tbuckley/cabot-search huggingface dataset:
The use of PARP inhibitors as single agents and as chemosensitizers in sporadic pancreatic cancer.
Authors: J. A. De Soto, R. Mullins
Journal: Journal of Clinical Oncology (2011)

e13542 Background: Introduction: After resection of pancreatic cancer local recurrence occurs in 50%-80% of the cases while distant metastasis develops 75% of the time. Most pancreatic cancers have impairments of DNA repair. PARP inhibitors may further inhibit the ability fo the cancer to undergo DNA repair. Current, adjuvant therapy often consist of gemcitabine, cisplatin and/or 5-fluorouracil which add a modest increase in median survival by 4-5 months. In this study, we treated human pancreatic cancer cells with poly(ADP-ribose) polymerase (PARP) Inhibitors (AG14361, veliparib and olaparib) alone or with gemcitabine, cisplatin or 5-fluorouracil. Methods: CFPAC-1 and BXPC-3 , HPAC human pancreatic cancer cell lines were treated for 72 hours with PARP inhibitors alone or in combination with gemcitabine, cisplatin, or 5-fluorouracil. Validated MTT assays were used to form dose response curves from which the IC50 values were calculated. PARP activity was measured indirectly through PAR levels and correlated with the IC50 values of PARP inhibition of each cell line. Results: The PARP1 IC50 values for CFPAC-1, BXPC-3 and HPAC pancreatic cancer cell lines were AG14361 (14.3 µM, 12.7 µM, 38.3 µM ), veliparib (52.6 µM, 100.9 µM 102.0 µM ) and olaparib (79.5 µM, 184.8 µM, 200.2 µM) .These values indicate a sensitivity to PARP1 inhibitors of pancreatic cancer cell lines that is at least as great as the sensitivity of ovarian and breast cancer cell lines to PARP1 inhibition. The IC50 values of cisplatin, were decreased up to 60 fold in the presence of clinically relevant amounts of PARP inhibitor while 5-fluorouracil IC50 values were decreased up to 6000 fold in the presence of clinically relevant amounts of PARP inhibitor. Gemcitabine was inhibited up to 73% by PARP inhibitors. The was poor correlation between PARP activity and teh ability of PARP inhibitors to inhibit pancreatic cancer growth. Conclusions: Sporadic pancreatic cancer cells are exquisitely sensitive to PARP inhibition. PARP inhibitors significantly enhanced the cytotoxicity of cisplatin and 5-fluorouracil while inhibiting gemcitabine. There is little correlation between endogenous PARP activity and the effectiveness of PARP inhibitors to inhibit cancer growth.
Impact of Proteomic Profile of Peripheral Blood and Bone Marrow Sera on Molecular Response in Patients with Chronic Myeloid Leukemia: Preliminary Data
Authors: Nicola Sgherza, Vito Garrisi, Giacoma De Tullio, Simona Serratì, Angela Iacobazzi, Antonello Rana, Angela La Pietra, Giacomo Loseto, Vito Cafagna, Vincenza de Fazio, Carla Minoia, Rosa Angarano, Ines Abbate, Attilio Guarini
Journal: Blood (2014)
Global Investigation of Therapeutic Decisions in Hepatocellular Carcinoma and of its Treatment with Sorafenib (GIDEON) second interim analysis in more than 1,500 patients: Clinical findings in patients with liver dysfunction.
Authors: J. A. Marrero, R. Lencioni, M. Kudo, S. Ye, K. Nakajima, F. Cihon, A. P. Venook
Journal: Journal of Clinical Oncology (2011)

