tbuckley/cabot-search huggingface dataset:
Combination of Imatinib Mesylate with Autologous Leukocyte-Derived Heat Shock Protein and Chronic Myelogenous Leukemia
Authors: Zihai Li, Yi Qiao, Bei Liu, Elizabeth J. Laska, Priyamvadha Chakravarthi, Judith M. Kulko, Robert D. Bona, Min Fang, Upendra Hegde, Victor Moyo, Susan H. Tannenbaum, Antoine Ménoret, Judy Gaffney, Laura Glynn, Carolyn D. Runowicz, Pramod K. Srivastava
Journal: Clinical Cancer Research (2005)

To test the feasibility, safety, immunogenicity, and clinical efficacy of an autologous vaccine of leukocyte-derived heat shock protein 70-peptide complexes (Hsp70PC), in conjunction with imatinib mesylate, in patients with chronic myeloid leukemia (CML) in chronic phase.Patients had cytogenetic or molecular evidence of disease, despite treatment with imatinib mesylate for all except one patient, at the beginning of study. Hsp70PCs were purified from the leukopheresed peripheral blood mononuclear cells and were administered in eight weekly intradermal injections at 50 microg/dose without adjuvant. Clinical responses were assessed by bone marrow analysis before and after vaccinations. An IFN-gamma enzyme-linked immunospot assay was used to estimate the effect of treatment on natural killer cells and T cells against CML.Twenty patients were treated. The manufacturing of Hsp70PCs was successful and the administration was safe for all patients. Minimal or no side effects were reported. Clinical responses were seen in 13 of 20 patients as measured by cytogenetic analysis of bone marrow Philadelphia chromosome-positive cells in metaphases and/or, when possible, the level of Bcr/Abl transcript by PCR. Immunologic responses were observed in 9 of 16 patients analyzed, characterized by an increase in the frequency of CML-specific IFN-gamma-producing cells and IFN-gamma-secreting natural killer cells in the blood. A significant correlation between clinical responses and immunologic responses was observed.Autologous Hsp70PC vaccination is feasible and safe. When combined with imatinib mesylate, it is associated with immunologic and possible clinical responses against CML in chronic phase.
RIDDLE: Reflective diffusion and local extension reveal functional associations for unannotated gene sets via proximity in a gene network
Authors: Peggy I Wang, Sohyun Hwang, Rodney P Kincaid, Christopher S Sullivan, Insuk Lee, Edward M Marcotte
Journal: Genome biology (2012)

The growing availability of large-scale functional networks has promoted the development of many successful techniques for predicting functions of genes. Here we extend these network-based principles and techniques to functionally characterize whole sets of genes. We present RIDDLE (Reflective Diffusion and Local Extension), which uses well developed guilt-by-association principles upon a human gene network to identify associations of gene sets. RIDDLE is particularly adept at characterizing sets with no annotations, a major challenge where most traditional set analyses fail. Notably, RIDDLE found microRNA-450a to be strongly implicated in ocular diseases and development. A web application is available at http://www.functionalnet.org/RIDDLE.
Race, Gender, and Socioeconomic Disparities in CKD in the United States
Authors: Keith Norris, Allen R. Nissenson
Journal: Journal of the American Society of Nephrology (2008)

Chronic kidney disease (CKD) is a national public health problem beset by inequities in incidence, prevalence, and complications across gender, race/ethnicity, and socioeconomic status. As health care providers, we can directly address some factors crucial for closing the disparities gap. Other factors are seemingly beyond our reach, entrenched within the fabric of our society, such as social injustice and human indifference. Paradoxically, the existence of health inequities provides unique, unrecognized opportunities for understanding biologic, environmental, sociocultural, and health care system factors that can lead to improved clinical outcomes. Several recent reports documented that structured medical care systems can reduce many CKD-related disparities and improve patient outcomes. Can the moral imperative to eliminate CKD inequities inspire the nephrology community not only to advocate for but also to demand high-quality, structured health care delivery systems for all Americans in the context of social reform that improves the ecology, health, and well-being of our communities? If so, then perhaps we can eliminate the unacceptable premature morbidity and mortality associated with CKD and the tragedy of health inequities. By so doing, we could become global leaders not only in medical technology, as we currently are, but also in health promotion and disease prevention, truly leaving no patient behind.
Perivalvular Fibrosis and Monomorphic Ventricular Tachycardia
Authors: Francis E. Marchlinski
Journal: Circulation (2007)

