tbuckley/cabot-search huggingface dataset:
The Failing Heart Relies on Ketone Bodies as a Fuel
Authors: Gregory Aubert, Ola J. Martin, Julie L. Horton, Ling Lai, Rick B. Vega, Teresa C. Leone, Timothy Koves, Stephen J. Gardell, Marcus Krüger, Charles L. Hoppel, E. Douglas Lewandowski, Peter A. Crawford, Deborah M. Muoio, Daniel P. Kelly
Journal: Circulation (2016)

Background— Significant evidence indicates that the failing heart is energy starved. During the development of heart failure, the capacity of the heart to utilize fatty acids, the chief fuel, is diminished. Identification of alternate pathways for myocardial fuel oxidation could unveil novel strategies to treat heart failure. Methods and Results— Quantitative mitochondrial proteomics was used to identify energy metabolic derangements that occur during the development of cardiac hypertrophy and heart failure in well-defined mouse models. As expected, the amounts of proteins involved in fatty acid utilization were downregulated in myocardial samples from the failing heart. Conversely, expression of β-hydroxybutyrate dehydrogenase 1, a key enzyme in the ketone oxidation pathway, was increased in the heart failure samples. Studies of relative oxidation in an isolated heart preparation using ex vivo nuclear magnetic resonance combined with targeted quantitative myocardial metabolomic profiling using mass spectrometry revealed that the hypertrophied and failing heart shifts to oxidizing ketone bodies as a fuel source in the context of reduced capacity to oxidize fatty acids. Distinct myocardial metabolomic signatures of ketone oxidation were identified. Conclusions— These results indicate that the hypertrophied and failing heart shifts to ketone bodies as a significant fuel source for oxidative ATP production. Specific metabolite biosignatures of in vivo cardiac ketone utilization were identified. Future studies aimed at determining whether this fuel shift is adaptive or maladaptive could unveil new therapeutic strategies for heart failure.
Concurrent chemoradiotherapy with or without low molecular weigth heparin (LWMH) in the treatment of locally advanced non-small cell lung cancer (NSCLC).
Authors: A. Isikdogan, M. A. Kaplan, S. B. Zincircioglu, M. Cit, T. Cil, B. Karadayi, A. Dirier, M. Kucukoner, A. Inal, I. Yildiz
Journal: Journal of Clinical Oncology (2010)

e17526 Background: Approximately one third of patients with NSCLC has locally advanced disease that is surgically unresectable. Current treatment in these cases is concurrent chemoradiotherapy (CRT). Recently, heparin and also LWMH have been shown inhibit tumor growth and incriase the efficacy of chemotherapy. In this study, we decided to assess the efficacy of LWMH in patients with concurrent CRT with a unresectable locally advanced NSCLC. Methods: Between February 2003 and May 2009, the patients with locally advanced or medical inoperable NSCLC in our oncology clinic were evaluated as retrospective. The patients are divided into two grups. Group I is; concurrent CRT (30 fraction, 60 Gy radiotherapy (RT) + weekly docetaxel 25 mg/m2 + cisplatin 25 mg/m2, n: 26) and second, concurrent CRT (17 fraction, 51 Gy RT + weekly docetaxel 25 mg/m2 + cisplatin 25 mg/m2) in addition LWMH (enoxaparine 0.4 mg/day/RT everyday, n:32 ). Overall response rate (ORR), progression free survival (PFS), overall survival (OS) and toxicities were compaired. Results: Totally 58 patients were evaluated. Median age was 65 year. There was no statisticly significant difference by age, histological subtypes, performance status and following period (p>0.05) between two groups. According to stage there was statistically significant difference between two groups (in group 1 and 2, stage III A was respectively (23% vs. 0%), stage IIIB was (77% vs. 100%), all patients in group 2 were stage IIIB, p<0.01). There was no significant difference between groups in the point of treatment. ORR (85% and 69%), median PFS (9 mo vs. 9 mo) were similar between two groups (p>0.05). Median OS (11 mo vs. 14 mo) were found longer in the group taken LWMH but it was not statisticly significant (p>0.05). Treatment toxicity was tolerable and similar in both groups. Applied number of CT (4 vs. 6) and imposed RT lower (51 vs. 60 Gy) in second group than first group. Conclusions: This study shown that additional LWMH not to provide statistically significant contribution to weekly concurrent CRT for treatment response and survival. Although patients exposure lower dose RT and less numbers CT in second group, obtained equal efficiency and advers event in both group. No significant financial relationships to disclose.
Acute Myeloid Leukemia: Pretreatment Biochemical and Clinical Variables Predictive For Risk Status Based On Validated Cytogenetic and Molecular Abnormalities
Authors: Samer A Srour, Michael G Machiorlatti, Mohamad Cherry, Namali Pierson, Usman Z Bhutta, David M Thompson, Carla D Kurkjian
Journal: Blood (2013)
Quantification of MRD in rituximab plus CHOP (R-CHOP) therapy in follicular lymphoma (FL): Results of a randomized trial comparing the concurrent and sequential administrations
Authors: T. Kinoshita, K. Hanyu, M. Yuge, H. Nagai, T. Naoe, Y. Morishima, K. Itoh, T. Hotta, J. Enami, K. Tobinai
Journal: Journal of Clinical Oncology (2004)

