tbuckley/cabot-search huggingface dataset:
Correlation of polymorphisms of JAK and STAT with gefitinib-induced hepatotoxicity in patients with non-small cell lung cancer.
Authors: Shuang Xin, Yuxiang Ma, Xueding Wang, Yan Huang, Chen Zhu, YuanYuan Zhao, Li Zhang, Min Huang
Journal: Journal of Clinical Oncology (2015)

e19102 Background: Drug-induced liver injury (DILI) is a major safety concern in drug development and clinical drug therapy. Severe hepatotoxicity of gefitinib often leads to discontinuation or termination of treatment, however, the mechanism of gefitinib-induced hepatotoxicity remains unrevealed. JAK/STAT pathway is the principal signaling mechanism for numerous cytokines, an effective approach for limiting inflammation in different organs, including the liver. Therefore, this research investigated the association between genetic polymorphisms in EGFR downstream JAK-STAT signal pathway genes and gefitinib-induced hepatotoxicity in patients with advanced non-small cell lung cancer (NSCLC). Methods: A total of 92 advanced NSCLC patients carrying EGFR sensitive mutations receiving gefitinib were enrolled. 39 SNPs(single nucleotide polymorphisms)in JAK1/ STAT1/ STAT3/ STAT4 were detected using Sequenom Massarray MALDI-TOF platform. The associations between polymorphisms of JAK1/ STAT1/ STAT3/ STAT4and gefitinib-induced hepatotoxicity were analyzed by Chi square test. Results: Among the 92 patients, 23 (25%) developed hepatotoxicity. JAK1 rs2780897, STAT3 rs1053023 and STAT1 rs3771300 were significantly correlated with this gefitinib-induced hepatotoxicity. For JAK1 rs2780897, the frequency of GG/GA was significantly higher than that of AA in patients with hepatotoxicity. (P= 0.041, OR = 0.300, 95%CI: 0.091-0.989) STAT3 rs1053023 GA/AA carriers have a less risk for developing severe hepatotoxicity than rs1053023 GG carriers.(P= 0.013, OR = 0.152, 95%CI:0.029-0.795) STAT1 rs3771300 AA/AC carriers have a less risk for developing severe hepatotoxicity than CC carriers. (P= 0.013, OR = 7.821, 95%CI: 1.449-42.215) Conclusions: These findings indicate that JAK1 rs2780897, STAT3 rs1053023 and STAT1 rs3771300 genotype are predictive markers for the development of gefitinib-induced hepatotoxicity in advanced NSCLC patients carrying EGFR sensitive mutations. Continued investigation of mechanism between germline JAK-STAT gene polymorphisms and the EGFR-TKI induced hepatotoxicity in NSCLC patients is warranted.
TAM receptors in cardiovascular disease
Authors: Lucy McShane, Ira Tabas, Greg Lemke, Mariola Kurowska-Stolarska, Pasquale Maffia
Journal: Cardiovascular Research (2019)

The TAM receptors are a distinct family of three receptor tyrosine kinases, namely Tyro3, Axl, and MerTK. Since their discovery in the early 1990s, they have been studied for their ability to influence numerous diseases, including cancer, chronic inflammatory and autoimmune disorders, and cardiovascular diseases. The TAM receptors demonstrate an ability to influence multiple aspects of cardiovascular pathology via their diverse effects on cells of both the vasculature and the immune system. In this review, we will explore the various functions of the TAM receptors and how they influence cardiovascular disease through regulation of vascular remodelling, efferocytosis and inflammation. Based on this information, we will suggest areas in which further research is required and identify potential targets for therapeutic intervention.
Assessment of Inpatient Time Allocation Among First-Year Internal Medicine Residents Using Time-Motion Observations
Authors: Krisda H. Chaiyachati, Judy A. Shea, David A. Asch, Manqing Liu, Lisa M. Bellini, C. Jessica Dine, Alice L. Sternberg, Yevgeniy Gitelman, Alyssa M. Yeager, Jeremy M. Asch, Sanjay V. Desai
Journal: JAMA Internal Medicine (2019)