T he basis for arrhythmogenesis in patients with nonische- mic cardiomyopathy and ventricular tachycardia (VT) needs further elucidation.Cardiac arrest and/or nonsustained VT are common arrhythmia presentations in the setting of nonischemic cardiomyopathy, with sustained monomorphic VT being relatively uncommon. 1,2Importantly, bundlebranch reentrant VT is identified as the VT mechanism in a significant percentage of patients with monomorphic VT in the setting of nonischemic cardiomyopathy. 3,4However, even in patients with nonischemic left ventricular (LV) or right ventricular (RV) cardiomyopathy, the majority of VT appears to originate from the myocardium and is not due to bundlebranch reentry. 4 -11 Detailed substrate, activation, and entrainment mapping has begun to provide some valuable clues related to the mechanism and pathophysiology of scar-based VT in the setting of nonischemic cardiomyopathy resulting from a variety of causes. 4 -11 Although not focusing on VT after valve surgery, these data have been helpful in identifying likely regions of origin for VT and facilitating ablative therapy in other nonischemic settings.
Tumor Growth Inhibition by Olaparib in <i>BRCA2</i> Germline-Mutated Patient-Derived Ovarian Cancer Tissue Xenografts
Authors: Ursula Kortmann, Jessica N. McAlpine, Hui Xue, Jun Guan, Gavin Ha, Sophie Tully, Sharaz Shafait, Alan Lau, Aaron N. Cranston, Mark J. O'Connor, David G. Huntsman, Yuzhuo Wang, C. Blake Gilks
Journal: Clinical Cancer Research (2010)

Most patients with ovarian carcinomas succumb to their disease and there is a critical need for improved therapeutic approaches. Carcinomas arising in BRCA mutation carriers display defective DNA double-strand break repair that can be therapeutically exploited by inhibition of PARP-1, a key enzyme in the repair of DNA single-strand breaks, creating synthetic lethality in tumor cells.To investigate synthetic lethality in vivo, we established a BRCA2 germline-mutated xenograft model that was developed directly from human ovarian cancer tissue, treated with the PARP inhibitor olaparib (AZD2281) alone and in combination with carboplatin.We show that olaparib alone and in combination with carboplatin greatly inhibit growth in BRCA2-mutated ovarian serous carcinoma. This effect was not observed in a serous carcinoma with normal BRCA function, showing a specific antitumor effect of olaparib in mutation carriers. Immunohistochemistry (cleaved caspase-3 and Ki-67 stains) of remnant tissue after olaparib treatment revealed significantly decreased proliferation and increased apoptotic indices in these tumors compared with untreated controls. Furthermore, olaparib-treated tumors showed highly reduced PARP-1 activity that correlated with olaparib levels.We established a BRCA2-mutated human ovarian cancer xenograft model suitable for experimental drug testing. The demonstrated in vivo efficacy of olaparib extends on the preclinical rationale for further clinical trials targeting ovarian cancer patients with BRCA mutations.
Hypoxia reduces endothelin production by rat alveolar type II cells in primary culture
Authors: B Crestani, C Odoux, C Rolland, F Moldovan, P Cornillet, J Fiet, M Aubier
Journal: European Respiratory Journal (1998)

