tbuckley/cabot-search huggingface dataset:
Detection of SARS-CoV-2 N-antigen in blood during acute COVID-19 provides a sensitive new marker and new testing alternatives
Authors: Quentin Le Hingrat, Benoit Visseaux, Cédric Laouenan, Sarah Tubiana, Lila Bouadma, Yazdan Yazdanpanah, Xavier Duval, Charles Burdet, Houria Ichou, Florence Damond, Mélanie Bertine, Nabil Benmalek, Christophe Choquet, Jean-François Timsit, Jade Ghosn, Charlotte Charpentier, Diane Descamps, Nadhira Houhou-Fidouh, Alpha Diallo, Soizic Le Mestre, Noémie Mercier, Christelle Paul, Ventzislava Petrov-Sanchez, Denis Malvy, Catherine Chirouze, Claire Andrejak, François Dubos, Patrick Rossignol, Olivier Picone, François Bompart, Tristan Gigante, Morgane Gilg, Bénédicte Rossignol, Claire Levy-Marchal, Marine Beluze, Jean Sébastien Hulot, Delphine Bachelet, Krishna Bhavsar, Lila Bouadma, Anissa Chair, Camille Couffignal, Charlene Da Silveira, Marie Pierre Debray, Diane Descamps, Xavier Duval, Philippine Eloy, Marina Esposito-Farese, Nadia Ettalhaoui, Nathalie Gault, Jade Ghosn, Isabelle Gorenne, Isabelle Hoffmann, Ouifiya Kafif, Sabrina Kali, Antoine Khalil, Cédric Laouénan, Samira Laribi, Minh Le, Quentin Le Hingrat, François-Xavier Lescure, Jean Christophe Lucet, France Mentré, Jimmy Mullaert, Nathan Peiffer-Smadja, Gilles Peytavin, Carine Roy, Marion Schneider, Nassima Si Mohammed, Lysa Tagherset, Coralie Tardivon, Marie Capucine Tellier, Jean-François Timsit, Théo Trioux, Sarah Tubiana, Benoit Visseaux, Noémie Vanel, Romain Basmaci, François Angoulvant, Florentia Kaguelidou, Justine Pages, Christelle Tual, Aurélie Veislinger, Sandrine Couffin-Cardiergues, Hélène Esperou, Ikram Houas, Salma Jaafoura, Aurélie Papadopoulos, Alexandra Coelho, Alphonsine Diouf, Alexandre Hoctin, Marina Mambert, Maude Bouscambert, Alexandre Gaymard, Bruno Lina, Manuel Rosa-Calatrava, Olivier Terrier, Dehbia Benkerrou, Céline Dorival, Amina Meziane, François Téoulé, Jérémie Guedj, Hervé Le Nagard, Guillaume Lingas, Nadège Neant, Laurent Abel, Mathilde Desvallée, Coralie Khan, Dominique Deplanque, Yazdan Yazdanpanah, Sylvie Behilill, Vincent Enouf, Hugo Mouquet, Sylvie Van Der Werf, Minerva Cervantes-Gonzalez, Eric D'ortenzio, Oriane Puéchal, Caroline Semaille, Marion Noret, Manuel Etienne, Yves Levy, Aurélie Wiedemann
Journal: Clinical Microbiology and Infection (2020)
RONC-18. ANALYSIS OF BRAIN TUMOR INDUCED BY IRRADIATION IN CHILDHOOD - A SINGLE INSTITUTIONAL ANALYSIS
Authors: Takashi Sano, Kaoru Tamura, Masae Kuroha, Kazutaka Sumita, Yukika Arai, Takashi Sugawara, Motoki Inaji, Yoji Tanaka, Tadashi Nariai, Taketoshi Maehara
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Radiation-induced brain tumors are rare tumors that appear during long-term follow-up after radiation therapy. Children are at greater risk for radiation -induced brain tumors than adults. The clinical characteristics of radiation-induced brain tumor treated at our hospital were retrospectively examined. PATIENTS AND METHODS Clinical characteristics of seven radiation-induced brain tumors that developed in 6 patients irradiated in their childhood at our hospital were analyzed. The background disease, age at irradiation, irradiation dose, period from irradiation to onset, pathological diagnosis, and treatment for radiation-induced brain tumor were examined. RESULTS Background diseases for irradiation were leukemia in 3 patients, germinoma in 2, medulloblastoma in 1, and the average cranial irradiation dose was 23.2 Gy. The patients tended to be young at irradiation (2–17 yeays; median:4 years old). The time between irradiation and the onset of radiation-induced brain tumors ranged from 9.5 to 39.1 years (median:28 years). Radiation-induced brain tumors comprised 6 meningioma（grade I:5, grade II:1）and 1 high-grade gliomas. All patients underwent surgical removal of the radiation-induced brain tumors and 2 received additional irradiation. During a median of 5.3 years of follow-up after the diagnosis of radiation-induced brain tumors, 2 underwent second surgery, while the remaining 4 have no recurrence. DISCUSSION: In most cases, radiation-induced brain tumors occur for a long time after irradiation in childhood. Monitoring of radiation-induced brain tumors as well as primary tumor recurrence was considered important.
DIPG-18. IDENTIFICATION OF TARGETABLE PATHWAY DEPENDENCIES IN DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Sarah Parackal, Wai Chin Chong, Gabrielle Bradshaw, Claire Sun, Paul Daniel, Enola Roussel, Samantha Jayasekara, Duncan Crombie, Ron Firestein, Jason Cain
Journal: Neuro-Oncology (2020)