4001 Background: GIDEON is an ongoing, global, prospective, noninterventional study of hepatocellular carcinoma (HCC) patients (pts) suitable for systemic therapy and receiving sorafenib (Sor) in real-life practice. Its aim is to evaluate Sor safety and efficacy in diverse settings and pt subgroups where data are limited such as pts with liver dysfunction ie Child-Pugh B (CP-B). Methods: Demographics, medical/disease/treatment history are recorded. At follow-up visits Sor dose, concomitant treatment, liver function, adverse events (AEs) and efficacy are recorded. From Jan 2009 to Dec 2010, 2,770 pts were enrolled in 37 countries. Per protocol, the 2nd interim analysis (IA) was planned when ~1,500 treated pts were followed ≥4 mos. Results: 1,586 pts comprise the safety population; CP-A, 965 (61%); CP- B, 368 (23%). Sor median daily dose was higher in the CP-B group, but median duration of therapy was shorter (Table). Treatment-emergent drug-related AE rates were similar in both groups, but a greater percentage of CP-B pts discontinued Sor due to AEs. Deaths during treatment up to 30 days of last Sor dose were greater in the CP-B group (34%) than in the CP-A group (15%). In the ITT population (1614 pts), preliminary median overall survival (OS) was 10.5 mos in the CP-A pts (n=982) and 5 mos in the CP-B pts (n=373). Conclusions: These preliminary second IA results indicate that the Sor safety profile is generally similar in the CP-B and CP-A pts. The shorter median OS in the CP-B pts most likely reflects the poorer prognosis and natural history of liver disease in this patient population. N = 1,586 CP-A n = 965 (61%) CP-B n = 368 (23%) 800 mg starting dose (n [%]) 738 (76) 261 (71) Daily dose (median, mg)* 684.5 721.0 No. dose reductions (n [%]) 353 (37) 99 (27) Treatment duration (median, wks)* 13.7 8.5 Treatment-emergent AEs (n [%]) All Drug-related All Drug-related All grades 768 (80) 632 (66) 322 (88) 227 (62) Grade 3 241 (25) 211 (22) 94 (26) 67 (18) Grade 4 37 (4) 16 (2) 20 (5) 9 (2) Serious, all grades (n (%)) 273 (28) 75 (8) 198 (54) 53 (14) Sor discontinued due to AEs (n [%]) 217 (23) 139 (38) * Missing data not tabulated.
Renal Effects of DPP-4 Inhibitor Sitagliptin or GLP-1 Receptor Agonist Liraglutide in Overweight Patients With Type 2 Diabetes: A 12-Week, Randomized, Double-Blind, Placebo-Controlled Trial
Authors: Lennart Tonneijck, Mark M. Smits, Marcel H.A. Muskiet, Trynke Hoekstra, Mark H.H. Kramer, A.H. Jan Danser, Piet M. ter Wee, Michaela Diamant, Jaap A. Joles, Daniël H. van Raalte
Journal: Diabetes Care (2016)

OBJECTIVE To investigate effects of dipeptidyl peptidase-4 inhibitor (DPP-4I) sitagliptin or glucagon-like peptide 1 (GLP-1) receptor agonist liraglutide treatment on renal hemodynamics, tubular functions, and markers of renal damage in overweight patients with type 2 diabetes without chronic kidney disease (CKD). RESEARCH DESIGN AND METHODS In this 12-week, randomized, double-blind trial, 55 insulin-naïve patients with type 2 diabetes (mean ± SEM: age 63 ± 7 years, BMI 31.8 ± 4.1 kg/m2, glomerular filtration rate [GFR] 83 ± 16 mL/min/1.73 m2; median [interquartile range]: albumin-to-creatinine ratio (ACR) 1.09 mg/mmol [0.47–3.31]) received sitagliptin (100 mg/day), liraglutide (1.8 mg/day), or matching placebos. GFR (primary end point) and effective renal plasma flow (ERPF) were determined by inulin and para-aminohippuric acid clearance, respectively. Intrarenal hemodynamic variables were estimated. Absolute and fractional excretions of sodium (FENa), potassium, and urea (FEU) and renal damage markers (ACR, neutrophil gelatinase–associated lipocalin [NGAL], and kidney injury molecule-1 [KIM-1]) were measured. Plasma renin concentration (PRC) and glycated hemoglobin (HbA1c) were assessed. At weeks 2 and 6, estimated GFR and fractional electrolyte excretions were determined. RESULTS At week 12, GFR was not affected by sitagliptin (−6 mL/min/1.73 m2 [95% CI −14 to 3], P = 0.17) or liraglutide (+3 mL/min/1.73 m2 [−5 to 11], P = 0.46), compared with placebo. Sitagliptin modestly reduced estimated glomerular hydraulic pressure (PGLO; P = 0.043). ERPF, other intrarenal hemodynamic variables, renal damage markers, and PRC did not change for both treatments. Both agents reduced HbA1c. Only at week 2, sitagliptin increased FENa and FEU (P = 0.005). CONCLUSIONS Twelve-week treatment with sitagliptin or liraglutide does not affect measured renal hemodynamics. No sustained changes in tubular functions or alteration in renal damage markers were observed. The validity and clinical relevance of the slight sitagliptin-induced PGLO reduction remains speculative.
Abstract 3661: Development of novel small-molecule inhibitors of ETS oncoproteins as anti-prostate cancer agents
Authors: Xiaohong Tian
Journal: Cancer Research (2015)

