tbuckley/cabot-search huggingface dataset:
Mapping genetic vulnerabilities reveals BTK as a novel therapeutic target in oesophageal cancer
Authors: Irene Yushing Chong, Lauren Aronson, Hanna Bryant, Aditi Gulati, James Campbell, Richard Elliott, Stephen Pettitt, Paul Wilkerson, Maryou B Lambros, Jorge S Reis-Filho, Anisha Ramessur, Michael Davidson, Ian Chau, David Cunningham, Alan Ashworth, Christopher J Lord
Journal: Gut (2017)

Objective Oesophageal cancer is the seventh most common cause of cancer-related death worldwide. Disease relapse is frequent and treatment options are limited. Design To identify new biomarker-defined therapeutic approaches for patients with oesophageal cancer, we integrated the genomic profiles of 17 oesophageal tumour-derived cell lines with drug sensitivity data from small molecule inhibitor profiling, identifying drug sensitivity effects associated with cancer driver gene alterations. We also interrogated recently described RNA interference screen data for these tumour cell lines to identify candidate genetic dependencies or vulnerabilities that could be exploited as therapeutic targets. Results By integrating the genomic features of oesophageal tumour cell lines with siRNA and drug screening data, we identified a series of candidate targets in oesophageal cancer, including a sensitivity to inhibition of the kinase BTK in MYC amplified oesophageal tumour cell lines. We found that this genetic dependency could be elicited with the clinical BTK/ERBB2 kinase inhibitor, ibrutinib. In both MYC and ERBB2 amplified tumour cells, ibrutinib downregulated ERK-mediated signal transduction, cMYC Ser-62 phosphorylation and levels of MYC protein, and elicited G 1 cell cycle arrest and apoptosis, suggesting that this drug could be used to treat biomarker-selected groups of patients with oesophageal cancer. Conclusions BTK represents a novel candidate therapeutic target in oesophageal cancer that can be targeted with ibrutinib. On the basis of this work, a proof-of-concept phase II clinical trial evaluating the efficacy of ibrutinib in patients with MYC and/or ERBB2 amplified advanced oesophageal cancer is currently underway ( NCT02884453 ). Trial registration number NCT02884453; Pre-results
Comprehensive profiling of small RNAs in cervical cancer
Authors: Weng-Onn Lui, Andrew Fire
Journal: Clinical Cancer Research (2007)

C59  Cervical cancer, the second most common cancer amongst women worldwide, is frequently associated with specific human papillomavirus (HPV) infections. Despite this association, only a small proportion of HPV-infected women develop cervical cancer. These clinical and epidemiological observations have led to a search for genetic and/or epigenetic processes (in the virus and/or host) that interact with HPV infection in tumor development.  	We have previously identified a set of microRNAs (miRNAs) with differential expression in cervical cancer cells and a number of other small RNAs which so far appear specific to cervical cancer cells. To further evaluate the significance of these findings, we are determining and comparing small RNA expression profiles in an extensive set of matched cervical cancer and normal cervical samples using ultra high throughput sequencing technology and other approaches. We anticipate that the comprehensive small RNA profiles and functional assays for their significance will provide (1) insight into the roles of miRNAs in cervical cancer development, and (2) critical tests for the potential value of miRNA profiles as contributory diagnostic/prognostic markers for this tumor type.
Improved Outcomes in HCV Patients Following Liver Transplantation During the Era of Direct-Acting Antiviral Agents
Authors: George Cholankeril, Andrew A. Li, Katherine L. March, Eric R. Yoo, Donghee Kim, Heather Snyder, Stevan A. Gonzalez, Zobair M. Younossi, Aijaz Ahmed
Journal: Clinical Gastroenterology and Hepatology (2017)
Clinical implications of neoepitope landscapes for adult and pediatric cancers
Authors: Yang-Yang Feng, Obi L. Griffith, Malachi Griffith
Journal: Genome Medicine (2017)

