tbuckley/cabot-search huggingface dataset:
Treatment outcomes of pediatric and young adult sporadic desmoid tumors.
Authors: Sara Helmig, Joseph Gerald Pressey, Joel Sorger
Journal: Journal of Clinical Oncology (2015)

10045 Background: Desmoid tumor (DT) is a non-malignant soft-tissue neoplasm of children and adults that is often treated with surgery, radiation and/or chemotherapy. DTs may recur even after complete resection, and the benefit of medical therapy is unpredictable. Data driven DT therapy guidelines are lacking for children and young adults. Methods: A retrospective review of DT patients treated at a single institution between 2003 and 2014. Results: Twenty-three patients, aged 3 months to 25 years of age at diagnosis, were identified from a complex patient population that included 7 patients with congenital deformity or syndromes. Anatomic locations included extremity (15), head/neck tumors (2), and trunk/abdomen (6). Both head/neck and 5 of 6 trunk patients demonstrated no evidence of disease (NED) at last follow-up, whereas only 1 extremity patient was NED (p = 0.0001). Of the 23 patients, all but 2 patients had at least one surgical resection. Six patients required a single surgery only: R0 (n = 4), R1 (n = 1), and R2 (n = 1). Eight patients received vinblastine and methotrexate (VBL/MTX), 5 received sorafenib, and tamoxifen (TAM) with sulindac, hydroxyurea, and liposomal doxorubicin were each administered to 1 patient. One VBL/MTX patient experienced a partial response while 3 others experienced prolonged stabilization ( > 36 months). Two of four patients treated with sorafenib experienced stabilization ( > 24 months). The single patient treated with TAM/sulindac experienced prolonged stabilization. Five patients received radiation therapy, with one developing a secondary sarcoma and two others stabilizing without further sequela. There were no deaths related to DT. Conclusions: Our findings demonstrate that a subset of tumors can be adequately treated with a single surgery. Head/neck and trunk tumors were more likely to be rendered NED than extremity tumors. Another subset of unresectable/recurrent tumors treated with mild medical therapy stabilized without significant morbidity, although RECIST response was rare in this complex cohort. Given the unpredictable benefit of therapies for unresectable/recurrent disease, genome directed approaches and observation-only strategies merit further exploration in this age group.
Guided self led or group therapy as effective as individual CBT for acute depression, finds review
Authors: Susan Mayor
Journal: BMJ (2019)

Guided self help treatment given by phone or in a group is as effective as individual cognitive behavioural therapy (CBT) for improving acute symptoms of depression in adults, a review of randomised trials has reported.

“Applying effective and acceptable CBT in a range of different formats will make CBT easier to implement, disseminate, and deliver across different settings and diverse patient populations,” said the authors, led by Pim Cuijpers, from Amsterdam Public Health Research Institute in the Netherlands.1

They said that the findings should inform future guidelines for managing depression.

CBT was originally developed as an individual therapy in which a therapist works with a …
LBO-01-Multicenter, double-blind, placebo-controlled, randomized trial of emricasan in subjects with NASH cirrhosis and severe portal hypertension
Authors: Guadalupe Garcia-Tsao, Jaime Bosch, Zeid Kayali, Stephen Harrison, Manal Abdelmalek, Eric Lawitz, Sanjaya Satapathy, Marwan Ghabril, Mitchell Shiffman, Ziad H. Younes, Paul J. Thuluvath, Annalisa Berzigotti, Agustin Albillos, James Robinson, Jean L. Chan, David Hagerty, Arun Sanyal
Journal: Journal of Hepatology (2019)
Topology Dictates Evolution of Regulatory Cysteines in a Family of Viral Oncoproteins
Authors: Damián Alvarez-Paggi, Juan Ramiro Lorenzo, Gabriela Camporeale, Luciano Montero, Ignacio E Sánchez, Gonzalo de Prat Gay, Leonardo G Alonso
Journal: Molecular Biology and Evolution (2019)

