tbuckley/cabot-search huggingface dataset:
Emphasis on harms of hepatocellular carcinoma surveillance: Just pretending innocence after taking advantage?
Authors: Zheng Wang, Jun Han, Han Zhang, Meng‐Chao Wu, Tian Yang
Journal: Hepatology (2017)

Potential conflict of interest: Nothing to report. To the Editor: We read with great interest the recent article by Atiq et al.1 in hepatology (April 2017), which showed a retrospective study among 680 patients with cirrhosis followed at a US safety‐net health system. By evaluating benefits and harms from hepatocellular carcinoma (HCC) surveillance, they declared that over one fourth of patients with cirrhosis experienced physical harms for false‐positive or indeterminate surveillance tests—more often related to ultrasound than alpha‐fetoprotein. However, we would like to raise the following comments. Firstly, the harms of HCC surveillance seem to be exaggerated by the authors, which directly made the results of this retrospective study gravitate toward the authors' anticipated assumption. In this study, an imperative computed tomography (CT)/magnetic resonance imaging (MRI) scan recalled by screening tests was regarded as having at least mild harms (radiation exposure) unless HCCs were found by these imaging tests. That means, in the authors' eyes, CT/MRI scans should be considered necessary and beneficial if HCCs are detected but regarded as harmful if the results are negative. This is obviously unconvincing because without initiatory screening tests and sequential CT/MRI scans, it would be a substantial challenge to capture early HCCs. Secondly, the benefits of HCC surveillance are more or less narrowed by Atiq et al .—they defined it only as the detection tool of early HCCs (within Milan criteria). However, in our opinion, the essential benefit of HCC surveillance is most likely to detect preclinical HCCs, not only early HCCs which could be cured but also those asymptomatic and mildly progressive HCCs which still have the chance of undergoing various treatments to prolong survival,2 including transarterial chemoembolization, radiation therapy, molecular targeted therapy, and even curative treatments like liver resection. Therefore, it is a narrow view to define the benefits of HCC surveillance only as the detection of early HCCs. In summary, the benefits of HCC surveillance are undoubted and far beyond the detection of early HCCs as the authors argued. Although a few patients with false‐positive or indeterminate results during screening tests need to conduct CT/MRI scans due to the limitation of current screening technology, these imaging tests should not be regarded as unnecessary or harmful. Should CT/MRI scans be regarded as necessary if HCCs are found by these imaging tests, while harmful if the results are negative? This viewpoint put forward by the authors is just pretending innocent after taking advantage, which is illogical and even misguided. In our opinion, the conclusion of this article is negative to stress the importance of HCC surveillance or to advance early detection and early treatment for HCC. So, it seems somehow alarmist.
ATRT-08. TARGETING GLUTAMINE METABOLISM IN MYC DRIVEN ATYPICAL TERATOID RHABDOID TUMORS
Authors: Jeffrey Rubens, Sabrina Wang, Antoinette Price, Sariah Allen, Brent Orr, Charles Eberhart, Eric Raabe
Journal: Neuro-Oncology (2017)

Atypical teratoid rhabdoid tumors (AT/RT) are deadly infantile brain tumors in dire need of new, targeted therapies. Recent molecular analyses revealed considerable tumor heterogeneity subdividing AT/RT into 3 distinct sub-groups - TYR, SHH, and MYC. The MYC subgroup is especially aggressive with a dismal survival. Directly targeting MYC has proven to be challenging, but MYC is known to drive reliance on glutamine for cellular metabolism. We hypothesize that high MYC expressing AT/RT can be targeted with glutamine antagonists to improve survival. 6-diazo-5-oxo L-norleucine (DON) is a glutamine analogue that has been well tolerated in phase I clinical trials in children but never tested against MYC-driven pediatric brain tumors. We find that DON slows cell growth in high MYC expressing AT/RT while it has no effect on low MYC expressing AT/RT cell lines (MTS assay; p< 0.01 DON 10uM compared to DMSO control) or normal neural stem cells. DON also causes G2/M cell cycle arrest in high MYC expressing cell lines (MUSE cell cycle analysis) and induces DNA damage and apoptosis (Western blot for pH2A.X and c-PARP respectively). DON treatment of MYC-expressing AT/RT orthotopic xenografts nearly doubles median survival (p<0.001 by log-rank test; median survival extended from 21 to 36 days). DON combines with cisplatin to synergistically slow cell growth (MTS assay, p<0.01) and induce further DNA damage (Western blot pH2A.X). This study takes a novel approach to targeting cancer metabolism and serves as the first therapeutic strategy addressing the most aggressive subgroup of AT/RT. Since the maximum tolerated dose in pediatric phase I trials of DON was never reached, these findings support the rationale for future clinical trials testing DON and similar drugs against the MYC subgroup of AT/RT as well as other deadly MYC-driven brain tumors.
Building a single proposition from imagistic and categorical components
Authors: Kathryn Davidson
Journal: Behavioral and Brain Sciences (2017)