Abstract Currently advanced prostate cancer is treated by suppressing androgen receptor (AR) signaling. Since AR could be activated via multiple mechanisms, inhibition of one or two of these mechanisms could be initially effective, but drug resistance can rapidly develop due to kick-in of other AR-activating mechanisms, resulting in lethal castration-resistant prostate cancer (CRPC). The therapeutic effects of all of the currently available AR-targeting agents are short-lived. To achieve long lasting therapeutic effect for prostate cancer, it appears we need to get out of the box of AR. Here, we propose to develop chemical inhibitors of oncogenic protein ERG, which is an ETS transcriptional factor. The rationale for inhibiting ERG as a possible treatment for prostate cancer has two folds: i) ERG plays a critical role in prostate cancer initiation and progression, and ii) Half of all prostate cancer patients are TMPRSS2-ERG fusion positive, which result in high level of ERG oncoprotein. ERG is a transcriptional factor that directly regulates EZH2, oncogene c-Myc and tumor suppressor Nkx3.1 and many other targets in prostate cancer. ERG cooperates with PI3K/AKT and AR in tumor initiation. ERG knockdown inhibits tumor growth in xenograft of VCaP cells. To date, accumulated studies in patients and experimental models have indicated that ERG overexpression as a result of TMPRSS2-ERG fusion plays a critical role in prostate cancer initiation and progression. However, ERG protein has no obvious functional sites or enzymatic activity to be inhibited and is considered ‘undruggable’. In contrast to such view, our laboratory has recently discovered a novel chemical inhibitor of ERG by combining virtual screening and reporter assay. We have built a structural model of ERG DBD and identified a putative binding-site for virtual screening study. We discovered a novel compound, which substantially inhibits ERG-dependent reporter activity in HEK293 cells and inhibits expression of ERG-regulated genes, such as EZH2 and c-Myc, in VCaP cells. We further showed that our compound inhibits proliferation of VCaP cells, and disrupts association of ERG with its essential coactivator PARP1 by co-IP assay. Surface Plasmon Resonance (SPR) analysis has confirmed that our compound has direct binding with recombinant ERG protein. As recent studies indicated that advanced prostate cancer with TMPRSS2-ERG fusion have substantial higher tendency to metastasize to lymph nodes, ERG inhibitors could be an effective therapeutics to prevent this progression. Importantly, ERG inhibitors could be effective therapeutics for advanced prostate cancer. Citation Format: Xiaohong Tian. Development of novel small-molecule inhibitors of ETS oncoproteins as anti-prostate cancer agents. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3661. doi:10.1158/1538-7445.AM2015-3661
Discrepancies between patient-reported outcomes, and endoscopic and histological appearance in UC
Authors: Jean-Frédéric Colombel, Mary E Keir, Alexis Scherl, Rui Zhao, Gert de Hertogh, William A Faubion, Timothy T Lu
Journal: Gut (2016)

