapamycin. Whether MMP9 mediates the inhibition of DCIS progression to IDC by everolimus was investigated with knockdown or overexpression of MMP9 in breast cancer cells. Results: Everolimus significantly inhibited the invasion of human breast cancer cells in vitro. Daily intragastric treatment with everolimus for 7 days significantly reduced the number of invasive lesions from intraductal DCIS foci and inhibited DCIS progression to IDC in the MMTV-Her2/neu mouse mammary tumor model. Mechanistically, everolimus treatment decreased the expression of MMP9 in the in vitro and in vivo models, and in breast tissues from patients with DCIS treated with rapamycin for 1 week. Moreover, overexpression of MMP9 stimulated the invasion, whereas knockdown of MMP9 inhibited the invasion of breast cancer cell–formed spheroids in vitro and DCIS in vivo. Knockdown of MMP9 also nullified the invasion inhibition by everolimus in vitro and in vivo. Conclusions: Targeting mTORC1 can inhibit DCIS progression to IDC via MMP9 and may be a potential strategy for DCIS or early-stage IDC therapy.
Risk of Psychiatric Disorders and Suicide Attempts in Emerging Adults With Diabetes
Authors: Marie-Eve Robinson, Marc Simard, Isabelle Larocque, Jai Shah, Meranda Nakhla, Elham Rahme
Journal: Diabetes Care (2019)

OBJECTIVE To determine the longitudinal risks of psychiatric disorders in adolescents and emerging adults with versus without diabetes. RESEARCH DESIGN AND METHODS We conducted a retrospective cohort study in Quebec, Canada, using linked health administrative databases of adolescents (age 15 years) with and without diabetes and without prior psychiatric disorders between 1997 and 2015, followed to age 25 years. RESULTS Our cohort included 3,544 individuals with diabetes and 1,388,397 without diabetes. Individuals with diabetes were more likely to suffer from a mood disorder (diagnosed in the emergency department or hospital) (adjusted hazard ratio 1.33 [95% CI 1.19–1.50]), attempt suicide (3.25 [1.79–5.88]), visit a psychiatrist (1.82 [1.67–1.98]), and experience any type of psychiatric disorder (1.29 [1.21–1.37]) compared with their peers without diabetes. CONCLUSIONS Between the ages of 15 and 25 years, the risks of psychiatric disorders and suicide attempts were substantially higher in adolescents and emerging adults with versus without diabetes.
The Association of Lipoprotein(a) Plasma Levels With Prevalence of Cardiovascular Disease and Metabolic Control Status in Patients With Type 1 Diabetes
Authors: Karin Littmann, Tigist Wodaje, Michael Alvarsson, Matteo Bottai, Mats Eriksson, Paolo Parini, Jonas Brinck
Journal: Diabetes Care (2019)

OBJECTIVE To investigate the association of the cardiovascular risk factor lipoprotein (Lp)(a) and vascular complications in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS Patients with type 1 diabetes receiving regular care were recruited in this observational cross-sectional study and divided into four groups according to their Lp(a) levels in nmol/L (very low &amp;lt;10, low 10–30, intermediate 30–120, high &amp;gt;120). Prevalence of vascular complications was compared between the groups. In addition, the association between metabolic control, measured as HbA1c, and Lp(a) was studied. RESULTS The patients (n = 1,860) had a median age of 48 years, diabetes duration of 25 years, and HbA1c of 7.8% (61 mmol/mol). The median Lp(a) was 19 (interquartile range 10–71) nmol/L. No significant differences between men and women were observed, but Lp(a) levels increased with increasing age. Patients in the high Lp(a) group had higher prevalence of complications than patients in the very low Lp(a) group. The age- and smoking-status–adjusted relative risk ratio of having any macrovascular disease was 1.51 (95% CI 1.01–2.28, P = 0.048); coronary heart disease, 1.70 (95% CI 0.97–3.00, P = 0.063); albuminuria, 1.68 (95% CI 1.12–2.50, P = 0.01); and calcified aortic valve disease, 2.03 (95% CI 1.03–4.03; P = 0.042). Patients with good metabolic control, HbA1c &amp;lt;6.9% (&amp;lt;52 mmol/mol), had significantly lower Lp(a) levels than patients with poorer metabolic control, HbA1c &amp;gt;6.9% (&amp;gt;52 mmol/mol). CONCLUSIONS Lp(a) is a significant risk factor for macrovascular disease, albuminuria, and calcified aortic valve disease in patients with type 1 diabetes. Poor metabolic control in patients with type 1 diabetes is associated with increased Lp(a) levels.
deSALT: fast and accurate long transcriptomic read alignment with de Bruijn graph-based index
Authors: Bo Liu, Yadong Liu, Junyi Li, Hongzhe Guo, Tianyi Zang, Yadong Wang
Journal: Genome biology (2019)

