tbuckley/cabot-search huggingface dataset:
Effect of EGFR inhibition on HER3/PI3K activation by feedback induction of ErbB heterodimers in cetuximab-sensitive colon cancer cells.
Authors: Bart Jacobs, Loredana Vecchione, Nicholas Hoe, Jef De Schutter, Bart Biesmans, Sharat Singh, Sabine Tejpar
Journal: Journal of Clinical Oncology (2013)

3626 Background: Although cetuximab treatment has been successful for the treatment of KRAS wild-type colorectal cancers, complete remissions are rarely seen in patients, leading ultimately to resistance. We hypothesized that in cetuximab-sensitive patients, the ErbB network is insufficiently targeted since network plasticity may occur. Methods: We have used EGFR-sensitive colorectal cancer cells and investigated ErbB network activity and adaptations by RTK arrays, western blot, and Collaborative Enzyme Enhance Reactive immunoassay (CEER). These were complemented by ErbB heterodimerization (HER2:3, HER1:2, HER1:3, HER3:PI3K) assays using CEER. Effects on cell survival were measured using colony formation assay. In addition to the EGFR sensitive cell line, 200 clinical colorectal cancer (CRC) samples were profiled utilizing CEER for RTKs, downstream signaling, and heterodimerization. Results: EGFR and downstream signaling proteins AKT, ERK, and RSK were potently inhibited by cetuximab or gefitinib at 24h of treatment in EGFR sensitive colorectal cancer cell line. At 24h of treatment, we observed approximately 2 folds increase in total HER2 and HER3 protein levels, 2.7 folds in phosphorylated HER3, and 5.4 folds in HER2:HER3 heterodimer formation. Concurrently, increased in ErbB heterodimer formation was accompanied by 5 folds increase in PI3K binding to HER3, resulting in enhanced HER3 signaling, with increase in AKT, ERK, and RSK. Co-treatment of these cells with cetuximab and HER2 inhibitor Trastuzumab or by treatment with lapatinib blocked the induction of HER2:HER3 heterodimer, HER3 phosphorylation, and PI3K binding to HER3. In 30% of the 200 clinical colorectal cancer samples profiled, we observed an increased in phosphorylated HER3, formation of HER2:HER3 and HER3:PI3K heterodimers along with HER1 activation (KRAS WT). Conclusions: Combination of HER2 inhibitor with an EGFR inhibitor could potentially increase the therapeutic index in cetuximab sensitive patients, and suppress activation of feedback mechanisms upon EGFR inhibition. Current findings suggest that CRC patients with similar profile would benefit from these combination therapies.
Predicting HBsAg Clearance Responses during ARC-520 RNA Interference (RNAI) Therapy Based on HBsAg Epitope Profile Analysis
Authors: R. Walsh, R. Hammond, L. Yuen, J. Deerain, B. Given, T. Schluep, M.-F. Yuen, H.L.-Y. Chan, C.-L. Lai, J. Hamilton, J.Y. Lau, C. Ferrari, R.G. Gish, S.A. Locarnini
Journal: Journal of Hepatology (2016)
Behavioral Patterns of Total Serum Bilirubin Prior to Major Clinical Endpoints in 3529 Patients with Primary Biliary Cholangitis
Authors: M.H. Harms, A. Pares, A.L. Mason, W.J. Lammers, P.M. Battezzati, A. Floreani, N.F. LaRusso, K. Lindor, F. Nevens, D. Thorburn, K.V. Kowdley, C. Ponsioen, C. Corpechot, G.M. Hirschfield, M.J. Mayo, H.L. Janssen, H.R. van Buuren, P. Invernizzi, B.E. Hansen
Journal: Journal of Hepatology (2016)
