tbuckley/cabot-search huggingface dataset:
Functional assessment and phenotypic heterogeneity of <i>SFTPA1</i> and <i>SFTPA2</i> mutations in interstitial lung diseases and lung cancer
Authors: Marie Legendre, Afifaa Butt, Raphaël Borie, Marie-Pierre Debray, Diane Bouvry, Emilie Filhol-Blin, Tifenn Desroziers, Valérie Nau, Bruno Copin, Florence Dastot-Le Moal, Mélanie Héry, Philippe Duquesnoy, Nathalie Allou, Anne Bergeron, Julien Bermudez, Aurélie Cazes, Anne-Laure Chene, Vincent Cottin, Bruno Crestani, Jean-Charles Dalphin, Christine Dombret, Bérénice Doray, Clairelyne Dupin, Violaine Giraud, Anne Gondouin, Laurent Gouya, Dominique Israël-Biet, Caroline Kannengiesser, Aurélie Le Borgne, Sylvie Leroy, Elisabeth Longchampt, Gwenaël Lorillon, Hilario Nunes, Clément Picard, Martine Reynaud-Gaubert, Julie Traclet, Paul de Vuyst, Aurore Coulomb L'Hermine, Annick Clement, Serge Amselem, Nadia Nathan
Journal: European Respiratory Journal (2020)

Introduction Interstitial lung diseases (ILDs) can be caused by mutations in the SFTPA1 and SFTPA2 genes, which encode the surfactant protein (SP) complex SP-A. Only 11 SFTPA1 or SFTPA2 mutations have so far been reported worldwide, of which five have been functionally assessed. In the framework of ILD molecular diagnosis, we identified 14 independent patients with pathogenic SFTPA1 or SFTPA2 mutations. The present study aimed to functionally assess the 11 different mutations identified and to accurately describe the disease phenotype of the patients and their affected relatives. Methods The consequences of the 11 SFTPA1 or SFTPA2 mutations were analysed both in vitro , by studying the production and secretion of the corresponding mutated proteins and ex vivo , by analysing SP-A expression in lung tissue samples. The associated disease phenotypes were documented. Results For the 11 identified mutations, protein production was preserved but secretion was abolished. The expression pattern of lung SP-A available in six patients was altered and the family history reported ILD and/or lung adenocarcinoma in 13 out of 14 families (93%). Among the 28 SFTPA1 or SFTPA2 mutation carriers, the mean age at ILD onset was 45 years (range 0.6–65 years) and 48% underwent lung transplantation (mean age 51 years). Seven carriers were asymptomatic. Discussion This study, which expands the molecular and clinical spectrum of SP-A disorders, shows that pathogenic SFTPA1 or SFTPA2 mutations share similar consequences for SP-A secretion in cell models and in lung tissue immunostaining, whereas they are associated with a highly variable phenotypic expression of disease, ranging from severe forms requiring lung transplantation to incomplete penetrance.
Interferon alpha therapy in essential thrombocythemia and polycythemia vera—a systematic review and meta-analysis
Authors: Jan Philipp Bewersdorf, Smith Giri, Rong Wang, Nikolai Podoltsev, Robert T. Williams, Martin S. Tallman, Raajit K. Rampal, Amer M. Zeidan, Maximilian Stahl
Journal: Leukemia (2020)
Abstract 1793: Interaction of MYC and SUMOylation machinery in an aggressive pancreatic cancer subtype
Authors: Zonera Hassan, Alex Biederstädt, Christian Schneeweis, Markus Schick, Nilsson Jonas, Mathias Wirth, Andrea Coluccio, Felix Orben, Katja Steiger, Jolanta Slawska, Steve Langston, Dieter Saur, Roland Rad, Maximilian Reichert, Guenter Schneider, Ulrich Keller
Journal: Cancer Research (2020)

