tbuckley/cabot-search huggingface dataset:
Anamorelin for the treatment of cancer anorexia-cachexia: Baseline characteristics from three phase III clinical trials (the ROMANA program).
Authors: Amy Pickar Abernethy, David Currow, Kenneth Fearon, Lyon L. Gleich, John Friend, Jennifer S. Temel
Journal: Journal of Clinical Oncology (2014)

e20694 Background: Cancer anorexia-cachexia (CACS) is a frequent, debilitating and life-threatening multifactorial syndrome in which altered metabolism, inflammation, and reduced food intake contribute to weight loss (mainly lean body mass [LBM]). Safe/effective treatments for CACS remain an unmet need. Anamorelin HCl (ANAM) is a new, oral, selective ghrelin receptor agonist. Methods: HT-ANAM-301 (NCT01387269) and HT-ANAM-302 (NCT01387282), known as ROMANA 1 and ROMANA 2, are double-blind, placebo-controlled, randomized (2:1 ANAM vs. placebo) Phase III trials in patients with non-small cell lung cancer (NSCLC) cachexia (target enrollment of 477 patients/study). Eligible patients must have unresectable Stage III/IV NSCLC and cachexia (≥5% weight loss within prior 6 months or BMI <20 kg/m2). Patients receive 100 mg ANAM or placebo once daily for 12 weeks. Co-primary endpoints are change from baseline in LBM and in muscle strength over 12 weeks (measured by DXA and handgrip strength [HGS], respectively). Secondary endpoints include change in body weight, overall survival, and quality of life (FACIT-F and FAACT). Population pharmacokinetcs is assessed at Week 6 in ROMANA 1. Patients completing 12 weeks of treatment with ECOG ≤2 are eligible for additional 12-week treatment in a safety extension study (HT-ANAM-303 [ROMANA 3] NCT01395914). Results: ROMANA 1 and 2 enrolled 484 and 495 patients, respectively. These are mainly Stage IV NSCLC patients (76.1%; 70.5%) that have not received previous chemotherapy (64.2%; 63.7%) or radiotherapy (83.5%; 80.2%), ECOG=1 (69.8%; 66.5%), weight loss ≤10% (61.8%; 52.3%) and baseline LBM/HGS lower than values commonly observed in healthy adults or patients without weight loss.As of January 2014, 510 patients who completed ROMANA 1 or 2 enrolled in ROMANA 3, mainly with ECOG=1 (71.9%) (340 completed the additional 12-week treatment, and 90 are still active). Conclusions: ANAM is undergoing Phase III evaluation. After completing 12 weeks of treatment in the ROMANA 1 or 2 studies, the majority of patients maintained an eligible performance score and chose to continue in the optional extension study. Efficacy and safety results are awaited. Clinical trial information: NCT01387269, NCT01387282 and NCT01395914.
Retrospective Comparison of Imatinib Versus Interferon Plus Cytarabine (IFN/Ara-c) for Chronic Myelogenous Leukemia (CML) Patients in Chronic Phase (CP).
Authors: Francois Guilhot, Lydia Roy, Joelle Guilhot, Tillmann Krahnke, Agnes Guerci, Brian Druker, Richard Larson, Steve O’Brien, Charlene So, Giorgio Massimini
Journal: Blood (2005)
In Vivo Post–Cardiac Arrest Myocardial Dysfunction Is Supported by Ca <sup>2+</sup> /Calmodulin-Dependent Protein Kinase II–Mediated Calcium Long-Term Potentiation and Mitigated by Alda-1, an Agonist of Aldehyde Dehydrogenase Type 2
Authors: Christopher E. Woods, Ching Shang, Fouad Taghavi, Peter Downey, Adrian Zalewski, Gabriel R. Rubio, Jing Liu, Julian R. Homburger, Zachary Grunwald, Wei Qi, Christian Bollensdorff, Porama Thanaporn, Ayyaz Ali, R. Kirk Riemer, Peter Kohl, Daria Mochly-Rosen, Edward Gerstenfeld, Stephen Large, Ziad A. Ali, Euan A. Ashley
Journal: Circulation (2016)

