tbuckley/cabot-search huggingface dataset:
Abstract PR16: Comprehensive transcriptomic characterization of 1,400 sarcomas for diagnosis and immune contexture
Authors: Julien Vibert, Sarah Watson, Camille Benoist, Joshua Waterfall, Gaëlle Pierron, Olivier Delattre
Journal: Cancer Research (2020)

Abstract Introduction: Sarcomas represent about 15 % of all childhood cancers and are still lethal in a large proportion of cases. They comprise a heterogeneous group of bone and soft tissue tumors with more than 100 distinct histologic entities, often presenting a diagnostic challenge to pathologists. Methods: To address this pathological complexity and better characterize the molecular biology of sarcomas, we performed whole-transcriptome RNA-seq on frozen tumor tissues as part of the diagnostic workflow for more than 1,400 patients, mainly children and young adults, addressed for sarcoma molecular diagnosis throughout France. Results: From a clinical perspective, RNA-seq proves to be a powerful complementary test to pathology for diagnosis of sarcomas: it allows agnostic detection of subtype-specific fusion transcripts, as well as diagnostic indication by gene-expression profile clustering. In addition to its diagnostic utility, RNA-seq provides a rich source of information for studying the molecular biology of sarcomas. Indeed, as shown recently in our group, it allows detection of previously uncharacterized sarcoma entities associated with novel fusion genes. Using dimensionality reduction techniques, either linear such as PCA, or nonlinear such as t-SNE or UMAP, we perform unsupervised clustering of our cohort, revealing insights into the global structure of the transcriptomic landscape of sarcomas. We show that many histologic entities have a distinct gene-expression profile, emphasizing the utility of RNA-seq for diagnosis. To explore the immune microenvironment of sarcomas and potential correlates of response to immunotherapy, we deconvolute bulk RNA-seq data to estimate the presence of immune and stromal cell types, allowing a comprehensive characterization of the immune landscape of sarcomas. Finally, we apply state-of-the-art deep learning tools to perform unsupervised clustering and nonlinear dimensional reduction of our RNA-seq samples, allowing a finer and more insightful representation of the structure of the sarcoma transcriptomic landscape. Conclusion: Besides improving the diagnostic workflow for patients, our comprehensive analysis of sarcoma RNA-seq allows characterization of distinct molecular subtypes and of the immune landscape, opening up perspectives for better diagnosis, classification, and biologic discoveries in sarcoma. This abstract is also being presented as Poster B75. Citation Format: Julien Vibert, Sarah Watson, Camille Benoist, Joshua Waterfall, Gaëlle Pierron, Olivier Delattre. Comprehensive transcriptomic characterization of 1,400 sarcomas for diagnosis and immune contexture [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr PR16.
Abstract A33: HIF2 in pediatric high-grade glioma and its targeting
Authors: Quentin Fuchs, Anne Florence Blandin, Isabelle Lelong Rebel, Marina Pierrevelcin, Monique Dontenwill, Natacha Entz-Werlé
Journal: Cancer Research (2020)

Abstract Pediatric high-grade gliomas (pHGGs) represent a very dismal disease that is needing new innovative compound for treatment. Despite the past discovery of histone H3 driver mutations, we are not able for instance to stop this induced process on epigenetic remodulation. Therefore, there is since a decade proactive works aimed to discover new targetable proteins in these tumors. In our recent previous works in pHGGs, we highlighted HIF2alpha as a biomarker of worse prognosis and outcome and a key in treatment resistance. Therefore, this new project was designed to determine in several patient-derived cell lines (5 PDCLs) the presence of HIF2alpha, its role and its induction in normoxic and hypoxic microenvironment concomitantly by immunofluorescence and Western blot assessments and RNA sequencing analyses. Complementary ChipSeq was also performed using HIF2 antibodies to determine its role as a transmission factor. Specific promoters were involved. After the confirmation of its frequent presence in multiple PDCLs initiated from thalamic pHGGs and DIPG, we used allosteric inhibitors to target HIF2alpha. Surprisingly, this protein was expressed constantly in hypoxic and normoxic conditions and specifically in PDCLs bearing stem cell features. Specific expression associations were established between stemness markers and HIF2alpha. To go further, we tested specific HIF2A inhibitors, which were having an impact on cell proliferation and on the decrease of the target itself. In conclusion, HIF2 seem to be a major biomarker in pHGGs that might be targeted, and it is a useful new opportunity for pHGGs treatments. Citation Format: Quentin Fuchs, Anne Florence Blandin, Isabelle Lelong Rebel, Marina Pierrevelcin, Monique Dontenwill, Natacha Entz-Werlé. HIF2 in pediatric high-grade glioma and its targeting [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr A33.
Association of Metformin With Pregnancy Outcomes in Women With Polycystic Ovarian Syndrome Undergoing In Vitro Fertilization
Authors: Yiqing Wu, Mixue Tu, Yun Huang, Yifeng Liu, Dan Zhang
Journal: JAMA Network Open (2020)