The United States spends more than $12 billion annually on graduate medical education. Understanding how residents balance patient care and educational activities may provide insights into how the modern physician workforce is being trained.To describe how first-year internal medicine residents (interns) allocate time while working on general medicine inpatient services.Direct observational secondary analysis, including 6 US university-affiliated and community-based internal medicine programs in the mid-Atlantic region, of the Comparative Effectiveness of Models Optimizing Patient Safety and Resident Education (iCOMPARE) trial, a cluster-randomized trial comparing different duty-hour policies. A total of 194 weekday shifts were observed and time motion data were collected, sampled by daytime, nighttime, and call shifts in proportion to the distribution of shifts within each program from March 10 through May 31, 2016. Data were analyzed from June 1, 2016, through January 5, 2019.Mean time spent in direct and indirect patient care, education, rounds, handoffs, and miscellaneous activities within a 24-hour period and in each of four 6-hour periods (morning, afternoon, evening, and night). Time spent multitasking, simultaneously engaged in combinations of direct patient care, indirect patient care, or education, and in subcategories of indirect patient care were tracked.A total of 80 interns (55% men; mean [SD] age, 28.7 [2.3] years) were observed across 194 shifts, totaling 2173 hours. A mean (SD) of 15.9 (0.7) hours of a 24-hour period (66%) was spent in indirect patient care, mostly interactions with the patient's medical record or documentation (mean [SD], 10.3 [0.7] hours; 43%). A mean (SD) of 3.0 (0.1) hours was spent in direct patient care (13%) and 1.8 (0.3) hours in education (7%). This pattern was consistent across the 4 periods of the day. Direct patient care and education frequently occurred when interns were performing indirect patient care. Multitasking with 2 or more indirect patient care activities occurred for a mean (SD) of 3.8 (0.4) hours (16%) of the day.This study's findings suggest that within these US teaching programs, interns spend more time participating in indirect patient care than interacting with patients or in dedicated educational activities. These findings provide an essential baseline measure for future efforts designed to improve the workday structure and experience of internal medicine trainees, without making a judgment on the current allocation of time.ClinicalTrials.gov identifier: NCT02274818.
Women's risk of stroke after heart surgery is greater than men's
Authors: Roger J G Stevens
Journal: BMJ (1999)

Women are more likely to have a stroke after heart surgery than men according to the latest North American research published in Circulation (1999;100:642-7). This is the first paper to show that female sex is an independent risk factor for stroke after heart surgery. The team, headed by Dr Charles Hogue, associate professor of anaesthesiology at Washington University School of Medicine in St Louis, Missouri, studied early …
GS-17-The integration of Hepatitis B virus into human genome is a common event in the setting of HBeAg negative disease: Implications for the treatment and management of CHB
Authors: Valentina Svicher, Romina Salpini, Arianna Battisti, Luna Colagrossi, Lorenzo Piermatteo, Matteo Surdo, Valeria Cacciafesta, Andrea Nuccitelli, Navjyot Hansi, Francesca Ceccherini Silberstein, Carlo Federico Perno, Upkar S. Gill, Patrick Kennedy
Journal: Journal of Hepatology (2019)
Protein tyrosine phosphatase non receptor 11 (<i>PTPN11</i>/Shp2) as a driver oncogene and a novel therapeutic target in non-small cell lung cancer (NSCLC).
Authors: Yasir Elamin, Sinead Toomey, Aoife Carr, Kathy Gately, Shereen Rafee, William Grogan, Patrick G. Morris, Oscar S. Breathnach, John Crown, Kenneth O'Byrne, Bryan Hennessy
Journal: Journal of Clinical Oncology (2015)

