tbuckley/cabot-search huggingface dataset:
Microtubule-regulatory phosphoproteins and NER system are involved in platinum and paclitaxel-based chemotherapy resistance in ovarian cancer
Authors: R. Nadal, M. L. Romero, B. Ojeda, A. Gallardo, M. Rodríguez, I. Boguñà, I. Gich, J. Prat, A. Barnadas
Journal: Journal of Clinical Oncology (2007)

5567 Background: The treatment of ovarian cancer is hindered by intrinsic resistance to platinum and paclitaxel-based chemotherapy (CT). Nucleotide excision repair system plays a central role in DNA repair and is related with resistance to platinum compounds. Excision repair cross-complementation 1 (ERCC1) and 3 (ERCC3) genes confer a differential sensitivity to CT. OP18/stathmin and mDIA are involved in regulation of microtubules dynamics and may represent a mechanism of resistance to paclitaxel. Both mechanisms have been recently investigated in ovarian cancer (OC). Methods: Formalin and paraffin-embedded tissues obtained from 33 patients with advanced OC were retrospectively collected to investigate ERCC1, ERCC3, OP18, and mDIA mRNA levels by quantitative RT- PCR. All patients received a median of 6 cycles platinum based CT in combination with taxanes. Median age was 62 years. Tumors were classified: 52% serous, 9% endometrioid, 27% clear cell, and 12% poorly differentiated carcinomas. FIGO stage: 4 (12%) stage II, 19 (58%) stage III, and 10 (30%) stage IV. 12 chemoresistant tumors (time to recurrence (TTR) &lt; 6 months) and 21 chemosensitive tumors (TTR = 6 months) were analyzed. Median follow-up was 31 months. Results: An increase in mRNA levels was consistently observed in the chemoresistent group: 1.9-fold increased in ERCC1 and 1.6-fold increased in ERCC3. Both genes exhibited comparable expression levels. Statistically significant differences on ERCC1 and ERCC3 mRNA levels were encountered when chemoresistant and chemosensitive tumors were compared (p=0.01 and p= 0.03, respectively). Statistically differences on OP18 mRNA levels were found when chemoresistant and chemosensitive tumors were compared (p=0.05). No differences in mDIA mRNA levels were encountered. Conclusions: Our results suggest that determination of ERCC1-ERCC3 before chemotherapy is potentially useful to predict the effectiveness of platinum-based therapy. Microtubule drug resistance in OC may be associated with altered OP18/stathmin expression. Novel treatment approaches based on molecular markers could be useful predictors of response and could identify targets for therapeutic strategies. Further studies are required. No significant financial relationships to disclose.
Evidence Collection and Evaluation for the Development of Dietary Guidelines and Public Policy on Nutrition
Authors: Dena Zeraatkar, Bradley C. Johnston, Gordon Guyatt
Journal: Annual Review of Nutrition (2019)

Dietary guidelines and recommendations, usually developed by government bodies or large authoritative organizations, have major downstream effects on public policy. A growing body of evidence supports the notion that there are serious deficiencies in the methods used to develop dietary guidelines. Such deficiencies include the failure to access or conduct comprehensive systematic reviews, a lack of systematic or rigorous evaluation of the quality of the evidence, a failure to acknowledge the limitations of the evidence base underlying recommendations, and insufficiently stringent management of conflicts of interest. These issues may be addressed by adhering to international standards for guideline development, including adopting systematic review methodology and using rigorous systems to evaluate the certainty of the evidence and to move from evidence to recommendations, of which the GRADE approach (Grading of Recommendations Assessment,Development and Evaluation) is the most rigorous and fully developed. Improving the methods by which dietary guidelines are produced has considerable potential to substantially improve public policy decision-making.
Multidirectional wall shear stress promotes advanced coronary plaque development: comparing five shear stress metrics
Authors: Ayla Hoogendoorn, Annette M Kok, Eline M J Hartman, Giuseppe de Nisco, Lorena Casadonte, Claudio Chiastra, Adriaan Coenen, Suze-Anne Korteland, Kim Van der Heiden, Frank J H Gijsen, Dirk J Duncker, Antonius F W van der Steen, Jolanda J Wentzel
Journal: Cardiovascular Research (2019)

Abstract Aims Atherosclerotic plaque development has been associated with wall shear stress (WSS). However, the multidirectionality of blood flow, and thus of WSS, is rarely taken into account. The purpose of this study was to comprehensively compare five metrics that describe (multidirectional) WSS behaviour and assess how WSS multidirectionality affects coronary plaque initiation and progression. Methods and results Adult familial hypercholesterolaemic pigs (n = 10) that were fed a high-fat diet, underwent imaging of the three main coronary arteries at three-time points [3 (T1), 9 (T2), and 10–12 (T3) months]. Three-dimensional geometry of the arterial lumen, in combination with local flow velocity measurements, was used to calculate WSS at T1 and T2. For analysis, arteries were divided into 3 mm/45° sectors (n = 3648). Changes in wall thickness and final plaque composition were assessed with near-infrared spectroscopy–intravascular ultrasound, optical coherence tomography imaging, and histology. Both in pigs with advanced and mild disease, the highest plaque progression rate was exclusively found at low time-averaged WSS (TAWSS) or high multidirectional WSS regions at both T1 and T2. However, the eventually largest plaque growth was located in regions with initial low TAWSS or high multidirectional WSS that, over time, became exposed to high TAWSS or low multidirectional WSS at T2. Besides plaque size, also the presence of vulnerable plaque components at the last time point was related to low and multidirectional WSS. Almost all WSS metrics had good predictive values for the development of plaque (47–50%) and advanced fibrous cap atheroma (FCA) development (59–61%). Conclusion This study demonstrates that low and multidirectional WSS promote both initiation and progression of coronary atherosclerotic plaques. The high-predictive values of the multidirectional WSS metrics for FCA development indicate their potential as an additional clinical marker for the vulnerable disease.
Management of adverse events with tailored sorafenib dosing prolongs survival of hepatocellular carcinoma patients
Authors: Francesco Tovoli, Luca Ielasi, Andrea Casadei-Gardini, Alessandro Granito, Francesco Giuseppe Foschi, Giulia Rovesti, Giulia Negrini, Giulia Orsi, Matteo Renzulli, Fabio Piscaglia
Journal: Journal of Hepatology (2019)
A Novel Intergenic Region between CENPA and DPYSL5-ALK Exon 20 Fusion Variant Responding to Crizotinib Treatment in a Patient with Lung Adenocarcinoma
Authors: Xiaodong Fei, Liqun Zhu, Hongxuan Zhou, Chuang Qi, Chun Wang
Journal: Journal of Thoracic Oncology (2019)
Abstract 11931: Plasma Metabolite Profiling in Heart Failure Patients: Risk Association and Heritability
Authors: David Lanfear, Albert Levin, Jia Li, Ruicong She, Yun Wang, L. Keoki Williams, Stephen Gardell, Hani Sabbah
Journal: Circulation (2015)