Metformin is widely used among women with polycystic ovary syndrome (PCOS). However, its associations with outcomes of in vitro fertilization or intracytoplasmic sperm injection and embryo transfer (IVF/ICSI-ET) in women with PCOS remain controversial.To assess whether metformin is associated with improved outcomes of IVF/ICSI-ET in women with PCOS.PubMed, Embase, and Cochrane were searched from database inception to January 31, 2020.Only randomized clinical trials (RCTs) were included. Eligible studies enrolled women with PCOS undergoing infertility treatment with IVF/ICSI-ET and reported at least 1 outcome of IVF/ICSI-ET.This study followed the Preferred Reporting Items for Systematic Reviews and Meta analyses guidelines. Two authors independently extracted the data. Study quality was evaluated using the GRADE system. Treatment effect was quantified using odds ratios (ORs) with 95% CIs using random-effect models with the Mantel-Haenszel method.Ovarian hyperstimulation syndrome (OHSS), clinical pregnancy rate, and live birth rate.A total of 12 RCTs, which collectively included 1123 women with PCOS undergoing infertility treatment with IVF/ICSI-ET, were identified. The risk of OHSS in women randomized to metformin was lower than in women not randomized to metformin (OR, 0.43; 95% CI, 0.24-0.78), although this difference was not significant for women with PCOS with a body mass index of less than 26 (OR, 0.67; 95% CI, 0.30-1.51). There was no significant difference in clinical pregnancy rate (OR, 1.24; 95% CI, 0.82-1.86) or live birth rate (OR, 1.23; 95% CI, 0.74-2.04) in the total population studied. However, in a post hoc analysis among women with a body mass index of 26 or greater, metformin treatment was associated with increased clinical pregnancy rates (OR, 1.71; 95% CI, 1.12-2.60).In this study, metformin treatment was associated with a decreased risk of OHSS but had no association with the overall clinical pregnancy rate or live birth rate among women with PCOS undergoing IVF/ICSI-ET. Metformin treatment should be carefully considered for women with PCOS undergoing IVF/ICSI-ET and may be more preferred for women with a body mass index greater than 26.
Autologous CMV-specific T cells are a safe adjuvant immunotherapy for primary glioblastoma multiforme
Authors: Corey Smith, Katie E. Lineburg, J. Paulo Martins, George R. Ambalathingal, Michelle A. Neller, Beth Morrison, Katherine K. Matthews, Sweera Rehan, Pauline Crooks, Archana Panikkar, Leone Beagley, Laetitia Le Texier, Sriganesh Srihari, David Walker, Rajiv Khanna
Journal: Journal of Clinical Investigation (2020)

BACKGROUND. The recent failure of checkpoint-blockade therapies for glioblastoma multiforme (GBM) in late-phase clinical trials has directed interest toward adoptive cellular therapies (ACTs). In this open-label, first-in-human trial, we have assessed the safety and therapeutic potential of cytomegalovirus-specific (CMV-specific) ACT in an adjuvant setting for patients with primary GBM, with an ultimate goal to prevent or delay recurrence and prolong overall survival.
A novel biodegradable external stent regulates vein graft remodeling via the Hippo-YAP and mTOR signaling pathways
Authors: Qi Yang, Dong Lei, Shixing Huang, Yang Yang, Chenyu Jiang, Hongpeng Shi, Wenyi Chen, Qiang Zhao, Zhengwei You, Xiaofeng Ye
Journal: Biomaterials (2020)
A Man in His 50s With Atrial Fibrillation and Abnormal Cardiac Computed Tomography Findings
Authors: Ethan J. Halpern
Journal: JAMA Cardiology (2020)