Objective Both endoscopy and histology may be included in the definition of mucosal healing in UC. This study aimed to establish the association between patient-reported outcomes, specifically symptom measures, and the presence of inflammation as measured by endoscopy and histology in UC. Design Using patient data from an observational multicentre study of UC (n=103), rectal bleeding (RB) and stool frequency (SF) symptom subscores of the Mayo Clinic Score (MCS) were compared with the endoscopic subscore (MCSe) and histology. Faecal calprotectin and biopsy cytokine expression were also evaluated. Results When identifying UC patients with inactive disease, RB scores were superior to SF scores and the combination (sensitivity/specificity: MCSe=0/1, RB 77%/81%, SF 62%/95%, RB+SF 54%/95%; MCSe=0, RB 87%/66%, SF 76%/83%, RB+SF 68%/86%). Across different definitions of mucosal healing (MCSe≤1; 0; or 0 plus inactive histology), a larger subset of patients reported increased SF (39%, 25% and 27%, respectively) compared with RB (24%, 13% and 10%). Faecal calprotectin and inflammatory cytokine expression were higher in patients with active disease compared with patients with mucosal healing, but there were no differences between patients using increasingly stringent definitions of mucosal healing. Conclusions Endoscopically inactive disease is associated with absence of RB but not with complete normalisation of SF. Achieving histological remission did not improve symptomatic relief. In addition, in these patients, higher inflammatory biomarker levels were not observed. These data suggest that non-inflammatory changes, such as bowel damage, may contribute to SF in UC.
Renal drug transporters and their significance in drug–drug interactions
Authors: Jia Yin, Joanne Wang
Journal: Acta Pharmaceutica Sinica B (2016)

The kidney is a vital organ for the elimination of therapeutic drugs and their metabolites. Renal drug transporters, which are primarily located in the renal proximal tubules, play an important role in tubular secretion and reabsorption of drug molecules in the kidney. Tubular secretion is characterized by high clearance capacities, broad substrate specificities, and distinct charge selectivity for organic cations and anions. In the past two decades, substantial progress has been made in understanding the roles of transporters in drug disposition, efficacy, toxicity and drug-drug interactions (DDIs). In the kidney, several transporters are involved in renal handling of organic cation (OC) and organic anion (OA) drugs. These transporters are increasingly recognized as the target for clinically significant DDIs. This review focuses on the functional characteristics of major human renal drug transporters and their involvement in clinically significant DDIs.
Improving Prediction of Suicide and Accidental Death After Discharge From General Hospitals With Natural Language Processing
Authors: Thomas H. McCoy, Victor M. Castro, Ashlee M. Roberson, Leslie A. Snapper, Roy H. Perlis
Journal: JAMA Psychiatry (2016)

Suicide represents the 10th leading cause of death across age groups in the United States (12.6 cases per 100 000) and remains challenging to predict. While many individuals who die by suicide are seen by physicians before their attempt, they may not seek psychiatric care.To determine the extent to which incorporating natural language processing of narrative discharge notes improves stratification of risk for death by suicide after medical or surgical hospital discharge.In this retrospective health care use study, clinical data were analyzed from individuals with discharges from 2 large academic medical centers between January 1, 2005, and December 31, 2013.The primary outcome was suicide as a reported cause of death based on Massachusetts Department of Public Health records. Regression models for prediction of death by suicide or accidental death were compared relying solely on coded clinical data and those using natural language processing of hospital discharge notes.There were 845 417 hospital discharges represented in the cohort, including 458 053 unique individuals. Overall, all-cause mortality was 18% during 9 years, and the median follow-up was 5.2 years. The cohort included 235 (0.1%) who died by suicide during 2.4 million patient-years of follow-up. Positive valence reflected in narrative notes was associated with a 30% reduction in risk for suicide in models adjusted for coded sociodemographic and clinical features (hazard ratio, 0.70; 95% CI, 0.58-0.85; P < .001) and improved model fit (χ22 = 14.843, P < .001 by log-likelihood test). The C statistic was 0.741 (95% CI, 0.738-0.744) for models of suicide with or without inclusion of accidental death.Multiple clinical features available at hospital discharge identified a cohort of individuals at substantially increased risk for suicide. Greater positive valence expressed in narrative discharge summaries was associated with substantially diminished risk. Automated tools to aid clinicians in evaluating these risks may assist in identifying high-risk individuals.
How mast cells make decisions
Authors: Jörn Karhausen, Soman N. Abraham
Journal: Journal of Clinical Investigation (2016)