SOF/VEL for 12 Weeks Is Well Tolerated and Results in High SVR12 Rates in People Receiving Opioid Substitution Therapy
Authors: J. Grebely, G.J. Dore, R. Aspinall, M. Rodriguez-Torres, R. Fox, L. Liu, X. Ding, J. McNally, A. Osinusi, D. Brainard, M. Subramanian, M. Sulkowski, J. Feld
Journal: Journal of Hepatology (2016)
Human ribonuclease variants with broad anti-cancer activity
Authors: Laura E. Strong, John A. Kink, Mark N. Shahan, Jennifer G. Reich, Kerry M. Ervin, Ronald T. Raines
Journal: Cancer Research (2006)

2175   Destroying RNA in cells disrupts the process of translation and transcription, precluding proteins from being made and ultimately resulting in cell death. Accomplishing this disruption in a cell-selective manner would provide a new means to kill cancer cells. Ribonucleases are ubiquitous enzymes that perform a variety of functions. Perhaps the most widely studied ribonuclease is bovine ribonuclease A (RNase A). RNase A is rendered inactive inside cells due to the presence of the cytosolic ribonuclease inhibitor protein (RI). Previous work has demonstrated that variants of bovine RNase A can be produced that have diminished binding to RI while maintaining ribonucleolytic function. These variants have been used to kill cancer cells  in vitro  and  in vivo . The primary objective of this study is to demonstrate that a variant of the human pancreatic ribonuclease I can be developed with a safety and efficacy profile supportive of advancing a candidate into pre-clinical studies. Variants of RNases with diminished binding to RI are called EVade ™  RNases. Safety data (including clinical pathology) as well as efficacy in xenograft models will be presented for EVade ™  RNases, with an emphasis on the lead candidate selected for IND-enabling studies. The RNases presented here are expressed in inclusion bodies in  E. coli  and purified by column chromatography. The enzymatic activity is determined using a FRET-based assay. The substrate is a mixed oligonucleotide with quenching fluorophores at either end. The enzymatic activity assay has been adapted measure binding of the ribonucleases to RI. The engineered RNases are tested for their ability to inhibit the growth of human tumors implanted in the flanks of nude mice (xenografts). Clinical chemistry and complete blood count for EVade ™  RNases will be provided. QBI-119 is a variant of human RNase I that retains 94% sequence identity with the native protein. QBI-119 has been studied in the following xenograft models: prostate (DU145 cell line), pancreas (Bx-PC-3), lung (A549), and ovarian (SKOV-3) cancer. The efficacy of QBI-119 at optimized doses consistently results in significant tumor growth inhibition. The efficacy of EVade ™  RNases has been compared to standard chemotherapy agents, including docetaxel (prostate) and cisplatin (lung), as well as newer therapies such as erlotinib (lung) and gemcitabine (pancreatic). QBI-119 demonstrates efficacy similar to these agents with less gross toxicity to the animals. EVade ™  RNases have potent anti-tumor activity  in vivo  compared to standard therapies and another RNase. EVade ™  RNases based on the human pancreatic RNase I are showing similar efficacy. These data suggest that the engineered ribonucleases are candidates for development as therapeutic agents.