Abstract Diffuse Intrinsic Pontine Glioma (DIPG) is a highly aggressive paediatric brainstem tumour with a dismal prognosis. Recurrent heterozygous mutations (p.K27M) in Histone H3 variant genes have been identified in the majority of DIPG cases. While the exact mechanism of H3K27M’s function is poorly understood, evidence suggests a role for epigenetic dysregulation in disease pathogenesis. This study aims to use functional genomics to identify novel therapeutic dependencies in H3K27M DIPG. DIPG drug sensitivity screening was carried out in twelve established and validated patient derived cell lines (10 H3.3K27M and 2 Wt) using an FDA approved drug library containing 1480 compounds. Highly prevalent targets identified from this screen include HDAC, microtubule, proteasome and CDK inhibitors. Additionally, a custom pooled CRISPR knockout library of druggable targets (300 genes, 1200 guide RNAs) was used to identify key DIPG cell survival pathways. To date five DIPG cell lines (1 Wt; 1 H3.1; 3 H3.3) have undergone screening. Knockdown of known DIPG driver genes (TP53; PDGFRA; PIK3CA and PIK3CR1) resulted in reduced cell viability, consistent with their proposed function and validating knockout screen utility. Preliminary data demonstrates Wt and H3K27M DIPGs cluster independently based on genes required for survival, suggesting differing tumorigenesis mechanisms and the potential for therapeutically targeting genotype specific pathways. Correlation of parallel drug screen and RNA-seq data will potentially reveal H3-dependent pathways for therapeutic exploitation. Collectively, we show a functional genomics approach is able to identify genotype-specific pathway dependencies in DIPG, paving the way for molecularly informed personalized therapies for patients.
CTNI-18. FINAL RESULTS OF A PHASE 2 STUDY OF EFFICACY, SAFETY AND INTRATUMORAL PHARMACOKINETICS (PK) OF SELINEXOR MONOTHERAPY IN RECURRENT GLIOBLASTOMA (rGBM)
Authors: Andrew Lassman, Patrick Wen, Martin van den Bent, Scott Plotkin, Annemiek Walenkamp, Adam Green, Hongwei Wang, Kai Li, Yang Liu, Hongmei Xu, Jatin Shah, Michael Kauffman, Sharon Shacham, Morten Mau-Soerensen
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Selinexor is an FDA-approved first-in-class, oral selective nuclear export inhibitor which forces nuclear retention of many tumor suppressor proteins. METHODS We conducted a phase 2 trial of selinexor monotherapy for adults with recurrent GBM including a surgical arm to explore intratumoral PK and 3 medical arms to optimize dosing. Prior treatment with radiotherapy and temozolomide was required; prior bevacizumab was exclusionary. The primary endpoint was 6-month progression-free survival (6mPFS) rate. RESULTS Selinexor administered ~2 hours pre-operatively yieleded average intratumoral concentration (136 nM, n=6) comparable to the in vitro IC50 (130 nM) from 7 primary human GBM cell lines. Among all 68 patients accrued to 3 medical arms (~85 mg BIW, n=24; 60 mg BIW, n=14; 80 mg QW, n=30), median age was 56 years (21–78). Median number of prior lines of therapies was 2 (1–7). At 80 mg QW, 28% patients were progression-free at the end of cycle 6; the 6mPFS was 17%; disese control rate by RANO was 37% (1 CR, 2 PRs, 7 SD) among 27 evaluable patients; responses were durable (median 11.1 months), and treatment lasted for 442, 547 and 1282 days in 3 responders, as of data lock, with one responder remaining on treatment off study; median overall survival was 10.2 months with 95% CI (7.0, 15.4). The ~85 mg BIW-schedule was abandoned due to poor tolerability. The related adverse events (all grades) in patients on ~85 mg BIW/60 mg BIW/80 mg QW were nausea (41.7%/64.3%/66.7%), fatigue (70.8%/71.4%/50.0%), neutropenia (29.2%/14.3%/33.3%), decreased appetite (45.8%/71.4%/26.7%), thrombocytopenia (66.7%/28.6%/23.3%) and weight loss (16.7%,/42.9%/6.7%). CONCLUSION Selinexor monotherapy demonstrated encouraging intratumoral penetration and efficacy, with durable disease control in rGBM. Monotherapy dose at 80 mg QW is recommended for further development in rGBM. A phase 1/2 study of combination therapy for newly diagnosed or rGBM has been initiated (NCT04421378).
Large-scale meta-analysis across East Asian and European populations updated genetic architecture and variant-driven biology of rheumatoid arthritis, identifying 11 novel susceptibility loci
Authors: Eunji Ha, Sang-Cheol Bae, Kwangwoo Kim
Journal: Annals of the Rheumatic Diseases (2020)

