tbuckley/cabot-search huggingface dataset:
Inhibition of Neutrophil Extracellular Trap Release through the Disruption of PAD4 Leads to Decreased Neutrophil and Platelet Accumulation at Sites of Venular Vascular Injury in a Murine Model of Heparin-Induced Thrombocytopenia
Authors: Kandace Gollomp, Vincent Hayes, Ian Johnston, Minna Kim, Guohua Zhao, Lubica Rauova, Mortimer Poncz
Journal: Blood (2017)
33MO A phase I study of SHC014748M capsules in patients with relapsed or refractory indolent B-cell malignancies
Authors: W. Xu, J. Qian, L. Wang, H. Zhu, K. Zhou, X. Xu, F. Zhou, L. Zhang, X. Zhang, Z. Wang, J. Jin, J. Li
Journal: Annals of Oncology (2020)
Serum uric acid is associated with increased risk of posttransplantation diabetes in kidney transplant recipients: a prospective cohort study
Authors: Camilo G. Sotomayor, Sara Sokooti Oskooei, Nicolás I. Bustos, Ilja M. Nolte, António W. Gomes-Neto, Marcia Erazo, Juan G. Gormaz, Stefan P. Berger, Gerjan J. Navis, Ramón Rodrigo, Robin P.F. Dullaart, Stephan J.L. Bakker
Journal: Metabolism (2020)

Serum uric acid (SUA) is associated with fasting glucose in healthy subjects, and prospective epidemological studies have shown that elevated SUA is associated with increased risk of type 2 diabetes. Whether SUA is independently associated with higher risk of posttransplantation diabetes mellitus (PTDM) in kidney transplant recipients (KTR) remains unknown.We performed a longitudinal cohort study of 524 adult KTR with a functioning graft ≥1-year, recruited at a university setting (2008-2011). Multivariable-adjusted Cox proportional-hazards regression analyses were performed to assess the association between time-updated SUA and risk of PTDM (defined according the American Diabetes Association's diagnostic criteria).Mean (SD) SUA was 0.43 (0.11) mmol/L at baseline. During 5.3 (IQR, 4.1-6.0) years of follow-up, 52 (10%) KTR developed PTDM. In univariate prospective analyses, SUA was associated with increased risk of PTDM (HR 1.75, 95% CI 1.36-2.26 per 1-SD increment; P < 0.001). This finding remained materially unchanged after adjustment for components of the metabolic syndrome, lifestyle, estimated glomerular filtration rate, immunosuppressive therapy, cytomegalovirus and hepatitis C virus infection (HR 1.89, 95% CI 1.32-2.70; P = 0.001). These findings were consistent in categorical analyses, and robust in sensitivity analyses without outliers.In KTR, higher SUA levels are strongly and independently associated with increased risk of PTDM. Our findings are in agreement with accumulating evidence supporting SUA as novel independent risk marker for type 2 diabetes, and extend the evidence, for the first time, to the clinical setting of outpatient KTR.