The Costs and Cost-effectiveness of Collaborative Care for Adolescents With Depression in Primary Care Settings
Authors: Davene R. Wright, Wren L. Haaland, Evette Ludman, Elizabeth McCauley, Jeffrey Lindenbaum, Laura P. Richardson
Journal: JAMA Pediatrics (2016)

Depression is one of the most common adolescent chronic health conditions and can lead to increased health care use. Collaborative care models have been shown to be effective in improving adolescent depressive symptoms, but there are few data on the effect of such a model on costs.To evaluate the costs and cost-effectiveness of a collaborative care model for treatment of adolescent major depressive disorder in primary care settings.This randomized clinical trial was conducted between April 1, 2010, and April 30, 2013, at 9 primary care clinics in the Group Health system in Washington State. Participants were adolescents (age range, 13-17 years) with depression who participated in the Reaching Out to Adolescents in Distress (ROAD) collaborative care intervention trial.A 12-month collaborative care intervention included an initial in-person engagement session, delivery of evidence-based treatments, and regular follow-up by master's level clinicians. Youth in the usual care control condition received depression screening results and could access mental health services and obtain medications through Group Health.Cost outcomes included intervention costs and per capita health plan costs, calculated from the payer perspective using administrative records. The primary effectiveness outcome was the difference in quality-adjusted life-years (QALYs) between groups from baseline to 12 months. The QALYs were calculated using Child Depression Rating Scale-Revised scores measured during the clinical trial. Cost and QALYs were used to calculate an incremental cost-effectiveness ratio.Of those screened, 105 youths met criteria for entry into the study, and 101 were randomized to the intervention (n = 50) and usual care (n = 51) groups. Overall health plan costs were not significantly different between the intervention ($5161; 95% CI, $3564-$7070) and usual care ($5752; 95% CI, $3814-$7952) groups. Intervention delivery cost an additional $1475 (95% CI, $1230-$1695) per person. The intervention group had a mean daily utility value of 0.78 (95% CI, 0.75-0.80) vs 0.73 (95% CI, 0.71-0.76) for the usual care group. The net mean difference in effectiveness was 0.04 (95% CI, 0.02-0.09) QALY at $883 above usual care. The mean incremental cost-effectiveness ratio was $18 239 (95% CI, dominant to $24 408) per QALY gained, with dominant indicating that the intervention resulted in both a net cost savings and a net increase in QALYs.Collaborative care for adolescent depression appears to be cost-effective, with 95% CIs far below the strictest willingness-to-pay thresholds. These findings support the use of collaborative care interventions to treat depression among adolescent youth.clinicaltrials.gov Identifier: NCT01140464.
Phase II study of anastrozole in recurrent estrogen (ER) / progesterone (PR) positive endometrial cancer: The PARAGON trial—ANZGOG 0903.
Authors: Linda R. Mileshkin, Richard J Edmondson, Rachel O'Connell, Katrin Marie Sjoquist, David Cannan, Rema Jyothirmayi, Philip James Beale, Tony Bonaventura, Jeffrey C. Goh, Marcia Hall, Andrew R. Clamp, John A. Green, Rosemary Lord, James Scurry, Michael Friedlander
Journal: Journal of Clinical Oncology (2016)

5520 Background: Many endometrial cancers express hormone receptors and may respond to hormonal therapy, but the impact on quality of life (QOL) is unclear. The aim of PARAGON is to investigate anastrozole, in patients (pts) with various ER/PR positive metastatic gynaecological cancers in a series of 7 individual phase 2 studies embedded in a basket protocol, with recruitment to the endometrial sub-group complete. Methods: Investigator initiated single arm, open label trial of anastrozole, 1 mg/d in pts with ER and /or PR positive hormone naive endometrial cancer. Pts were treated until progressive disease (PD) or unacceptable toxicity. The primary end-point was clinical benefit (response + stable disease) at 3 months. Secondary endpoints include progression-free survival (PFS), quality of life (QOL) and toxicity. QOL was assessed using the EORTC QLQ-C30 at baseline, monthly for the first 3 months and then 3 monthly until PD. The proportion of pts whose score improved by ≥10-points (considered clinically relevant) was calculated for each QLQ-C30 subscale. Linear regression was used to compare the change in scores between pts who achieved a 3-month clinical benefit and those with PD. Results: Clinical benefit rate in 82 evaluable pts at 3 months was 44 % (95% CI:34-55%) with a RECIST partial response in 6 (7%). The median PFS was 3.2 months (95% CR: 2.8-5.4). Median duration of clinical benefit was 5.6 months. Treatment was well tolerated with toxicity as expected. Pts achieving a 3-month clinical benefit were significantly more likely than progressors to achieve clinically significant improvements in several QOL domains by 2 months including: emotional functioning (39 vs 6%:p = 0.002), cognitive functioning (45 vs 19%:p = 0.021), fatigue (47 vs19%:p = 0.015) and global health status (42 vs 9%:p = 0.003). Clinical benefit was associated with significantly improved mean change scores at 2-3 months compared to progressors for these domains as well as for social functioning, financial problems, pain, appetite loss and constipation. Conclusions: 44% of patients with ER/PR positive endometrial cancer derived clinical benefit from anastrozole, associated with a significant improvement in QOL. Clinical trial information: ACTRN12610000796088.