The alignment of long-read RNA sequencing reads is non-trivial due to high sequencing errors and complicated gene structures. We propose deSALT, a tailored two-pass alignment approach, which constructs graph-based alignment skeletons to infer exons and uses them to generate spliced reference sequences to produce refined alignments. deSALT addresses several difficult technical issues, such as small exons and sequencing errors, which break through bottlenecks of long RNA-seq read alignment. Benchmarks demonstrate that deSALT has a greater ability to produce accurate and homogeneous full-length alignments. deSALT is available at: https://github.com/hitbc/deSALT.
Enhancers Facilitate the Birth of De Novo Genes and Gene Integration into Regulatory Networks
Authors: Paco Majic, Joshua L Payne
Journal: Molecular Biology and Evolution (2019)

Abstract Regulatory networks control the spatiotemporal gene expression patterns that give rise to and define the individual cell types of multicellular organisms. In eumetazoa, distal regulatory elements called enhancers play a key role in determining the structure of such networks, particularly the wiring diagram of “who regulates whom.” Mutations that affect enhancer activity can therefore rewire regulatory networks, potentially causing adaptive changes in gene expression. Here, we use whole-tissue and single-cell transcriptomic and chromatin accessibility data from mouse to show that enhancers play an additional role in the evolution of regulatory networks: They facilitate network growth by creating transcriptionally active regions of open chromatin that are conducive to de novo gene evolution. Specifically, our comparative transcriptomic analysis with three other mammalian species shows that young, mouse-specific intergenic open reading frames are preferentially located near enhancers, whereas older open reading frames are not. Mouse-specific intergenic open reading frames that are proximal to enhancers are more highly and stably transcribed than those that are not proximal to enhancers or promoters, and they are transcribed in a limited diversity of cellular contexts. Furthermore, we report several instances of mouse-specific intergenic open reading frames proximal to promoters showing evidence of being repurposed enhancers. We also show that open reading frames gradually acquire interactions with enhancers over macroevolutionary timescales, helping integrate genes—those that have arisen de novo or by other means—into existing regulatory networks. Taken together, our results highlight a dual role of enhancers in expanding and rewiring gene regulatory networks.
Switch hitter: Bcl11b in T cells and ILC2s
Authors: Christelle Harly, Avinash Bhandoola
Journal: The Journal of Experimental Medicine (2019)

In this issue of JEM, Hosokawa et al. (https://doi.org/10.1084/jem.20190972) establish that transcription factor Bcl11b regulates almost completely distinct sets of genes in T cell precursors and ILC2s. To understand how this occurs, they identify multiple levels of functional regulation for Bcl11b that are used differently by T cell precursors and ILC2s.
Hs.500667 and DNTT (TdT): ‘Partners in crime’ in a novel t(5;10) translocation in ALL
Authors: Sheryl M. Gough, Peter Ganly, Ruth Spearing, Christine M. Morris
Journal: Cancer Research (2006)