Abstract Despite recent improvements in treatment regimen such as combination chemotherapies, pancreatic ductal adenocarcinoma still carries a dismal prognosis with an overall survival rate of 9%. The oncogenic transcription factor MYC is amplified in about 12% of all PDAC, which is connected to a worse survival. It is clear that hyperactivation of MYC generates dependencies that can be exploited therapeutically. Therefore, the aim of the study was to find and to target MYC-associated dependencies. Human PDAC gene expression data sets were analyzed. Moreover, analysis of the SUMO pathway in large cohort of PDAC was performed by IHC. Furthermore, a novel, pharmacological SUMO inhibitor was used and characterized by using human and murine 2D-, organoid-, and in vivo-models of PDAC. In addition, this connection was also verified by the genetically modified human and murine models. Large-scale gene expression datasets of human PDACs analysis revealed a connection of MYC to the SUMOylation machinery in PDAC. Moreover, results were also corroborated by the hyperactivation of SUMO pathway in a large patient cohort which characterized a PDAC subtype with a dismal prognosis. We furthermore corroborated these results by using the novel SUMO inhibitor ML093 by in vitro studies that hyperactivation of MYC is connected to an increased sensitivity to pharmacological SUMO inhibition. In conclusion, SUMO inhibitor-based therapies should be further developed for an aggressive PDAC subtype. Citation Format: Zonera Hassan, Alex Biederstädt, Christian Schneeweis, Markus Schick, Nilsson Jonas, Mathias Wirth, Andrea Coluccio, Felix Orben, Katja Steiger, Jolanta Slawska, Steve Langston, Dieter Saur, Roland Rad, Maximilian Reichert, Guenter Schneider, Ulrich Keller. Interaction of MYC and SUMOylation machinery in an aggressive pancreatic cancer subtype [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1793.
Abstract 4497: A single-cell multiomics approach to study tumor-driven perturbations during hematopoiesis in mice
Authors: Nihan Kara, Xiaoshan Shi, Nikolay Samusik, Stephanie Widmann, Aaron J. Tyznik
Journal: Cancer Research (2020)

Abstract Cancer is associated with concomitant myeloid cell responses that are characterized by an expansion of tumor associated myeloid cells including, myeloid derived suppressor cells (MDSCs), tumor associated macrophages (TAMs) and neutrophils (TANs). These myeloid derived cells are known to modulate immune responses that enhance cancer cell stemness, angiogenesis, metastasis, invasion and immune escape. The prevailing paradigm is that cancer interferes with hematopoiesis and skews the host system to generate cells of myeloid origin with tumor-promoting functions. Intriguingly, tumor derived factors can perturbate normal bone marrow hematopoiesis and promote extramedullary hematopoiesis in organs such as the spleen. Advances in single cell multiomic technologies now enable the analysis of high dimensional protein and mRNA expression from thousands of cells simultaneously. Using the power of the BD Rhapsody™ Single-Cell Analysis system, we have carefully investigated melanoma associated extramedullary hematopoiesis in mice. To do this, we isolated four hematopoietic stem and progenitor cell populations simultaneously, including Lin- Sca-1+ c-Kit+ (LSK), common myeloid progenitor (CMP), granulocyte-macrophage progenitor (GMP) and megakaryocyte-erythrocyte progenitor (MEP) cells from the spleen and bone marrow of melanoma-bearing mice using the BD FACSMelody™ cell sorter in combination with a multiplex BD® AbSeq Oligos panel for surface protein expression and a single-cell whole transcriptome analysis. Using advanced analysis plugins in SeqGeq™ software, we were able to delineate the developmental trajectories of these hematopoietic stem and progenitor cells in this systemic immuno-suppressive myeloid environment. These advanced technologies are critical to uncover tumor mediated abnormalities in hematopoiesis. Disclaimers: For Research Use Only. Not for use in diagnostic or therapeutic procedures. Class 1 Laser Product. BD, the BD Logo, FACSMelody and Rhapsody are trademarks of Becton, Dickinson and Company or its affiliates. © 2019 BD. All rights reserved. Citation Format: Nihan Kara, Xiaoshan Shi, Nikolay Samusik, Stephanie Widmann, Aaron J. Tyznik. A single-cell multiomics approach to study tumor-driven perturbations during hematopoiesis in mice [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4497.
Abstract 4389: Glycogen synthase kinase 3A (GSK3A) gene alterations are negatively correlated with overall and disease-free survival in breast cancer patients: <i>In silico</i> analysis
Authors: Jasmeet Kaur, Karandeep Kaur
Journal: Cancer Research (2020)