Mast cells (MCs) are present in various tissues and are responsible for initiating many of the early inflammatory responses to extrinsic challenges. Recent studies have demonstrated that MCs can tailor their responses, depending on the stimulus encountered and the tissue in which they are stimulated. In this issue of the JCI, Gaudenzio and colleagues examine the mechanistic differences between MC responses observed after engagement of Fcε receptor I and those seen after MC stimulation via the recently identified G protein–coupled receptor MRGPRX2. By showing that discrete cellular activation patterns affect the phenotype of the MC response in vivo and in vitro, the authors provide important information about how MCs differentially process various stimuli into distinct degranulation programs.
Distributed and Mixed Information in Monosynaptic Inputs to Dopamine Neurons
Authors: Ju Tian, Ryan Huang, Jeremiah Y. Cohen, Fumitaka Osakada, Dmitry Kobak, Christian K. Machens, Edward M. Callaway, Naoshige Uchida, Mitsuko Watabe-Uchida
Journal: Neuron (2016)
Activité grippale faible à modérée en Europe, et détection de nouveaux variants A(H1N2) et B durant l’hiver 2001-02
Authors: W J Paget, T J Meerhoff, N L Goddard
Journal: Eurosurveillance (2002)

L’activite de la grippe en Europe au cours de la saison 2001-02 etait faible a moderee. Par rapport aux donnees historiques, la grippe etait faible dans six pays, moyenne dans onze, et forte dans un pays (l’Espagne). La souche virale A(H3N2) a circule de facon predominante en Europe. Deux nouvelles souches ont ete isolees durant la saison 2001-02 : le sous-type A(H1N2) (principalement detecte au Royaume-Uni, Irlande, mais aussi Belgique, France, Allemagne, Pays-Bas, Portugal, Suede, Suisse et Roumanie), et le sous-type B appartenant a la lignee B/Victoria/2/87 (principalement isole en Allemagne, mais aussi sporadiquement en France, Italie, Pays-Bas et Norvege). Hormis la detection du sous-type H1N2 en Angleterre et en Irlande, et celle du sous-type B/Victoria/2/87 en Allemagne, ces deux souches n’ont pas largement circule en Europe, et n’ont pas contribue a l’activite grippale. Un virus grippal de sous-type B/Victoria/2/87 sera inclus dans la prochaine composition vaccinale pour 2002-03. Le nouveau sous-type A(H1N2) est couvert par le vaccin 2002-03, puisque les composants de l’hemagglutinine et de la neuraminidase des virus H1N2 sont antigeniquement proches de ceux des souches vaccinales (H1N1 et H3N2).
Mutational Status of IgVH Genes in B-Cell Chronic Lymphocytic Leukemia (B-CLL) and Prognosis: Percent Mutations or Evaluation of Antigen-Driven Selection?
Authors: Valter Gattei, Michele Dal, Antonella Zucchetto, Dania Benedetti, Eva Zaina, Paola Nanni, Paolo Sonego, Giovanni Del Poeta, Massimo Degan, Riccardo Bomben
Journal: Blood (2005)
P2-047: Putative biomarker genes for pemetrexed theatment in small and non-small cell lung cancer cell lines, detected by microarray analysis
Authors: Eiji Nakajima, Michio Sugita, Barbara Helfrich, Daniel C. Chan, Harubumi Kato, Paul A. Bunn, Wilbur A. Franklin, Fred R. Hirsch
Journal: Journal of Thoracic Oncology (2007)
Diagnosis and management of esophageal achalasia
Authors: Stavros N Stavropoulos, David Friedel, Rani Modayil, Henry P Parkman
Journal: BMJ (2016)