6704
Final Overall Survival (Os) Analysis of Cou-Aa-302, a Randomized Phase 3 Study of Abiraterone Acetate (Aa) in Metastatic Castration-Resistant Prostate Cancer (Mcrpc) Patients (Pts) Without Prior Chemotherapy
Authors: C.J. Ryan, M.R. Smith, K. Fizazi, K. Miller, P. Mulders, C.N. Sternberg, F. Saad, T. Griffin, P. De Porre, Y.C. Park, J. Li, T. Kheoh, V. Naini, A. Molina, D.E. Rathkopf
Journal: Annals of Oncology (2014)
Genomic DNA Hypomethylation and Risk of Renal Cell Carcinoma: A Case–Control Study
Authors: Julia Mendoza- Pérez, Jian Gu, Luis A. Herrera, Nizar M. Tannir, Surena F. Matin, Jose A. Karam, Maosheng Huang, David W. Chang, Christopher G. Wood, Xifeng Wu
Journal: Clinical Cancer Research (2015)

Genomic DNA hypomethylation is a hallmark of most cancer genomes, promoting genomic instability and cell transformation. In the present study, we sought to determine whether global DNA methylation in peripheral blood is associated with risk of renal cell carcinoma (RCC).A retrospective case-control study consisting of 889 RCC cases and an equal number of age, gender, and ethnicity-matched controls was applied. Global DNA methylation was measured as 5-mC% content. Logistic regression was used to estimate odds ratio (OR) and 95% confidence interval (CI) for the association between DNA methylation level and the risk of RCC.The median 5-mC% was significantly lower in cases than in healthy controls (P< 0.001). In multivariate logistic regression analysis, individuals in the lowest tertile (T1) of 5-mC% had higher risk of RCC with OR of 1.40 (95% CI, 1.06-1.84), compared with individuals in the highest tertile (T3;Pfor trend= 0.02). When stratified by RCC risk factors, associations between hypomethylation and increased RCC risk appeared to be stronger among males (OR, 1.61;Pfor trend= 0.01), younger age (OR, 1.47;Pfor trend= 0.03), never smokers (OR, 1.55;Pfor trend= 0.02), family history of other cancer (OR, 1.64;Pfor trend= 1.22E-03), and late stage (OR, 2.06,Pfor trend= 4.98E-04). Additionally, we observed significant interaction between gender and 5-mC% in elevating RCC risk (Pfor interaction= 0.03).Our findings suggest an association between global DNA hypomethylation and RCC risk. To establish global DNA hypomethylation as a risk factor for RCC, future prospective studies are warranted. This study may provide further understanding of the etiology of RCC tumorigenesis.
Treatment patterns and clinical outcomes in lung cancer patients with brain metastasis
Authors: J. R. Gingerich, E. Lau, L. Xie, S. Navaratnam
Journal: Journal of Clinical Oncology (2007)