Plaque rupture and intracoronary thrombus in nonculprit vessels: An eyewitness account**Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
Authors: John A. Ambrose, David J. D’Agate
Journal: Journal of the American College of Cardiology (2005)
A Three-Arm Randomized Clinical Trial Comparing the Efficacy of a Mindfulness-Based Intervention with an Active Comparison Group and Fluoxetine Treatment for Adults with Generalized Anxiety Disorder
Authors: Marianna de Abreu Costa, Francine Guimarães Gonçalves, Tiago Tatton-Ramos, Natasha Kim de Oliveira da Fonseca, Julia Karl Schwinn, Sofia Giusti Alves, Giovanni Abrahão Salum, Gisele Gus Manfro
Journal: Psychotherapy and Psychosomatics (2020)

&lt;b&gt;&lt;i&gt;Introduction:&lt;/i&gt;&lt;/b&gt; Mindfulness-based interventions have been studied as an alternative treatment for anxiety disorders, but there are only a few studies comparing these with established treatments. &lt;b&gt;&lt;i&gt;Objective:&lt;/i&gt;&lt;/b&gt; To evaluate the efficacy of a Body in Mind Training (BMT) program for adults with generalized anxiety disorder (GAD), an active comparison protocol called Quality of Life and Psychoeducation (QoL), and treatment with fluoxetine (FLX). &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; This study comprises a 3-arm parallel-group, randomized clinical trial (ClinicalTrials.gov ID: NCT03072264). Adults with a primary diagnosis of GAD and no current treatment were recruited from the community and randomized in a ratio 1:1:1. The primary outcomes were assessed by means of the Hamilton Anxiety Rating Scale (HAM-A) and the Penn State Worry Questionnaire (PSWQ) at week 8. Data were analyzed using a superiority analysis (BMT vs. QoL) and a noninferiority analysis (BMT vs. FLX). &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; A total of 249 participants were included and 223 were analyzed (76 BMT, 79 FLX, and 68 QoL). All groups improved after intervention. However, BMT was not superior to QoL at week 8 (mean difference = –1.36; &lt;i&gt;p&lt;/i&gt; = 0.47), nor was it noninferior to FLX as assessed with theHAM-A (mean difference = 3.5; 95% CI –0.06 to 7.06; noninferiority margin = –2.43; &lt;i&gt;p&lt;/i&gt; = 0.054). QoL (mean difference = 3.54; &lt;i&gt;p&lt;/i&gt; = 0.04) and FLX (mean difference = –7.72; 95% CI –10.89 to –4.56; noninferiority margin = –2.09; &lt;i&gt;p&lt;/i&gt; &amp;#x3c; 0.001) were superior to BMT in reducing PSWQ score. &lt;b&gt;&lt;i&gt;Conclusion:&lt;/i&gt;&lt;/b&gt; Our data suggest that BMT, in its current format, cannot be considered an effective mindfulness protocol to improve GAD.
Pan-AKT Inhibitor Capivasertib With Docetaxel and Prednisolone in Metastatic Castration-Resistant Prostate Cancer: A Randomized, Placebo-Controlled Phase II Trial (ProCAID)
Authors: Simon J. Crabb, Gareth Griffiths, Ellice Marwood, Denise Dunkley, Nichola Downs, Karen Martin, Michelle Light, Josh Northey, Sam Wilding, Amy Whitehead, Emily Shaw, Alison J. Birtle, Amit Bahl, Tony Elliott, Charlotte Westbury, Santhanam Sundar, Angus Robinson, Satinder Jagdev, Satish Kumar, Claire Rooney, Carolina Salinas-Souza, Christine Stephens, Vincent Khoo, Robert J. Jones
Journal: Journal of Clinical Oncology (2020)

Capivasertib is a pan-AKT inhibitor. Preclinical data indicate activity in metastatic castration-resistant prostate cancer (mCRPC) and synergism with docetaxel.
