tbuckley/cabot-search huggingface dataset:
<i>CCR</i> 20th Anniversary Commentary: MAPK/ERK Pathway Inhibition in Melanoma—Kinase Inhibition Redux
Authors: Diwakar Davar, John M. Kirkwood
Journal: Clinical Cancer Research (2015)

Abstract In the January 15, 2012, issue of Clinical Cancer Research, Kirkwood and colleagues published a study comparing the MEK inhibitor selumetinib with temozolomide in unselected metastatic melanoma. Although selumetinib did not improve survival or response, most responders had BRAF-activating mutations, and selumetinib has since demonstrated efficacy in BRAF-mutant melanoma. This study laid the groundwork for the evaluation of BRAF/MEK inhibitors in BRAF-mutant melanoma. Clin Cancer Res; 21(24); 5412–4. ©2015 AACR. See related article by Kirkwood et al., Clin Cancer Res 2011;18(2) January 15, 2012;555–67
P9754 therapeutic intensification in non-metastatic osteosarcoma: A COG trial
Authors: C. L. Schwartz, L. H. Wexler, M. Devidas, A. Goorin, H. Grier, P. Meyers, M. Bernstein
Journal: Journal of Clinical Oncology (2004)

8514 Background: Outcome in osteosarcoma (OS) is predicted by percent necrosis (% NEC) after pre-operative chemotherapy. Efforts to improve outcome by post-operative therapeutic intensification have had limited success. Historically, 70% are standard responders (SR: < 98% NEC) whose outcomes justify efforts to intensify therapy. Methods: Patients <31 yrs diagnosed with non-metastatic OS were eligible for P9754. The objectives were 1) to assess feasibility of dose intensified regimens for SR and 2) to determine whether the cardioprotectant dexrazoxane (DXR) would adversely impact % NEC vs. historical outcomes. All received doxorubicin (75 mg/m2/cycle × 6; each dose with DXR), methotrexate (12 mg/m2 [20 mg max] × 10), cisplatin (120 mg/m2/cycle × 4). Pilots 2 and 3 also included
Development of a decision tree based on real life primary care data: Can we predict the diagnoses asthma, COPD and asthma/COPD overlap syndrome based on automatic data analysis?
Authors: Esther Metting, Niels Chavannes, Richard Dekhuizen, Daniel Dresden, Frederiek Swart, Hans In 't Veen, Thys van der Molen
Journal: European Respiratory Journal (2014)

Introduction The Asthma/COPD(AC) tele-medicine service in the North of the Netherlands supports general practitioner(GP)s in managing their patients by cooperating with pulmonologists. GPs (n=352) can refer patients (current n=17,000) with respiratory complaints to the service where patients are assessed according to a strict protocol. The pulmonologists (n=13) evaluate the outcomes online and send diagnosis (asthma, COPD, asthma/COPD-overlap syndrome (ACOS) or diagnosis uncertain) and management advice to the GP. Data from 12,0000 patients is stored and available for research.

Aim To explore if a decision tree could support the evaluation of individual assessments automatically.

Method A decision tree was developed using exhaustive Chi-squared Automatic Interaction Detection(CHAID) analysis. The database was randomly divided in a training file (n=4,697) and test file (n=4,623). The post-bronchodilator FEV1/FVC ratio was used as first predictor, other predictors in order of significance were age of onset, smoking, allergy, hyperreactivity, reversibility, post-FEV1 , wheezing, family history and age.

Result The current decision tree (50% men, mean age 54±17 years, 49% smoker) was able to correctly predict 80% of the asthma patients, 81% of the COPD patients and 31% of the ACOS patients.