Many immunotherapies rely on the presence of neoepitopes derived from somatic mutations that lead to altered peptide sequences. Several studies have now analyzed the neoepitope landscape of different cancer subtypes, predominantly for adult samples, which tend to feature significantly higher mutational burden. However, a new report publishing the first comprehensive analysis of the pediatric neoepitope landscape suggests that immunotherapies could also hold promise for pediatric cancers. See related research article 10.1186/s13073-017-0468-3
Can Secure Patient-Provider Messaging Improve Diabetes Care?
Authors: Sukyung Chung, Laura Panattoni, Jeffrey Chi, Latha Palaniappan
Journal: Diabetes Care (2017)

OBJECTIVE Internet-based secure messaging between patients and providers through a patient portal is now common in the practice of modern medicine. There is limited evidence on how messaging is associated with use and clinical quality measures among patients with type 2 diabetes. We examine whether messaging with physicians for medical advice is associated with fewer face-to-face visits and better diabetes management. RESEARCH DESIGN AND METHODS Patients with diabetes who were enrolled in an online portal of an outpatient health care organization in 2011–2014 were studied (N = 37,762 patient-years). Messages from/to primary care physicians or diabetes-related specialists for medical advice were considered. We estimated the association of messaging with diabetes quality measures, adjusting for patient and provider characteristics and patient-level clustering. RESULTS Most patients (72%) used messaging, and those who made frequent visits were also more likely to message. Given visit frequency, no (vs. any) messaging was negatively associated with the likelihood of meeting an HbA1c target of &amp;lt;8% (64 mmol/mol) (odds ratio [OR] 0.83 [95% CI 0.77, 0.90]). Among message users, additional messages (vs. 1) were associated with better outcome (two more messages: OR 1.17 [95% CI 1.06, 1.28]; three more messages: 1.38 [1.25, 1.53]; four more messages: 1.55 [1.43, 1.69]). The relationship was stronger for noninsulin users. Message frequency was also positively associated, but to a smaller extent, with process measures (e.g., eye examination). Physician-initiated messages had effects similar to those for patient-initiated messages. CONCLUSIONS Patients with diabetes frequently used secure messaging for medical advice in addition to routine visits to care providers. Messaging was positively associated with better diabetes management in a large community outpatient practice.
加齢脳のための栄養:最適飼料の証拠に向けて【Powered by NICT】
Authors: Vauzour David, Camprubi-Robles Maria, Miquel-Kergoat Sophie, Andres-Lacueva Cristina, Banati Diana, Barberger-Gateau Pascale, L Bowman Gene, Caberlotto Laura, Clarke Robert, Hogervorst Eef, J Kiliaan Amanda, Lucca Ugo, Manach Claudine, Minihane Anne-Marie, Mitchell Ellen Siobhan, Perneczky Robert, Perry Hugh, Roussel Anne-Marie, Schuermans Jeroen, Sijben John, P E Spencer Jeremy, Thuret Sandrine, van de Rest Ondine, Vandewoude Maurits, Wesnes Keith, J Williams Robert, S B Williams Robin, Ramirez Maria
Journal: Ageing Research Reviews (2017)
PTH-122 Is there a role for intra-sphincteric botulinum toxin injection in the management of type iii sphincter of oddi dysfunction?
Authors: S Menon, R Mathew
Journal: Gut (2017)