Nearly 110 susceptibility loci for rheumatoid arthritis (RA) with modest effect sizes have been identified by population-based genetic association studies, suggesting a large number of undiscovered variants behind a highly polygenic genetic architecture of RA. Here, we performed the largest-ever trans-ancestral meta-analysis with the aim to identify new RA loci and to better understand RA biology underlying genetic associations.Genome-wide RA association summary statistics in three large case-control collections consisting of 311 292 individuals of Korean, Japanese and European populations were used in an inverse-variance-weighted fixed-effects meta-analysis. Several computational analyses using public omics resources were conducted to prioritise causal variants and genes, RA variant-implicating features (tissues, pathways and transcription factors) and potentially repurposable drugs for RA treatment.We identified 11 new RA susceptibility loci that explained 6.9% and 1.8% of the single-nucleotide polymorphism-based heritability in East Asians and Europeans, respectively, and confirmed 71 known non-human leukocyte antigens (HLA) susceptibility loci, identifying 90 independent association signals. The RA variants were preferentially located in binding sites of various transcription factors and in cell type-specific transcription-activation histone marks that simultaneously highlighted the importance of CD4+ T-cell activation and the potential role of non-immune organs in RA pathogenesis. A total of 615 plausible effector genes, based on gene-based associations, expression-associated variants and chromatin interaction, included targets of drugs approved for RA treatments and potentially repurposable drugs approved for other indications.Our findings provide useful insights regarding RA genetic aetiology and variant-driven RA pathogenesis.
Compounded Bioidentical Hormone Therapy
Authors: Cynthia A. Stuenkel, JoAnn E. Manson
Journal: JAMA Internal Medicine (2020)

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31P Integrated safety analysis of anti-programmed cell death-1 (PD-1) antibody penpulimab in advanced solid tumour or lymphoma
Authors: N. Xu, B. Han, S. Jiao, C. Hu, A. Mislang, J. Coward, A. Cooper, C. Underhill, Y. Xia, D. Xia, X. Jin, Z.M. Wang, B. Li
Journal: Annals of Oncology (2020)
QOL-51. LISTENING BEFORE WE SPEAK: A PATIENT-CENTERED APPROACH TO DEVELOPING RESOURCES FOR PEDIATRIC BRAIN TUMOR SURVIVORS AND THEIR FAMILIES
Authors: Kathy Riley
Journal: Neuro-Oncology (2020)

Abstract In the United States, more than 28,000 children and teenagers live with the diagnosis of a primary brain tumor (Porter, McCarthy, Freels, Kim, &amp; Davis, 2010). In 2017, an estimated 4,820 new cases of childhood primary brain and other central nervous system tumors were expected to be diagnosed in children ages 0 – 19 in the United States (Central Brain Tumor Registry of the United States, 2017). Survivors suffer from lifelong side effects caused by their illness or by various treatments. Commonly identified late effects of treatment include a decline in intellectual functioning and processing speed, performance IQ deficits, memory deficits, psychological difficulties, deficits in adaptive functioning (daily life skills), and an overall decrease in health-related quality of life (Castellino, Ullrich, Whelen, &amp; Lange, 2014). To address the ongoing challenges these survivors and their families face, the Pediatric Brain Tumor Foundation (PBTF) met extensively with working groups comprised of survivors and caregivers to develop the outline for a comprehensive Survivorship Resource Guidebook. In 2019, the PBTF published the guidebook which categorizes survivor and caregiver needs into three primary areas: physical and mental health, quality of life, and working the system. Expert authors included survivors and caregivers themselves in addition to medical and mental health professionals. Key outcomes discovered during the creation and production of this resource highlight how caregivers, survivors and professionals can collaborate to provide needed information and practical help to one segment of the pediatric cancer population who experience profound morbidities as a result of their diagnosis and treatment.
BIOM-38. PI3K/AKT/mTOR SIGNALING PATHWAY ACTIVITY IN IDH-MUTANT DIFFUSE GLIOMA
Authors: Esraa Mohamed, Anupam Kumar, Stephanie Hilz, Albert Wang, Anny Shai, Jennie Taylor, Jennifer Clarke, Annette Molinaro, Julieann Lee, Joseph Costello, David Solomon, Joanna Phillips
Journal: Neuro-Oncology (2020)