2577  Molecular dissection of chromosome translocations has identified many genes important to the cause or progression of leukemia. Aside from their diagnostic and prognostic value, the identification of these genes is critical to our understanding of the molecular pathways of leukemogenesis and a necessary precedent to the design of targeted, less toxic treatments. However, the genetic basis of up to 40% of acute lymphoblastic leukemia (ALL) cases remains unknown. We hypothesize that novel chromosome translocations may mark the location of genes potentially rearranged more frequently by cryptic submicroscopic mechanisms in leukemia patients. We have targeted the breakpoints of a novel t(5;10)(q22;q24) translocation found as the sole abnormality in the leukemic cells of a 59 year old male with ALL. Our positional cloning efforts using a combination of fluorescent in situ hybridization, large-insert bacterial-, yeast- and P1-artificial chromosome (BAC, YAC, PAC) clones, end-sequencing, in silico analyses, leukemic t(5;10) metaphase studies, custom PCR analyses and Southern hybridization studies of patient DNA, have mapped the 10q24 breakpoint to a 700 bp genomic region, physically disrupting UniGene Hs.500667 which encodes a novel RNA transcript. Using RACE and Northern blot analyses we have confirmed the unique transcriptional activity of Hs.500667, a novel gene now newly implicated in this case of ALL. Chromosome 5 sequences abnormally fused to Hs.500667, disrupt its normal transcription and unknown function, and potentially links it to the etiology of this ALL. In addition, Hs.500667 overlaps the promoter of the deoxynucleotidyltransferase terminal (DNTT) gene and transcribes in the opposite direction of, and from within, DNTT intron 1, suggesting a possible coordinated regulation or shared promoter between Hs.500667 and DNTT. The breakpoint site within Hs.500667 is less than 5 kb centromeric of DNTT and only 27 kb telomeric of the B-cell linker protein (BLNK) gene, in a tightly regulated genomic region directly involved in lymphocyte development that has not previously been associated with leukemia. This translocation likely causes or contributes to the genetic basis of this ALL and may still prove to generate a fusion gene and/or deregulate the transcription of DNTT. Suspicions have previously focused on DNTT which exhibits abnormal activity in many leukemias, but this remains to be explained and the genomic evidence has so far been absent. Any deregulation of DNTT is likely to have major downstream effects, as this gene is expressed stage-specifically in lymphoid cells and encodes terminal deoxynucleotidyltransferase (TdT), the enzymatic component of a recombinase complex essential for N-region antibody diversity in V(D)J recombination and which is active in double strand break repair.
Exome Sequencing Identifies Glycosylation Defects As a Probable Cause of Immune Thrombotic Thrombocytopenic Purpura
Authors: Felipe Massicano, Elizabeth M. Staley, Konstantine Halkidis, Nicole K. Kocher, Lance A. Williams, Marisa B. Marques, Bryan K. Guillory, Wenjing Cao, Malay K. Basu, X. Long Zheng
Journal: Blood (2019)
Abstract PR04: STING and TLR-independent activation of T-cell responses against pancreatic cancer using agonistic CD40 antibody
Authors: Katelyn T. Byrne, Alexander H. Morrison, Robert H. Vonderheide
Journal: Cancer Research (2019)

Abstract Immunotherapy is increasingly used in combination with current standard-of-care treatments such as chemotherapy that likely provides danger signals via immunogenic tumor cell death and activation of STING or TLR pathways. However, both the toxicity and immunosuppressive effects of chemotherapy risks hindering clinical benefit. Agonistic CD40 antibody is a potent activator of immune responses, acting upstream of immune checkpoint blockade (ICB) by driving T-cell priming. Here, we show that anti-CD40 is sufficient to drive potent T-cell responses against murine KPC (KrasG12D;Trp53R172H;Pdx-Cre) pancreatic tumors if combined with ICB. CD40/ICB was more effective than CD40/ICB/chemotherapy (median overall survival 76 days vs. 44 days in CD40/ICB vs. CD40/ICB/chemotherapy-treated mice, p&amp;lt;0.01). Therapeutic efficacy of CD40/ICB was fully independent of the STING, MyD88, and IFNAR pathways, requiring instead host expression of CD40, cross-presenting dendritic cells, and an intact T-cell compartment. Therapy-induced CD4 and CD8 T cell responses displayed enhanced polyfunctional cytokine secretion (48.9% vs. 29.5% of CD8+ T cells in vehicle control treated mice), cleared established primary tumors (43% vs. 0% in vehicle control or single-treatment cohorts p&amp;lt;0.0001), and formed protective memory responses in 57% of CD40/ICB cured mice. Immunosuppressive regulatory T cells were noticeably absent from the tumor site after CD40 treatment (7% of CD4+ T cells vs. 33% in mice treated with ICB alone, p&amp;lt;0.01), concomitant with improved T-cell activation and proliferation, whereas ICB was needed to potentiate the full activation and reinvigoration of the T-cell response both locally and systemically. The efficacy of CD40/ICB in in this ICB-resistant KPC model opens the possibility of optimized immunotherapy regimens free of the toxicity and immunosuppressive effects of cytotoxic therapy. This abstract is also being presented as Poster B08. Citation Format: Katelyn T. Byrne, Alexander H. Morrison, Robert H. Vonderheide. STING and TLR-independent activation of T-cell responses against pancreatic cancer using agonistic CD40 antibody [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr PR04.
Cardiomyocyte-specific KLF5 deletion accelerates diet-induced obesity via cardiac FGF21
Authors: Christine J. Pol, Nina M. Pollak, Michael J. Jurczak, Iordanes Karagiannides, Panagiotis Ntziachristos, Diego A. Scerbo, Brett R. Brown, Mesele C. Valenti, Iannis Aifantis, Gerald I. Shulman, Ira J. Goldberg, Konstantinos Drosatos
Journal: Circulation (2017)
Beneficial bacteria activate type-I interferon production via the intracellular cytosolic sensors STING and MAVS
Authors: Jorge Gutierrez-Merino, Beatriz Isla, Theo Combes, Fernando Martinez-Estrada, Carlos Maluquer De Motes
Journal: Gut Microbes (2020)