The purpose of the study was to describe endothelin (ET) production and to characterize the effect of hypoxia on preproendothelin-1 (preproET-1) messenger ribonucleic acid (mRNA) expression and ET secretion by rat type II pneumocytes in vitro. Rat type II pneumocytes were incubated in a sealed chamber containing a normoxic (21% O2) or hypoxic (1% O2) atmosphere for increasing durations. Immunoreactive ET (irET) was measured in cell supernatants using a radioimmunoassay. Rat preproET-1 mRNA was detected by Northern blot. Rat type II pneumocytes expressed preproET-1 mRNA, contained irET and secreted irET in a time-dependent manner. ET secretion was dependent on de novo ribonucleic acid (RNA) and protein synthesis. Hypoxia decreased irET secretion by 27% and reduced the steady-state level of preproET-1 mRNA by 60% whereas intracellular irET concentration was unchanged. Inhibition was partially reversible with the return to a normoxic atmosphere. Inhibition of nitric oxide synthesis did not prevent the inhibitory effect of hypoxia. In conclusion, rat type II pneumocytes in primary culture secreted immunoreactive endothelin and expressed preproendothelin-1 messenger ribonucleic acid. Hypoxia reversibly reduced endothelin-1 production through a reduction of the steady-state preproendothelin-1 messenger ribonucleic acid level. Nitric oxide synthesis did not mediate the inhibitory effect of hypoxia.
Phase I/II Trial of Carboplatin and Paclitaxel Chemotherapy in Combination with Intravenous Oncolytic Reovirus in Patients with Advanced Malignancies
Authors: Eleni M. Karapanagiotou, Victoria Roulstone, Katie Twigger, Mercel Ball, MaryAnne Tanay, Chris Nutting, Kate Newbold, Martin E. Gore, James Larkin, Konstantinos N. Syrigos, Matt Coffey, Brad Thompson, Karl Mettinger, Richard G. Vile, Hardev S. Pandha, Geoff D. Hall, Alan A. Melcher, John Chester, Kevin J. Harrington
Journal: Clinical Cancer Research (2012)

Reovirus type 3 Dearing (RT3D) replicates preferentially in Ras-activated cancers. RT3D shows synergistic in vitro cytotoxicity in combination with platins and taxanes. The purpose of this phase I/II study was to assess RT3D combined with carboplatin/paclitaxel in patients with advanced cancers.Patients were initially treated in a dose-escalating, phase I trial with intravenous RT3D days 1 to 5, carboplatin [area under curve (AUC) 5, day 1] and paclitaxel (175 mg/m(2), day 1) 3-weekly. RT3D was escalated through three dose levels: 3 × 10(9), 1 × 10(10), and 3 × 10(10) TCID(50) in cohorts of three. Primary endpoints were to define the maximum tolerated dose and dose-limiting toxicity and to recommend a dose for phase II studies. Secondary endpoints included pharmacokinetics, immune response, and antitumor activity. A subsequent phase II study using the 3 × 10(10) TCID(50) dose characterized the response rate in patients with head and neck cancer.Thirty-one heavily pretreated patients received study therapy. There were no dose-limiting toxicities during dose-escalation and most toxicities were grade I/II. Overall effectiveness rates were as follows: one patient had a complete response (3.8%), six patients (23.1%) had partial response, two patients (7.6%) had major clinical responses clinically evaluated in radiation pretreated lesions which are not evaluable by Response Evaluation Criteria in Solid Tumors (RECIST), nine patients (34.6%) had stable disease, and eight patients (30.8%) had disease progression. Viral shedding was minimal and antiviral immune responses were attenuated compared with previous single-agent data for RT3D.The combination of RT3D plus carboplatin/paclitaxel is well tolerated with evidence of activity in cancer of the head and neck. A randomized phase III study is currently open for recruitment.
<b> <i>p53</i> </b> Polymorphism and Age of Onset of Hereditary Nonpolyposis Colorectal Cancer in a Caucasian Population
Authors: J. Shawn Jones, Xuedong Chi, Xiangjun Gu, Patrick M. Lynch, Christopher I. Amos, Marsha L. Frazier
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant syndrome of familial malignancies. Colorectal and endometrial cancers are most frequently observed. The syndrome results mainly from germ-line mutations in DNA mismatch repair genes. A common G-to-C polymorphism at codon 72 in the p53 gene has been associated with increased risk for lung, nasopharyngeal, oral, prostate, and breast cancers and may be a marker for genetic susceptibility to colorectal cancer. We studied the influence of this p53 polymorphism on HNPCC age of onset. Experimental Design: We determined the p53 genotype of 92 Caucasian mismatch repair mutation carriers, of which, 47 had colorectal cancer. The subjects were genotyped by single-strand conformational polymorphism analysis. We tested the association between age of onset and the p53 genotypes by comparing Kaplan-Meier survival curves, evaluating the homogeneity of the curves using the log-rank test and Wilcoxon’s test, and estimating the association using the Cox proportional hazards regression model to adjust for potential demographic confounding factors. Results: The HNPCC patients who were heterozygous developed their colorectal cancer 13 years earlier than HNPCC patients who were homozygous for the wild-type allele. Conclusions: Combining knowledge of an individual’s p53 genotype with information on other genetic and environmental risk factors may improve risk estimates and help to identify individuals who are genetically susceptible to developing HNPCC at an earlier age.
A novel informatics concept for high-throughput shotgun lipidomics based on the molecular fragmentation query language
Authors: Ronny Herzog, Dominik Schwudke, Kai Schuhmann, Julio L Sampaio, Stefan R Bornstein, Michael Schroeder, Andrej Shevchenko
Journal: Genome biology (2011)