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Direct Delivery of Antisense Oligonucleotides to the Middle and Inner Ear Improves Hearing and Balance in Usher Mice
Authors: Jennifer J. Lentz, Bifeng Pan, Abhilash Ponnath, Christopher M. Tran, Carl Nist-Lund, Alice Galvin, Hannah Goldberg, Katelyn N. Robillard, Francine M. Jodelka, Hamilton E. Farris, Jun Huang, Tianwen Chen, Hong Zhu, Wu Zhou, Frank Rigo, Michelle L. Hastings, Gwenaëlle S.G. Géléoc
Journal: Molecular Therapy (2020)

Usher syndrome is a syndromic form of hereditary hearing impairment that includes sensorineural hearing loss and delayed-onset retinitis pigmentosa (RP). Type 1 Usher syndrome (USH1) is characterized by congenital profound sensorineural hearing impairment and vestibular areflexia, with adolescent-onset RP. Systemic treatment with antisense oligonucleotides (ASOs) targeting the human USH1C c.216G>A splicing mutation in a knockin mouse model of USH1 restores hearing and balance. Herein, we explore the effect of delivering ASOs locally to the ear to treat hearing and vestibular dysfunction associated with Usher syndrome. Three localized delivery strategies were investigated in USH1C mice: inner ear injection, trans-tympanic membrane injection, and topical tympanic membrane application. We demonstrate, for the first time, that ASOs delivered directly to the ear correct Ush1c expression in inner ear tissue, improve cochlear hair cell transduction currents, restore vestibular afferent irregularity, spontaneous firing rate, and sensitivity to head rotation, and successfully recover hearing thresholds and balance behaviors in USH1C mice. We conclude that local delivery of ASOs to the middle and inner ear reach hair cells and can rescue both hearing and balance. These results also demonstrate the therapeutic potential of ASOs to treat hearing and balance deficits associated with Usher syndrome and other ear diseases.
Nonadherence or Nonpersistence to Intravitreal Injection Therapy for Neovascular Age-Related Macular Degeneration
Authors: Mali Okada, Paul Mitchell, Robert P. Finger, Bora Eldem, S. James Talks, Ceri Hirst, Luciano Paladini, Jane Barratt, Tien Yin Wong, Anat Loewenstein
Journal: Ophthalmology (2020)
Use of DREADD Technology to Identify Novel Targets for Antidiabetic Drugs
Authors: Lei Wang, Lu Zhu, Jaroslawna Meister, Derek B.J. Bone, Sai P. Pydi, Mario Rossi, Jürgen Wess
Journal: The Annual Review of Pharmacology and Toxicology (2020)

G protein-coupled receptors (GPCRs) form a superfamily of plasma membrane receptors that couple to four major families of heterotrimeric G proteins, Gs, Gi, Gq, and G12. GPCRs represent excellent targets for drug therapy. Since the individual GPCRs are expressed by many different cell types, the in vivo metabolic roles of a specific GPCR expressed by a distinct cell type are not well understood. The development of designer GPCRs known as DREADDs (designer receptors exclusively activated by a designer drug) that selectively couple to distinct classes of heterotrimeric G proteins has greatly facilitated studies in this area. This review focuses on the use of DREADD technology to explore the physiological and pathophysiological roles of distinct GPCR/G protein cascades in several metabolically important cell types. The novel insights gained from these studies should stimulate the development of GPCR-based treatments for major metabolic diseases such as type 2 diabetes and obesity.
Impact of Iron Deficiency Anemia on Inpatient Mortality, Hospital Cost, and Length of Stay in Patients with Luminal Gastrointestinal Cancers: Data from the Healthcare Cost and Utilization Project from 1999-2014
Authors: Praneeth Baratam, Erika Correa, Stuthi Perimbeti, Michael Styler, David Topolsky, Pamela Ann Crilley, Maneesh Jain, Kristine Ward
Journal: Blood (2017)
Abstract B16: <i>MECOM</i> dysregulation is associated with poor outcome in pediatric therapy-related myeloid neoplasms
Authors: Tamara Lamprecht, Jason R. Schwartz, Jing Ma, Michael P. Walsh, Jeffery M. Klco
Journal: Cancer Research (2020)