<i>BIRC6</i> Targeting as Potential Therapy for Advanced, Enzalutamide-Resistant Prostate Cancer
Authors: Iris Sze Ue Luk, Raunak Shrestha, Hui Xue, Yuwei Wang, Fang Zhang, Dong Lin, Anne Haegert, Rebecca Wu, Xin Dong, Colin C. Collins, Amina Zoubeidi, Martin E. Gleave, Peter W. Gout, Yuzhuo Wang
Journal: Clinical Cancer Research (2016)

Abstract Purpose: Enzalutamide resistance has emerged as a major problem in the management of castration-resistant prostate cancer (CRPC). Research on therapy resistance of CRPCs has primarily focused on the androgen receptor pathway. In contrast, there is limited information on antiapoptotic mechanisms that may facilitate the treatment resistance. The inhibitor of apoptosis proteins (IAP) family is well recognized for its role in promoting treatment resistance of cancers by inhibiting drug-induced apoptosis. Here, we examined whether BIRC6, an IAP family member, has a role in enzalutamide resistance of CRPCs and could provide a therapeutic target for enzalutamide-resistant CRPC. Experimental Design: Use of enzalutamide-resistant CRPC models: (i) the transplantable, first high-fidelity LTL-313BR patient-derived enzalutamide-resistant CRPC tissue xenograft line showing primary enzalutamide resistance, (ii) MR42D and MR49F CRPC cells/xenografts showing acquired enzalutamide resistance. Specific BIRC6 downregulation in these models was produced using a BIRC6-targeting antisense oligonucleotide (ASO-6w2). Gene expression was determined by qRT-PCR and gene expression profiling. Molecular pathways associated with growth inhibition were assessed via gene enrichment analysis. Results: Of eight IAPs examined, BIRC6 was the only one showing elevated expression in both enzalutamide-resistant CRPC models. Treatment with ASO-6w2 markedly suppressed growth of LTL-313BR xenografts and increased tumor apoptosis without inducing major host toxicity. Pathway enrichment analysis indicated that GPCR and matrisome signaling were the most significantly altered pathways. Furthermore, ASO-6w2 inhibited expression of prosurvival genes that were upregulated in the LTL-313BR line. Conclusions: BIRC6 targeting inhibited the growth of enzalutamide-resistant CRPC models and may represent a new option for clinical treatment of advanced, enzalutamide-resistant prostate cancer. Clin Cancer Res; 23(6); 1542–51. ©2016 AACR.
Dissecting the Molecular Antifibrotic Effect of the TGF-Beta(I) Receptor Kinase Inhibitor Galunisertib in Precision-Cut Liver Slices
Authors: T. Luangmonkong, S. Suriguga, E. Bigaeva, D. Oosterhuis, K. de Jong, D. Schuppan, H. Mutsaers, P. Olinga
Journal: Journal of Hepatology (2016)
Global Assessment of Promoter Methylation in a Murine Model of Cancer Identifies ID4 as a Putative Novel Tumor Suppressor Gene in Human Leukemia.