Survival after sudden cardiac arrest is limited by postarrest myocardial dysfunction, but understanding of this phenomenon is constrained by a lack of data from a physiological model of disease. In this study, we established an in vivo model of cardiac arrest and resuscitation, characterized the biology of the associated myocardial dysfunction, and tested novel therapeutic strategies.We developed rodent models of in vivo postarrest myocardial dysfunction using extracorporeal membrane oxygenation resuscitation followed by invasive hemodynamics measurement. In postarrest isolated cardiomyocytes, we assessed mechanical load and Ca(2) (+)-induced Ca(2+) release (CICR) simultaneously using the microcarbon fiber technique and observed reduced function and myofilament calcium sensitivity. We used a novel fiberoptic catheter imaging system and a genetically encoded calcium sensor, GCaMP6f, to image CICR in vivo.We found potentiation of CICR in isolated cells from this extracorporeal membrane oxygenation model and in cells isolated from an ischemia/reperfusion Langendorff model perfused with oxygenated blood from an arrested animal but not when reperfused in saline. We established that CICR potentiation begins in vivo. The augmented CICR observed after arrest was mediated by the activation of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII). Increased phosphorylation of CaMKII, phospholamban, and ryanodine receptor 2 was detected in the postarrest period. Exogenous adrenergic activation in vivo recapitulated Ca(2+) potentiation but was associated with lesser CaMKII activation. Because oxidative stress and aldehydic adduct formation were high after arrest, we tested a small-molecule activator of aldehyde dehydrogenase type 2, Alda-1, which reduced oxidative stress, restored calcium and CaMKII homeostasis, and improved cardiac function and postarrest outcome in vivo.Cardiac arrest and reperfusion lead to CaMKII activation and calcium long-term potentiation, which support cardiomyocyte contractility in the face of impaired postarrest myofilament calcium sensitivity. Alda-1 mitigates these effects, normalizes calcium cycling, and improves outcome.
Immunotherapy of non-Hodgkin’s lymphoma with a defined ratio of CD8 <sup>+</sup> and CD4 <sup>+</sup> CD19-specific chimeric antigen receptor–modified T cells
Authors: Cameron J. Turtle, Laïla-Aïcha Hanafi, Carolina Berger, Michael Hudecek, Barbara Pender, Emily Robinson, Reed Hawkins, Colette Chaney, Sindhu Cherian, Xueyan Chen, Lorinda Soma, Brent Wood, Daniel Li, Shelly Heimfeld, Stanley R. Riddell, David G. Maloney
Journal: Science Translational Medicine (2016)