18010 Background: Controversies still exist in the optimal management of patients with meta- static brain cancer. Lung cancer is the most common cause of metastatic brain cancer and the present study examines the treatment pattern and clinical outcome of this group of patients. Methods: Using the provincial cancer registry, all patients in Manitoba, Canada, with a history of lung cancer diagnosed with brain metastases during 2003 and 2004 were identified and a detailed chart review was carried out. Univariate and multivariate logistic analysis were used to identify significant variables affecting 1-year survival. Results: A total of 229 patients were identified of which 112 were male. The median age was 65 (range = 39–90). Of these patients, 69% had non-small cell lung cancer, 17% had small cell cancer, and 14% did not have the histological diagnosis available. A single brain metastasis, 2–4 brain metastases, and &gt;4 brain metastases was identified in 25%, 25%, and 44% of the patients, respectively. The treatments for brain metastases were surgery (8%), gamma-knife radiosurgery (GKS) (7%), whole brain radiotherapy (WBRT) (62%), and no treatment (22%). Median survival for all patients was 98 days. On univariate analysis, 1-year survival was significantly influenced by surgery/GKS, age &lt; 65, and controlled systemic disease (Odds ratio = 7.90; 5.43; 3.72 respectively, P &lt; 0.02 for all) but not by sex, number of brain metastases or time from initial diagnosis to brain metastasis. On multivariate analysis, surgery/GKS and age remained significant (Odds ratio = 5.56, and 4.80, P &lt; 0.01). Median survival (days) by treatment type were: surgery/GKS = 297(178–461), WBRT = 105(82–119), none = 39(29–50); log rank &lt;0.001. Conclusions: In our patient population, with metastatic brain cancer arising from the lung, aggressive focal therapy (surgery or GKS) in younger patients (&lt; 65) was associated with significantly better overall survival. No significant financial relationships to disclose.
Phase I Study Of Inotuzumab Ozogamicin (InO) Combined With R-GDP For Relapsed/Refractory CD22+ B-Cell Non-Hodgkin Lymphoma (B-NHL)
Authors: Randeep Sangha, Andrew Davies, Nam H. Dang, Michinori Ogura, David A. MacDonald, Angela Volkert, Revathi Ananthakrishnan, Kenneth Luu, Joseph P. Boni, Erik Vandendries, Yeow-Tee YT Goh
Journal: Blood (2013)
A phase I, pharmacokinetic (PK) and pharmacodynamic (PD) study of weekly (qW) MK-0646, an insulin-like growth factor-1 receptor (IGF1R) monoclonal antibody (MAb) in patients (pts) with advanced solid tumors
Authors: F. Atzori, J. Tabernero, A. Cervantes, M. Botero, K. Hsu, H. Brown, W. Hanley, T. Macarulla, S. Rosello, J. Baselga
Journal: Journal of Clinical Oncology (2008)

3519 Background: IGF1R is a tyrosine kinase receptor that mediates both mitogenic and antiapoptotic pathways and that is expressed in a variety of tumor types. IGF1R activation also mediates resistance to a broad range of cytotoxic and targeted agents. MK-0646 is a humanized IgG1 MAb that binds to IGF1R with a Kd <1 nM, competes with ligand-binding, prevents receptor activation and promotes receptor internalization. This first in man phase I trial with MK-0646 was designed to study its safety; to identify an optimal dose and schedule; and to seek for in vivo evidence of IGF1R signaling blockade in tumors. Methods: Pts with IGF1R-expressing tumors by IHC were allocated to dose escalating cohorts of at least 6 patients each of MK-0646 given IV qW (1.25, 2.5, 5.0, 10, 15 and 20 mg/kg). Sequential (baseline and day 14) skin and tumor biopsies were collected for PD analysis. FDG-PET was also performed prior and on-treatment. Results: 48 pts (23 m, 25 f, median age 59 yrs), with chemo-refractory solid tumors (13 colorectal, 11 breast, 5 Ewing’s and 19 other) have been entered to date and are evaluable for safety assessment. One dose limiting toxicity (G3 purpura) was noted at 5.0 mg/Kg. Grade I-II hyperglycemia responding to metformin occurred in 10% of pts. MTD has not been identified. Plasma IGF1 levels increased in all pts. PK data support dose proportionality with a mean terminal t1/2 of 95 hours, and clearance saturation and a mean Cmin over the target at doses >5 mg/Kg. For pts with evaluable paired tumor biopsies (n=13), decreases in IGF1R expression, inhibition of IGF1R signaling (decreases in pAKT, pMAPK and pS6) and a decrease in Ki67 was observed at doses >5 mg/kg. FDG-PET metabolic responses occurred in 3 pts. One pt. with Ewing’s showed a mixed radiological response. Three pts had stable disease for >3 months. Conclusions: MK-0646 is safe and tolerable, exhibits approximately dose-proportional PK, inhibits IGF1R signaling and proliferation in treated tumors and has clinical activity. PK findings support a more extended dose-interval that is currently being evaluated (q2W & q3W). Updated clinical and biomarker data will be presented. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Merck Merck Merck Merck
Repeated Measurements of Hepatitis B Surface Antigen Identify Carriers of Inactive HBV During Long-term Follow-up
Authors: Willem P. Brouwer, Henry Lik-Yuen Chan, Maurizia R. Brunetto, Michelle Martinot-Peignoux, Pauline Arends, Markus Cornberg, Beatrice Cherubini, Alex J.V. Thompson, Yun-Fan Liaw, Patrick Marcellin, Harry L.A. Janssen, Bettina E. Hansen
Journal: Clinical Gastroenterology and Hepatology (2016)
Abstract P181: Long-term Exposure to Air Pollution and Risk of Systemic Inflammation-induced Multimorbidity among the Elderly: Results from the Population-based KORA-Age Study
Authors: Christine Autenrieth, Regina Hampel, Kathrin Wolf, Josef Cyrys, Angela Doring, Goran Pershagen, Annette Peters
Journal: Circulation (2013)