Discussion The diagnosis asthma and COPD could be correctly predicted in most patients by using this instrument. Our decision tree is considered to be promising because it was based on real life primary care data and used diagnoses made by pulmonologists. The clinical implication of the decision tree needs further debate.
Sequential Assessment Of Molecular Aberrations In Chronic Myelomonocytic Leukemia By Next Generation Sequencing
Authors: Clara Ricci, Elena Trombetta, Giorgia Saporiti, Wilma Barcellini, Alessandra Freyrie, Giulia Galassi, Agostino Cortelezzi, Domenico Delia, Francesco Onida
Journal: Blood (2013)
Incidence of isolated brain metastases (CNS mets) following complete response (CR) in esophageal cancer
Authors: Y. Akmal, A. Bernath, N. Siegelmann-Danieli, S. Dubagunta, O. Yumen, D. Christie, A. Petrick, C. Wood, D. Bertsch, A. Law
Journal: Journal of Clinical Oncology (2005)

4242 Background: Preoperative chemoradiation (CRT) followed by surgery has recently become a promising treatment for esophageal cancer. CNS mets are rare and reported <5% (Weinberg, Cancer 98:1925). The lungs, liver, and adrenal glands are common sites of metastases. Methods: We reviewed 51 patients (pts) with stage II (17), III (28), and IV (6) esophageal cancers treated with preoperative CRT followed by surgery when possible. Pts were treated from 1995–2004. Twenty-six pts received 2 cycles of cisplatin 80–100mg/m2 day 1, 5-FU 1000mg/m2 days 1–4; 25 pts received weekly taxane 30–40mg/m2, cisplatin 30mg/m2, together with 50.4 Gy given as 180 cGy fraction. Results: Males (48). Females (3). Median age 62 yrs (range,42–82). Adenocarcinoma (42), squamous (5), other (4). Twenty-seven of 51 pts (52%) had CR following preoperative CRT. Twenty of 27 pts underwent surgical resection. Sites of recurrent disease in CR pts: CNS (2), CNS+liver(1), lung (1), lymph nodes (ln) (4), liver (1), local (2). 2 pts have CNS mets as the sole site of recurrent disease and occurred within 18 months of diagnosis. Sites of recurrent disease in pts who did not have CR: liver (4), liver+bone(1), peritoneum (2), bone (1), ln (4), lung (1), ln+lung (1), local+ln (2), local (1). The 3-yr survival estimate of CR pts underwent surgical resection was 59% with 10 of 26 resected pts alive ≥ 3 yrs after complete surgical resection of the primary esophageal cancer. The 3-yr survival estimate of pts without CR was 18%. Conclusions: Preoperative CRT appears to impact the natural history of disease and pattern of disease failure. Overall incidence of CNS mets was 11% (3/28). Incidence of isolated CNS mets following CR was 18% (2/11). Although the current series is small, the data suggest that pts with advanced esophageal cancer who achieved CR are at high risk for CNS mets as sole site of recurrence during the first 2 yrs of treatment. No significant financial relationships to disclose.
Re: Alberto Briganti, Thomas Wiegel, Steven Joniau, et al. Early Salvage Radiation Therapy Does Not Compromise Cancer Control in Patients with pT3N0 Prostate Cancer After Radical Prostatectomy: Results of a Match-controlled Multi-institutional Analysis. Eur Urol 2012;62:472–87
Authors: Emily Vertosick, Andrew Vickers
Journal: European Urology (2013)
Checkpoint inhibitors synergize with therapeutic platforms, ZVex™ and GLAAS™ by enhancing lentiviral vector-induced tumor-specific immunity and adjuvant-mediated anti-tumor efficacy
Authors: Tina C Albershardt, Andrea J Parsons, Jan ter Meulen, Peter Berglund
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts The dysregulation of immune checkpoints by tumors is an important mechanism of immune resistance, as administration of checkpoint inhibitors has resulted in impressive clinical responses in patients with late stage cancers. However, a subset of patients exhibits insufficient or no
Long-term Safety and Efficacy of Mexiletine for Patients With Skeletal Muscle Channelopathies
Authors: Karen Joan Suetterlin, Enrico Bugiardini, Juan P. Kaski, Jasper M. Morrow, Emma Matthews, Michael G. Hanna, Doreen Fialho
Journal: JAMA Neurology (2015)