Type-I interferon (IFN-I) cytokines are produced by immune cells in response to microbial infections, cancer and autoimmune diseases, and subsequently, trigger cytoprotective and antiviral responses through the activation of IFN-I stimulated genes (ISGs). The ability of intestinal microbiota to modulate innate immune responses is well known, but the mechanisms underlying such responses remain elusive. Here we report that the intracellular sensors stimulator of IFN genes (STING) and mitochondrial antiviral signaling (MAVS) are essential for the production of IFN-I in response to lactic acid bacteria (LAB), common gut commensal bacteria with beneficial properties. Using human macrophage cells we show that LAB strains that potently activate the inflammatory transcription factor NF-κB are poor inducers of IFN-I and conversely, those triggering significant amounts of IFN-I fail to activate NF-κB. This IFN-I response is also observed in human primary macrophages, which modulate CD64 and CD40 upon challenge with IFN-I-inducing LAB. Mechanistically, IFN-I inducers interact more intimately with phagocytes as compared to NF-κB-inducers, and fail to activate IFN-I in the presence of phagocytosis inhibitors. These bacteria are then sensed intracellularly by the cytoplasmic sensors STING and, to a lesser extent, MAVS. Accordingly, macrophages deficient for STING showed dramatically reduced phosphorylation of TANK-binding kinase (TBK)-1 and IFN-I activation, which resulted in lower expression of ISGs. Our findings demonstrate a major role for intracellular sensing and STING in the production of IFN-I by beneficial bacteria and the existence of bacteria-specific immune signatures, which can be exploited to promote cytoprotective responses and prevent overreactive NF-κB-dependent inflammation in the gut.
Next-Generation Sequencing of Retinoblastoma Identifies Pathogenic Alterations beyond RB1 Inactivation That Correlate with Aggressive Histopathologic Features
Authors: Armin R. Afshar, Melike Pekmezci, Michele M. Bloomer, Nicola J. Cadenas, Meredith Stevers, Anuradha Banerjee, Ritu Roy, Adam B. Olshen, Jessica Van Ziffle, Courtney Onodera, W. Patrick Devine, James P. Grenert, Boris C. Bastian, David A. Solomon, Bertil E. Damato
Journal: Ophthalmology (2019)
Make medical training more flexible to accommodate doctors’ changing needs, says GMC
Authors: Abi Rimmer
Journal: BMJ (2019)

Existing training pathways are too inflexible to meet doctors’ desire for a better work-life balance, the General Medical Council (GMC) has said.

The regulator’s ninth State of Medical Education and Practice in the UK report,1 published on 18 December, said that doctors also needed more support during career transitions.

In a foreword to the report the GMC’s chair, Clare Marx, and its chief executive, Charlie Massey, said that today’s doctors were pursuing different career paths from their older peers.