Introduction  The management of Type III sphincter of oddi dysfunction or functional biliary pain syndrome remains challenging and the EPISOD study established that there is no role for biliary or pancreatic endoscopic sphincterotomy in the management of this condition. Intra-sphincteric botulinum toxin injection has been reported to be effective in alleviating symptoms.  Aim  To examine the utility of intra-sphincteric botulinum toxin injection in the management of Type III sphincter of oddi dysfunction.  Method  A prospective observational study was conducted in patients with Type III sphincter of oddi dysfunction, as defined by typical pancreatobiliary pain in a post-cholecystectomy setting. The diagnosis of Type III sphincter of oddi dysfunction was established using the modified Milwaukee criteria. All patients additionally underwent cross-sectional imaging (CT/MRI), EUS and had a positive morphine-TBIDA scan (reproduction of symptoms on intravenous Morphine injection and delayed excretion of dye from the bile duct). 100 units of botulinum toxin was injected into the ampullary sphincter, identified sonographically at EUS or endoscopically A numeric pain rating scale (NPS) (0–10, linear scale) was used to determine response to treatment. Symptoms were assessed prospectively in an outpatient setting.  Results  Over a period of 3 years, 45 patients (43 females, mean age 44 (23-73) years) underwent intra-sphincteric botulinum toxin injection using an echoendoscope (EUS) or a duodenoscope (66 procedures, mean 1.4 procedures per patient (range 1–6).. There were no procedure-related complications.  On follow up (mean 10 (range 1–45) months, pancreatobiliary pain scores reduced from a mean value of 7 to 3 (t=16.7, df 64, p  Conclusion  Intra-sphincteric botulinum toxin injection seems to be a useful adjunct in the management of Type III sphincter of oddi dysfunction.  Disclosure of Interest  None Declared
Vascular Burden Impact on Echocardiographic Valvular Graft Degeneration Following a Ross Procedure in Young Adults
Authors: Louis Simard, Jean Perron, Mylène Shen, Lionel Tastet, Siamak Mohammadi, Marine Clisson, Anthony Poulin, Marie-Annick Clavel
Journal: Journal of the American College of Cardiology (2017)
Ahead of their time
Authors: Sophie Cook
Journal: BMJ (2017)

The arrival of a newborn is usually a time of excitement and happiness, accompanied by a healthy degree of trepidation about what lies ahead. But for parents or carers of preterm babies feelings of fear and anxiety may predominate.

In England and Wales around one in 13 babies is born preterm and one in 250 extremely preterm (before 28 weeks). In 2015 this amounted to 53 209 preterm and 3014 extremely preterm babies (Office for National Statistics http://bit.ly/2vFagTL). Neonatal …
Phase II study of cabozantinib in patients with progressive glioblastoma: subset analysis of patients naive to antiangiogenic therapy
Authors: Patrick Y Wen, Jan Drappatz, John de Groot, Michael D Prados, David A Reardon, David Schiff, Marc Chamberlain, Tom Mikkelsen, Annick Desjardins, Jaymes Holland, Jerry Ping, Ron Weitzman, Timothy F Cloughesy
Journal: Neuro-Oncology (2017)

Cabozantinib is a tyrosine kinase inhibitor with activity against vascular endothelial growth factor receptor 2 (VEGFR2) and MET that has demonstrated clinical activity in advanced solid tumors. This open-label, phase II trial evaluated cabozantinib in patients with recurrent or refractory glioblastoma (GBM). Patients were initially enrolled at a starting dose of 140 mg/day, but the starting dose was amended to 100 mg/day because of toxicity. Treatment continued until disease progression or unacceptable toxicity. The primary endpoint was objective response rate assessed by an independent radiology facility using modified Response Assessment in Neuro-Oncology criteria. Additional endpoints included duration of response, 6-month and median progression-free survival, overall survival, and safety. Among 152 patients naive to prior antiangiogenic therapy, the objective response rate was 17.6% and 14.5% in the 140 mg/day and 100 mg/day groups, respectively, which did not meet the predefined statistical target for success. The proportions of patients alive and progression free at 6 months were 22.3% and 27.8%, respectively. Median progression-free survival was 3.7 months in both groups, and median overall survival was 7.7 months and 10.4 months, respectively. The incidence of grade 3/4 adverse events (AEs) was 79.4% and 84.7% in the 140 mg/day and 100 mg/day groups, respectively, and dose reductions due to AEs were experienced by 61.8% and 72.0%, respectively. Common grade 3/4 AEs included fatigue, diarrhea, and palmar-plantar erythrodysesthesia syndrome. Cabozantinib showed evidence of clinical activity in patients with recurrent GBM naive to antiangiogenic therapy, although the predefined statistical target for success was not met. At the starting doses assessed, AEs were frequently managed with dose reductions. NCT00704288 (https://www.clinicaltrials.gov/ct2/show/NCT00704288)
Abstract 15262: Cardiac Nuclear High Mobility Group Box 1 Attenuates Angiotensin 2 Induced Pathological Cardiac Hypertrophy by Inhibiting Cardiomyocyte DNA Damage
Authors: Tetsuya Takahashi, Tetsuro Shishido, Tetsu Watanabe, Takayuki Sugai, Taku Toshima, Miyuki Yokoyama, Daisuke Kinoshita, Satoshi Nishiyama, Hiroki Takahashi, Takanori Arimoto, Takuya Miyamoto, Tsuneo Konta, Isao Kubota
Journal: Circulation (2016)