Abstract Bimodal bilingual language provides further evidence for the viewpoint advocated by Goldin-Meadow &amp; Brentari (G-M&amp;B) that sign, speech, and gesture work together to create a single proposition, illustrating the potential in each set of articulators for both imagistic and categorical components. Recent advances in formal semantics provide a framework for incorporating both imagistic and categorical components into a single compositional system.
Ago1 and microRNA mediated gene silencing in prostate cancer cells
Authors: Deepa Pookot, Robert Place, Hong Zhao, Zong Chen, Rajvir Dahiya, Long-cheng Li
Journal: Cancer Research (2007)

4521   Small RNA molecules have been recently found to regulate gene expression through many different mechanisms. Argonaute (AGO) proteins are the core components of effector complexes that facilitate RNA interference (RNAi). It has been reported that Ago1 aids in both siRNA-mediated post-transcriptional and transcriptional gene silencing in human cells. To determine if Ago1 is involved in mircoRNA (miRNA)-mediated gene silencing, we designed specific small interfering RNAs (siRNAs) to knockdown Ago1-4 expression. Transfection of the Ago siRNAs revealed several genes including estrogen receptor (ER) beta, HMOX, MYPN, and BMP4 that were up-regulated by Ago1 knockdown in PC-3 prostate cancer cells. To determine whether microRNA biogenesis is coupled to Ago1-dependent gene regulation, we also designed siRNAs to knockdown the expression of several microRNA processing genes including Dicer, Drosha, and Exportin-5. Similar to Ago1, microRNA processing genes also regulate the expression of ER beta, HMOX, MYPN, and BMP4. These results suggest that Ago1 is capable of facilitating microRNA-mediated gene silencing and further implicate microRNAs as fundamental regulators of gene expression in cancer cells.
Obinutuzumab (GA101) in Combination with Pixantrone for the Treatment of Patients with Relapsed Aggressive B-Cell Lymphoma: Report on an Ongoing Phase II Trial (GOAL)
Authors: Georg Hess, Andreas Hüttmann, Reinhard Marks, Mathias Witzens-Harig, Martin H. Dreyling, Andreas Viardot, Georg Lenz, Christiane Pott, Annegret Kuhn, Christian Ruckes, Matthias Theobald, Ulrich Keller
Journal: Blood (2016)
Lymphoid differentiation of hematopoietic stem cells requires efficient Cxcr4 desensitization
Authors: Christelle Freitas, Monika Wittner, Julie Nguyen, Vincent Rondeau, Vincent Biajoux, Marie-Laure Aknin, Françoise Gaudin, Sarah Beaussant-Cohen, Yves Bertrand, Christine Bellanné-Chantelot, Jean Donadieu, Françoise Bachelerie, Marion Espéli, Ali Dalloul, Fawzia Louache, Karl Balabanian
Journal: The Journal of Experimental Medicine (2017)

The CXCL12/CXCR4 signaling exerts a dominant role in promoting hematopoietic stem and progenitor cell (HSPC) retention and quiescence in bone marrow. Gain-of-function CXCR4 mutations that affect homologous desensitization of the receptor have been reported in the WHIM Syndrome (WS), a rare immunodeficiency characterized by lymphopenia. The mechanisms underpinning this remain obscure. Using a mouse model with a naturally occurring WS-linked gain-of-function Cxcr4 mutation, we explored the possibility that the lymphopenia in WS arises from defects at the HSPC level. We reported that Cxcr4 desensitization is required for quiescence/cycling balance of murine short-term hematopoietic stem cells and their differentiation into multipotent and downstream lymphoid-biased progenitors. Alteration in Cxcr4 desensitization resulted in decrease of circulating HSPCs in five patients with WS. This was also evidenced in WS mice and mirrored by accumulation of HSPCs in the spleen, where we observed enhanced extramedullary hematopoiesis. Therefore, efficient Cxcr4 desensitization is critical for lymphoid differentiation of HSPCs, and its impairment is a key mechanism underpinning the lymphopenia observed in mice and likely in WS patients.
Podocyte Activation of NLRP3 Inflammasomes Contributes to the Development of Proteinuria in Lupus Nephritis
Authors: Rong Fu, Chaohuan Guo, Shuang Wang, Yuefang Huang, Ou Jin, Haoqiang Hu, Jingxian Chen, Bihua Xu, Mianjing Zhou, Jijun Zhao, Sun‐sang J. Sung, Hongyang Wang, Felicia Gaskin, Niansheng Yang, Shu Man Fu
Journal: Arthritis & Rheumatology (2017)

