tbuckley/cabot-search huggingface dataset:
Adjuvant therapy for margin positive pancreatic cancer.
Authors: Caitlin Takahashi, Ravi Shridhar, Cynthia L. Harris, Justin Lee, Anjan Jayantilal Patel, Richard H. Brown, Jamie Huston, Stephen Kucera, Ken Lee Meredith
Journal: Journal of Clinical Oncology (2018)

390 Background: Pancreatic cancer continues to have a dismal prognosis despite improvements in surgical care. Approximately 26% of patients are deemed resectable, and at the time of operation, 28% will have R1 resections. Adjuvant chemotherapy (AC) or chemoradiation (CRT) is recommended, however the magnitude of benefit is unclear. We sought to examine the impact these therapies on R1 resected pancreatic cancer. Methods: Utilizing the National Cancer Database we identified patients who underwent pancreatic resection for adenocarcinoma. Patients were stratified by resection status and adjuvant therapy. Baseline comparisons of patient characteristics were made using Mann-Whitney U, Kruskal Wallis and Pearson’s Chi-square test as appropriate. Survival analyses were performed using the Kaplan-Meier method. Multivariable cox proportional models(MVA) were developed to identify predictors of survival. All statistical tests were two-sided and α &lt;0.05 was considered significant. Results: We identified 28,440 patients: 22,005 (77.4%) underwent R0 resections and 6,435 (22.4%) underwent R1 resections with a median age of 67.5 years (18-90) and median tumor size of 3.1 cm (2.4-4.2). Patients with tumor size &gt;2cm were more likely to undergo R1 resections, p&lt;0.001. Within the R1 resection group, AC was administered in 1,802 (19.4%), CRT 2,153 (28.5%), and no adjuvant therapy (NA) 2,480 (21.4%). Adjuvant therapy improved survival in all patients with median and 5-year survival of: AC (21.7 months, 17.45%), CRT (23.3 months, 20.9%) vs NA (19.5 months, 19.1%), p&lt;0.001. In the R1 resection cohort survival was also improved with adjuvant therapy with CRT demonstrating the most significant improvement: AC (15.9 months, 6.5%), CRT (18.7 months. 11.2%) vs NA (12.5 months, 8.7%), p&lt;0.001. Additionally CRT but not AC improved survival in the R1 node negative, p&lt;0.004, and node positive, p&lt;0.001. AC benefited survival in R1 node positive patients, p&lt;0.001. MVA revealed age, tumor grade, tumor size &gt;2cm, T-stage, N-stage, AC, and CRT were predictive of survival. Conclusions: Patients with pancreatic cancer who undergo R1 resection have significant improvement in survival when treated with adjuvant CRT and AC. However, benefits were greater in those receiving adjuvant CRT.
CDK9 Inhibitor FIT-039 Suppresses Viral Oncogenes E6 and E7 and Has a Therapeutic Effect on HPV-Induced Neoplasia
Authors: Masahiko Ajiro, Hiroyuki Sakai, Hiroshi Onogi, Makoto Yamamoto, Eriko Sumi, Teruo Sawada, Takashi Nomura, Kenji Kabashima, Takamitsu Hosoya, Masatoshi Hagiwara
Journal: Clinical Cancer Research (2018)

Purpose: Cervical cancer is one of the leading causes of cancer-related deaths among women worldwide. The purpose of this study is to assess the therapeutic effect of the newly developed cyclin-dependent kinase 9 (CDK9) inhibitor FIT-039 on cervical neoplasia induced by human papillomavirus (HPV) infection.Experimental Design: We examined FIT-039 for its effect on HPV gene expression in HPV+ cervical cancer cells. Primary keratinocytes monolayer and organotypic raft culture models were used to evaluate HPV viral replication and cervical intraepithelial neoplasia (CIN) phenotypes. Preclinical pharmacokinetics and toxicity tests for FIT-039 were also conducted. Finally, the anti-HPV effect of FIT-039 was further examined in vivo, using HPV+ cervical cancer xenografts.Results: FIT-039 inhibits HPV replication and expression of E6 and E7 viral oncogenes, restoring tumor suppressors p53 and pRb in HPV+ cervical cancer cells. The therapeutic effect of FIT-039 was demonstrated in CIN model of an organotypic raft culture, where FIT-039 suppressed HPV18-induced dysplasia/hyperproliferation with reduction in viral load. FIT-039 also repressed growth of HPV16+, but not HPV- cervical cancer xenografts without any significant adverse effects. Safety and pharmacokinetics of FIT-039 were confirmed for systemic and topical routes.Conclusions: The CDK9 inhibitor FIT-039 showed potent anti-HPV activity without significant toxicity in preclinical studies. Thus, FIT-039 is expected to be a novel therapeutic for CIN to prevent cervical cancer. Clin Cancer Res; 24(18); 4518-28. ©2018 AACR.
FXR agonist obeticholic acid increases gallbladder FGF19 in gallstone patients
Authors: S. Al-Dury, A. Wahlström, P. Katrin, T. Anders, M. Ståhlman, L. Olsson, M. Trauner, P. Fickert, D. Moore, F. Backhed, L. Fändriks, M. Wagner, H.-U. Marschall
Journal: Journal of Hepatology (2018)
Long noncoding RNA H19 interacts with polypyrimidine tract‐binding protein 1 to reprogram hepatic lipid homeostasis
Authors: Chune Liu, Zhihong Yang, Jianguo Wu, Li Zhang, Sangmin Lee, Dong‐Ju Shin, Melanie Tran, Li Wang
Journal: Hepatology (2017)