Redox regulation in biology is largely operated by cysteine chemistry in response to a variety of cell environmental and intracellular stimuli. The high chemical reactivity of cysteines determines their conservation in functional roles, but their presence can also result in harmful oxidation limiting their general use by proteins. Papillomaviruses constitute a unique system for studying protein sequence evolution since there are hundreds of anciently evolved stable genomes. E7, the viral transforming factor, is a dimeric, cysteine-rich oncoprotein that shows both conserved structural and variable regulatory cysteines constituting an excellent model for uncovering the mechanism that drives the acquisition of redox-sensitive groups. By analyzing over 300 E7 sequences, we found that although noncanonical cysteines show no obvious sequence conservation pattern, they are nonrandomly distributed based on topological constrains. Regulatory residues are strictly excluded from six positions stabilizing the hydrophobic core while they are enriched in key positions located at the dimerization interface or around the Zn+2 ion. Oxidation of regulatory cysteines is linked to dimer dissociation, acting as a reversible redox-sensing mechanism that triggers a conformational switch. Based on comparative sequence analysis, molecular dynamics simulations and biophysical analysis, we propose a model in which the occurrence of cysteine-rich positions is dictated by topological constrains, providing an explanation to why a degenerate pattern of cysteines can be achieved in a family of homologs. Thus, topological principles should enable the possibility to identify hidden regulatory cysteines that are not accurately detected using sequence based methodology.
Secukinumab shows high efficacy irrespective of <i>HLA‐Cw6</i> status in patients with moderate‐to‐severe plaque‐type psoriasis: results from extension phase of the SUPREME study
Authors: M. Papini, F. Cusano, M. Romanelli, M. Burlando, G. Stinco, G. Girolomoni, K. Peris, C. Potenza, A. Offidani, M. Bartezaghi, E. Aloisi, A. Costanzo, Luca Bianchi, Ugo Bottoni, Cinzia Buligan, Valeria Brazzelli, Anna Campanati, Franca Cantoresi, Alessandra Capo, Angelo Cattaneo, Paolo Dapavo, Micol Giglio, Vito Lernia, Sergio Nuzzo, Clara Simone, Daniele Dusi, Concetta Fargnoli, Laura Flori, Chiara Franchi, Marco Galluzzo, Alberto Ghilardi, Katharina Hansel, Francesco Loconsole, Viviana Lora, Piergiorgio Malagoli, Giovanna Malara, Valentina Mastrandrea, Matteo Megna, Raffaele Mercuri, Letizia Musumeci, Luigi Naldi, Alessandra Narcisi, Diego Orsini, Gianluca Pagnanelli, Annalisa Patrizi, Monica Pau, Giovanni Pellacani, Severino Persechino, Stefano Piaserico, Lucia Pietroleonardo, Francesca Prignano, Alberto Reseghetti, Filomena Russo, Riccardo Sirna, Nevena Skroza, Luca Stingeni, Sara Trevisini, Cristina Zane, Leonardo Zichichi, Antonio Zini
Journal: British Journal of Dermatology (2019)
Hypomethylating agents as potential therapy for pediatric/young adult AML with EVI-1 hyper expression.
Authors: Nupur Mittal, Liping Li, Zhijian Qian
Journal: Journal of Clinical Oncology (2015)