Development of proteinuria in lupus nephritis (LN) is associated with podocyte dysfunction. The NLRP3 inflammasome has been implicated in the pathogenesis of LN. The purpose of this study was to investigate whether NLRP3 inflammasome activation is involved in the development of podocyte injury in LN.A fluorescence-labeled caspase 1 inhibitor probe was used to detect the activation of NLRP3 inflammasomes in podocytes derived from lupus-prone NZM2328 mice and from renal biopsy tissues obtained from patients with LN. MCC950, a selective inhibitor of NLRP3, was used to treat NZM2328 mice. Proteinuria, podocyte ultrastructure, and renal pathology were evaluated. In vitro, sera from diseased NZM2328 mice were used to stimulate a podocyte cell line, and the cells were analyzed by flow cytometry.NLRP3 inflammasomes were activated in podocytes from lupus-prone mice and from patients with LN. Inhibition of NLRP3 with MCC950 ameliorated proteinuria, renal histologic lesions, and podocyte foot process effacement in lupus-prone mice. In vitro, sera from diseased NZM2328 mice activated NLRP3 inflammasomes in the podocyte cell line through the production of reactive oxygen species.NLRP3 inflammasomes were activated in podocytes from lupus-prone mice and from LN patients. Activation of NLRP3 is involved in the pathogenesis of podocyte injuries and the development of proteinuria in LN.
Decline in Americans without insurance appears to have halted
Authors: Michael McCarthy
Journal: BMJ (2017)

The sharp decline in the number of uninsured people in the US that followed the implementation of the Affordable Care Act (ACA) came to a stop after 2015, a report from the National Center for Health Statistics has found.1

Since the passage of the 2010 health reform law, the number of people without coverage fell by 20 million, from 48.6 million in 2010 to 28.6 million in 2015, driving the percentage of Americans without health insurance down from 16% to 9.1%, an historic low.

However, the new report found that between 2015 and 2016, the number of uninsured people remained at 28.6 …
GENE-06. CO-OCCURRENCE OF DOUBLE MUTATION H3F3A/BRAF IN PEDIATRIC GANGLIOGLIOMAS
Authors: Mélanie Pagès, Arnault Tauziède-Espariat, Kevin Beccaria, Nathalie Boddaert, Raphaël Saffroy, Aurore Besnard, David Castel, Frédéric Fina, Doriane Barets, Emilie Barret, Ludovic Lacroix, Franck Bielle, Felipe Andreiuolo, Dominique Figarella-Branger, Stéphanie Puget, Jacques Grill, Fabrice Chrétien, Pascale Varlet
Journal: Neuro-Oncology (2017)

Grade I or III ganglioglioma (GG) is characterized by alterations in the MAPK pathway, including BRAF mutation. Diffuse midline glioma H3 K27M mutated was added to the WHO 2016 classification as a new grade IV entity. A co-occurrence of H3F3A/BRAF mutations has been reported in midline tumors. Firstly, we searched for BRAF V600E and H3 K27M mutations in a series of 54 pediatric midline grade I GG to determine the frequency of double mutations in grade I GG. We then studied the clinico-radiological and histo-molecular features of 12 grade I to III double-mutated tumors to explore the therapeutic and prognostic relevance. The frequency of the co-occurrence of H3F3A/BRAF mutations in grade I midline GG at diagnosis was 9.3%. Double-immunostaining revealed that BRAF V600E and H3 K27M mutant proteins colocalized in both the glial and neuronal components, The series of double-mutated GG included 8 grade I, and 4 grade III at diagnosis. The median survival was 8 years. Three grade I tumors showed a malignant transformation at 0.5, 3.5 and 7 years and two of them showed a loss of the BRAF mutation in recurrent tumor samples. Five patients with grade I were alive with stable disease without adjuvant therapy at the last follow-up. One grade III showed a paradoxical response under BRAF inhibitor. In this work we stress that H3F3A mutation can occur, in association with the BRAF mutation, in grade I GG, and that these have a better spontaneous outcome than classic diffuse midline H3 K27M-mutant gliomas. These data highlight the importance of an integrated histomolecular diagnosis especially in the context of targeted therapy.
Abstract 16371: High Levels of Tumor Necrosis Factor-α in Patients With Continuous-Flow Left Ventricular Assist Devices Mediate Altered Vessel Growth and Are Associated With Higher Non-Surgical Bleeding
Authors: Corey E Tabit, Mitchell J Coplan, Phetcharat Chen, James K Liao
Journal: Circulation (2016)