H19 is an imprinted long noncoding RNA abundantly expressed in embryonic liver and repressed after birth. We show that H19 serves as a lipid sensor by synergizing with the RNA‐binding polypyrimidine tract‐binding protein 1 (PTBP1) to modulate hepatic metabolic homeostasis. H19 RNA interacts with PTBP1 to facilitate its association with sterol regulatory element‐binding protein 1c mRNA and protein, leading to increased stability and nuclear transcriptional activity. H19 and PTBP1 are up‐regulated by fatty acids in hepatocytes and in diet‐induced fatty liver, which further augments lipid accumulation. Ectopic expression of H19 induces steatosis and pushes the liver into a “pseudo‐fed” state in response to fasting by promoting sterol regulatory element‐binding protein 1c protein cleavage and nuclear translocation. Deletion of H19 or knockdown of PTBP1 abolishes high‐fat and high‐sucrose diet–induced steatosis. Conclusion : Our study unveils an H19/PTBP1/sterol regulatory element‐binding protein 1 feedforward amplifying signaling pathway to exacerbate the development of fatty liver. (H epatology 2018;67:1768‐1783)
Addressing Incomplete Psychiatric Histories in Adult ADHD: Response to Agnew-Blais and Arseneault
Authors: Margaret H. Sibley, L. Eugene Arnold, James M. Swanson, Traci M. Kennedy, Brooke S.G. Molina, Lily T. Hechtman, Arunima Roy, John T. Mitchell
Journal: American Journal of Psychiatry (2018)
Publisher Correction: The sea lamprey germline genome provides insights into programmed genome rearrangement and vertebrate evolution
Authors: Jeramiah J. Smith, Nataliya Timoshevskaya, Chengxi Ye, Carson Holt, Melissa C. Keinath, Hugo J. Parker, Malcolm E. Cook, Jon E. Hess, Shawn R. Narum, Francesco Lamanna, Henrik Kaessmann, Vladimir A. Timoshevskiy, Courtney K. M. Waterbury, Cody Saraceno, Leanne M. Wiedemann, Sofia M. C. Robb, Carl Baker, Evan E. Eichler, Dorit Hockman, Tatjana Sauka-Spengler, Mark Yandell, Robb Krumlauf, Greg Elgar, Chris T. Amemiya
Journal: Nature Genetics (2018)
Regular aspirin use is not protective against advanced fibrosis in type-2 diabetics with biopsy-proven nonalcoholic fatty liver disease
Authors: A. Singh, F. Gosai, R. Lopez, A. Vigni, A. Tabbaa, E. Lawitz, F. Poordad, A. Scott, T. Okubote, M. Scott, M. Mansouri, N. Alkhouri
Journal: Journal of Hepatology (2018)
Impact of proprotein convertase subtilisin/kexin type 7 genetic variation in patients with non-alcoholic fatty liver disease
Authors: P. Dongiovanni, M. Meroni, A. Cespiati, G.A. Baselli, R. Rametta, S. Pelusi, V. Borroni, A.L. Fracanzani, S. Badiali, J. Pihlajamaki, S. Romeo, S. Petta, A. Craxi, V. Nobili, S. Fargion, L. Valenti
Journal: Journal of Hepatology (2018)
Clinical, dermoscopic, histological and molecular analysis of BAP1-inactivated melanocytic naevus/tumour in two familial cases of BAP1 syndrome
Authors: S. Moawad, M. Reigneau, A. de la Fouchardière, N. Soufir, J.-L. Schmutz, F. Granel-Brocard, A. Phan, A.-C. Bursztejn
Journal: British Journal of Dermatology (2018)
Combination treatment of a TLR7 agonist RO7020531and a capsid assembly modulator RO7049389 achieved sustainable viral loadsuppression and HBsAg loss in an AAV-HBV mouse model
Authors: L. Dai, Y. Yu, L. Gu, J. Zhao, L. Zhu, H. Yun, Y. Ji, W. Zhu, J. Young, L. Gao
Journal: Journal of Hepatology (2018)
Exposure to the gut microbiota drives distinct methylome and transcriptome changes in intestinal epithelial cells during postnatal development
Authors: Wei-Hung Pan, Felix Sommer, Maren Falk-Paulsen, Thomas Ulas, Philipp Best, Antonella Fazio, Priyadarshini Kachroo, Anne Luzius, Marlene Jentzsch, Ateequr Rehman, Fabian Müller, Thomas Lengauer, Jörn Walter, Sven Künzel, John F. Baines, Stefan Schreiber, Andre Franke, Joachim L. Schultze, Fredrik Bäckhed, Philip Rosenstiel
Journal: Genome Medicine (2018)