Background: Traffic-related exposure to air pollution is suggested to have adverse health effects on several chronic diseases including cardiovascular disease. However, studies on the association b...
Anaphylactoid reaction in a normal donor given granulocyte colony-stimulating factor.
Authors: D R Adkins
Journal: Journal of Clinical Oncology (1998)

Article Tools Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.1998.16.2.812 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 9469385 Anaphylactoid reaction in a normal donor given granulocyte colony-stimulating factor. D R AdkinsxD R AdkinsSearch for articles by this author https://doi.org/10.1200/JCO.1998.16.2.812 PDF "Anaphylactoid reaction in a normal donor given granulocyte colony-stimulating factor.." Journal of Clinical Oncology, 16(2), pp. 812–813© 1998 by American Society of Clinical Oncology
Bronchial hyperresponsiveness is associated with both increased methacholine-induced reduction in airway volume and reduced baseline airway volume
Authors: Laurent Plantier
Journal: European Respiratory Journal (2014)

Background. Airflow reduction in response to bronchoconstrictory stimuli, or bronchial hypersponsiveness (BHR), is a central feature of asthma. However, whether BHR indeed involves excessive reductions in airway caliber, and thus airway volume, was never demonstrated in humans. In addition, whether anatomical determinants predispose to BHR is a matter of debate.  Methods. 75 patients with normal baseline spirometry and referred for plethysmographic measurement of lung volumes and methacholine (Mch) challenge because of chronic cough, dyspnea, or wheezing, were included. Airway volume (Vaw) was determined before and after Mch challenge by volumetric capnography using the equal area (Fletcher9s) method, and expressed relative to total lung capacity (TLC). BHR was defined by a decrease of FEV1≥20% after exposure to up to 1.6 mg Mch. FEV1/Mch and Vaw/Mch dose response slopes were calculated. Data were analysed with Student9s t-test and Spearman9s rank order correlation.  Results. Patients with BHR had lower baseline Vaw/TLC in comparison with patients without BHR (31.8+/-8 ml/l, N=22 vs 37.8+/-11.7 ml/l, N=53, p=0.047). Patients with BHR also showed considerably higher Vaw reduction relative to the Mch dose (44.3+/-62 %/mg vs 2+/-9 %/mg, p=0.001). Vaw/Mch correlated with FEV1/ Mch (Rho=0.567, p=0.0001).  Discussion. This report demonstrates for the first time that patients with BHR exhibited higher Mch-induced reduction in airway volume, i.e. bronchoconstriction. It remains to define whether lower baseline airway volume in patients with BHR relates to underlying disease or anatomical predisposition.
OP0122 Fine Mapping of the CHR 22Q13.1 Juvenile Idiopathic Arthritis Risk Locus
Authors: H. Moncrieffe, A. Lele, K.A. Shams, B.E. Levy, M. Marion, M. Sudman, L. Brungs, J. Cobb, A. Hinks, J. Bohnsack, L.R. Wedderburn, J.-P. Haas, V. Videm, M. Rygg, E. Nordal, R.S. Yeung, M.T. Weirauch, L.C. Kottyan, S. Prahalad, C.D. Langefeld, W. Thomson, S.D. Thompson
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background</h3> Juvenile Idiopathic Arthritis (JIA) patients have arthritis onset of unknown cause that lasts &gt;6 weeks in the inflamed joints of children younger than 16 years. JIA is a complex genetic trait with established increased familial risk and robustly replicated genetic associations (e.g. HLA, <i>PTPN2</i>). Multiple single nucleotide polymorphisms (SNPs) in the 22q13.1 locus have reached genome-wide significance in recent genetic association studies using the Immunochip. The 22q13.1 locus contains both <i>IL2RB</i> and <i>RAC2</i> which are attractive candidates to influence JIA pathology and have respective roles in IL-2 signaling and cell migration. <h3>Objectives</h3> To identify the statistically, bioinformatically and experimentally most plausible causal SNPs associated with risk of JIA in the 22q13 region. <h3>Methods</h3> We fine mapped the <i>22q13.1</i> locus using data from large scale genotyping projects of a European ancestry cohort of subjects with (3,905) and without JIA (14,388) to predict variants most likely causal at the <i>22q13.1</i> locus. Logistic regression conditional analysis was used to define regions of association followed by Bayesian analysis to define variants with large posterior probabilities. Transcription factor binding predictions were used to identify variants for experimental testing by electrophoretic mobility shift assay (EMSA). We limited our investigation to polyarticular RF<sup>-</sup> and oligoarticular JIA cases to reduce phenotypic heterogeneity. <h3>Results</h3> Conditional analyses showed independent associations to JIA in both the <i>IL2RB</i> and <i>RAC2</i> loci. We identified two SNPs that can account for all of the JIA genetic association in this region. Using a Bayesian analysis we identified the SNPs that explained 95% of the posterior probability in the region and are the most likely to be causal. Altered nuclear extract binding was observed with risk and non-risk alleles in the <i>IL2RB</i> locus but not <i>RAC2.</i> These experimental data are consistent with the predicted alteration in transcription factor binding. <h3>Conclusions</h3> Polymorphic variants in the <i>RAC2</i> and the nearby <i>IL2RB</i> locus are independent JIA risk loci. Use of the statistical and bioinformatics approach to produce candidates for laboratory validation is an important strategy in defining the function of risk variants in JIA. <h3>Disclosure of Interest</h3> None declared
Neo-adjuvant treatment with erlotinb in squamous cell carcinoma head and neck (SCCHN) patients before surgery provides an opportunity to find predictive factors of response
Authors: J. Delord, F. Thomas, A. Benlyazid, J. Sarini, M. Rives, M. Begue, F. Courbon, J. Lefebvre, P. Rochaix
Journal: Journal of Clinical Oncology (2006)