11077 Background: PTPN11/Shp2 somatic mutations occur in 25% of Juvenile myelomonocytic leukemias (JMML) and less commonly in adult solid tumors. PTPN11/Shp2 activates the mitogen-activated protein kinase (MAPK) pathway, upstream of KRAS and MEK. Accordingly, PTPN11 mutations were shown to sensitize leukemia cells to MEK inhibitors. Methods: We applied mass-spectrometry based genotyping (Sequenom Inc., Germany) to DNA extracted from tumor and matched normal tissue of 299 NSCLC patients (98 adenocarcinomas and 201 squamous cell (SCC)). PTPN11 constructs with mutations (E76A, A72D) were generated and stably expressed in IL-3 dependent BaF3 cells and NSCLC cell lines (H1703, H157). The acquisition of MAPK pathway activation was evaluated using western blotting and reverse phase protein array (RPPA). PTPN11/Shp2 phosphatase activity was measured in whole cell protein lysates using Shp2 assay kit (R&D Systems). Results: Somatic PTPN11 hotspot mutations occurred in 3 (3.1%) and 9 (4.5%) of adenocarcinomas and SCCs, respectively. Mutant PTPN11, compared to PTPN11 wild type, promoted ten-fold IL-3 independent BaF3 cell survival. BaF3, H1703, and H157 cells expressing mutant PTPN11 exhibited increased PTPN11/Shp2 phosphatase activity and phospho-ERK1/2 levels. shRNA was used to silence PTPN11/Shp2 in the NSCLC cell line H661, which has an activating PTPN11 mutation (N58S). Silencing of PTPN11/Shp2 led to reduced cell proliferation and decreased phospho-ERK1/2 levels, suggesting that PTPN11 mutation is crucial for cell tumorigenicity and MAPK pathway activation in H661 cells. Parental H661 (PTPN11-mutated, KRAS-wild type) and H1703 (PTPN11/KRAS-wild type) cells were treated with the novel MEK inhibitor BAY86-9766. IC50 values were 2.88 ± 0.6 µM in H661 cells and < 50% growth inhibition at 10 µM in H1703 cells. Conclusions: PTPN11/Shp2 demonstrates the in vitro features of a driver oncogene, and potentially represents a new target in NSCLC.
SAT-482-Incidence of hepatocellular carcinoma after hepatitis C cure with DAA in a cohort of patients with advanced liver disease: Results from a prospective screening program
Authors: Marco Sanduzzi Zamparelli, Sabela Lens, Víctor Sapena, Neus Llarch, Anna Pla, Gemma Iserte, Concepció Bartres, Ramón Vilana, Luis Bianchi, Nuñez Isabel, Anna Darnell, Ernest Belmonte, Carmen Ayuso, Maria Ángeles García-Criado, Alba Díaz, Carla Fuster, Ferran Torres, Jordi Bruix, Xavier Forns, María Reig, Zoe Mariño
Journal: Journal of Hepatology (2019)
PS-125-Gut pathobionts underlie intestinal barrier dysfunction and liver Th17 immune response in primary sclerosing cholangitis
Authors: Nobuhiro Nakamoto, Nobuo Sasaki, Ryo Aoki, Kentaro Miyamoto, Toshiaki Teratani, Takahiro Suzuki, Yuzo Koda, Po-Sung Chu, Nobuhito Taniki, Toshiro Sato, Takanori Kanai
Journal: Journal of Hepatology (2019)
A self-healing hydrogel eye drop for the sustained delivery of decorin to prevent corneal scarring
Authors: Gurpreet Chouhan, Richard J.A. Moakes, Maryam Esmaeili, Lisa J. Hill, Felicity deCogan, Joseph Hardwicke, Saaeha Rauz, Ann Logan, Liam M. Grover
Journal: Biomaterials (2019)