e21004 Background: EVI-1 high is implicated in 25% of AML in pediatric/ young adult patients with significantly lower 5-year OS/ EFS compared to EVI-1 low. We showed in primary murine bone marrow cells that EVI-1 hyper-expression leads to down-regulation of miR-9 by DNA hypermethylation resulting in myeloid differentiation block. The mechanism of EV1-1 high leukemia is unclear in patients and targeted therapy is unavailable. Hypomethylating agents reverse the abnormal epigenetic silencing and have been used in adults with AML. Pediatric experience with these drugs in molecular subtypes of AML is lacking and limited to salvage therapy for relapse. Objective: To determine a) Correlation of EVI-1 and miR-9 expression in pediatric/young adult AML b) Whether EVI-1 regulates miR-9 by hypermethylation in patients. Methods: AML-UCSD and U 937 cell lines and 35 primary AML pediatric samples were checked for EVI-1 and miR-9 expression by q-RT PCR. The methylation status of the miR-9 promoter was evaluated by direct sequencing of bisulfite-converted genomic DNA. EVI-1 high and low AML cell lines were treated with 5 AZA-dc and the cells were analyzed for growth and apoptosis using flow cytometry. The expression of EVI-1 and miR-9 as well as methylation status of miR-9 promoter was reassessed. Results: The expression of EVI-1 was significantly higher and miR-9 lower in AML-UCSD cell line compared to U 937. A clear correlation was seen in primary leukemia samples between high EVI-1 and low miR-9 expression (p < 0.05). EVI-1 high primary leukemia cells and cell lines, showed increased CpG island methylation on miR-9 promoter compared to EVI-1 low (p < 0.05). Treatment of cells with 5-AZA-dc inhibited cell growth and increased apoptosis more in EVI-1 high vs low cell line (p < 0.05). Reversal of methylation in cell lines after drug treatment correlated with greater increase in miR-9 expression in EVI-1 high vs EVI-1 low line ( p < 0.05) . Conclusions: EVI-1 hyper expression in pediatric AML leads to repression of miR-9 through DNA hypermethylation. 5 AZA-dc leads to more growth inhibition and apoptosis in EVI-1 high vs low cell line. Hypomethylating agents may prove as new adjunct therapeutic strategy in pediatric AML with EVI-1 hyperexpression.
XBP1S Regulates MUC5B in a Promoter Variant–Dependent Pathway in Idiopathic Pulmonary Fibrosis Airway Epithelia
Authors: Gang Chen, Carla M. P. Ribeiro, Ling Sun, Kenichi Okuda, Takafumi Kato, Rodney C. Gilmore, Mary B. Martino, Hong Dang, Aiman Abzhanova, Jennifer M. Lin, Emily A. Hull-Ryde, Allison S. Volmer, Scott H. Randell, Alessandra Livraghi-Butrico, Yingfeng Deng, Philipp E. Scherer, Barry R. Stripp, Wanda K. O’Neal, Richard C. Boucher
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