Final Evaluation of Randomized CML-Study IV: 10-Year Survival and Evolution of Terminal Phase
Authors: Rüdiger Hehlmann, Michael Lauseker, Susanne Saussele, Markus Pfirrmann, Stefan W. Krause, Hans-Jochem Kolb, Andreas Neubauer, Dieter K. Hossfeld, Christoph Nerl, Alois Gratwohl, Gabriela M. Baerlocher, Dominik Heim, Tim Henrik Bruemmendorf, Alice Fabarius, Claudia Haferlach, Brigitte Schlegelberger, Martin C. Müller, Sabine Jeromin, Ulrike Proetel, Katharina Kohlbrenner, Astghik Voskanyan, Sébastien Rinaldetti, Wolfgang Seifarth, Birgit Spiess, Leopold Balleisen, Maria E Goebeler, Mathias Hänel, Anthony D. Ho, J Dengler, C Falge, Lothar Kanz, Claus-Henning Köhne, Andreas Burchert, Michael Kneba, Frank Stegelmann, C Köhne, Hans-Walter Lindemann, C Waller, Michael Pfreundschuh, Karsten Spiekermann, Wolfgang E Berdel, L Müller, Matthias Edinger, Jiri Mayer, Dietrich W Beelen, Martin Bentz, Hartmut Link, Bernd Hertenstein, R Fuchs, Martin Wernli, F Schlegel, Rudolph Schlag, M de Wit, Lorenz Trümper, H Hebarth, M Hahn, Jörg Thomalla, Christof Scheid, Philippe Schafhausen, Walter Verbeek, Michael J. Eckart, Winfried Gassmann, Antonio Pezzutto, Michael Schenk, Peter Brossart, Thomas Geer, Stephan Bildat, E Schäfer, Andreas Hochhaus, Joerg Hasford
Journal: Blood (2017)
CSIG-19. THE DEUBIQUITINASE BRCC3 LINKS ALT TELOMERES TO SUPPRESSION OF INNATE IMMUNITY IN IDH1-MUTANT GLIOMA
Authors: Joydeep Mukherjee, Yongjian Tang, Tor-Christian Johanessen, Ajay Pandita, Shigeo Ohba, Daniel Cahill, Russell Pieper
Journal: Neuro-Oncology (2020)

Abstract Approximately 10% of tumors including all IDH1-mutant lower-grade glioma resolve telomeric shortening using Alternative Lengthening of Telomere (ALT) mechanism. Although the ALT process lengthens telomeres, it also generates small bits of extrachromosomal, telomere-containing DNA (ECTRs). These ECTRs can bind and activate cyclic GMP-AMP synthase (cGAS), the major cytosolic sensor of double-stranded DNA, which in turn can activate expression of stimulator of IFN genes (STING) and the interferon-based innate immune response. To limit the immune response, ALT cells inactivate the cGAS-STING pathway, although the mechanism by which this occurs is unknown. Here we show that the deubiquitinase BRCC3 links ALT telomeres to suppression of the cGAS-STING pathway and the innate immune response. Astrocytoma cells dependent on the ALT-mechanism (IDH1-mutant and ATRX-deficient genetically-modified human astrocytes and MGG119 PDX) contained ECTR and had reduced expression of the cGAS and the downstream components of the cGAS-STING pathway (STING, and IFN-β) relative to matched non-ALT (isogenic ATRX WT astrocytes and MGG152 PDX) cells lacking ECTRs. Decreased levels of cGAS in ALT cells were in turn associated with deubiquitiantion and destabilization of cGAS. The telomere-derived ECTR in ALT-dependent cells lacked two proteins normally found in ALT telomeres (TRF2 or PARP), but retained two other proteins, Mre11 and its binding partner, normally nuclear deubiquitinase BRCC3. Furthermore, either pharmacologic inhibition or genetic suppression of BRCC3 levels had no effect on ECTR levels but stabilized cGAS and activated the cGAS-STING pathway. This cGAS-mediated activation could be blocked by exogenous expression of WT BRCC3, but not by expression of a mutant BRCC3 incapable of deubiquitination. These results show that BRCC3 translocated along with ECTRs to the cytoplasm degrades cGAS and protects ALT-dependent cells from activating the innate immune response. The BRCC3-controlled cGAS-STING pathway may therefore represent a therapeutically targetable means to enhance the immune response in IDH1-mutant lower grade glioma.