Abstract Background The interplay of epigenetic processes and the intestinal microbiota may play an important role in intestinal development and homeostasis. Previous studies have established that the microbiota regulates a large proportion of the intestinal epithelial transcriptome in the adult host, but microbial effects on DNA methylation and gene expression during early postnatal development are still poorly understood. Here, we sought to investigate the microbial effects on DNA methylation and the transcriptome of intestinal epithelial cells (IECs) during postnatal development. Methods We collected IECs from the small intestine of each of five 1-, 4- and 12 to 16-week-old mice representing the infant, juvenile, and adult states, raised either in the presence or absence of a microbiota. The DNA methylation profile was determined using reduced representation bisulfite sequencing (RRBS) and the epithelial transcriptome by RNA sequencing using paired samples from each individual mouse to analyze the link between microbiota, gene expression, and DNA methylation. Results We found that microbiota-dependent and -independent processes act together to shape the postnatal development of the transcriptome and DNA methylation signatures of IECs. The bacterial effect on the transcriptome increased over time, whereas most microbiota-dependent DNA methylation differences were detected already early after birth. Microbiota-responsive transcripts could be attributed to stage-specific cellular programs during postnatal development and regulated gene sets involved primarily immune pathways and metabolic processes. Integrated analysis of the methylome and transcriptome data identified 126 genomic loci at which coupled differential DNA methylation and RNA transcription were associated with the presence of intestinal microbiota. We validated a subset of differentially expressed and methylated genes in an independent mouse cohort, indicating the existence of microbiota-dependent “functional” methylation sites which may impact on long-term gene expression signatures in IECs. Conclusions Our study represents the first genome-wide analysis of microbiota-mediated effects on maturation of DNA methylation signatures and the transcriptional program of IECs after birth. It indicates that the gut microbiota dynamically modulates large portions of the epithelial transcriptome during postnatal development, but targets only a subset of microbially responsive genes through their DNA methylation status.
No Association Between Consumption of Sweetened Beverages and Risk of Later-Onset Crohn’s Disease or Ulcerative Colitis
Authors: Hamed Khalili, Niclas Hakansson, Simon S. Chan, Jonas F. Ludvigsson, Ola Olen, Andrew T. Chan, Andrew R. Hart, Alicja Wolk
Journal: Clinical Gastroenterology and Hepatology (2018)
Circumstances of child deaths in Mali and Uganda: a community-based confidential enquiry
Authors: Merlin L Willcox, Elias Kumbakumba, Drissa Diallo, Vincent Mubangizi, Peter Kirabira, Florence Nakaggwa, Birungi Mutahunga, Chiaka Diakité, Eugene Dembélé, Mamadou Traoré, Pierre Daou, Drissa Bamba, Amadou Traoré, Diafara Berthé, Nick Wooding, Kieran Dinwoodie, Sarah Capewell, Hamish Foster, Rowena Neville, Joseph Ngonzi, Jerome Kabakyenga, David Mant, Anthony Harnden
Journal: The Lancet Global Health (2018)