The goal was to connect elements of idiopathic pulmonary fibrosis (IPF) pathogenesis, including chronic endoplasmic reticulum stress in respiratory epithelia associated with injury/inflammation and remodeling, distal airway mucus obstruction and honeycomb cyst formation with accumulation of MUC5B (mucin 5B), and associations between IPF risk and polymorphisms in the
Evaluating in vivo efficacy – toxicity profile of TEG001 in humanized mice xenografts against primary human AML disease and healthy hematopoietic cells
Authors: Inez Johanna, Trudy Straetemans, Sabine Heijhuurs, Tineke Aarts-Riemens, Håkan Norell, Laura Bongiovanni, Alain de Bruin, Zsolt Sebestyen, Jürgen Kuball
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> γ9δ2T cells, which express Vγ9 and Vδ2 chains of the T cell receptor (TCR), mediate cancer immune surveillance by sensing early metabolic changes in malignant leukemic blast and not their healthy hematopoietic stem counterparts via the γ9δ2TCR targeting joined conformational and spatial changes of CD277 at the cell membrane (CD277J). This concept led to the development of next generation CAR-T cells, so-called TEGs: αβT cells Engineered to express a defined γδTCR. The high affinity γ9δ2TCR clone 5 has recently been selected within the TEG format as a clinical candidate (TEG001). However, exploring safety and efficacy against a target, which reflects an early metabolic change in tumor cells, remains challenging given the lack of appropriate tools. Therefore, we tested whether TEG001 is able to eliminate established leukemia in a primary disease model, without harming other parts of the healthy hematopoiesis in vivo. <h3>Methods</h3> Separate sets of NSG mice were respectively injected with primary human acute myeloid leukemia (AML) blasts and cord blood-derived human progenitor cells from healthy donors. These mice were then treated with TEG001 and mock cells. Tumor burden and human cells engraftment were measured in peripheral blood and followed up over time by quantifying for absolute cell number by flow cytometry. Statistical analysis was performed using non-parametric 2-tailed Mann-Whitney t-test. <h3>Results</h3> We successfully engrafted primary AML blasts and healthy hematopoietic cells after 6–8 weeks. Here we report that metabolic cancer targeting through TEG001 eradicated established primary leukemic blasts in vivo, while healthy hematopoietic compartments derived from human cord-blood remained unharmed in spite of TEGs persistence up to 50 days after infusion. No additional signs of off-target toxicity were observed in any other tissues. <h3>Conclusion</h3> Within the limitations of humanized PD-X models, targeting CD277J by TEG001 is safe and efficient. Therefore, we have initiated clinical testing of TEG001 in a phase I first-in-human clinical trial (NTR6541; date of registration 25 July 2017).
SAT-196-The integrated use of highly sensitive HBV markers can predict HBV reactivation in HBsAg-negative/Anti-HBc positive patients from oncohematological setting
Authors: Romina Salpini, Carlotta Cerva, Arianna Battisti, Lorenzo Piermatteo, Angelica Sacco, Vincenzo Malagnino, William Arcese, Maria Cantonetti, Francesca Ceccherini Silberstein, Carlo Federico Perno, Massimo Andreoni, Loredana Sarmati, Valentina Svicher
Journal: Journal of Hepatology (2019)
SAT-232-Reinfection following successful HCV DAA therapy among people with recent injecting drug use
Authors: Jason Grebely, Evan B Cunningham, Olav Dalgard, Behzad Hajarizadeh, Brian Conway, Jeff Powis, Julie Bruneau, Jordan Feld, Phillip Read, Curtis Cooper, Janaki Amin, Philip Bruggmann, Karine Lacombe, Catherine Stedman, Margaret Hellard, Pip Marks, Adrian Dunlop, Alberto Moriggia, Tanya Applegate, Alain Litwin, Gail Matthews, Gregory Dore
Journal: Journal of Hepatology (2019)
SAT-308-The optimal cut-off points of FIB-4 index for predicting the incidences of HCC and extra-hepatic malignancies in biopsy-proven Japanese NAFLD patients
Authors: Takanori Ito, Masatoshi Ishigami, Yoji Ishizu, Teiji Kuzuya, Takashi Honda, Mitsuhiro Fujishiro
Journal: Journal of Hepatology (2019)
Prolonged evolution of the memory B cell response induced by a replicating adenovirus-influenza H5 vaccine
Authors: Kenta Matsuda, Jinghe Huang, Tongqing Zhou, Zizhang Sheng, Byong H. Kang, Elise Ishida, Trevor Griesman, Sarah Stuccio, Lyuba Bolkhovitinov, Teddy J. Wohlbold, Veronika Chromikova, Alberto Cagigi, Kwanyee Leung, Sarah Andrews, Crystal S. F. Cheung, Alyssa A. Pullano, Jason Plyler, Cinque Soto, Baoshan Zhang, Yongping Yang, M. Gordon Joyce, Yaroslav Tsybovsky, Adam Wheatley, Sandeep R. Narpala, Yicheng Guo, Sam Darko, Robert T. Bailer, April Poole, C. Jason Liang, Jon Smith, Jeff Alexander, Marc Gurwith, Stephen A. Migueles, Richard A. Koup, Hana Golding, Surender Khurana, Adrian B. McDermott, Lawrence Shapiro, Florian Krammer, Peter D. Kwong, Mark Connors
Journal: Science Immunology (2019)