Background: Oxidative stress leads to the cellular DNA damage. However, the mechanism by which oxidative DNA damage contributes to cardiac remodeling is unclear. High-mobility group box 1 (HMGB1) i...
Editorial authors’ reply to Barlow
Authors: Ben Barr, David Taylor-Robinson
Journal: BMJ (2016)

We thank Barlow for his comment on our commentary about the systematic review by Parmar and colleagues.1 2 3 Barlow suggests that our studies4 5 6 may have been excluded from Parmar and colleagues’ review on the basis of their risk of bias assessment: this is not the case. As is clear from figure 1 in the paper by Parmar and colleagues, no studies were excluded on the basis of the risk of bias assessment. This, however, highlights the issue we raise in the commentary. Because the exposure of interest—the financial crisis—is poorly defined, the evidence is difficult to synthesise and interpret. In particular, this presents problems in deciding which search terms should …
Management of rivaroxaban- or apixaban-associated major bleeding with prothrombin complex concentrates: a cohort study
Authors: Ammar Majeed, Anna Ågren, Margareta Holmström, Maria Bruzelius, Roza Chaireti, Jacob Odeberg, Eva-Lotta Hempel, Maria Magnusson, Tony Frisk, Sam Schulman
Journal: Blood (2017)
Targeting cellular senescence prevents age-related bone loss in mice
Authors: Joshua N Farr, Ming Xu, Megan M Weivoda, David G Monroe, Daniel G Fraser, Jennifer L Onken, Brittany A Negley, Jad G Sfeir, Mikolaj B Ogrodnik, Christine M Hachfeld, Nathan K LeBrasseur, Matthew T Drake, Robert J Pignolo, Tamar Pirtskhalava, Tamara Tchkonia, Merry Jo Oursler, James L Kirkland, Sundeep Khosla
Journal: Nature Medicine (2017)
Short- and long-term outcomes of early stage non-small cell lung cancer (NSCLC) surgery.
Authors: Michael J. Kelley, David Harpole, Christina D. Williams
Journal: Journal of Clinical Oncology (2017)