Background:  Angiodysplasia is common in patients with LVADs. Thrombin-induced expression of Angiopoietin-2 (Ang-2) in LVAD patients leads to altered angiogenesis and is associated with loss of Angiopoietin-1 (Ang-1). However, Ang-2 alone is insufficient to induce angiogenesis, suggesting involvement of other factors. The reason for decreased Ang-1 expression in LVAD patients is also not known. We hypothesized that high levels of Tumor Necrosis Factor-α (TNF-α) in LVAD patients regulate angiogenesis, downregulate Ang-1 expression, induce pericyte apoptosis, and induce Tissue Factor (TF) expression.   Methods:  TNF-α and TF levels were measured by ELISA in blood from 101 patients with heart failure (HF), LVAD, or orthotopic heart transplant (OHT). Cultured endothelial cells were incubated on Matrigel with serum from each patient with or without TNF-α-blocking antibody and tube formation was measured by microscopy. Then, cultured pericytes were incubated with serum from each patient with or without TNF-α blockade. Ang-1 expression was measured by RT-PCR and pericyte death was measured by fluorescent live/dead stain. Finally, TF gene expression was measured by RT-PCR in cultured endothelial cells incubated with plasma from each patient with or without TNF-α inhibitor. TF expression in endothelial biopsy samples from these patients was measured by quantitative immunofluorescence.   Results:  Compared with HF or OHT, levels of TNF-α were higher in LVAD patients. This corresponded with increased angiogenic potential of serum from patients with LVADs, which was normalized with TNF-α blockade. Serum from LVAD patients reduced Ang-1 expression and induced more pericyte cell death than serum from HF or OHT patients and this effect was blunted by TNF-α blockade. Further, plasma from LVAD patients induced more TF expression in endothelial cells than plasma from HF or OHT patients and this effect was reduced with TNF-α blockade. Compared with HF or OHT patients, plasma and endothelial cells from LVAD patients contained higher amounts of TF.   Conclusions:  Elevated TNF-α in LVAD patients is a central regulator of altered angiogenesis, pericyte apoptosis, and expression of thrombotic factors. Blockade of TNF-α may decrease vascular complications in LVAD patients.
Oh, the number of things you will process (in parallel)!
Authors: Alejandro Lleras, Deborah A Cronin, Anna M Madison, Marshall Wang, Simona Buetti
Journal: Behavioral and Brain Sciences (2017)

Abstract We highlight the importance of considering the variance produced during the parallel processing stage in vision and present a case for why it is useful to consider the “item” as a meaningful unit of study when investigating early visual processing in visual search tasks.
Annual baseline drift in professional rugby league players
Authors: Lisa Hodgson, Conor Gissane, P Walker, Paul Maruff, D Darby
Journal: British Journal of Sports Medicine (2017)

Objective Annual baseline testing within professional Rugby League has been mandatory since 2004. The question, do annual baselines drift over time or as a result of a concussion in rugby league players is unanswered. If they do drift, what is the magnitude and in what tasks and is this correlated to associated concussions. The study evaluated if baselines drift over time and if so is this related to concussive injury or accumulating injury. Design Retrospective study Method Participant players were those who held a professional contract between the 2006–2012 season. It is mandatory to provide an annual baseline test using CogSport and following any diagnosed concussion, with full symptom resolution, a valid return to play test. Concussion test data was provided by CogState Australia from tests performed over 7 seasons. Results Over the 7-year period 4762 players suffered 470 concussions (2.65/1000 hours, 95% Confidence Interval 2.4 to 2.9). Identification increased with previous concussion (0.017, 0.001 to 0.029, P=0.05) but not season. One Back Memory decreased with concussion (−.05 to −.05, P=0.001). One Card Learning decreased with previous concussion (−0.041, −0.049 to −0.34, P=0.001) and season (−0.006, −0.007 to −0.005, P=0.001). Conclusions Over seven seasons, item scores within the CogSport test varied as a function of previous concussion and time. Individual items within the CogSport test were influenced by differing factors and further examination of the individual items is warranted. Competing interests Lisa Hodgson, Conor Gissane, P Walker – None. Paul Maruff – Full time employee of CogState D Darby – Former Founder and Director of Cogstate
Erratum for the Research Article: “Identification of a New Modulator of the Intercalated Disc in a Zebrafish Model of Arrhythmogenic Cardiomyopathy” by A. Asimaki, S. Kapoor, E. Plovie, A. Karin Arndt, E. Adams, Z. Liu, C. A. James, D. P. Judge, H. Calkins, J. Churko, J. C. Wu, C. A. MacRae, A. G. Kléber, J. E. Saffitz
Journal: Science Translational Medicine (2014)
Abstract 136: Distinct Temporal Requirements for Scl to Repress Cardiomyogenesis in Endothelial-derived Cells in Hemogenic Tissues and the Heart
Authors: Ben Van Handel, Tonis Org, Amelie Montel-Hagen, Haruko Nakano, Atsushi Nakano, Sylvia Evans, Hanna Mikkola
Journal: Circulation Research (2013)