Abstract Therapy-related myeloid neoplasms (tMN) occur in children as a consequence of cytotoxic therapies used to treat childhood malignancies, are typically resistant to conventional chemotherapies, require hematopoietic cell transplantation as the only curative option, and typically have a dismal prognosis. While the genomic alterations that drive tMN in children have yet to be comprehensively described, alterations involving the MECOM locus have been described in some myeloid neoplasms like tMN. Overexpression of MECOM is associated with poor prognosis in myeloid malignancies, is present in ~10% of adult cases, and occurs at an increased frequency in pediatric AML with KMT2A rearrangements (KMT2Ar). RNA sequencing from a cohort of 56 pediatric tMN cases collected at St. Jude shows that 24 (43%) cases within our cohort express high levels of MECOM (FPKM value &amp;gt;5). In these 24 cases, we identified one with a canonical fusion (RUNX1-MECOM), one with a NUP98 fusion (NUP98-HHEX), and 18 with KMT2Ar. Whole-genome sequencing demonstrated that two of the remaining MECOMHigh cases have a t(2;3)(p21;q26.2) involving MECOM on chromosome 3 and noncoding regions of chromosome 2 adjacent to ZFP36L2, a gene highly expressed in hematopoietic cells. Further, ENCODE data support that this region of the genome is an active enhancer, suggesting a proximity effect in which this enhancer has been hijacked to drive high levels of MECOM expression. The two remaining cases with aberrant and unexplained MECOM expression are currently under evaluation. In our cohort, MECOM expression levels are predictive of a worse outcome (overall survival at 2 years: MECOMHigh=12.5% vs. MECOMLow=40.6%; log rank p&amp;lt;0.01). Although KMT2Ar was frequently present in our cohort 28/56 (50%) and enriched in the MECOMHigh group (MECOMHigh=75% (18/24) vs. MECOMLow=31% (10/32; p&amp;lt;0.01), high MECOM expression did not confer a significant survival difference within the KMT2Ar group (overall survival at 2 years: MECOMHigh=16.7% vs. MECOMLow=40%; log rank p=0.33). In conclusion, we report a large cohort of pediatric tMN and show that high levels of MECOM expression predicts a worse outcome. Additionally, we identify enhancer hijacking as the mechanism through which at least a portion of high MECOM expression may be explained. Citation Format: Tamara Lamprecht, Jason R. Schwartz, Jing Ma, Michael P. Walsh, Jeffery M. Klco. MECOM dysregulation is associated with poor outcome in pediatric therapy-related myeloid neoplasms [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr B16.
<i>NCKAP1L</i>defects lead to a novel syndrome combining immunodeficiency, lymphoproliferation, and hyperinflammation
Authors: Carla Noemi Castro, Michelle Rosenzwajg, Raphael Carapito, Mohammad Shahrooei, Martina Konantz, Amjad Khan, Zhichao Miao, Miriam Groß, Thibaud Tranchant, Mirjana Radosavljevic, Nicodème Paul, Tristan Stemmelen, Fabien Pitoiset, Aurélie Hirschler, Benoit Nespola, Anne Molitor, Véronique Rolli, Angélique Pichot, Laura Eva Faletti, Bruno Rinaldi, Sylvie Friant, Mark Mednikov, Hatice Karauzum, M. Javad Aman, Christine Carapito, Claudia Lengerke, Vahid Ziaee, Wafaa Eyaid, Stephan Ehl, Fayhan Alroqi, Nima Parvaneh, Seiamak Bahram
Journal: The Journal of Experimental Medicine (2020)