8544 Background: The goal of this study was to determine patient factors associated with short- vs long-term survival after surgery for stage I/II NSCLC and assess the distribution of causes of death over time. Methods: Using the VA Central Cancer Registry, we identified patients diagnosed 2001-2005 with stage I/II NSCLC who had surgery and survived 30 days after resection. We used multivariate logistic regression models to determine the impact of patient characteristics on 1 year (1Y), 5 year (5Y), and 10 year (10Y) mortality. We compared causes of death at 1Y versus 5Y after diagnosis. Results: The analysis included 4,693 patients. Among these patients, the 1Y, 5Y, and 10Y overall survival (OS) rates were 87%, 45%, and 22%, respectively. 50% of patients alive at 5 year survived to 10 years. For each survival time period, highest survival rates were among patients who were younger (≤65), had stage I disease, had lobectomy, and had fewer comorbidities (all p &lt; 0.0001). Significant differences in 1Y and 10Y OS were noted for histology, with highest 1Y OS among adenocarcinoma (88%) and squamous cell (87%) and highest 10Y OS among large cell (28%) and adenocarcinoma (25%). Racial differences were only observed in 10Y OS (whites 22%, blacks 26%, p = 0.01). In multivariate analyses, age &gt; 65, stage II disease, surgery other than lobectomy, and ≥3 comorbidities were associated with increased likelihood of 1Y, 5Y, and 10Y mortality. Large cell and other histology were the only additional significant predictors of 1Y mortality [OR: 1.94 (1.33-2.84) and OR:1.36 (1.05-1.77), respectively], and squamous cell histology was a significant predictor of 10Y mortality [OR: 1.19 (1.02-1.40)] relative to adenocarcinoma. Among patients who died within 1 year of diagnosis (n = 616), the primary causes of death were lung cancer (63%), cardiovascular disease (10%), other cancer (8%), respiratory disease (3%), and other causes (15). The contribution of these causes of 5Y mortality (n = 2602) were 60%, 11%, 10%, 4%, and 12%, respectively. Conclusions: Half of patients alive at 5Y after resection of stage I/II NSCLC were alive at 10Y. 10Y survival is associated with younger age, earlier stage, non-squamous histology, lobectomy, and fewer comorbidities, but not race.
設計された細胞外小胞の効率的生産と強化された腫瘍送達【Powered by NICT】
Authors: C Watson Dionysios, Bayik Defne, Srivatsan Avinash, Bergamaschi Cristina, Valentin Antonio, Niu Gang, Bear Jenifer, Monninger Mitchell, Sun Mei, Morales-Kastresana Aizea, C Jones Jennifer, K Felber Barbara, Chen Xiaoyuan, Gursel Ihsan, N Pavlakis George
Journal: Biomaterials (2016)
Macrophage heme oxygenase-1-SIRT1-p53 axis regulates sterile inflammation in liver ischemia-reperfusion injury
Authors: Kojiro Nakamura, Min Zhang, Shoichi Kageyama, Bibo Ke, Takehiro Fujii, Rebecca A. Sosa, Elaine F. Reed, Nakul Datta, Ali Zarrinpar, Ronald W. Busuttil, Jesus A. Araujo, Jerzy W. Kupiec-Weglinski
Journal: Journal of Hepatology (2017)
Mapping and predicting mortality from systemic sclerosis
Authors: Muriel Elhai, Christophe Meune, Marouane Boubaya, Jérôme Avouac, Eric Hachulla, Alexandra Balbir-Gurman, Gabriela Riemekasten, Paolo Airò, Beatriz Joven, Serena Vettori, Franco Cozzi, Susanne Ullman, László Czirják, Mohammed Tikly, Ulf Müller-Ladner, Paola Caramaschi, Oliver Distler, Florenzo Iannone, Lidia P Ananieva, Roger Hesselstrand, Radim Becvar, Armando Gabrielli, Nemanja Damjanov, Maria J Salvador, Valeria Riccieri, Carina Mihai, Gabriella Szücs, Ulrich A Walker, Nicolas Hunzelmann, Duska Martinovic, Vanessa Smith, Carolina de Souza Müller, Carlo Maurizio Montecucco, Daniela Opris, Francesca Ingegnoli, Panayiotis G Vlachoyiannopoulos, Bojana Stamenkovic, Edoardo Rosato, Stefan Heitmann, Jörg H W Distler, Thierry Zenone, Matthias Seidel, Alessandra Vacca, Ellen De Langhe, Srdan Novak, Maurizio Cutolo, Luc Mouthon, Jörg Henes, Carlo Chizzolini, Carlos Alberto von Mühlen, Kamal Solanki, Simona Rednic, Lisa Stamp, Branimir Anic, Vera Ortiz Santamaria, Maria De Santis, Sule Yavuz, Walter Alberto Sifuentes-Giraldo, Emmanuel Chatelus, Jiri Stork, Jacob van Laar, Esthela Loyo, Paloma García de la Peña Lefebvre, Kilian Eyerich, Vanesa Cosentino, Juan Jose Alegre-Sancho, Otylia Kowal-Bielecka, Grégoire Rey, Marco Matucci-Cerinic, Yannick Allanore
Journal: Annals of the Rheumatic Diseases (2017)