Identification of precursors with the capacity to generate cardiomyocytes is critical for advancing cardiac regenerative medicine. By analyzing knockout embryos for the bHLH factor Scl, we demonstrated that endothelial cells in hematopoietic tissues and the heart possess latent cardiomyogenic capacity. Furthermore, analysis of tamoxifen-inducible Rosa26-Cre ERT2 Scl fl/fl embryos suggested that the time window during which Scl is required for cardiac repression extends later in the heart versus the yolk sac. However, the cell types in which Scl acts remained elusive. We then deleted Scl in a cell-type specific manner in early mesoderm using Mesp1-Cre and in endothelial cells using Tie2-Cre. Lineage tracing in Mesp1-Cre Rosa26-YFP embryos demonstrated that at E9.5, a large majority of hematopoietic and endothelial cells in the yolk sac and heart were labeled. Moreover, deletion of Scl in Mesp1-Cre Scl fl/fl embryos phenocopied the germline knockout, essentially abrogating hematopoiesis and promoting the emergence of CD31 + PDGFRα + cardiomyogenic precursors and ectopic expression of the cardiomyocyte genes Myl7 and Tnnt2 in yolk sac vasculature. In contrast, deletion of Scl after endothelium had been specified in Tie2-Cre Scl fl/fl embryos did not grossly affect yolk sac hematopoiesis, nor did it induce ectopic cardiomyogenesis in hemogenic tissues. However, endothelial-derived cells in the hearts of Tie2-Cre Scl fl/fl embryos evidenced profound expansion of CD31 + PDGFRα + cardiogenic precursors at E11.5 and E13.5, as well as displayed dramatic upregulation of Myl7 and Tnnt2 , showing that the requirement for Scl to repress the cardiomyogenic program extends longer in endothelial derivatives in the heart than in the yolk sac. These data demonstrate that endocardial-derived cells in the heart retain latent cardiomyogenic potential until mid-gestation and nominate Scl as a critical regulator of endocardial fate.
Abstract P159: Th17 Cells Are Indispensable for Cardiac Inflammation in Autoimmune Myocarditis
Authors: Tomomi Yamashita, Hiroyuki Nakayama, Yasushi Fujio
Journal: Circulation Research (2011)

Background: Chronic inflammation is closely associated with heart failure; however, the molecular and cellular mechanisms of inflammatory reactions remain to be fully elucidated. Interleukin(IL)-17 is a pro-inflammatory cytokine that is produced by Th17 cells. Th17 cells are induced by IL-6 and transforming growth factor(TGF-β), through up-regulation of its specific transcriptional factor, retinoic acid receptor-related orphan nuclear receptor(ROR)γt. Th17 cells are reported to participate in pathogenesis of chronic inflammatory disease. In this study, we examined the functional roles of Th17 signaling in cardiac inflammation using murine experimental autoimmune myocarditis(EAM) model. Methods and Results: EAM was induced in wild-type(WT) and/or RORγt-eGFP knock-in Balb/c mice by immunization twice with α-myosin heavy chain peptide. Three weeks after the first immunization, the mRNA expression of RORγt was up-regulated and correlated with the disease severity in heart. Additionally, in immunostaining and flow cytometry analysis, we observed a significant number of Th17 cells among inflammatory cells infiltrating myocardium from WT and RORγt-eGFP knock-in heterozygous mice. These data showed that Th17 cells were remarkably recruited in EAM heart. Moreover, depression of Th17 differentiation suppressed disease severity completely with inhibition of RORγt and IL-17 transcriptional activity, whereas IL-17 neutralizing antibody to lesser extent. Finally, RORγt-eGFP knock-in homozygous mice were protected from cardiac inflammation. Conclusion: Our results indicated that Th17 activation through RORγt pathway is a critical mechanism for the development of myocarditis. However, IL-17 is not crucial for induction of EAM, suggesting that other Th17 producing pro-inflammatory cytokines are involved. It could be proposed that Th17 cells are novel therapeutic target against chronic inflammation in heart.