CD19-specific chimeric antigen receptor (CAR)-modified T cells have antitumor activity in B cell malignancies, but factors that affect toxicity and efficacy have been difficult to define because of differences in lymphodepletion and heterogeneity of CAR-T cells administered to individual patients. We conducted a clinical trial in which CD19 CAR-T cells were manufactured from defined T cell subsets and administered in a 1:1 CD4(+)/CD8(+) ratio of CAR-T cells to 32 adults with relapsed and/or refractory B cell non-Hodgkin's lymphoma after cyclophosphamide (Cy)-based lymphodepletion chemotherapy with or without fludarabine (Flu). Patients who received Cy/Flu lymphodepletion had increased CAR-T cell expansion and persistence, and higher response rates [50% complete remission (CR), 72% overall response rate (ORR)] than patients who received Cy-based lymphodepletion without Flu (8% CR, 50% ORR). The CR rate in patients treated with Cy/Flu at the maximally tolerated dose was 64% (82% ORR; n = 11). Cy/Flu minimized the effects of an immune response to the murine single-chain variable fragment component of the CAR, which limited CAR-T cell expansion and clinical efficacy in patients who received Cy-based lymphodepletion without Flu. Severe cytokine release syndrome (sCRS) and grade ≥3 neurotoxicity were observed in 13 and 28% of all patients, respectively. Serum biomarkers, one day after CAR-T cell infusion, correlated with subsequent sCRS and neurotoxicity. Immunotherapy with CD19 CAR-T cells in a defined CD4(+)/CD8(+) ratio allowed identification of correlative factors for CAR-T cell expansion, persistence, and toxicity, and facilitated optimization of lymphodepletion that improved disease response and overall and progression-free survival.
An AMP-activated protein kinase–stabilizing peptide ameliorates adipose tissue wasting in cancer cachexia in mice
Authors: Maria Rohm, Michaela Schäfer, Victor Laurent, Bilgen Ekim Üstünel, Katharina Niopek, Carolyn Algire, Oksana Hautzinger, Tjeerd P Sijmonsma, Annika Zota, Dasa Medrikova, Natalia S Pellegata, Mikael Ryden, Agné Kulyte, Ingrid Dahlman, Peter Arner, Natasa Petrovic, Barbara Cannon, Ez-Zoubir Amri, Bruce E Kemp, Gregory R Steinberg, Petra Janovska, Jan Kopecky, Christian Wolfrum, Matthias Blüher, Mauricio Berriel Diaz, Stephan Herzig
Journal: Nature Medicine (2016)
Genome-Wide Analysis of MDS/MPD Disclosed Frequent Homozygous C-Cbl mutations Tightly Associated with 11q-UPD
Authors: Sanada Masashi, Shih Lee Yung, Takahiro Suzuki, Motohiro Kato, Mamiko Yanagimoto Sakata, Keiki Kumano, Norihiko Kawamata, Junko Takita, Hiraku Mori, Mineo Kurokawa, Shigeru Chiba, Mitsuhiro Omine, H. Phillip Koeffler, Seishi Ogawa
Journal: Blood (2008)
Cell-Aligning Substrates: Anisotropically Stiff 3D Micropillar Niche Induces Extraordinary Cell Alignment and Elongation (Adv. Healthcare Mater. 15/2016)
Authors: Yunus Alapan, Mousa Younesi, Ozan Akkus, Umut A. Gurkan
Journal: Advanced Healthcare Materials (2016)

On Page 1884, Y. Alapan, M. Younesi, O. Akkus, and U. A. Gurkan demonstrate a microfabricated pillar substrate to confine, align, and elongate cells for decoupled analysis of stiffness and directionality in 3D. Mesenchymal stem cells and cardiomyocytes are successfully confined in a 3D micromechanical environment with precisely tunable stiffness anisotropy. Cell alignment in the stiffer direction and extraordinary elongation is discovered with 3D cellular confinement in anisotropically stiff micropillar substrates.
Celecoxib for the Prevention of Colorectal Adenomas: Results of a Suspended Randomized Controlled Trial
Authors: Patricia A Thompson, Erin L Ashbeck, Denise J Roe, Liane Fales, Julie Buckmeier, Fang Wang, Achyut Bhattacharyya, Chiu-Hsieh Hsu, Sherry H H Chow, Dennis J Ahnen, C Richard Boland, Russell I Heigh, David E Fay, Stanley R Hamilton, Elizabeth T Jacobs, Elena Maria Martinez, David S Alberts, Peter Lance
Journal: JNCI Journal of the National Cancer Institute (2016)

Cyclooxygenase (COX)-2 inhibitors such as celecoxib were designed to preserve anti-inflammatory activity without inhibiting COX-1. Downregulation of COX-2 inhibits colorectal carcinogenesis. The Selenium and Celecoxib Trial was a randomized, placebo-controlled trial of once-daily selenium 200 µg and celecoxib 400 mg, alone or together, for colorectal adenoma prevention. Men and women between age 40 and 80 years were eligible following colonoscopic removal of adenomas. The primary outcome was development of new adenomas. Celecoxib was suspended early because of cardiovascular toxicity in other trials. Accrual to selenium or placebo continued. Before suspension, 824 participants were randomly assigned to celecoxib or placebo, of whom 712 (86.4%) were available for analysis. All statistical tests were two-sided. In the placebo and celecoxib arms of 356 participants each, adenoma detection was 47.5% and 49.7% (relative risk [RR] = 1.04, 95% confidence interval [CI] = 0.90 to 1.21, P = .58), respectively, after median periods of 13.6 and 14.2 months on intervention. Among participants colonoscoped within 12 months of discontinuing intervention (n = 244), overall adenoma recurrence (RR = 0.69, 95% CI = 0.48 to 0.98, P = .04) and recurrence with advanced adenomas (RR = 0.23, 95% CI = 0.07 to 0.80, P = .02) were reduced with celecoxib. Reduction of adenoma recurrence was greatest in participants with previous advanced adenomas. Celecoxib increased risk of hypertension in participants with pre-existing cardiovascular risk factors compared with placebo (hazard ratio = 2.19, 95% CI = 1.07 to 4.50, P = .03). Limited-duration celecoxib prevents adenoma recurrence in patients with prior high-risk adenomas, in whom strategies to minimize cardiovascular toxicity might be feasible.
Epithelial-to-mesenchymal plasticity of cancer stem cells: therapeutic targets in hepatocellular carcinoma
Authors: Aparna Jayachandran, Bijay Dhungel, Jason C. Steel
Journal: Journal of Hematology & Oncology (2016)