Authors: Li Yu, Chunhui Liu, Jeff Vandeusen, Brian Becknell, Zunyan Dai, Yue-Zhong Wu, Aparna Raval, Te-Hui Liu, Wei Ding, Charlene Mao, Shujun Liu, Laura T. Smith, Stephen Lee, Laura Rassenti, Guido Marcucci, John Byrd, Michael A. Caligiuri, Christoph Plass
Journal: Blood (2004)
Shared Gene Effects between Hepatic Steatosis and Fibrosis: A Prospective Twin Study
Authors: J.Y. Cui, C.-H. Chen, M.-T. Lo, N. Schork, R. Bettencourt, A. Bhatt, J. Hooker, K.E. Nelson, M.T. Long, D.A. Brenner, C.B. Sirlin, R. Loomba
Journal: Journal of Hepatology (2016)
CAC Score Improves Coronary and CV Risk Assessment Above Statin Indication by ESC and AHA/ACC Primary Prevention Guidelines
Authors: Amir A. Mahabadi, Stefan Möhlenkamp, Nils Lehmann, Hagen Kälsch, Iryna Dykun, Noreen Pundt, Susanne Moebus, Karl-Heinz Jöckel, Raimund Erbel
Journal: JACC. Cardiovascular imaging (2016)
Real-World Safety and Effectiveness of Ombitasvir/ Paritaprevir/R with Dasabuvir and/or Ribavirin in the German Hepatitis C Registry
Authors: H. Hinrichsen, H. Wedemeyer, S. Christensen, C.M. Sarrazin, A. Baumgarten, S. Mauss, J. Hettinger, H. Kleine
Journal: Journal of Hepatology (2016)
Neural Mechanisms of Harm-Avoidance Learning
Authors: Tobias U. Hauser, Eran Eldar, Raymond J. Dolan
Journal: JAMA Psychiatry (2016)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Psychiatry HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Psychiatry journal
Prevalence and Correlation of Diabetes with Severity of Chronic Liver Disease and Utility of HBA1C in these Patients as Compared with Oral Glucose Tolerance Test
Authors: T. Sehrawat, P. Kohli, A. Thour, R. Nagra, A. Jindal, J. Kaur, A. Sachdev, Y. Gupta
Journal: Journal of Hepatology (2016)
Mechanosensing is critical for axon growth in the developing brain
Authors: David E Koser, Amelia J Thompson, Sarah K Foster, Asha Dwivedy, Eva K Pillai, Graham K Sheridan, Hanno Svoboda, Matheus Viana, Luciano da F Costa, Jochen Guck, Christine E Holt, Kristian Franze
Journal: Nature Neuroscience (2016)
Next-Generation Proteasome Inhibitor Oprozomib Synergizes with Modulators of the Unfolded Protein Response to Suppress Hepatocellular Carcinoma
Authors: Y.-P. Vandewynckel, C. Coucke, D. Laukens, L. Devisscher, A. Paridaens, E. Bogaerts, A. Vandierendonck, S. Raevens, X. Verhelst, C. Van Steenkiste, L. Libbrecht, A. Geerts, H. Van Vlierberghe
Journal: Journal of Hepatology (2016)
Urinary Biomarker NGAL in Patients with Cirrhosis and Bacterial Infections: Accuracy Study in Acute Kidney Injury Prediction Defined by KDIGO Criteria
Authors: R.O. Ximenes, C. Helou, M. Diniz, D. Barbeiro, H. Souza, L.A. D’Albuquerque, F. Carrilho, A. Farias
Journal: Journal of Hepatology (2016)
Pharmacokinetics of the Antifibrotic Drug Pirfenidone in Child Pugh A and B Cirrhotic Patients Compared to Healthy Age-Matched Controls
Authors: J.L. Poo, R. Bernal, J.R. Aguilar, R. Alonso, R. Balderas, E. Piñeyro, M. Gómez, J. Escobar, C. Mora, N. Hernandez, R. Magaña, P. Peña
Journal: Journal of Hepatology (2016)
Long Term Outcome of Splanchnic Vein Thrombosis in Cirrhosis
Authors: M. Senzolo, N. Riva, F. Dentali, S.M. Bang, I. Martinelli, S. Schulman, A. Alatri, J. Beyer-Westendorf, M.N.D. Di Minno, K. Rodriguez, M.T. Sartori, W. Ageno
Journal: Journal of Hepatology (2016)
Reason for optimism: How a shifting focus on neural population codes is moving cognitive neuroscience beyond phrenology
Authors: Carolyn Parkinson, Thalia Wheatley
Journal: Behavioral and Brain Sciences (2016)

Multivariate pattern analysis can address many of the challenges for cognitive neuroscience highlighted in After Phrenology (Anderson 2014) by illuminating the information content of brain regions and by providing insight into whether functional overlap reflects the recruitment of common or distinct computational mechanisms. Further, failing to consider submaximal but reliable population responses can lead to an overly modular account of brain function.