BackgroundInterventions to reduce child deaths in Africa have often underachieved, causing the Millennium Development Goal targets to be missed. We assessed whether a community enquiry into the circumstances of death could improve intervention effectiveness by identifying local avoidable factors and explaining implementation failures.MethodsDeaths of children younger than 5 years were ascertained by community informants in two districts in Mali (762 deaths) and three districts in Uganda (442 deaths) in 2011–15. Deaths were investigated by interviewing parents and health workers. Investigation findings were reviewed by a panel of local health-care workers and community representatives, who formulated recommendations to address avoidable factors and, subsequently, oversaw their implementation.FindingsAt least one avoidable factor was identified in 97% (95% CI 96–98, 737 of 756) of deaths in children younger than 5 years in Mali and 95% (93–97, 389 of 409) in Uganda. Suboptimal newborn care was a factor in 76% (146 of 194) of neonatal deaths in Mali and 64% (134 of 194) in Uganda. The most frequent avoidable factor in postneonatal deaths was inadequate child protection (mainly child neglect) in Uganda (29%, 63 of 215) and malnutrition in Mali (22%, 124 of 562). 84% (618 of 736 in Mali, 328 of 391 in Uganda) of families had consulted a health-care provider for the fatal illness, but the quality of care was often inadequate. Even in official primary care clinics, danger signs were often missed (43% of cases in Mali [135 of 396], 39% in Uganda [30 of 78]), essential treatment was not given (39% in Mali [154 of 396], 35% in Uganda [27 of 78]), and patients who were seriously ill were not referred to a hospital in time (51% in Mali [202 of 396], 45% in Uganda [35 of 78]). Local recommendations focused on quality of care in health-care facilities and on community issues influencing treatment-seeking behaviour.InterpretationLocal investigation and review of circumstances of death of children in sub-Saharan Africa is likely to lead to more effective interventions than simple consideration of the biomedical causes of death. This approach discerned local public health priorities and implementable solutions to address the avoidable factors identified.FundingEuropean Union's 7th Framework Programme for research and technological development.
P491Therapeutic effect of carvedilol on cardiac function in streptozotocin-diabetic rats
Authors: B Guven, Z Kara, A Onay-Besikci
Journal: Cardiovascular Research (2018)

Conclusion: GA activates caspase-8 to cleave N-term of IjBa, leading to decrease of NF-jB activity and hypertrophy, consequently induces autophgy, thereby providing the molecular basis by which
A Guide to Emerging Technologies for Large-Scale and Whole-Brain Optical Imaging of Neuronal Activity
Authors: Siegfried Weisenburger, Alipasha Vaziri
Journal: Annual Review of Neuroscience (2018)

The mammalian brain is a densely interconnected network that consists of millions to billions of neurons. Decoding how information is represented and processed by this neural circuitry requires the ability to capture and manipulate the dynamics of large populations at high speed and resolution over a large area of the brain. While there has been a rapid increase in use of optical approaches in the neuroscience community over the last two decades, most microscopy approaches lack the ability to record the activity of all neurons comprising a functional network across the mammalian brain at relevant temporal and spatial resolution. In this review, we survey the recent development in the optical calcium imaging technologies in this regard and provide an overview of the strengths and limitations of each modality and their potential for scalability. We provide a guidance from a biological user perspective that is driven by the typical biological applications and sample conditions. We also discuss the potential for future advances and synergies that could be obtained through hybrid approaches or other modalities.
Somatic mutation landscape of a meningioma and its pulmonary metastasis
Authors: Yaran Du, Ting Lu, Song Huang, Fangfang Ren, Gang Cui, Jian Chen
Journal: Cancer Communications (2018)

Extracranial metastasis (ENM) of meningiomas is extremely rare, and typically occurs several years after a primary tumor is diagnosed. However, the genetic changes underlying ENM events have not yet been investigated.A 58-year-old male patient was sent to the emergency room of our hospital because of a sudden fall. Magnetic resonance imaging detected a mass at the right frontal sagittal sinus. He underwent tumor resection and recovered well, but post-operative computed tomography revealed three lumps on the right side of his chest. Thoracic surgery was performed to remove two of the lumps. Pathological findings revealed that the brain and lung tumors were grade I meningiomas. The patient received no additional radiation or chemotherapy post-surgery, and there was no sign of tumor recurrence in the brain or progression of the remaining lump in the chest 1 year after surgery. We performed whole exome sequencing of the patient's blood, primary brain tumor, and lung metastatic tumor tissues to identify somatic genetic alterations that had occurred during ENM. This revealed that a frameshift deletion of the neurofibromin 2 gene likely drove formation of the meningioma. Surprisingly, we found that the brain tumor was relatively homogeneous and contained only one dominant clone; both the pulmonary metastasis and the original brain tumor were derived from the same clone, and no obvious additional driver mutations were detected in the metastatic tumor.Although ENM of meningiomas is very rare, brain tumor cells appear to be more adaptable to tissue microenvironments outside of the central nervous system than was commonly thought.
Targeting the NAFLD metabolome and the shaping of precision medicine for patients with NASH
Authors: M. Iruarrizaga-Lejarreta, I. Martínez-Arranz, M.C. Morrison, M. Varela-Rey, D.F. Ramos, L. Delacruz-Villar, M. Noureddin, M.L. Martínez-Chantar, R. Kleemann, C. Alonso, S.C. Lu, J.M. Mato
Journal: Journal of Hepatology (2018)
Rapid virological response, as a predictor of sustained virological response of Sofosbuvir and Ribavirin in Korean patients with genotype 2 chronic hepatitis C virus infection
Authors: H.Y. Woo, J. Heo, S.Y. Han, Y.J. Park, D.H. Baek, D.U. Kim, G.H. Kim, G.A. Song
Journal: Journal of Hepatology (2018)
Anti–Tumor Necrosis Factor Therapy and Incidence of Parkinson Disease Among Patients With Inflammatory Bowel Disease
Authors: Inga Peter, Marla Dubinsky, Susan Bressman, Andrew Park, Changyue Lu, Naijun Chen, Anthony Wang
Journal: JAMA Neurology (2018)