Long-term Safety and Efficacy of Mexiletine for Patients With Skeletal Muscle ChannelopathiesThe skeletal muscle channelopathies include the nondystrophic myotonias and the periodic paralyses.Myotonia is the core clinical feature of the nondystrophic myotonias and may be a feature of hyperkalemic periodic paralysis.It is caused by mutations in the skeletal muscle voltage-gated chloride channel gene CLCN1 or sodium channel gene SCN4A.Adequate treatment of myotonia is important for quality of life, mobility, and functional independence. 1Mexiletine acts on voltage-gated sodium channels.Its most frequent adverse effect is gastrointestinal 2,3 but minor neurological effects (eg, tremor) are also reported. 4,5 Two randomized clinical trials have demonstrated the efficacy of mexiletine for the short-term treatment of myotonia 2,3 but long-term safety and efficacy data outside a trial setting are lacking.We performed a retrospective review of our large skeletal muscle channelopathy patient cohort to address this.
Prostate Cancer Early Detection, Version 1.2014
Authors: Peter R. Carroll, J. Kellogg Parsons, Gerald Andriole, Robert R. Bahnson, Daniel A. Barocas, William J. Catalona, Douglas M. Dahl, John W. Davis, Jonathan I. Epstein, Ruth B. Etzioni, Veda N. Giri, George P. Hemstreet, Mark H. Kawachi, Paul H. Lange, Kevin R. Loughlin, William Lowrance, Paul Maroni, James Mohler, Todd M. Morgan, Robert B. Nadler, Michael Poch, Chuck Scales, Terrence M. Shanefelt, Andrew J. Vickers, Robert Wake, Dorothy A. Shead, Maria Ho
Journal: Journal of the National Comprehensive Cancer Network (2014)

The NCCN Guidelines for Prostate Cancer Early Detection provide recommendations for men choosing to participate in an early detection program for prostate cancer. These NCCN Guidelines Insights highlight notable recent updates. Overall, the 2014 update represents a more streamlined and concise set of recommendations. The panel stratified the age ranges at which initiating testing for prostate cancer should be considered. Indications for biopsy include both a cutpoint and the use of multiple risk variables in combination. In addition to other biomarkers of specificity, the Prostate Health Index has been included to aid biopsy decisions in certain men, given recent FDA approvals.
Differences Between Graft-Versus-Leukemia and Graft-Versus-Host Reactivity. I. Interaction of Donor Immune T Cells With Tumor and/or Host Cells
Authors: Marian Rocha, Victor Umansky, Kyeong-Hee Lee, Hans-Jörg Hacker, Axel Benner, Volker Schirrmacher
Journal: Blood (1997)
Abstract #5484 : SN-38 encapsulated in targeted polymer micelles induce tumor regression in multiple colorectal cancer models
Authors: Kevin Sill, Jonathan Rios-Doria, Adam Carie, Gregoire Cardoen, Richard Slama, Habib Skaff
Journal: Cancer Research (2009)

SN-38, the active metabolite of irinotecan, is up to 1000 times more cytotoxic to cancer cells in vitro, but cannot be used clinically because it is insoluble in aqueous solutions. Based upon the IVECT\#8482; drug delivery platform, we have developed an amphiphilic triblock copolymer capable of encapsulating up to 14 wt % SN-38 in a polymer micelle (IT-141). The particle size of the micelle is approximately 50 nm as determined by dynamic light scattering. In vitro, these SN38-micelles induce S-phase arrest and exhibits potent cytotoxicity in a wide array of cancer cell lines. In vivo, injection of the polymer alone was tolerated up to 2400 mg/kg and displayed no gross toxicities or reduction in body weight. The single dose MTD of IT-141 was 150 mg/kg, whereas the multi-dose MTD was determined to be 45 mg/kg. IT-141 induced tumor regression in colorectal cancer xenograft models HT-29 and HCT116, with tumor growth inhibition observed at doses as low as 5 mg/kg. The differences between untargeted micelles and micelles decorated with integrin-targeting peptides will be discussed. In summary, we have developed a potent formulation of micelle-encapsulated SN-38 for the treatment of colorectal cancer.   Citation Information:  In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5484 .
Modulation of EZH2 Expression by MEK-ERK or PI3K-AKT Signaling in Lung Cancer Is Dictated by Different KRAS Oncogene Mutations
Authors: Erick Riquelme, Carmen Behrens, Heather Y. Lin, George Simon, Vassiliki Papadimitrakopoulou, Julie Izzo, Cesar Moran, Neda Kalhor, J. Jack Lee, John D. Minna, Ignacio I. Wistuba
Journal: Cancer Research (2015)