Ad4-H5 vaccine induces prolonged increases in H5-specific B cell frequency, antibody affinity, and somatic hypermutation.
N6-Methylation of Adenosine of <i>FZD10</i> mRNA Contributes to PARP Inhibitor Resistance
Authors: Takeshi Fukumoto, Hengrui Zhu, Timothy Nacarelli, Sergey Karakashev, Nail Fatkhutdinov, Shuai Wu, Pingyu Liu, Andrew V. Kossenkov, Louise C. Showe, Stephanie Jean, Lin Zhang, Rugang Zhang
Journal: Cancer Research (2019)

Abstract Despite the high initial response rates to PARP inhibitors (PARPi) in BRCA-mutated epithelial ovarian cancers (EOC), PARPi resistance remains a major challenge. Chemical modifications of RNAs have emerged as a new layer of epigenetic gene regulation. N6-methyladenosine (m6A) is the most abundant chemical modification of mRNA, yet the role of m6A modification in PARPi resistance has not previously been explored. Here, we show that m6A modification of FZD10 mRNA contributes to PARPi resistance by upregulating the Wnt/β-catenin pathway in BRCA-mutated EOC cells. Global m6A profile revealed a significant increase in m6A modification in FZD10 mRNA, which correlated with increased FZD10 mRNA stability and an upregulation of the Wnt/β-catenin pathway. Depletion of FZD10 or inhibition of the Wnt/β-catenin sensitizes resistant cells to PARPi. Mechanistically, downregulation of m6A demethylases FTO and ALKBH5 was sufficient to increase FZD10 mRNA m6A modification and reduce PARPi sensitivity, which correlated with an increase in homologous recombination activity. Moreover, combined inhibition of PARP and Wnt/β-catenin showed synergistic suppression of PARPi-resistant cells in vitro and in vivo in a xenograft EOC mouse model. Overall, our results show that m6A contributes to PARPi resistance in BRCA-deficient EOC cells by upregulating the Wnt/β-catenin pathway via stabilization of FZD10. They also suggest that inhibition of the Wnt/β-catenin pathway represents a potential strategy to overcome PARPi resistance. Significance: These findings elucidate a novel regulatory mechanism of PARPi resistance in EOC by showing that m6A modification of FZD10 mRNA contributes to PARPi resistance in BRCA-deficient EOC cells via upregulation of Wnt/β-catenin pathway.
SAT-114-Impact of farnesoid X receptor polymorphisms on hepatic decompensation and mortality in cirrhotic patients with portal hypertension
Authors: Georg Semmler, Bernhard Scheiner, Benedikt Simbrunner, Philipp Schwabl, Rafael Paternostro, Theresa Bucsics, Albert Stättermayer, David JM Bauer, Matthias Pinter, Peter Ferenci, Michael Trauner, Mattias Mandorfer, Thomas Reiberger
Journal: Journal of Hepatology (2019)
Resolving and Rescuing Developmental Miswiring in a Mouse Model of Cognitive Impairment
Authors: Mattia Chini, Jastyn A. Pöpplau, Christoph Lindemann, Laura Carol-Perdiguer, Marilena Hnida, Victoria Oberländer, Xiaxia Xu, Joachim Ahlbeck, Sebastian H. Bitzenhofer, Christoph Mulert, Ileana L. Hanganu-Opatz
Journal: Neuron (2019)