Achalasia is a rare esophageal motility disorder that is usually idiopathic in origin. It is characterized by dysphagia, and patients often have chest pain, regurgitation, weight loss, and an abnormal barium radiograph showing esophageal dilation with narrowing at the gastroesophageal junction. Abnormal or absent esophageal peristalsis and impaired relaxation of the lower esophageal sphincter (LES) are typically seen on esophageal manometry. The advent of high resolution manometry (HRM) has allowed more precise diagnosis of achalasia, subtype designation, and differentiation from other esophageal motor disorders with an initial seminal publication in 2008 followed by further refinements of what has been termed the Chicago classification. Potential treatments include drugs, endoscopic botulinum toxin injection, balloon dilation, traditional surgery (usually laparoscopic Heller myotomy; LHM), and a novel, less invasive, natural orifice transluminal endoscopic surgery (NOTES) approach to Heller myotomy termed peroral endoscopic myotomy (POEM). The first human POEM was performed in 2008, with the first publication appearing in 2010 and evidence now rapidly accumulating showing POEM to be comparable to traditional surgery in terms of clinical success and radiologic and manometric post-therapy outcomes. This review discusses the diagnosis and management of achalasia with particular emphasis on the recent developments of HRM and POEM, which arguably represent the most important advances in the field since the advent of laparoscopic Heller myotomy in the 1990s.
Serial cfDNA assessment of response and resistance to EGFR-TKI for patients with EGFR-L858R mutant lung cancer from a prospective clinical trial
Authors: Qing Zhou, Jin-Ji Yang, Zhi-Hong Chen, Xu-Chao Zhang, Hong-Hong Yan, Chong-Rui Xu, Jian Su, Hua-Jun Chen, Hai-Yan Tu, Wen-Zhao Zhong, Xue-Ning Yang, Yi-Long Wu
Journal: Journal of Hematology & Oncology (2016)

Detecting epidermal growth factor receptor (EGFR) activating mutations in plasma could guide EGFR-tyrosine kinase inhibitor (EGFR-TKI) treatment for advanced non-small cell lung cancer (NSCLC). However, dynamic quantitative changes of plasma EGFR mutations during the whole course of EGFR-TKI treatment and its correlation with clinical outcomes were not determined. The aim of this study was to measure changes of plasma EGFR L858R mutation during EGFR-TKI treatment and to determine its correlation with the response and resistance to EGFR-TKI. This study was a pre-planned exploratory analysis of a randomized phase III trial conducted from 2009 to 2014 comparing erlotinib with gefitinib in advanced NSCLC harboring EGFR mutations in tumor (CTONG0901). Totally, 256 patients were enrolled in CTONG0901 and randomized to receive erlotinib or gefitinib. One hundred and eight patients harbored L858R mutation in their tumors and 80 patients provided serial blood samples as pre-planned scheduled. Serial plasma L858R was detected using quantitative polymerase chain reaction. Dynamic types of plasma L858R were analyzed using Ward's hierarchical clustering method. Progression-free survival (PFS) and overall survival (OS) were compared between different types. As a whole, the quantity of L858R decreased and reached the lowest level at the time of best response to EGFR-TKI. After the analysis of Ward's hierarchical clustering method, two dynamic types were found. In 61 patients, L858R increased to its highest level when disease progressed (ascend type), while in 19 patients, L858R maintained a stable level when disease progressed (stable type). Median PFS was 11.1 months (95 % CI, 6.6–15.6) and 7.5 months (95 % CI, 1.4–13.6) in patients with ascend and stable types, respectively (P = 0.023). Median OS was 19.7 months (95 % CI, 16.5–22.9) and 16.0 months (95 % CI, 13.4–18.5), respectively (P = 0.050). This is the first report finding two different dynamic types of plasma L858R mutation during EGFR-TKI treatment based on a prospective randomized study. Different dynamic types were correlated with benefits from EGFR-TKI. The impact of plasma L858R levels at disease progression on subsequent treatment strategy needs further exploration. ClinicalTrials.gov, NCT01024413