Abstract EZH2 overexpression promotes cancer by increasing histone methylation to silence tumor suppressor genes, but how EZH2 levels become elevated in cancer is not understood. In this study, we investigated the mechanisms by which EZH2 expression is regulated in non–small cell lung carcinoma cells by oncogenic KRAS. In cells harboring KRASG12C and KRASG12D mutations, EZH2 expression was modulated by MEK–ERK and PI3K/AKT signaling, respectively. Accordingly, MEK–ERK depletion decreased EZH2 expression in cells harboring the KRASG12C mutation, whereas PI3K/AKT depletion decreased EZH2 expression, EZH2 phosphorylation, and STAT3 activity in KRASG12D-mutant cell lines. Combined inhibition of EZH2 and MEK–ERK or PI3K/AKT increased the sensitivity of cells with specific KRAS mutations to MEK–ERK and PI3K/AKT–targeted therapies. Our work defines EZH2 as a downstream effector of KRAS signaling and offers a rationale for combining EZH2 inhibitory strategies with MEK–ERK- or PI3K/AKT–targeted therapies to treat lung cancer patients, as stratified into distinct treatment groups based on specific KRAS mutations. Cancer Res; 76(3); 675–85. ©2015 AACR.
Natural History of Stage IV Epithelial Ovarian Cancer
Authors: H. Bonnefoi, R. P. A'Hern, C. Fisher, V. Macfarlane, D. Barton, P. Blake, J. H. Shepherd, M. E. Gore
Journal: Journal of Clinical Oncology (1999)

PURPOSE: In this report we present the natural history, prognostic factors, and therapeutic implications of stage IV epithelial ovarian cancer (EOC). PATIENTS AND METHODS: We reviewed 192 patients with stage IV EOC as defined in 1985 by the International Federation of Gynecology and Obstetrics. RESULTS: The site of stage IV–defining disease was cytologically positive pleural effusion in 63 patients, liver in 50 patients, lymph nodes in 26 patients, lung in six patients, other sites in 15 patients, and disease at multiple stage IV–defining metastatic sites in 32 patients. Surgery was performed before chemotherapy in 169 patients; 25 patients (14.8%) were left with only microscopic residual disease or less than 2 cm of macroscopic residual disease. The overall response rate to chemotherapy was 56%; the complete response rate was 18%. The median progression-free survival was 7.1 months, and the median overall survival was 13.4 months. The median overall survival of patients with positive pleural effusions only was 13.4 months as compared with 10.5 months for patients with visceral disease only, but this difference was not statistically significant. The 5-year survival rate was 7.6%, with only six patients surviving more than 5 years. Univariate and multivariate analysis showed that two parameters were associated with a shorter survival time: visceral involvement (lung or liver) and diagnosis before 1984. CONCLUSION: Patients with stage IV EOC initially respond to chemotherapy as often as those with less advanced disease, but the long-term prognosis is very poor. The size of residual disease is not a prognostic factor in this group of patients, and, therefore, the role of debulking surgery in these patients needs to be reconsidered.
The Time Scale of Recombination Rate Evolution in Great Apes
Authors: Laurie S. Stevison, August E. Woerner, Jeffrey M. Kidd, Joanna L. Kelley, Krishna R. Veeramah, Kimberly F. McManus, Carlos D. Bustamante, Michael F. Hammer, Jeffrey D. Wall
Journal: Molecular Biology and Evolution (2015)