Scarring/Opacity on the surface of the eye and vascularisation following infectious diseases, inflammation and corneal trauma are often a leading cause of blindness. The 'gold standard' treatment to prevent corneal scarring is the application of amniotic membrane (AM) to the ocular surface in the acute stage of injury. Although clinically effective, the use of the AM is associated with biological variability and unpredictable responses. Potential health risks including disease transmission, significant ethical issues surrounding the tissue donation process and stringent regulations/storage conditions, preclude widespread use. Consequently, there is a demand for the development of a new, synthetic alternative, that is stable at room temperature, capable of protecting the wound and has the capacity to deliver anti-scarring and anti-inflammatory mediators. Here we have developed a micro-structured fluid gel eye drop, to deliver a potent anti-scarring molecule, decorin. We have compared the release of decorin from the formulated dressing to a typical gel film, demonstrating enhanced release for the fluid gel eye-drops. Therefore, we have investigated the effect of the fluid gel system in 2D human corneal fibroblast culture models, as well as shown the retention of the gellan fluid gel in an in vivo rat model. At the same time the efficacy of the fluid gel eye drop was studied in an organ culture model, whereby the fluid gel containing decorin, significantly (P < 0.05) increased re-epithelialisation within 4 days of treatment.
Abstract 16448: Adult Human Cardiac Progenitor Cells Enhance Contractile Force in Human Engineered Cardiac Tissues
Authors: Jack Murphy, Joshua Mayourian, Sophia I Salazar, Delaine K Ceholski, Venu M Pothula, Francesca Stillitano, Jaydev Dave, Kathleen Broughton, Mark Sussman, Roger J Hajjar, Kevin D Costa, Irene C Turnbull
Journal: Circulation (2018)

Introduction: Growing evidence supports the benefits of adult stem cells as a therapy for patients with heart disease. In Phase I clinical trials, intracoronary infusion of exogenous human cardiac ...
Biliary dilatation in a 67-year-old woman: seeing is believing
Authors: Peng Pan, Sheng-bing Zhao, Shuling Wang, Zhaoshen Li, Yu Bai
Journal: Gut (2019)

A 67-year-old woman presented with paroxysmal epigastric pain for 3 months, without jaundice. She gave a history of cholecystectomy. Physical examination and blood tests were unremarkable. Magnetic resonance cholangiopancreatography showed cystic dilatation of the common bile duct (CBD), intrahepatic and extrahepatic bile duct dilatation and suspicious intrahepatic bile duct stones (figure 1). CT scan showed intrahepatic and extrahepatic bile duct dilatation and multiple intrahepatic bile duct stones (figure 2).



Figure 1 
Magnetic resonance cholangiopancreatography showed cystic dilatation of the common bile duct, intrahepatic …
SIRT6, a novel direct transcriptional target of FoxO3a, mediates colon cancer therapy
Authors: Yingjie Zhang, Liming Nie, Keqian Xu, Yang Fu, Juchang Zhong, Kongzhen Gu, Lingling Zhang
Journal: Theranostics (2019)

SIRT6, NAD+-dependent deacetylase sirtuin 6, has recently shown to suppress tumor growth in several types of cancer.Colon cancer is a challenging carcinoma associated with high morbidity and death.However, whether SIRT6 play a direct role in colon tumorigenesis and the underlying mechanism are not understood.Methods: To investigate the role of SIRT6 in colon cancer, we firstly analyzed the specimens from 50 colorectal cancer (CRC) patients.We generated shSIRT6 LoVo cells and xenograft mouse to reveal the essential role of SIRT6 in cell apoptosis and tumor growth.To explore the underlying mechanism of SIRT6 regulation, we performed FRET and real-time fluorescence imaging in living cells, real-time PCR, immunoprecipitaion, immunohistochemistry, flow cytometry and luciferase reporter assay. Results:The expression level of SIRT6 in patients' specimens is lower than that of normal controls, and patients with higher SIRT6 level have a better prognosis.Here, we identified that transcriptional factor FoxO3a is a direct up-stream of SIRT6 and positively regulated SIRT6 expression, which in turn, promotes apoptosis by activating Bax and mitochondrial pathway.Functional studies reveal that Akt inactivation increases FoxO3a activity and augment its binding to SIRT6 promoter, leading to elevated SIRT6 expression.Knocking down SIRT6 abolished apoptotic responses and conferred resistance to the treatment of BKM120.Combinational therapies with conventional drugs showed synergistic chemosensitization, which was SIRT6-dependent both in vitro and in vivo. Conclusion:The results uncover SIRT6 as a new potential biomarker for colon cancer, and its unappreciated mechanism about transcription and expression via Akt/FoxO3a pathway.
Invasive diagnostic investigation-related complications and its impact on treatment initiation in lung cancer patients in a rapid access lung lesion clinic in regional Australia
Authors: K. McCann, W. Faisal
Journal: Annals of Oncology (2019)