Abstract PI3K/AKT/mTOR signaling pathway activation is a common mechanism of tumor progression in diffuse lower grade glioma. Robust and accurate biomarkers are needed to stratify patients for therapies targeting this pathway. To investigate the potential of phosphoprotein quantification to provide a direct and functional pathway readout, we analyzed 90 tumors from 83 patients with IDH-mutant diffuse glioma. The cohort comprised 50 IDH-mutant astrocytomas, 40 IDH-mutant and 1p/19q-codeleted oligodendrogliomas, 7 of whom had paired samples from initial diagnosis and recurrence. We developed and validated a pipeline using multiplex immunofluorescence to quantify tumor cell-specific phospho-protein expression of 3 pathway nodes, ribosomal protein S6 (RPS6), PRAS40, and 4E-BP1. In oligodendroglioma the fraction of tumor cells expressing each of the three phosphorylated proteins increased with tumor grade (p&amp;lt; 0.05). Comparing tumors at initial diagnosis (n=48) and at recurrence (n=42), p-RPS6 and p-PRAS40 increased in tumor cells (p&amp;lt; 0.05) and there was an overall increase in intertumoral heterogeneity of signaling activity at recurrence (p&amp;lt; 0.04). Analysis of paired samples demonstrated increased signaling pathway activity in a subset at recurrence. Robust signaling activity, defined as a phospho-positive tumor cell fraction ≥ median for all three phosphoproteins, was identified in 71.4% of grade 3 IDH-mutant astrocytoma(5/7) and 45.4% of grade 3 IDH-mutant, 1p/19q-codeleted oligodendroglioma(5/11). In a subset of cases analyzed by targeted NGS, robust signaling pathway activity was identified in 38%(11/29) at the protein level while genetic alterations predicted to activate the pathway were present in only 17.2% (5/29). Our results demonstrate robust PI3K/AKT/mTOR signaling activity in a significant fraction of IDH-mutant diffuse glioma, an association with increasing tumor grade in oligodendroglioma, and an increase at recurrence in both oligodendroglioma and astrocytoma. Overall, our data suggest that quantitative evaluation of phosphoproteins may be a sensitive method to detect PI3K/AKT/mTOR pathway activity and may be useful for patient stratification.
STEM-13. FUNCTIONAL CHARACTERIZATION OF THE ZFHX4-CHD4 INTERACTION IN GLIOBLASTOMA CANCER STEM CELLS
Authors: Luciano Galdieri, Mitchell Grinwald, Zibi Gugala, Edward Oates, Milan Chheda
Journal: Neuro-Oncology (2020)

Abstract Glioblastoma stem cells (GSCs) they may be one reason for inevitable recurrence of GBM. We previously discovered that Zinc Finger Homeobox 4 (ZFHX4), a 450kD transcription factor, is required to maintain the GSC state. ZFHX4 interacts with CHD4, a core member of the nucleosome remodeling and deacetylase (NuRD) complex, which activates or represses gene expression via two distinct functions - histone deacetylation and ATP-dependent chromatin remodeling. CHD4 suppression phenocopies ZFHX4 suppression. The precise nature and function of the ZFHX4 interaction with CHD4 is not understood. Here we report that the ZFHX4-CHD4 interaction requires a single zinc-finger domain. An incremental truncation screen revealed that ZFHX4 amino acids 1838 to 2387, which contains zinc fingers 14 and 15, are required to bind CHD4. Disrupting the zinc coordination of zinc finger 14 impaired the ZFHX4-CHD4 interaction. Moreover, by overexpressing ZFHX4 amino acids 1838 to 2487, we decreased CHD4 recruitment to transcription regulatory regions of the stem cell genes SOX2 and SOX9, decreased transcription, and reduced clonogenic self-renewal. These results may provide the structural basis for new treatments to target GSCs and prevent recurrence in this devastating disease.
Phosphoproteomics identify arachidonic-acid-regulated signal transduction pathways modulating macrophage functions with implications for ovarian cancer
Authors: Raimund Dietze, Mohamad K. Hammoud, María Gómez-Serrano, Annika Unger, Tim Bieringer, Florian Finkernagel, Anna M. Sokol, Andrea Nist, Thorsten Stiewe, Silke Reinartz, Viviane Ponath, Christian Preußer, Elke Pogge von Strandmann, Sabine Müller-Brüsselbach, Johannes Graumann, Rolf Müller
Journal: Theranostics (2020)