Hepatocellular carcinoma (HCC) remains one of the most common and lethal malignancies worldwide despite the development of various therapeutic strategies. A better understanding of the mechanisms responsible for HCC initiation and progression is essential for the development of more effective therapies. The cancer stem cell (CSC) model has provided new insights into the development and progression of HCC. CSCs are specialized tumor cells that are capable of self-renewal and have long-term repopulation potential. As they are important mediators of tumor proliferation, invasion, metastasis, therapy resistance, and cancer relapse, the selective targeting of this crucial population of cells has the potential to improve HCC patient outcomes and survival. In recent years, the role of epithelial-to-mesenchymal transition (EMT) in the advancement of HCC has gained increasing attention. This multi-step reprograming process resulting in a phenotype switch from an epithelial to a mesenchymal cellular state has been closely associated with the acquisition of stem cell-like attributes in tumors. Moreover, CSC mediates tumor metastasis by maintaining plasticity to transition between epithelial or mesenchymal states. Therefore, understanding the molecular mechanisms of the reprograming switches that determine the progression through EMT and generation of CSC is essential for developing clinically relevant drug targets. This review provides an overview of the proposed roles of CSC in HCC and discusses recent results supporting the emerging role of EMT in facilitating hepatic CSC plasticity. In particular, we discuss how these important new insights may facilitate rational development of combining CSC- and EMT-targeted therapies in the future.
Thrombotic Microangiopathy with Tacrolimus/Sirolimus-Based GVHD Prophylaxis Regimen in Patients Undergoing Hematopoietic Stem Cell Transplant from a Matched Unrelated Donor
Authors: Tam Khuu, Sepideh Shayani, Joycelynne Palmer, Roberto Rodriguez, Pablo Miguel Parker, David S. Snyder, Vinod Pullarkat, Joseph Rosenthal, Auayporn P. Nademanee, David Senitzer, Ryotaro Nakamura, Stephen J. Forman
Journal: Blood (2008)
Descriptive epidemiology of Escherichia coli bacteraemia in England, April 2012 to March 2014
Authors: Sabine Bou-Antoun, John Davies, Rebecca Guy, Alan P Johnson, Elizabeth A Sheridan, Russell J Hope
Journal: Eurosurveillance (2016)

We determined the incidence, risk factors and antimicrobial susceptibility associated with Escherichia coli bacteraemia in England over a 24 month period. Case data were obtained from the national mandatory surveillance database, with susceptibility data linked from LabBase2, a voluntary national microbiology database. Between April 2012 and March 2014, 66,512 E. coli bacteraemia cases were reported. Disease incidence increased by 6% from 60.4 per 100,000 population in 2012-13 to 63.5 per 100,000 population in 2013-14 (p < 0.0001). Rates of E. coli bacteraemia varied with patient age and sex, with 70.5% (46,883/66,512) of cases seen in patients aged ≥ 65 years and 52.4% (33,969/64,846) of cases in females. The most common underlying cause of bacteraemia was infection of the genital/urinary tract (41.1%; 27,328/66,512), of which 98.4% (26,891/27,328) were urinary tract infections (UTIs). The majority of cases (76.1%; 50,617/66,512) had positive blood cultures before or within two days of admission and were classified as community onset cases, however 15.7% (10,468/66,512) occurred in patients who had been hospitalised for over a week. Non-susceptibility to ciprofloxacin, third-generation cephalosporins, piperacillin-tazobactam, gentamicin and carbapenems were 18.4% (8,439/45,829), 10.4% (4,256/40,734), 10.2% (4,694/46,186), 9.7% (4,770/49,114) and 0.2% (91/42,986), respectively. Antibiotic non-susceptibility was higher in hospital-onset cases than for those presenting from the community (e.g. ciprofloxacin non-susceptibility was 22.1% (2,234/10,105) for hospital-onset vs 17.4% (5,920/34,069) for community-onset cases). Interventions to reduce the incidence of E. coli bacteraemia will have to target the community setting and UTIs if substantial reductions are to be realised.
Prognostic value of Gli1 expression and its association with hormone receptors in localized breast cancer.
Authors: G. B. Roldan, K. Koro, A. Klimowicz, S. Petrillo, A. Yau, P. Tang, A. M. Magliocco
Journal: Journal of Clinical Oncology (2010)