Objectives To determine the causes of death and risk factors in systemic sclerosis (SSc). Methods Between 2000 and 2011, we examined the death certificates of all French patients with SSc to determine causes of death. Then we examined causes of death and developed a score associated with all-cause mortality from the international European Scleroderma Trials and Research (EUSTAR) database. Candidate prognostic factors were tested by Cox proportional hazards regression model by single variable analysis, followed by a multiple variable model stratified by centres. The bootstrapping technique was used for internal validation. Results We identified 2719 French certificates of deaths related to SSc, mainly from cardiac (31%) and respiratory (18%) causes, and an increase in SSc-specific mortality over time. Over a median follow-up of 2.3 years, 1072 (9.6%) of 11 193 patients from the EUSTAR sample died, from cardiac disease in 27% and respiratory causes in 17%. By multiple variable analysis, a risk score was developed, which accurately predicted the 3-year mortality, with an area under the curve of 0.82. The 3-year survival of patients in the upper quartile was 53%, in contrast with 98% in the first quartile. Conclusion Combining two complementary and detailed databases enabled the collection of an unprecedented 3700 deaths, revealing the major contribution of the cardiopulmonary system to SSc mortality. We also developed a robust score to risk-stratify these patients and estimate their 3-year survival. With the emergence of new therapies, these important observations should help caregivers plan and refine the monitoring and management to prolong these patients’ survival.
Erratum. Response to Comment on Pathak et al. Severe Hypoglycemia Requiring Medical Intervention in a Large Cohort of Adults With Diabetes Receiving Care in U.S. Integrated Health Care Delivery Systems: 2005–2011. Diabetes Care 2016;39:363–370. Diabetes Care 2017;40:e26
Authors: Ram D. Pathak, Emily B. Schroeder, Elizabeth R. Seaquist, Chan Zeng, Jennifer Elston Lafata, Abraham Thomas, Jean M. Lawrence, Andrew J. Karter, John F. Steiner, Jodi Segal, Patrick J. O’Connor
Journal: Diabetes Care (2017)

In the article cited above, the duality of interest for author Emily B. Schroeder reads “E.B.S. received industry-sponsored research support …
SWI/SNF複合体:SMARCB1が仲介するSWI/SNF複合体機能はエンハンサーの調節に不可欠である
Authors: Wang Xiaofeng, Lee Ryan S, Haswell Jeffrey R, Tzvetkov Evgeni P, Troisi Emma C, Roberts Charles W M, Alver Burak H, Wang Su, Park Peter J, Mieczkowski Jakub, Tolstorukov Michael Y, Drier Yotam, Gillespie Shawn M, Bernstein Bradley E, Archer Tenley C, Pomeroy Scott L, Biegel Jaclyn A
Journal: Nature Genetics (2017)
NIR染料自己集合および光disassembledナノ粒子を誘導することにより皮膚光増感を低減するためのスイッチ可能なPDT【Powered by NICT】
Authors: Zhang Yifan, He Lingyi, Wu Jie, Wang Kaikai, Wang Juan, Dai Weimin, Yuan Ahu, Wu Jinhui, Hu Yiqiao
Journal: Biomaterials (2016)
水溶液合成した量子ドットはNF‐κB経路を阻害すると抗腫瘍,抗ウイルスおよび抗炎症作用を付与する【Powered by NICT】
Authors: Hu Zhilin, Song Bin, Xu Lei, Zhong Yiling, Peng Fei, Ji Xiaoyuan, Zhu Fang, Yang Chengkui, Zhou Jinying, Su Yuanyuan, Chen Suning, He Yao, He Sudan
Journal: Biomaterials (2016)
AR-V7 in Peripheral Whole Blood of Patients with Castration-resistant Prostate Cancer: Association with Treatment-specific Outcome Under Abiraterone and Enzalutamide
Authors: Anna Katharina Seitz, Silvia Thoene, Andreas Bietenbeck, Roman Nawroth, Robert Tauber, Mark Thalgott, Sebastian Schmid, Ramona Secci, Margitta Retz, Jürgen E. Gschwend, Jürgen Ruland, Christof Winter, Matthias M. Heck
Journal: European Urology (2017)