Shotgun lipidome profiling relies on direct mass spectrometric analysis of total lipid extracts from cells, tissues or organisms and is a powerful tool to elucidate the molecular composition of lipidomes. We present a novel informatics concept of the molecular fragmentation query language implemented within the LipidXplorer open source software kit that supports accurate quantification of individual species of any ionizable lipid class in shotgun spectra acquired on any mass spectrometry platform.
Vaccination of colorectal cancer patients with CEA-loaded dendritic cells: antigen-specific T cell responses in DTH skin tests
Authors: W.J. Lesterhuis, I.J.M. de Vries, D.H. Schuurhuis, A.C.I. Boullart, J.F.M. Jacobs, A.J. de Boer, N.M. Scharenborg, H.M.H. Brouwer, M.W.M.M. van de Rakt, C.G. Figdor, T.J. Ruers, G.J. Adema, C.J.A. Punt
Journal: Annals of Oncology (2006)
Effectiveness of bacteriophages in the sputum of cystic fibrosis patients
Authors: E. Saussereau, I. Vachier, R. Chiron, B. Godbert, I. Sermet, N. Dufour, J.-P. Pirnay, D. De Vos, F. Carrié, N. Molinari, L. Debarbieux
Journal: Clinical Microbiology and Infection (2014)
Constitutive activation of p38 MAPK in tumor cells contributes to osteolytic bone lesions in multiple myeloma
Authors: J Yang, J He, J Wang, Y Cao, J Ling, J Qian, Y Lu, H Li, Y Zheng, Y Lan, S Hong, J Matthews, M W Starbuck, N M Navone, R Z Orlowski, P Lin, L W Kwak, Q Yi
Journal: Leukemia (2012)
The Numbers Game: The Risky Business of Projecting Risk
Authors: K. J. Helzlsouer
Journal: JNCI Journal of the National Cancer Institute (2011)

JNCI Vol. 103, Issue 13 | July 6, 2011 In this issue of the Journal, Petracci et al. ( 1 ) present a model to estimate the degree of benefit in terms of breast cancer risk reduction that may be achieved with risk factor modification. By how much would breast cancer risk change over a 10-year period for a 45-yearold Italian woman making changes in modifiable risk factors such as exercise, weight , and/or alcohol use? According to this well-designed and conducted study, all of the following answers are correct: 0.4% , 0.6%, and 20.5%. These figures refer to individual absolute risk reduction, population-level absolute risk reduction, and population fractional risk reduction (akin to the population attributable risk), respectively, and are associated with change in one (individual absolute risk reduction) or all modifiable risk factors (population-level risk reduction estimates). The compatible, yet disparate numbers, for the absolute risk reduction and fractional risk reduction risk estimates is a difficult concept to grasp — even more challenging is when and how to apply the estimates. The results of this study provide a welcome spotlight on the complexity of predicting, interpreting, and communicating risk on both an individual and population level. By sound statistical methodology and data from a welldesigned , large , Italian , multicenter case – control study of invasive breast cancer, Petracci et al. ( 1 ) extend previous work on breast cancer prediction models by incorporating modifi able risk factors and assessing the potential reductions in risk that might result if the modifi able risk factor profi le could be optimized. The calibration and discriminatory ability of the model when evaluated in an independent cohort was similar to other prediction models ( 1 , 2 ). The Numbers Game: The Risky Business of Projecting Risk
Safety and Antitumor Activity of Anti–PD-1 Antibody, Nivolumab, in Patients With Platinum-Resistant Ovarian Cancer
Authors: Junzo Hamanishi, Masaki Mandai, Takafumi Ikeda, Manabu Minami, Atsushi Kawaguchi, Toshinori Murayama, Masashi Kanai, Yukiko Mori, Shigemi Matsumoto, Shunsuke Chikuma, Noriomi Matsumura, Kaoru Abiko, Tsukasa Baba, Ken Yamaguchi, Akihiko Ueda, Yuko Hosoe, Satoshi Morita, Masayuki Yokode, Akira Shimizu, Tasuku Honjo, Ikuo Konishi
Journal: Journal of Clinical Oncology (2015)