HLA B*1402, Cw*0802 Haplotype and DRB1*1501 Allele Are Significantly Increased in Italian Paroxysmal Nocturnal Hemoglobinuria Affected Patients.
Authors: Fiorella Alfinito, Elena Cosentini, Rosa Camerlengo, Giuseppe Terrazzano, Michela Sica, Antonio Risitano, Stefania Costagliola, Roberta Della Pepa, Carmela Palladino, Lucio Luzzatto, Bruno Rotoli, Rosario Notaro, Giuseppina Ruggiero
Journal: Blood (2007)
A Contemporary Estimate of Total Mortality and Cardiovascular Disease Risk in Young Adults With Type 1 Diabetes: The Pittsburgh Epidemiology of Diabetes Complications Study
Authors: Rachel G. Miller, Hemant D. Mahajan, Tina Costacou, Akira Sekikawa, Stewart J. Anderson, Trevor J. Orchard
Journal: Diabetes Care (2016)

The degree to which mortality and cardiovascular disease (CVD) incidence remains elevated in young U.S. adults with type 1 diabetes (T1DM) is unclear. We determined contemporary rates for adults <45 years old with long-standing, childhood-onset T1DM from the Pittsburgh Epidemiology of Diabetes Complications (EDC) Study.Members of the EDC Study cohort <45 years old during the 1996-2012 follow-up period (n = 502) were studied. Mortality and CVD rates were calculated for those aged 30-39 and 40-44 years. Data from the background Allegheny County, Pennsylvania, population were used to calculate age- and sex-matched standardized mortality (SMR) and incidence rate ratios (IRR).In both age groups, the SMR for total mortality was ∼5 (95% CIs: 30-39-year-olds, 2.8, 7.2; 40-44-year-olds, 3.4, 7.8). CVD mortality SMRs ranged from 19 (95% CI 11, 32) to 33 (95% CI 17, 59). Hospitalized CVD IRR was ∼8 (95% CIs: 30-39-year-olds, 2.5, 18.9; 40-44-year-olds, 4.5, 12.8); revascularization procedures account for much of the increased risk. For all outcomes, the relative risk was larger in women. Participants aged 30-39 years had 6.3% (95% CI 3.8, 9.8) absolute 10-year CVD risk, approaching the American College of Cardiology/American Heart Association-recommended cut point of 7.5% for initiation of statin therapy in older adults.Total and CVD mortality and hospitalized CVD are all significantly increased in this contemporary U.S. cohort of young adults with long-standing T1DM. These findings support more aggressive risk factor management in T1DM, especially among women.
Identification of Heat Shock Protein 32 (Hsp32) as a Novel Target in Acute Lymphoblastic Leukemia (ALL).
Authors: Renata A. Meyer, Harald Herrmann, Karoline V. Gleixner, Alexander Gruze, Sabine Cerny-Reiterer, Rainer Hubmann, Medhat Shehata, Matthias Mayerhofer, Wolfgang R. Sperr, Winfried F. Pickl, Junia V. Melo, Gahininath Y. Bharate, Ulrich Jäger, Hiroshi Maeda, Peter Valent
Journal: Blood (2008)