The Nck-associated protein 1–like (NCKAP1L) gene, alternatively called hematopoietic protein 1 (HEM-1), encodes a hematopoietic lineage–specific regulator of the actin cytoskeleton. Nckap1l-deficient mice have anomalies in lymphocyte development, phagocytosis, and neutrophil migration. Here we report, for the first time, NCKAP1L deficiency cases in humans. In two unrelated patients of Middle Eastern origin, recessive mutations in NCKAP1L abolishing protein expression led to immunodeficiency, lymphoproliferation, and hyperinflammation with features of hemophagocytic lymphohistiocytosis. Immunophenotyping showed an inverted CD4/CD8 ratio with a major shift of both CD4+ and CD8+ cells toward memory compartments, in line with combined RNA-seq/proteomics analyses revealing a T cell exhaustion signature. Consistent with the core function of NCKAP1L in the reorganization of the actin cytoskeleton, patients’ T cells displayed impaired early activation, immune synapse morphology, and leading edge formation. Moreover, knockdown of nckap1l in zebrafish led to defects in neutrophil migration. Hence, NCKAP1L mutations lead to broad immune dysregulation in humans, which could be classified within actinopathies.
Subcutaneous or Transvenous Defibrillator Therapy
Authors: Reinoud E. Knops, Louise R.A. Olde Nordkamp, Peter-Paul H.M. Delnoy, Lucas V.A. Boersma, Jürgen Kuschyk, Mikhael F. El-Chami, Hendrik Bonnemeier, Elijah R. Behr, Tom F. Brouwer, Stefan Kääb, Suneet Mittal, Anne-Floor B.E. Quast, Lonneke Smeding, Willeke van der Stuijt, Anouk de Weger, Koen C. de Wilde, Nick R. Bijsterveld, Sergio Richter, Marc A. Brouwer, Joris R. de Groot, Kirsten M. Kooiman, Pier D. Lambiase, Petr Neuzil, Kevin Vernooy, Marco Alings, Tim R. Betts, Frank A.L.E. Bracke, Martin C. Burke, Jonas S.S.G. de Jong, David J. Wright, Jan G.P. Tijssen, Arthur A.M. Wilde
Journal: New England Journal of Medicine (2020)

The subcutaneous implantable cardioverter-defibrillator (ICD) was designed to avoid complications related to the transvenous ICD lead by using an entirely extrathoracic placement. Evidence comparing these systems has been based primarily on observational studies.We conducted a noninferiority trial in which patients with an indication for an ICD but no indication for pacing were assigned to receive a subcutaneous ICD or transvenous ICD. The primary end point was the composite of device-related complications and inappropriate shocks; the noninferiority margin for the upper boundary of the 95% confidence interval for the hazard ratio (subcutaneous ICD vs. transvenous ICD) was 1.45. A superiority analysis was prespecified if noninferiority was established. Secondary end points included death and appropriate shocks.A total of 849 patients (426 in the subcutaneous ICD group and 423 in the transvenous ICD group) were included in the analyses. At a median follow-up of 49.1 months, a primary end-point event occurred in 68 patients in the subcutaneous ICD group and in 68 patients in the transvenous ICD group (48-month Kaplan-Meier estimated cumulative incidence, 15.1% and 15.7%, respectively; hazard ratio, 0.99; 95% confidence interval [CI], 0.71 to 1.39; P = 0.01 for noninferiority; P = 0.95 for superiority). Device-related complications occurred in 31 patients in the subcutaneous ICD group and in 44 in the transvenous ICD group (hazard ratio, 0.69; 95% CI, 0.44 to 1.09); inappropriate shocks occurred in 41 and 29 patients, respectively (hazard ratio, 1.43; 95% CI, 0.89 to 2.30). Death occurred in 83 patients in the subcutaneous ICD group and in 68 in the transvenous ICD group (hazard ratio, 1.23; 95% CI, 0.89 to 1.70); appropriate shocks occurred in 83 and 57 patients, respectively (hazard ratio, 1.52; 95% CI, 1.08 to 2.12).In patients with an indication for an ICD but no indication for pacing, the subcutaneous ICD was noninferior to the transvenous ICD with respect to device-related complications and inappropriate shocks. (Funded by Boston Scientific; PRAETORIAN ClinicalTrials.gov number, NCT01296022.).
Prognostic Relevance of Clonal Circulating Plasma Cells Detected By Multiparameter Flow Cytometry in Patients with Newly Diagnosed Multiple Myeloma Treated with Novel Agents: Comparative Investigation with the Revised International Staging System
Authors: Yoshiaki Abe, Kentaro Narita, Hiroki Kobayashi, Akihiro Kitadate, Masami Takeuchi, Kosei Matsue
Journal: Blood (2017)