MBRS-04. MEDULLOBLASTOMA DETECTION BY BLOOD TEST
Authors: Michal Yalon, Amos Toren, Shany Freedman, Marc Remke, Ruty Meharian-Shai
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Long non coding RNAs (lincRNAs) are functionally defined as transcripts longer than 200 nucleotides in length with no protein coding potential. lincRNA involvement in human cancers etiology is being increasingly proved. Cancer-secreted long non-coding RNAs (lncRNAs) in exosomes are emerging mediators of cancer-host cross talk communication in tumor microenvironments. The ability to monitor and detect tumor markers in real time enables access to tumor biology and may allow highly personalized treatment for each patient. METHODS AND RESULTS We analyzed RNA sequencing of 64 Medulloblastoma samples and quantified the genome wide long non coding RNAs (lincRNA) expression levels. We identified a lincRNA that is distinctively highly expressed in group 4 (MB4). MB4 expression was further examined in microarray analysis on a larger cohort of medulloblastoma patient samples and a large cohort (n=1405) of patient samples that include normal brain and different brain tumor samples. MB4 proved to be specific and highly expressed in group 4 Medulloblastoma. MB4 was detected in the plasma of medulloblastoma patients with active disease, or subtotal resection. MB4 was not detected in patients that their tumors were resected. MB4 expression is not detected in the serum of medulloblastoma type SHH, penioblastoma, ewing sarcoma and neuroblastoma patients. CONCLUSIONS We have found that MB4 lncRNA is a highly specific medulloblastoma tumor biomarker and is sensitive and noninvasive biomarker that can be quantified from a blood test. MB4 can be a good diagnostic marker, and in future both may also be a good target for therapy.
Molecular Imaging of Prostate Cancer Targeting CD46 Using ImmunoPET
Authors: Sinan Wang, Jun Li, Jun Hua, Yang Su, Denis R. Beckford-Vera, Walter Zhao, Mayuri Jayaraman, Tony L. Huynh, Ning Zhao, Yung-hua Wang, Yangjie Huang, Fujun Qin, Sui Shen, Daniel Gioeli, Robert Dreicer, Renuka Sriram, Emily A. Egusa, Jonathan Chou, Felix Y. Feng, Rahul Aggarwal, Michael J. Evans, Youngho Seo, Bin Liu, Robert R. Flavell, Jiang He
Journal: Clinical Cancer Research (2020)

We recently identified CD46 as a novel therapeutic target in prostate cancer. In this study, we developed a CD46-targeted PET radiopharmaceutical, [89Zr]DFO-YS5, and evaluated its performance for immunoPET imaging in murine prostate cancer models.[89Zr]DFO-YS5 was prepared and its in vitro binding affinity for CD46 was measured. ImmunoPET imaging was conducted in male athymic nu/nu mice bearing DU145 [AR-, CD46+, prostate-specific membrane antigen-negative (PSMA-)] or 22Rv1 (AR+, CD46+, PSMA+) tumors, and in NOD/SCID gamma mice bearing patient-derived adenocarcinoma xenograft, LTL-331, and neuroendocrine prostate cancers, LTL-331R and LTL-545.[89Zr]DFO-YS5 binds specifically to the CD46-positive human prostate cancer DU145 and 22Rv1 xenografts. In biodistribution studies, the tumor uptake of [89Zr]DFO-YS5 was 13.3 ± 3.9 and 11.2 ± 2.5 %ID/g, respectively, in DU145 and 22Rv1 xenografts, 4 days postinjection. Notably, [89Zr]DFO-YS5 demonstrated specific uptake in the PSMA- and AR-negative DU145 model. [89Zr]DFO-YS5 also showed uptake in the patient-derived LTL-331 and -331R models, with particularly high uptake in the LTL-545 neuroendocrine prostate cancer tumors (18.8 ± 5.3, 12.5 ± 1.8, and 32 ± 5.3 %ID/g in LTL-331, LTL-331R, and LTL-545, respectively, at 4 days postinjection).[89Zr]DFO-YS5 is an excellent PET imaging agent across a panel of prostate cancer models, including in both adenocarcinoma and neuroendocrine prostate cancer, both cell line- and patient-derived xenografts, and both PSMA-positive and -negative tumors. It demonstrates potential for clinical translation as an imaging agent, theranostic platform, and companion biomarker in prostate cancer.