<h3>Importance</h3> Despite established genetic and pathophysiologic links between inflammatory bowel disease (IBD) and Parkinson disease (PD), clinical data supporting this association remain scarce. Although systemic inflammation is considered a potential biological mechanism shared between the 2 diseases, the role of reduced systemic inflammation through IBD-directed anti–tumor necrosis factor (anti-TNF) therapy in PD risk is largely unknown. <h3>Objective</h3> To compare the incidence of PD among individuals with or without IBD and to assess whether PD risk among patients with IBD is altered by anti-TNF therapy. <h3>Design, Setting, and Participants</h3> This is a retrospective cohort study analyzing information in the Truven Health MarketScan administrative claims database and the Medicare Supplemental Database between January 1, 2000, and March 31, 2016. Individuals were selected who had at least 2 claims for IBD diagnoses, at least 6 months of follow-up, and no prior diagnosis of PD on or before the IBD index date. Exposure to Anti-TNF therapy was measured from the anti-TNF index date to the last date of anti-TNF coverage or the end of enrollment or PD index date, whichever was earliest. Incidence rates per 1000 person-years were calculated, and crude and adjusted incidence rate ratios were estimated by Poisson regression models and presented with 95% CIs. <h3>Main Outcomes and Measures</h3> Incidence of PD among patients with IBD with or without exposure to anti-TNF therapy. <h3>Results</h3> In total, 144 018 individuals with IBD were matched on age, sex, and year of index date with 720 090 unaffected controls. Of them, 1796 individuals had at least 2 PD diagnoses and at least 1 filled PD-related prescription. The mean (SD) age of individuals with IBD was 51 (17) years, and 44% were men. The incidence of PD among patients with IBD was 28% higher than that among unaffected matched controls (adjusted incidence rate ratio, 1.28; 95% CI, 1.14-1.44;<i>P</i> &lt; .001). A 78% reduction in the incidence rate of PD was detected among patients with IBD who were exposed to anti-TNF therapy compared with those who were not exposed (adjusted incidence rate ratio, 0.22; 95% CI, 0.05-0.88;<i>P</i> = .03). <h3>Conclusions and Relevance</h3> A higher incidence of PD was observed among patients with IBD than among individuals without IBD. Early exposure to antiinflammatory anti-TNF therapy was associated with substantially reduced PD incidence. These findings support a role of systemic inflammation in the pathogenesis of both diseases. Further studies are required to determine whether anti-TNF treatment administered to high-risk individuals may mitigate PD risk.
P178DNA methylation in bicuspid aortic valve aortopathy: potential contribution of oscillatory flow to an epithelial-to-mesenchymal transition signature
Authors: H Bjorck, L Du, S Pulignani, V Paloschi, K Lundstromer, A Kostina, A Evangelista, S Maleki, A Franco-Cereceda, P Eriksson
Journal: Cardiovascular Research (2018)
STING signalling protects against chronic pancreatitis by modulating Th17 response
Authors: Qinglan Zhao, Murli Manohar, Yi Wei, Stephen J Pandol, Aida Habtezion
Journal: Gut (2019)

Chronic pancreatitis (CP) is an inflammatory disease with progressive fibrosis leading to exocrine and endocrine dysfunction. Currently, there are no approved effective therapies for CP. Stimulator of interferon genes (STING) signalling is a key innate immune sensor of DNA. In this study, we evaluated the role of STING signalling in CP.
Switching immunoglobulin base therapy to nucleoside/nucleotide analogues monotherapy is safe and effective as preventive therapy of reccurent HBV in liver transplanted patients- single centre experience
Authors: O. Sneh, M. Cohen-Naftaly, Y. Harif, A. Issachar, E. Mor, R. Tur-Kaspa, M. Brown
Journal: Journal of Hepatology (2018)