We present three linkage-disequilibrium (LD)-based recombination maps generated using whole-genome sequence data from 10 Nigerian chimpanzees, 13 bonobos, and 15 western gorillas, collected as part of the Great Ape Genome Project (Prado-Martinez J, et al. 2013. Great ape genetic diversity and population history. Nature 499:471–475). We also identified species-specific recombination hotspots in each group using a modified LDhot framework, which greatly improves statistical power to detect hotspots at varying strengths. We show that fewer hotspots are shared among chimpanzee subspecies than within human populations, further narrowing the time scale of complete hotspot turnover. Further, using species-specific PRDM9 sequences to predict potential binding sites (PBS), we show higher predicted PRDM9 binding in recombination hotspots as compared to matched cold spot regions in multiple great ape species, including at least one chimpanzee subspecies. We found that correlations between broad-scale recombination rates decline more rapidly than nucleotide divergence between species. We also compared the skew of recombination rates at centromeres and telomeres between species and show a skew from chromosome means extending as far as 10–15 Mb from chromosome ends. Further, we examined broad-scale recombination rate changes near a translocation in gorillas and found minimal differences as compared to other great ape species perhaps because the coordinates relative to the chromosome ends were unaffected. Finally, on the basis of multiple linear regression analysis, we found that various correlates of recombination rate persist throughout the African great apes including repeats, diversity, and divergence. Our study is the first to analyze within- and between-species genome-wide recombination rate variation in several close relatives.
Re: Idir Ouzaid and Karim Bensalah. Results of the First Trial Assessing Adjuvant Tyrosine Kinase Inhibitors in Renal Cell Carcinoma Do Not reASSURE. Eur Urol 2015;68:542–3
Authors: Matteo Santoni, Marina Scarpelli, Antonio Lopez-Beltran, Liang Cheng, Alberto Briganti, Francesco Montorsi, Rodolfo Montironi, Daniele Santini
Journal: European Urology (2015)
Association between injectable progestin-only contraceptives and HIV acquisition and HIV target cell frequency in the female genital tract in South African women: a prospective cohort study
Authors: Elizabeth H Byrne, Melis N Anahtar, Kathleen E Cohen, Amber Moodley, Nikita Padavattan, Nasreen Ismail, Brittany A Bowman, Gregory S Olson, Amanda Mabhula, Alasdair Leslie, Thumbi Ndung'u, Bruce D Walker, Musie S Ghebremichael, Krista L Dong, Douglas S Kwon
Journal: The Lancet Infectious Diseases (2015)
Cost savings using fractional exhaled nitric oxide (FeNO) testing in asthma management by specialists
Authors: Paul Dorinsky, Craig LaForce, Kathy Rickard, Nancy Herje, Elizabeth Brooks
Journal: European Respiratory Journal (2013)

INTRODUCTION  Routine clinical assessments including spirometry and asthma control tests (ACT) or questionnaires (ACQ) do not provide information about underlying airway inflammation in asthma. Whether measuring airway inflammation with a biomarker such as FeNO leads to more cost effective asthma management decisions remains unclear.  OBJECTIVES  To determine whether the use of FeNO in the specialist management of asthma results in more effective/cost effective treatment decisions.  METHODS  Fifty subjects ages 7-60 with established asthma participated in this single center, observational study. After performing spirometry and standard asthma assessments, health care practitioners (HCPs) clinically estimated airway inflammation and made treatment decisions. FeNO was then measured and any management changes based on knowing FeNO were made.  RESULTS  HCP assessments of airway inflammation were incorrect in 25 of 50 patients. Importantly, treatment decisions were substantially altered in 40% of subjects following FeNO determination. Medication reductions were made in 8 (16%) subjects with the average per month reduction estimated to be $221.38/subject. In 4 other patients, FeNO and clinical measures indicated changes could have been made. Finally, HCPs added/increased medications in 9 suboptimally managed patients to prevent worsening asthma, likely resulting in significant long term cost savings.  CONCLUSION  These results demonstrate that FeNO testing resulted in more effective/cost effective treatment decisions by asthma specialists with potential for substantial cost savings. Longitudinal studies will help further quantify the health economic benefit of FeNO testing for managing asthma.
Abstract 15690: Fibroblasts From Failing Human Heart Exhibit Increased Sensitivity to Dronedarone-Induced Oxidative Stress and Cell Death
Authors: Larisa Emelyanova, Mingyuan Liu, Guangyuan Yang, Elizabeth Stoeckl, Ekhson Holmuhamedov, Farhan Rizvi, Gracious Ross, Francis X. Downey, A. Jamil Tajik, Arshad Jahangir
Journal: Circulation (2015)