Purpose Programmed death-1 (PD-1), a coinhibitory immune signal receptor expressed in T cells, binds to PD-1 ligand and regulates antitumor immunity. Nivolumab is an anti–PD-1 antibody that blocks PD-1 signaling. We assessed the safety and antitumor activity of nivolumab in patients with platinum-resistant ovarian cancer. Patients and Methods Twenty patients with platinum-resistant ovarian cancer were treated with an intravenous infusion of nivolumab every 2 weeks at a dose of 1 or 3 mg/kg (constituting two 10-patient cohorts) from October 21, 2011. This phase II trial defined the primary end point as the best overall response. Patients received up to six cycles (four doses per cycle) of nivolumab treatment or received doses until disease progression occurred. Twenty nivolumab-treated patients were evaluated at the end of the trial on December 7, 2014. Results Grade 3 or 4 treatment-related adverse events occurred in eight (40%) of 20 patients. Two patients had severe adverse events. In the 20 patients in whom responses could be evaluated, the best overall response was 15%, which included two patients who had a durable complete response (in the 3-mg/kg cohort). The disease control rate in all 20 patients was 45%. The median progression-free survival time was 3.5 months (95% CI, 1.7 to 3.9 months), and the median overall survival time was 20.0 months (95% CI, 7.0 months to not reached) at study termination. Conclusion This study, to our knowledge, is the first to explore the effects of nivolumab against ovarian cancer. The encouraging safety and clinical efficacy of nivolumab in patients with platinum-resistant ovarian cancer indicate the merit of additional large-scale investigations (UMIN Clinical Trials Registry UMIN000005714).
Can clinical factors at presentation be used to predict outcome of treatment with methotrexate in patients with early inflammatory polyarthritis?
Authors: S L Hider, A J Silman, W Thomson, M Lunt, D Bunn, D P M Symmons
Journal: Annals of the Rheumatic Diseases (2008)

Purpose: Methotrexate (MTX) is the first choice conventional disease-modifying antirheumatic drug (DMARD) for rheumatoid arthritis. It is not universally effective, however; although to date it is not possible to predict with any accuracy which patients will respond to treatment. The aim of this analysis was to examine whether clinical and genetic variables could be used to predict response to MTX. Methods: Patients recruited to the Norfolk Arthritis Register (NOAR), a primary care based inception cohort of patients with inflammatory polyarthritis, were eligible for this analysis if they were commenced on MTX as their first DMARD within 3 months of their baseline visit and had at least 2 years of follow-up data. Outcome on MTX was defined as: (1) stopped for adverse events; (2) stopped for inefficacy or second DMARD added; (3) stopped for other reasons; or (4) remained on MTX monotherapy. Multiple logistic regression was used to establish which variables (including demographics, disease activity and Health Assessment Questionnaire score) predicted stopping monotherapy for inefficacy or adverse event (with those remaining on treatment taken as the referent category). The area under the Receiver Operating Characteristic curves (AUC ROC), were used to determine how accurate the model was at predicting outcome. Results: 309 patients were included in this analysis. At 1 year (2 years), 34 (46) patients had stopped for adverse events and 25 (49) had either stopped monotherapy for inefficacy or had a second DMARD added. 231 (188) patients remained on MTX monotherapy. The strongest predictor of inefficacy at both time points was shared epitope positivity: odds ratios (OR) 5.8 (95% confidence intervals (CI) 1.3 to 25.6) at 1 year, OR 3.0 (95% CI 1.3 to 7.3) at 2 years. High Health Assessment Questionnaire score (OR 1.84 95% CI 1.12 to 3.01) and female gender (OR 2.2, 95% CI 0.92 to 5.28) were associated with adverse events on MTX at 1 year. However, even the most optimal combinations of the factors analysed were only weakly predictive of treatment outcome: AUC ROC for adverse events 0.68 (95% CI 0.58 to 0.78) and for inefficacy AUC ROC 0.71 (95% CI 0.6 to 0.81). Conclusions: Within this cohort, routine clinical and laboratory factors were poor at predicting outcome of treatment with MTX. Given the major therapeutic advantage to be derived from accurate prediction of treatment outcome, further studies will need to investigate novel biological and other markers.