e21041 Background: Gli1 is a transcription factor member of the hedgehog signaling pathway and is also induced by other signaling pathways, including TGFb and Ras. About 40%–100% of breast cancers overexpress Gli1 and its value as a prognostic factor is focus of active research. In this study we evaluate the relation between the expression of estrogen receptor a (ERa), progesterone receptor (PR), Her2neu, clinical characteristics and Gli1 in a series of patients with breast cancer. Methods: Institutional Ethics Review Board approval was obtained to identify patients with localized breast cancer whose initial treatment included hormonal therapy ± radiotherapy. Those that had paraffin embedded tissue available from the initial surgery for molecular analysis were included. Tissue Microarrays were built and ERa, PR and Her2neu immunohistochemistry staining were graded 1-3. The AQUA system was used for quantitative protein analysis measuring the Gli1 fluorescent staining intensity within cytokeratin positive cells as a continuous variable. Gli1 levels were dichotomized as high/low at percentile 60 and ERa/PR scores 2-3 vs 0-1. P-values less than 0.05 were considered statistically significant and all results were 2-tailed. Results: 84 female patients, median age 71 years (range;38-89); 35%, 35% and 28% were stage I, II and III, respectively with one initially unrecognized stage IV. All were recommended initial hormonal therapy (tamoxifen 94%; aromatase inhibitors 6%). 91%, 74%, 46% and 41% were ERa positive, PR positive, HER2 positive and Gli1 high, respectively. Using Fisher's exact test, high Gli1 was associated with ERa scores 2-3 (p = 0.036) and PR scores 2-3 (p = 0.037). High Gli1 tended to be inversely correlated with triple negative tumors (Fisher's exact test; p = 0.07). High Gli1 was inversely correlated with tubular grading (Spearman correlation; p = 0.020) but not associated with histologic grade, age, size of tumor, resection margins, lymphovascular invasion, nodal positivity or stage. High Gli1 was associated with a lower risk recurrence at 5 years (p = 0.042; Chi square test). Conclusions: Tumor Gli1 level may identify patients with localized breast cancer with a higher risk of early recurrence. No significant financial relationships to disclose.
Wnt Signaling Promotes Breast Cancer by Blocking ITCH-Mediated Degradation of YAP/TAZ Transcriptional Coactivator WBP2
Authors: Shen Kiat Lim, Ssu Yi Lu, Shin-Ae Kang, Hock Jin Tan, Zilin Li, Zhen Ning Adrian Wee, Jye Swei Guan, Vishnu Priyanka Reddy Chichili, J. Sivaraman, Thomas Putti, Aye Aye Thike, Puay Hoon Tan, Marius Sudol, David M. Virshup, Siew Wee Chan, Wanjin Hong, Yoon Pin Lim
Journal: Cancer Research (2016)