Cognitive deficits, core features of mental illness, largely result from dysfunction of prefrontal networks. This dysfunction emerges during early development, before a detectable behavioral readout, yet the cellular elements controlling the abnormal maturation are still unknown. Here, we address this open question by combining in vivo electrophysiology, optogenetics, neuroanatomy, and behavioral assays during development in mice mimicking the dual genetic-environmental etiology of psychiatric disorders. We report that pyramidal neurons in superficial layers of the prefrontal cortex are key elements causing disorganized oscillatory entrainment of local circuits in beta-gamma frequencies. Their abnormal firing rate and timing relate to sparser dendritic arborization and lower spine density. Administration of minocycline during the first postnatal week, potentially acting via microglial cells, rescues the neuronal deficits and restores pre-juvenile cognitive abilities. Elucidation of the cellular substrate of developmental miswiring causing later cognitive deficits opens new perspectives for identification of neurobiological targets amenable to therapies.
THU-313-Differences between non-alcoholic steatohepatitis patient characterisation and management approaches: A multinational real-world study
Authors: Quentin Anstee, Kate Hallsworth, Niall Lynch, Adrien Hauvespre, Eid Mansour, John-Paul Marino, Juliana Bottomley, Claudia Knight, Nathan Williams, James Piercy, Victoria Higgins
Journal: Journal of Hepatology (2019)
Effects of obesity and smoking on survival in non-small cell lung cancer.
Authors: Damien Mikael Hansra, Tulay Koru-Sengul, Wei Zhao, Feng Miao, Stacey Tannenbaum, Alicia P Monedero, David J Lee, Margaret M Byrne, Judith Hurley
Journal: Journal of Clinical Oncology (2013)

1586 Background: Tobacco is the leading cause of preventable death in the US and is linked to many cancers most notably lung cancer. It is established that smoking not only causes lung cancer but is also associated with decreased survival. Obesity is an emerging leading cause of morbidity and mortality in the US and the relationship between obesity, tobacco, and survival in NSCLC is unclear. Methods: Data (n= 87,631) were obtained from linkage of the 1996-2007 Florida Cancer Data System, a population-based cancer registry, to the Agency for Health Care Administration database providing procedure and diagnoses codes. Survival time was calculated from date of diagnosis to date of death. Smoking status was categorized as never, current, and former. Obesity (yes/no) was determined by body mass index greater than 30. Cox proportional regression models were used to predict survival; demographic, clinical, treatment factors, and comorbidities were included in adjusted models with smoking status and obesity as the main factors. Results: The majority of patients were either former (49%) or current (40%) smokers, and non-obese (93%). There were significant differences between survival curves and median survival (months) for obese vs. non-obese patients (19.9 vs.9.8; P&lt;.001). Former and current smokers had shorter median survival than never smokers (10.8 &amp; 9.2 vs. 11.9; P&lt;.001). Survival rates (%) at 1-yr (60.0 vs. 44.8; P&lt;.001), 3-yr (38.4 vs. 22.1; P&lt;.001) and 5-yr (30.2 vs. 15.0; P&lt;.001) were better for obese vs. non-obese patients. Independent predictor of worse survival in the unadjusted model was former (HR 1.08; P&lt;.001) and current (HR 1.20; P&lt;.001) smokers compared to never. Obese patients had better survival vs. non-obese patients (HR 0.64; P&lt;.001). In the adjusted model, controlling for extensive variables and comorbidities, former (HR 1.14; P&lt;.001) and current (HR 1.22; P&lt;.001) smokers still had significantly worse survival vs. never smokers. Obese patients still had better survival (HR 0.84; P&lt;.001) vs. non-obese patients. Conclusions: Our results show that being a former or current smoker worsens survival while obesity improved survival regardless of smoking status when compared with non obese patients.
PS-168-Novel real time prediction of liver graft function during hypothermic oxygenated machine perfusion prior to liver transplantation
Authors: Philipp Dutkowski, Xavier Muller, Andrea Schlegel, Philipp Kron, Dilmurodjon Eshmuminov, Michael Würdinger, David Meierhofer, Pierre-Alain Clavien
Journal: Journal of Hepatology (2019)
Global Longitudinal Strain by CMR Feature Tracking Is Associated With Outcome in HFPEF
Authors: Andreas A. Kammerlander, Jakob A. Kraiger, Christian Nitsche, Carolina Donà, Franz Duca, Caroline Zotter-Tufaro, Christina Binder, Stefan Aschauer, Christian Loewe, Christian Hengstenberg, Diana Bonderman, Julia Mascherbauer
Journal: JACC. Cardiovascular imaging (2019)