Abstract Breast cancer is a heterogeneous disease and most widespread malignancy in women. It is one of three leading causes of deaths worldwide, together with lung and colon cancer. Glycogen synthase kinase 3 (GSK3) is a serine/threonine protein kinase involved in glucose regulation, inflammation, immune responses, proliferation, migration and apoptosis. GSK3 is expressed in all mammalian tissues and has a role in diseases including mood disorders, Alzheimer disease, diabetes and cancer. GSK3A and GSK3B are two isoforms, encoded by distinct genes and are 98% identical within their kinase domain. Gene knockout studies demonstrate that the two isoforms are not completely redundant, but perform similar functions in several settings. So far, very little is known about GSK3A role in cancer. We analyzed correlation of GSK3A gene mutations and copy number changes with overall and disease-free survival in breast cancer patients using cBioPortal for cancer genomics. Fourteen datasets for breast cancer studies were analyzed and GSK3A alterations were found in seven datasets. These alterations included mutations (missense and truncating), amplifications and deep deletions; with amplifications being the most abundant alteration. Out of the seven datasets, three datasets showed significant negative correlation of GSK3A alterations with overall and disease-free survival in breast cancer patients. Kaplan-Meier curve analysis demonstrated that amplification of GSK3A gene is significantly correlated with poor overall and disease-free survival of breast cancer patients, specifically in estrogen receptor positive (ER+) tumors. Further, missense and truncating mutations leads to poor disease-free survival in patients with ER+ tumors and truncating mutation showed poor overall survival in patients with Her2+ tumors. Collectively, analysis of GSK3A genomic profile in breast cancer patients provides a novel insight that GSK3A is crucial in the biological behavior and/or pathogenesis of breast cancer and hence is an important therapeutic target for breast cancer treatment. Citation Format: Jasmeet Kaur, Karandeep Kaur. Glycogen synthase kinase 3A (GSK3A) gene alterations are negatively correlated with overall and disease-free survival in breast cancer patients: In silico analysis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4389.
The effect of carbon nanotubes on osteogenic functions of adipose-derived mesenchymal stem cells in vitro and bone formation in vivo compared with that of nano-hydroxyapatite and the possible mechanism
Authors: Zhipo Du, Xinxing Feng, Guangxiu Cao, Zhending She, Rongwei Tan, Katerina E. Aifantis, Ruihong Zhang, Xiaoming Li
Journal: Bioactive Materials (2020)

It has been well recognized that the development and use of artificial materials with high osteogenic ability is one of the most promising means to replace bone grafting that has exhibited various negative effects. The biomimetic features and unique physiochemical properties of nanomaterials play important roles in stimulating cellular functions and guiding tissue regeneration. But efficacy degree of some nanomaterials to promote specific tissue formation is still not clear. We hereby comparatively studied the osteogenic ability of our treated multi-walled carbon nanotubes (MCNTs) and the main inorganic mineral component of natural bone, nano-hydroxyapatite (nHA) in the same system, and tried to tell the related mechanism. In vitro culture of human adipose-derived mesenchymal stem cells (HASCs) on the MCNTs and nHA demonstrated that although there was no significant difference in the cell adhesion amount between on the MCNTs and nHA, the cell attachment strength and proliferation on the MCNTs were better. Most importantly, the MCNTs could induce osteogenic differentiation of the HASCs better than the nHA, the possible mechanism of which was found to be that the MCNTs could activate Notch involved signaling pathways by concentrating more proteins, including specific bone-inducing ones. Moreover, the MCNTs could induce ectopic bone formation in vivo while the nHA could not, which might be because MCNTs could stimulate inducible cells in tissues to form inductive bone better than nHA by concentrating more proteins including specific bone-inducing ones secreted from M2 macrophages. Therefore, MCNTs might be more effective materials for accelerating bone formation even than nHA.
Genomic Consequences of Long-Term Population Decline in Brown Eared Pheasant
Authors: Pengcheng Wang, John T Burley, Yang Liu, Jiang Chang, De Chen, Qi Lu, Shou-Hsien Li, Xuming Zhou, Scott Edwards, Zhengwang Zhang
Journal: Molecular Biology and Evolution (2020)