Background: Rapid Access Lung Lesions Clinic (RALLC) is designed to expedite the diagnostic pathway of suspected lung cancer, to allow treatment in a timely fashion. Invasive investigations (i.e. bronchoscopy, EBUS biopsy, CT-guided biopsy) are the usual tools to obtain tissue for histological diagnosis and each carries a small procedure-related complications risk, which could potentially delay definitive treatment initiation until the complication resolves. Methods: Data was prospectively collected of all patients referred to a RALLC clinic in a tertiary cancer centre in regional Australia between July 2017 and December 2018. The need and choice of invasive investigation was determined based on tumour location, clinical suspicion of malignancy and multidisciplinary recommendation. Time to treatment was calculated from the date of diagnostic investigation to the first date of treatment (i.e. chemo/radio/immunotherapy, surgery). All data were analysed using descriptive statistics. Results: Over 18-months 202 patients were referred to the RALLC clinic for evaluation. 105 patients underwent invasive investigation [CT-guided lung biopsy 46 (44%), Bronchoscopy 32 (30%), EBUS biopsy 22 (21%) & Surgical biopsy 5 (5%)]. Malignancy was confirmed in 89 patients (85% diagnostic yield), 80 being lung cancer. The only investigation-related complication was pneumothorax, which occurred in 15 of the CT-guided lung biopsy (33%) with 11 patients needing hospital admission. The median time to first treatment for the overall cohort of lung biopsy patients was 28 days (mean 28.3, range 0-72). In the non-pneumothorax group, the median was 27 days (mean 27.7, range 0-65) while the pneumothorax group was 29 days (mean 29.8, range 5-72). Conclusions: Although CT-guided lung lesion biopsy resulted in a significant number of pneumothorces in our cohort of patients, ultimately this did not significantly delay definitive treatment compared to the overall cohort. However, the high pneumothorax rate increases health care burden and additional invasive management procedures for the patient. Further investigation is warranted to explore factors associated with this. Legal entity responsible for the study: Ballarat Health Services, Ballarat, Victoria, Australia. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
Most clinical anti-EGFR antibodies do not neutralize both wtEGFR and EGFRvIII activation in glioma
Authors: Sameer A Greenall, Mathew McKenzie, Ekatarina Seminova, Olan Dolezal, Lesley Pearce, John Bentley, Mani Kuchibhotla, Shengnan C Chen, Kerrie L McDonald, Harley I Kornblum, Raelene Endersby, Timothy E Adams, Terrance G Johns
Journal: Neuro-Oncology (2019)