GCT-34. ELUCIDATION OF THE MECHANISMS OF TUMORIGENESIS IN INTRACRANIAL GERM CELL TUMOR BY WHOLE GENOME SEQUENCE
Authors: Yuki Yamagishi, Hirokazu Takami, Daichi Narushima, Yuko Matsushita, Eiji Sugihara, Ryo Nishikawa, Mamoru Kato, Koichi Ichimura
Journal: Neuro-Oncology (2020)

Abstract Intracranial germ cell tumors (iGCT) are heterogenous group of primary brain tumors that consist of various subtype, and driver genetic alterations in iGCTs remain largely unknown. We have previously reported in a study of whole exome sequence that iGCTs frequently harbored mutations in the KIT gene and its downstream MAPK/PI3K pathway, regardless of tumor subtype. However, no mutations were detected in about one-quarter of germinomas and half of non-germinomatous germ cell tumors. A genome-wide methylation profiling revealed that only germinomas exhibited extreme DNA hypomethylation among iGCTs. Moreover, in mixed iGCT tumors which contained more than one tumor subtypes, each component exhibited distinct methylation status depending on the subtype, while they shared the same mutations. These data suggested that not only mutations in the coding region as previously reported, but also genetic alterations in regulatory regions including promoters and enhancers as well as non-coding RNA genes may be involved in the tumorigenesis of iGCTs. In order to comprehensively search for driver gene alterations, we performed whole genome sequence in 18 paired tumor blood samples from iGCT tumors (16germinomas and two yolk sac tumors (YST)) registered in the Intracranial Germ Cell Tumor Genome Analysis Consortium. In a preliminary analysis of four cases, YSTs harbored a significantly higher number of structural abnormalities, compared with germinomas. Of note, 62 structural abnormalities were clustered within the small genomic region of 95Mb at 1q21-44 in one YST case, suggesting a possibility of chromothripsis. A full analysis of somatic alterations is underway and will be reported.
A Bayesian approach for diagnostic accuracy of malignant peripheral nerve sheath tumors: a systematic review and meta-analysis
Authors: Enrico Martin, Ritchie T J Geitenbeek, J Henk Coert, David F Hanff, Laura H Graven, Dirk J Grünhagen, Cornelis Verhoef, Walter Taal
Journal: Neuro-Oncology (2020)

Malignant peripheral nerve sheath tumors (MPNST) carry a dismal prognosis and require early detection and complete resection. However, MPNSTs are prone to sampling errors and biopsies or resections are cumbersome and possibly damaging in benign peripheral nerve sheath tumor (BPNST). This study aimed to systematically review and quantify the diagnostic accuracy of noninvasive tests for distinguishing MPNST from BPNST.Studies on accuracy of MRI, FDG-PET (fluorodeoxyglucose positron emission tomography), and liquid biopsies were identified in PubMed and Embase from 2000 to 2019. Pooled accuracies were calculated using Bayesian bivariate meta-analyses. Individual level-patient data were analyzed for ideal maximum standardized uptake value (SUVmax) threshold on FDG-PET.Forty-three studies were selected for qualitative synthesis including data on 1875 patients and 2939 lesions. Thirty-five studies were included for meta-analyses. For MRI, the absence of target sign showed highest sensitivity (0.99, 95% CI: 0.94-1.00); ill-defined margins (0.94, 95% CI: 0.88-0.98); and perilesional edema (0.95, 95% CI: 0.83-1.00) showed highest specificity. For FDG-PET, SUVmax and tumor-to-liver ratio show similar accuracy; sensitivity 0.94, 95% CI: 0.91-0.97 and 0.93, 95% CI: 0.87-0.97, respectively, specificity 0.81, 95% CI: 0.76-0.87 and 0.79, 95% CI: 0.70-0.86, respectively. SUVmax ≥3.5 yielded the best accuracy with a sensitivity of 0.99 (95% CI: 0.93-1.00) and specificity of 0.75 (95% CI: 0.56-0.90).Biopsies may be omitted in the presence of a target sign and the absence of ill-defined margins or perilesional edema. Because of diverse radiological characteristics of MPNST, biopsies may still commonly be required. In neurofibromatosis type 1, FDG-PET scans may further reduce biopsies. Ideal SUVmax threshold is ≥3.5.