Abstract Population genetic theory and empirical evidence indicate that deleterious alleles can be purged in small populations. However, this viewpoint remains controversial. It is unclear whether natural selection is powerful enough to purge deleterious mutations when wild populations continue to decline. Pheasants are terrestrial birds facing a long-term risk of extinction as a result of anthropogenic perturbations and exploitation. Nevertheless, there are scant genomics resources available for conservation management and planning. Here, we analyzed comparative population genomic data for the three extant isolated populations of Brown eared pheasant (Crossoptilon mantchuricum) in China. We showed that C. mantchuricum has low genome-wide diversity and a contracting effective population size because of persistent declines over the past 100,000 years. We compared genome-wide variation in C. mantchuricum with that of its closely related sister species, the Blue eared pheasant (C. auritum) for which the conservation concern is low. There were detrimental genetic consequences across all C. mantchuricum genomes including extended runs of homozygous sequences, slow rates of linkage disequilibrium decay, excessive loss-of-function mutations, and loss of adaptive genetic diversity at the major histocompatibility complex region. To the best of our knowledge, this study is the first to perform a comprehensive conservation genomic analysis on this threatened pheasant species. Moreover, we demonstrated that natural selection may not suffice to purge deleterious mutations in wild populations undergoing long-term decline. The findings of this study could facilitate conservation planning for threatened species and help recover their population size.
Abstract 973: Telomere stress potentiates host STING-dependent anti-tumor immunity
Authors: Anli Zhang, Ilgen Mender, Zhenhua Ren, Chuanhui Han, Yafang Deng, Silvia Siteni, Huiyu Li, Jerry W. Shay, Yang-Xin Fu
Journal: Cancer Research (2020)

Abstract Telomerase is an attractive target for anti-tumor therapy as it is almost universally expressed in cancer cells but not in normal cells. Here we show that treatment with a telomerase-mediated telomere-targeting drug, 6-thio-2'-deoxyguanosine (6-thio-dG), leads to tumor regression in innate and adaptive immune-dependent manners in syngeneic and humanized mouse colon cancer models. 6-thio-dG treatment causes telomere-associated DNA damages that are sensed by dendritic cells (DCs) and activates the host cytosolic DNA sensing STING/IFN-I pathway, resulting in enhanced cross-priming capacity of DCs and tumor-specific CD8 T-cell activation. Moreover, 6-thio-dG overcomes resistances to checkpoint blockade in advanced mouse cancer models. Together, our results unveil how 6-thio-dG induced telomere stress increases innate sensing and adaptive anti-tumor immunity and provide a strong rationale for sequentially combining telomerase directed telomere-targeted therapy with immunotherapy. Citation Format: Anli Zhang, Ilgen Mender, Zhenhua Ren, Chuanhui Han, Yafang Deng, Silvia Siteni, Huiyu Li, Jerry W. Shay, Yang-Xin Fu. Telomere stress potentiates host STING-dependent anti-tumor immunity [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 973.
Moderate resting hypoxaemia in fibrotic interstitial lung disease
Authors: Yet H. Khor, Amelia Harrison, Julien Robinson, Nicole S.L. Goh, Ian Glaspole, Christine F. McDonald
Journal: European Respiratory Journal (2020)

<b>Moderate resting hypoxaemia is an independent prognostic factor in fibrotic ILD. Potential therapeutic effects of reversing moderate resting hypoxaemia need to be evaluated in this population.</b>https://bit.ly/30PFtoC
Payer Mix Among Patients Receiving Dialysis—Reply
Authors: Abby Hoffman, Matthew L. Maciejewski, Virginia Wang
Journal: JAMA (2020)

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Effect of Intensive Blood Pressure Lowering on Cardiovascular Outcomes: A Systematic Review Prepared for the 2020 U.S. Department of Veterans Affairs/U.S. Department of Defense Guidelines
Authors: Kristen E. D'Anci, Kelley Tipton, Allison Hedden-Gross, Benjamin Rouse, Linnea Hermanson, Joann Fontanarosa
Journal: Annals of Internal Medicine (2020)