5513 Background: To date, neither immunohistochemistry (IHC) nor molecular analyses have identified prognostic markers of response to epidermal growth factor receptor (EGFR) tyrosine kinase (TK) inhibitors in SCCHN. Thus, the selection of patients who could benefit from such agents remains a challenge. We designed a ‘pilot’ clinical trial of patients (pts) with SCCHN pending first-line surgery of their disease. Methods: Pts with resectable SCCHN received erlotinib at 150mg/day during the period between pan-endoscopy and surgery. Pharmacokinetic (PK) samples were collected during treatment, which ceased the day before surgery. Results: Thirty five pts were recruited. All of them had resectable SCCHN: oral cavity (17 pts), oropharyngeal (7 pts), hypopharyngeal (5 pts), larygeal (6 pts). Thirty pts received full treatment with erlotinib and the main reason for discontinuation was rash. The median duration of treatment was 21 days (14–27). All pts were evaluated clinically and their tumors assessed radiologically before and after treatment. Out of 30 evaluable pts, 8 were considered as good responders (30–80% decrease in tumor size), 18 had stable disease and 2 had minor progression. Expected toxicities were observed: rash (grade 2/3 in 11 pts), diarrhea (grade 2 in 1 pt). All pts underwent surgery. The incidence of post-operative complications was similar to our historical series. No mutations in the catalytic domain of EGFR TK were found. All tumors were positive for EGFR by IHC. Correlative statistical analyses between PK, toxicity and response data are ongoing and will be presented. Neither over expression of EGFR nor other IHC markers alone were found to be good predictive markers of efficacy. Retrospective analysis of morphological and IHC evaluation in some cell cycle regulators (mainly p21) appeared to be predictive of erlotinib efficacy (sensitivity 87.5%, specificity 88%). Conclusions: Neo-adjuvant treatment with erlotinib in SCCHN pts is well-tolerated. This trial demonstrated a useful prospective method to potentially aid patient selection to improve the design of post-operative adjuvant treatment combinations. No significant financial relationships to disclose.