<i>F. nucleatum</i> targets lncRNA ENO1-IT1 to promote glycolysis and oncogenesis in colorectal cancer
Authors: Jie Hong, Fangfang Guo, Shi-Yuan Lu, Chaoqin Shen, Dan Ma, Xinyu Zhang, Yile Xie, Tingting Yan, TaChung Yu, Tiantian Sun, Yun Qian, Ming Zhong, Jinxian Chen, Yanshen Peng, Cheng Wang, Xiang Zhou, Jianjun Liu, Qiang Liu, Xiong Ma, Ying-Xuan Chen, Haoyan Chen, Jing-Yuan Fang
Journal: Gut (2020)

Objective Microbiota disorder promotes chronic inflammation and carcinogenesis. High glycolysis is associated with poor prognosis in patients with colorectal cancer (CRC). However, the potential correlation between the gut microbiota and glucose metabolism is unknown in CRC. Design 18 F-FDG ( 18 F-fluorodeoxyglucose) PET (positron emission tomography)/CT image scanning data and microbiota PCR analysis were performed to measure the correlation between metabolic alterations and microbiota disorder in 33 patients with CRC. Multiple colorectal cancer models, metabolic analysis and Seahorse assay were established to assess the role of long non-coding RNA (lncRNA) enolase1-intronic transcript 1 (ENO1-IT1) in Fusobacterium (F.) nucleatum -induced glucose metabolism and colorectal carcinogenesis. RNA immunoprecipitation and chromatin immunoprecipitation sequencing were conducted to identify potential targets of lncRNA ENO1-IT1. Results We have found F . nucleatum abundance correlated with high glucose metabolism in patients with CRC. Furthermore, F. nucleatum supported carcinogenesis via increasing CRC cell glucose metabolism. Mechanistically, F. nucleatum activated lncRNA ENO1-IT1 transcription via upregulating the binding efficiency of transcription factor SP1 to the promoter region of lncRNA ENO1-IT1. Elevated ENO1-IT behaved as a guider modular for KAT7 histone acetyltransferase, specifying the histone modification pattern on its target genes, including ENO1, and consequently altering CRC biological function. Conclusion F. nucleatum and glucose metabolism are mechanistically, biologically and clinically connected to CRC. Targeting ENO1 pathway may be meaningful in treating patients with CRC with elevated F. nucleatum .
STEM-01. TARGETING BRAIN METASTASIS-INITIATING CELLS: A PREVENTATIVE APPROACH
Authors: Agata Kieliszek, Chitra Venugopal, Blessing Bassey-Archibong, Fred Lam, Sheila Singh, Nikoo Aghaei
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND The incidence of brain metastases (BM) is tenfold higher than primary brain tumors. BM commonly originate from primary lung, breast, and melanoma tumors with a 90% mortality rate within one year of diagnosis. Current standard of care for BM includes surgical resection with concurrent chemoradiation, but does not extend median survival past 16 months, posing a large unmet need to identify novel therapies against BM. METHODS From a large in-house biobank of patient-derived BM cell lines, the Singh Lab has generated murine orthotopic patient-derived xenograft (PDX) models of lung, breast, and melanoma BM that recapitulate the stages of BM progression as seen in humans. Using these three PDX models, we identified a population of “pre-metastatic” brain metastasis-initiating cells (BMICs) that are newly arrived in the brain but have yet to form detectable tumors. Pre-metastatic BMICs are not detectable in human patients but are important therapeutic targets with the potential to prevent BM in at-risk patients. RESULTS RNA sequencing of pre-metastatic BMICs from all three PDX primary tumor models with subsequent Connectivity Map analysis identified novel compounds that have the potential of killing all three types of BMICs. In particular, we identified two compounds that have selective killing of BMICs in vitro from all three primary tumor cohorts while sparing non-cancerous cells. We further characterized their ability to inhibit the self-renewal and proliferative properties of BMICs. Ongoing in vivo work will investigate the compounds’ preclinical utilities in preventing BM. CONCLUSION Identification of novel small molecules that target BMICs could prevent the formation of BM completely and dramatically improve the prognosis of at-risk cancer patients.