Introduction: Dronedarone (DR), a structural analog of amiodarone designed to reduce its extracardiac toxicity, recently was shown in clinical trials to increase heart failure (HF) and cardiovascular death in patients with severe myocardial dysfunction, but the mechanisms for these adverse cardiac effects are not known. Hypothesis: We hypothesized that DR increases oxidative stress and cell death in failing hearts with compromised energetic reserves compared to nonfailing hearts. Methods: Ventricular fibroblasts (VFB) from patients without HF (trauma victims) and with HF (left ventricular assist device implants) were cultured under similar conditions to passage 3 and treated with DR (0-10 μM) for 24h. Reactive oxygen species (ROS) production was assessed in cells loaded with general oxidative stress indicator CM-H2DCFDA (2μM), mitochondrial superoxide indicator MitoSOX Red (5 μM), and Hoechst 33342 (1μg/ml) for nuclear staining using confocal microscopy. Cell viability was assessed by counting the number of viable cells and lactate dehydrogenase assay. Results: VFB from HF patients exhibited a higher baseline level of total ROS (CM-H2DCFDA green fluorescence) when compared with non-HF patients (Fig. A). DR dose-dependently increased ROS production in VFB from HF patients (Fig. B) exhibiting a higher sensitivity to oxidative stress and cell death (Fig. C). Conclusions: The sensitivity of DR-induced oxidative stress and cytotoxicity is significantly increased in VFB from patients with HF and provides an explanation for adverse effects of DR reported in HF patients in clinical trials.
Balancing Protein Stability and Activity in Cancer: A New Approach for Identifying Driver Mutations Affecting CBL Ubiquitin Ligase Activation
Authors: Minghui Li, Stephen C. Kales, Ke Ma, Benjamin A. Shoemaker, Juan Crespo-Barreto, Andrew L. Cangelosi, Stanley Lipkowitz, Anna R. Panchenko
Journal: Cancer Research (2015)

Abstract Oncogenic mutations in the monomeric Casitas B-lineage lymphoma (Cbl) gene have been found in many tumors, but their significance remains largely unknown. Several human c-Cbl (CBL) structures have recently been solved, depicting the protein at different stages of its activation cycle and thus providing mechanistic insight underlying how stability—activity tradeoffs in cancer-related proteins—may influence disease onset and progression. In this study, we computationally modeled the effects of missense cancer mutations on structures representing four stages of the CBL activation cycle to identify driver mutations that affect CBL stability, binding, and activity. We found that recurrent, homozygous, and leukemia-specific mutations had greater destabilizing effects on CBL states than random noncancer mutations. We further tested the ability of these computational models, assessing the changes in CBL stability and its binding to ubiquitin-conjugating enzyme E2, by performing blind CBL-mediated EGFR ubiquitination assays in cells. Experimental CBL ubiquitin ligase activity was in agreement with the predicted changes in CBL stability and, to a lesser extent, with CBL-E2 binding affinity. Two thirds of all experimentally tested mutations affected the ubiquitin ligase activity by either destabilizing CBL or disrupting CBL-E2 binding, whereas about one-third of tested mutations were found to be neutral. Collectively, our findings demonstrate that computational methods incorporating multiple protein conformations and stability and binding affinity evaluations can successfully predict the functional consequences of cancer mutations on protein activity, and provide a proof of concept for mutations in CBL. Cancer Res; 76(3); 561–71. ©2015 AACR.