Abstract Cross-talk between the Hippo and Wnt pathways has been implicated recently in breast cancer development, but key intersections have yet to be fully defined. Here we report that WBP2, a transcription coactivator that binds the Hippo pathway transcription factor YAP/TAZ, contributes to Wnt signaling and breast cancer pathogenesis. Clinically, overexpression of WBP2 in breast cancer specimens correlated with malignant progression and poor patient survival. In breast cancer cells, nuclear entry and interaction of WBP2 with β-catenin was stimulated by Wnt3A, thereby activating TCF-mediated transcription and driving malignant invasive character. Mechanistic investigations showed WBP2 levels were controlled by the E3 ligase ITCH, which bound and target WBP2 for ubiquitin-dependent proteasomal degradation. Accordingly, ITCH silencing could elevate WBP2 levels. Wnt signaling upregulated WBP2 by disrupting ITCH–WBP2 interactions via EGFR-mediated tyrosine phosphorylation of WBP2 and TAZ/YAP competitive binding. Conversely, ITCH-mediated downregulation of WBP2 inhibited TCF/β-catenin transcription, in vitro transformation, and in vivo tumorigenesis. We identified somatic mutations in ITCH, which impaired its ability to degrade WBP2 and to block its function in cancer, even while retaining binding capacity to WBP2. Thus, the Wnt pathway appeared to engage WBP2 primarily by affecting its protein stability. Our findings show how WBP2/ITCH signaling functions to link the intricate Wnt and Hippo signaling networks in breast cancer. Cancer Res; 76(21); 6278–89. ©2016 AACR.
Pleiotropic Analysis of Lung Cancer and Blood Triglycerides
Authors: Verena Zuber, Crystal N. Marconett, Jianxin Shi, Xing Hua, William Wheeler, Chenchen Yang, Lei Song, Anders M. Dale, Marina Laplana, Angela Risch, Aree Witoelar, Wesley K. Thompson, Andrew J. Schork, Francesco Bettella, Yunpeng Wang, Srdjan Djurovic, Beiyun Zhou, Zea Borok, Henricus F. M. van der Heijden, Jacqueline de Graaf, Dorine Swinkels, Katja K. Aben, James McKay, Rayjean J. Hung, Heike Bikeböller, Victoria L. Stevens, Demetrius Albanes, Neil E. Caporaso, Younghun Han, Yongyue Wei, Maria Angeles Panadero, Jose I. Mayordomo, David C. Christiani, Lambertus Kiemeney, Ole A. Andreassen, Richard Houlston, Christopher I. Amos, Nilanjan Chatterjee, Ite A. Laird-Offringa, Ian G. Mills, Maria Teresa Landi
Journal: JNCI Journal of the National Cancer Institute (2016)

Epidemiologically related traits may share genetic risk factors, and pleiotropic analysis could identify individual loci associated with these traits. Because of their shared epidemiological associations, we conducted pleiotropic analysis of genome-wide association studies of lung cancer (12 160 lung cancer case patients and 16 838 control subjects) and cardiovascular disease risk factors (blood lipids from 188 577 subjects, type 2 diabetes from 148 821 subjects, body mass index from 123 865 subjects, and smoking phenotypes from 74 053 subjects). We found that 6p22.1 (rs6904596, ZNF184) was associated with both lung cancer (P = 5.50x10-6) and blood triglycerides (P = 1.39x10-5). We replicated the association in 6097 lung cancer case patients and 204 657 control subjects (P = 2.40 × 10-4) and in 71 113 subjects with triglycerides data (P = .01). rs6904596 reached genome-wide significance in lung cancer meta-analysis (odds ratio = 1.15, 95% confidence interval = 1.10 to 1.21,Pcombined = 5.20x10-9). The large sample size provided by the lipid GWAS data and the shared genetic risk factors between the two traits contributed to the uncovering of a hitherto unidentified genetic locus for lung cancer.
Association of Exposure to Cow's Milk Protein and β-Cell Autoimmunity-Reply
Authors: Jill M. Norris
Journal: JAMA (1996)

In Reply.  —We concur with Drs Holmes and Johnston and Ms Spear that breast-feeding should be encouraged for almost all mothers. Currently, there is no evidence that breast-feeding increases IDDM risk, although it has been shown to have numerous advantages over formula feeding.  We are aware of only 6 independent case-control studies examining exposure to cow's milk formula and diabetes, 1-3 and 2 of these studies found no association. Moreover, all of these studies were subject to both selection bias and recall bias. 1 The unique design of our study eliminated recall bias by collecting exposure data before disease status was known and selection bias by drawing both our cases and controls from the same cohort. These are methodological strengths that should not be ignored when comparisons are made with previous research.  Follow-up data on our patients with BCA were not available when the article was written, but we now have data