Background: Recent clinical trials suggest that treating patients with hypertension to lower blood pressure (BP) targets improves cardiovascular outcomes. Purpose: To summarize the effects of intensive (or targeted) systolic BP (SBP) and diastolic BP (DBP) lowering with pharmacologic treatment on cardiovascular outcomes and harms in adults with hypertension. Data Sources: Multiple databases, including MEDLINE and EMBASE, were searched for relevant systematic reviews (SRs) published in English from 15 December 2013 through 25 March 2019, with updated targeted searches through 8 January 2020. Study Selection: 8 SRs of randomized controlled trials examining either a standardized SBP target of −10 mm Hg (1 SR) or BP lowering below a target threshold (7 SRs). Data Extraction: One investigator abstracted data, assessed study quality, and performed GRADE assessments; a second investigator checked abstractions and assessments. Data Synthesis: The main outcome of interest was reduction in composite cardiovascular outcomes. High-strength evidence showed benefit of a 10–mm Hg reduction in SBP for cardiovascular outcomes among patients with hypertension in the general population, patients with chronic kidney disease, and patients with heart failure. Evidence on reducing SBP for cardiovascular outcomes in patients with a history of cardiovascular disease (moderate strength) or diabetes mellitus (high strength) to a lower SBP target was mixed. Low-strength evidence supported intensive lowering to a 10–mm Hg reduction in SBP for cardiovascular outcomes in patients with a history of stroke. All reported harms were considered, including general adverse events, serious adverse events, cognitive impairment, fractures, falls, syncope, hypotension, withdrawals due to adverse events, and acute kidney injury. Safety results were mixed or inconclusive. Limitations: This was a qualitative synthesis of new evidence with existing meta-analyses. Data were sparse for outcomes related to treating DBP to a lower target or for patients older than 60 years. Conclusion: Overall, current clinical literature supports intensive BP lowering in patients with hypertension for improving cardiovascular outcomes. In most subpopulations, intensive lowering was favored over less-intensive lowering, but the data were less clear for patients with diabetes mellitus or cardiovascular disease. Primary Funding Source: U.S. Department of Veterans Affairs, Veterans Health Administration.
Effect of Adding Ticagrelor to Standard Aspirin on Saphenous Vein Graft Patency in Patients Undergoing Coronary Artery Bypass Grafting (POPular CABG)
Authors: Laura M. Willemsen, Paul W.A. Janssen, Joyce Peper, Mohamed A. Soliman-Hamad, Albert H.M. van Straten, Patrick Klein, Chris M. Hackeng, Uday Sonker, Margreet W.A. Bekker, Clemens von Birgelen, Marc A. Brouwer, Pim van der Harst, Eline A. Vlot, Vera H.M. Deneer, Dean R.P.P. Chan Pin Yin, Marieke E. Gimbel, Kasper F. Beukema, Edgar J. Daeter, Johannes C. Kelder, Jan G.P. Tijssen, Benno J.W.M. Rensing, Hendrik W. van Es, Martin J. Swaans, Jurrien M. ten Berg
Journal: Circulation (2020)

BACKGROUND: Approximately 15% of saphenous vein grafts (SVGs) occlude during the first year after coronary artery bypass graft surgery (CABG) despite aspirin use. The POPular CABG trial (The Effect of Ticagrelor on Saphenous Vein Graft Patency in Patients Undergoing Coronary Artery Bypass Grafting Surgery) investigated whether ticagrelor added to standard aspirin improves SVG patency at 1 year after CABG. METHODS: In this investigator-initiated, randomized, double-blind, placebo-controlled, multicenter trial, patients with ≥1 SVGs were randomly assigned (1:1) after CABG to ticagrelor or placebo added to standard aspirin (80 or 100 mg). The primary outcome was SVG occlusion at 1 year, assessed with coronary computed tomography angiography, in all patients who had primary outcome imaging available. A generalized estimating equation model was used to perform the primary analysis per SVG. The secondary outcome was 1-year SVG failure, which was a composite of SVG occlusion, SVG revascularization, myocardial infarction in myocardial territory supplied by a SVG, or sudden death. RESULTS: Among 499 randomized patients, the mean age was 67.9±8.3 years, 87.1% were male, the indication for CABG was acute coronary syndrome in 31.3%, and 95.2% of procedures used cardiopulmonary bypass. Primary outcome imaging was available in 219 patients in the ticagrelor group and 224 patients in the placebo group. The SVG occlusion rate in the ticagrelor group was 9.6% (44 of 457 SVGs) versus 10.1% in the placebo group (50 of 497 SVGs; odds ratio, 0.87 [95% CI, 0.49–1.55]; P =0.64). SVG failure occurred in 32 patients (12.9%) in the ticagrelor group versus 32 patients (13.0%) in the placebo group (hazard ratio, 1.04 [95% CI, 0.63–1.69]). CONCLUSIONS: In this randomized, placebo-controlled trial, the addition of ticagrelor to standard aspirin did not reduce SVG occlusion at 1 year after CABG. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02352402. URL: https://eudract.ema.europa.eu/ ; Unique identifier: 2014-002142-50.