Arachidonic acid (AA) is a polyunsaturated fatty acid present at high concentrations in the ovarian cancer (OC) microenvironment and associated with a poor clinical outcome. In the present study, we have unraveled a potential link between AA and macrophage functions. Methods: AA-triggered signal transduction was studied in primary monocyte-derived macrophages (MDMs) by phosphoproteomics, transcriptional profiling, measurement of intracellular Ca2+ accumulation and reactive oxygen species production in conjunction with bioinformatic analyses. Functional effects were investigated by actin filament staining, quantification of macropinocytosis and analysis of extracellular vesicle release. Results: We identified the ASK1 - p38δ/α (MAPK13/14) axis as a central constituent of signal transduction pathways triggered by non-metabolized AA. This pathway was induced by the Ca2+-triggered activation of calmodulin kinase II, and to a minor extent by ROS generation in a subset of donors. Activated p38 in turn was linked to a transcriptional stress response associated with a poor relapse-free survival. Consistent with the phosphorylation of the p38 substrate HSP27 and the (de)phosphorylation of multiple regulators of Rho family GTPases, AA impaired actin filament organization and inhibited actin-driven macropinocytosis. AA also affected the phosphorylation of proteins regulating vesicle biogenesis, and consistently, AA enhanced the release of tetraspanin-containing exosome-like vesicles. Finally, we identified phospholipase A2 group 2A (PLA2G2A) as the clinically most relevant enzyme producing extracellular AA, providing further potentially theranostic options. Conclusion: Our results suggest that AA contributes to an unfavorable clinical outcome of OC by impacting the phenotype of tumor-associated macrophages. Besides critical AA-regulated signal transduction proteins identified in the present study, PLA2G2A might represent a potential prognostic tool and therapeutic target to interfere with OC progression.
The oral microbiome and lung cancer risk
Authors: David C Christiani
Journal: Thorax (2020)

The oral cavity is instrumental to the human body in several ways. It is the entry point for both ingested (to the GI tract) and inhaled (to the respirable tract) substances. The oral microbiome resides within biofilms throughout the oral cavity and forms an ecosystem that helps to maintain health. The breadth and depth of the oral microbiome is impressive: 1 mL of saliva contains 108 microbial cells and 700 distinct prokaryotic taxa. There are rich communities such as bacteria, fungi, viruses, archaea and protists, among which about 54% are cultivatable and identified, 14% are cultivatable, but not identified, and 32% are not even cultivatable.1 Caselli et al defined the oral microbiome in 20 healthy individuals from Europe by whole genome sequencing (WGS) and reported that α-diversity differed significantly among the different microsites in the mouth of each participant, but not among the participants, supporting the notion of a recognisable healthy oral microbiome.1 

With its rich microenvironment, the oral cavity remains less understood than the gut as to its health effects. Metagenomic studies have associated the oral microbiome with oral cancer and at least one with oesophageal cancer, and another with head and neck cancer.2 

The use of recent 16 s rRNA gene next-generation sequencing methods have provided an important look into the complexity of the bacterial inhabitants of the oral microbiome and have helped to distinguish the differences between healthy microbiome and …
A Binary Cre Transgenic Approach Dissects Microglia and CNS Border-Associated Macrophages
Authors: Jung-Seok Kim, Masha Kolesnikov, Shany Peled-Hajaj, Isabelle Scheyltjens, Yuan Xia, Sebastien Trzebanski, Zhana Haimon, Anat Shemer, Alisa Lubart, Hannah Van Hove, Louise Chappell-Maor, Sigalit Boura-Halfon, Kiavash Movahedi, Pablo Blinder, Steffen Jung
Journal: Immunity (2020)
Dominant optic atrophy: Culprit mitochondria in the optic nerve
Authors: Guy Lenaers, Albert Neutzner, Yannick Le Dantec, Christoph Jüschke, Ting Xiao, Sarah Decembrini, Sebastian Swirski, Sinja Kieninger, Cavit Agca, Ungsoo S. Kim, Pascal Reynier, Patrick Yu-Wai-Man, John Neidhardt, Bernd Wissinger
Journal: Progress in Retinal and Eye Research (2020)