Abstract Background Although epidermal growth factor receptor (EGFR) and its truncated, autoactive mutant EGFR variant (v)III are bona fide drivers of tumorigenesis in some gliomas, therapeutic antibodies developed to neutralize this axis have not improved patient survival in a limited number of trials. Previous studies using cells transduced to exogenously express EGFRvIII may have compromised mechanistic studies of anti-EGFR therapeutics. Therefore, we re-assessed the activity of clinical EGFR antibodies in patient-derived gliomaspheres that endogenously express EGFRvIII. Methods The antitumor efficacy of antibodies was assessed using in vitro proliferation assays and intracranial orthografts. Receptor activation status, antibody engagement, oncogenic signaling, and mechanism of action after antibody treatment were analyzed by immunoprecipitation and western blotting. Tracking of antibody receptor complexes was conducted using immunofluorescence. Results The EGFR domain III–targeting antibodies cetuximab, necitumumab, nimotuzumab, and matuzumab did not neutralize EGFRvIII activation. Chimeric monoclonal antibody 806 (ch806) neutralized EGFRvIII, but not wild-type (wt)EGFR activation. Panitumumab was the only antibody that neutralized both EGFRvIII and wtEGFR, leading to reduction of p-S6 signaling and superior in vitro and in vivo antitumor activity. Mechanistically, panitumumab induced recycling of receptor but not degradation as previously described. Panitumumab, via its unique avidity, stably cross-linked EGFRvIII to prevent its activation, while ch806 induced a marked reduction in the active EGFRvIII disulphide-bonded dimer. Conclusions We discovered a previously unknown major resistance mechanism in glioma in that most EGFR domain III–targeting antibodies do not neutralize EGFRvIII. The superior in vitro and in vivo antitumor activity of panitumumab supports further clinical testing of this antibody against EGFRvIII-stratified glioma.
EPSILoN score: Validation cohort of a prognostic score in advanced non-small cell lung cancer (aNSCLC) patients treated with immunotherapy
Authors: A. Prelaj, G. Lo Russo, D. Signorelli, R. Ferrara, M. Imbimbo, G. Galli, A. De Toma, G. Randon, M. Brambilla, B. Trevisan, M. Ganzinelli, N. Zilembo, F. De Braud, M.C. Garassino, C. Proto
Journal: Annals of Oncology (2019)

Background: Despite the benefit in overall survival (OS), only 18-20% of aNSCLC patients (pts) respond to immunotherapy (IO) in second-line (2nd) with a median progression-free survival (mPFS) of 2-4 months (mo). We previously reported the role of EPSILoN score (Ecog-Ps, Smoke, lIver, Ldh, Nlr) as a clinical and biochemical prognostic score of survival in 154 pts treated with 2nd IO. In this study we aim to validate the EPSILoN score in a different patient population group treated with IO in the same setting. Methods: We enrolled 193 eligible patients at the National Cancer Institute of Milan, Italy. From 193 aNSCLC patients receiving single-agent anti-PD-(L)-1 as 2nd (61%) and ≥ 3rd line (39%) we collected baseline complete blood cell count and estimated their ratio such as neutrophil-lymphocyte ratio (NLR). Also we evaluated baseline LDH level. Survival analyses using Kaplan–Meier method and multivariate analysis (Cox progression model) were performed to identify and confirm independent variables. Results: Of 193 pts mPFS and mOS were 2.3 and 7.6 mo, respectively. Univariate and multivariate analyses for PFS adjusted for age, sex, smoke status, ECOG-PS, histology, disease site, confirmed heavy smoking status (≥40 pack/years) (HR 0.71, p = 0.036) and baseline LDH <400 mg/dl (HR 0.66, p = 0.026) as independent positive factors while ECOG-PS 2 (HR 1.79, p < 0.001), baseline liver mets (HR 1.48, p = 0.04) and NLR≥4 (HR 1.49, p = 0.029) as negative factors. The five baseline clinical and blood biomarkers (smoking status, ECOG PS, liver metastases, LDH and NLR), were included in the EPSILoN score to validate it in this cohort. Finally, three different survival groups defined as high, intermediate and low for PFS (6.0 vs 3.8 vs 1.9 mo respectively, HR 1.94 95% IC 1.51–2.48, p < 0.001) and OS (24.5 vs 8.9 vs 3.4 months, respectively HR 2.40, 95% IC 1.82–3.17, p < 0.001) were identified. Conclusions: EPSILoN score which combine five baseline clinical and blood biomarkers may help identify patients who most likely will benefit or not from IO in clinical practice in aNSCLC patients treated with second-line IO. Furthermore, it seems to play an important role in both PFS and OS. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: M.C. Garassino: Consultancies, honoraria: AstraZeneca, Roche, Boehringer Ingelheim, BMS, MSD, Eli Lilly, Novartis, Bayer, Pfizer, Sanofy, Italfarmaco. D. Signorelli: Consultancies, honoraria: AstraZeneca. All other authors have declared no conflicts of interest.