They wrote, “Be it taking a year out, reducing their hours, or stepping out of practice earlier, these shifts are having a direct impact …
A Bibliometric Analysis of Top-Cited Journal Articles in Obstetrics and Gynecology
Authors: Justin S. Brandt, Ola Hadaya, Meike Schuster, Todd Rosen, Mark V. Sauer, Cande V. Ananth
Journal: JAMA Network Open (2019)

<h3>Importance</h3> Citation analysis is a bibliometric method that uses citation rates to evaluate research performance. This type of analysis can identify the articles that have shaped the modern history of obstetrics and gynecology (OBGYN). <h3>Objectives</h3> To identify and characterize top-cited OBGYN articles in the Institute for Scientific Information Web of Science's Science Citation Index Expanded and to compare top-cited OBGYN articles published in specialty OBGYN journals with those published in nonspecialty journals. <h3>Design, Setting, and Participants</h3> Cross-sectional bibliometric analysis of top-cited articles that were indexed in the Science Citation Index Expanded from 1980 to 2018. The Science Citation Index Expanded was queried using search terms from the American Board of Obstetrics and Gynecology's 2018 certifying examination topics list. The top 100 articles from all journals and the top 100 articles from OBGYN journals were evaluated for specific characteristics. Data were analyzed in March 2019. <h3>Main Outcomes and Measures</h3> The articles were characterized by citation number, publication year, topic, study design, and authorship. After excluding articles that featured on both lists, top-cited articles were compared. <h3>Results</h3> The query identified 3 767 874 articles, of which 278 846 (7.4%) were published in OBGYN journals. The top-cited article was published by Rossouw and colleagues in<i>JAMA</i>(2002). Top-cited articles published in nonspecialty journals were more frequently cited than those in OBGYN journals (median [interquartile range], 1738 [1490-2077] citations vs 666 [580-843] citations, respectively;<i>P</i> &lt; .001) and were more likely to be randomized trials (25.0% vs 2.2%, respectively; difference, 22.8%; 95% CI, 13.5%-32.2%;<i>P</i> &lt; .001). Whereas articles from nonspecialty journals focused on broad topics like osteoporosis, articles from OBGYN journal focused on topics like preeclampsia and endometriosis. <h3>Conclusions and Relevance</h3> This study found substantial differences between top-cited OBGYN articles published in nonspecialty vs OBGYN journals. These differences may reflect the different goals of the journals, which work together to ensure optimal dissemination of impactful articles.
Abstract 10725: Oncostatin M Promotes Cardiomyocyte Dedifferentiation and Proliferation Via Gp130-Src-Yap Module in Neonatal Heart Regeneration
Authors: Yandong Li, Jie Feng, Yu Nie
Journal: Circulation (2018)

Background: Cardiomyocyte dedifferentiation is an essential way of existing myocytes returning to cell cycle and initiating proliferation. Oncostatin M (OSM) was demonstrated to promote cardiomyocy...
Development of a biomarker-based calculator to predict the probability to achieve a pathologic complete response after neoadjuvant pembrolizumab in muscle-invasive bladder cancer
Authors: L. Marandino, M. Bandini, R. Madison, D. Raggi, A. Gallina, M. Colecchia, R. Lucianò, P. Giannatempo, E. Farè, F. Pederzoli, M. Bianchi, R. Colombo, U. Capitanio, S.M. Ali, J.H. Chung, J. Ross, A. Salonia, A. Briganti, F. Montorsi, A. Necchi
Journal: Annals of Oncology (2019)
European Society of Gastrointestinal Endoscopy (ESGE) Publications Policy – Update 2020
Authors: Cesare Hassan, Thierry Ponchon, Raf Bisschops, Jeanin E. van Hooft, Helmut Messmann, Ian M. Gralnek, Mario Dinis-Ribeiro
Journal: Endoscopy (2019)

Because of the new educational and other activities launched by the ESGE Governing Board and its Committees/Working Groups, ESGE now publishes a greater range of documents than described in the 2012 policy document on ESGE guideline development [1]. [Table 1] presents details of the current types of ESGE publications and the corresponding responsible Committees/Working Groups:
Treatment of Hyperglycemia in Patients With Acute Stroke
Authors: Micah T. Long, Douglas B. Coursin, James S. Krinsley
Journal: JAMA (2019)

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A theory stuck in evolutionary and historical time
Authors: Mathias Osvath, Can Kabadayi
Journal: Behavioral and Brain Sciences (2019)

Abstract We argue that the two temporal cognition systems are conceptually too confined to be helpful in understanding the evolution of temporal cognition. In fact, we doubt there are two systems. In relation to this, we question that the authors did not describe the results of our planning study on ravens correctly, as this is of consequence to their theory.