Background: Metabolite profiling can unveil biomarker signatures for health and disease. We tested whether the plasma metabolite profile in heart failure (HF) patients could predict survival independent of established factors, and whether the metabolite levels are heritable. Methods: Patients (n=400) who met Framingham criteria for HF were included. Fasting blood samples were obtained, and DNA and plasma isolated and stored at -70 o C. Amino acids, organic acids, and acyl carnitines were quantified using mass spectrometry. Genome wide genotyping was also performed. Association of metabolites with survival was tested using lasso penalized Cox regression; a resulting multi-metabolite risk score (MRS) was tested in 10-fold cross validation using time-dependent ROC curves. We retested the MRS in Cox models adjusted for conventional covariates (age, gender, race, ejection fraction (EF), CAD, COPD, creatinine, atrial fibrillation, stroke, NTproBNP). We estimated heritability of the MRS components using genome-wide data, calculated separately in African Americans and whites. Results: The cohort was 50% African American, 50% female, 67% low EF, and mean age 70 y. In cross-validation the MRS had AUC of 0.705 and 0.658 at 1 and 5 years, respectively. Dichotomized MRS was associated with a 4.5 fold risk of death (FDR=1.49x10 -8 , Figure). When added to a conventional risk model, the MRS still carried a HR of 2.6 (p=2.38 x 10 -4 ). Among 14 MRS analytes, 4 had heritability estimates &gt;20% in each race group (Table). Conclusion: Plasma metabolite profile is an independent predictor of survival among HF patients, and risk-associated metabolite levels may be heritable. Validation is needed.
Comparison of total solids and creatinine in urinary biomarker analysis
Authors: Joshua E. Muscat, Stephen G. Colosimo, Ana Calcagnotto, Irene Delgado, John Weisburger, John P. Richie
Journal: Cancer Research (2004)

1962  The accurate measurement of urinary biomarkers of exposure such as cotinine often requires correcting for urinary dilution using creatinine concentrations. Creatinine reflects renal function in a steady state and is the most commonly used measure of urinary dilution in spot samples. However, differences in creatinine clearance or muscle mass can result in substantial interindividual variation in urinary creatinine levels. This could confound comparisons of creatinine-corrected urinary biomarker values between dissimilar groups. For example, a urinary biomarker comparison between men and women would be affected by differences in muscle mass and creatinine clearance. The present goal was to assess the use of total urine solids as measured by refractive index (RI) as a more appropriate means of accounting for urinary dilution since levels are less dependent on creatinine output. Two hundred and ten healthy adult smokers with similar proportions of men and women, and blacks and whites were recruited from Westchester County, NY. Subjects were non-obese individuals with an average age of about 33 years in each race-sex group. Urine and serum creatinine was measured on a Vitros 500 clinical chemistry analyzer. Urine cotinine was measured by an enzyme immunoassay, and total solids was assessed by refractometry using the following equation: TS=RI20 X 6774-9030. Creatinine clearance was calculated from serum creatinine values using the method of Cockroft and Gault. All analyses were conducted on morning void specimens. There was a high correlation between cotinine/creatinine and cotinine/total solids (r=0.73). The Pearson correlation coefficient ranged from 0.59 in white men to 0.88 in black men. In men, both cotinine measures were about 20% higher in blacks than in whites. There were little differences in creatinine clearance between black and white men. In women, the cotinine/creatinine was higher by 10% in blacks (P=N.S.) and the cotinine/total solids was higher by 35% (P
Efficacy of tyrosine kinase inhibitors in Ph-like acute lymphoblastic leukemia harboring ABL-class rearrangements
Authors: Ilaria Tanasi, Ibrahima Ba, Nicolas Sirvent, Thorsten Braun, Wendy Cuccuini, Paola Ballerini, Nicolas Duployez, Aline Tanguy-Schmidt, Jérôme Tamburini, Sébastien Maury, Eric Doré, Chantal Himberlin, Cédric Duclos, Patrice Chevallier, Philippe Rousselot, Massimiliano Bonifacio, Hélène Cavé, André Baruchel, Hervé Dombret, Jean Soulier, Judith Landman-Parker, Nicolas Boissel, Emmanuelle Clappier
Journal: Blood (2019)
Multiomics Prediction of Response Rates to Therapies to Inhibit Programmed Cell Death 1 and Programmed Cell Death 1 Ligand 1
Authors: Joo Sang Lee, Eytan Ruppin
Journal: JAMA Oncology (2019)

Therapies to inhibit programmed cell death 1 and its ligand (anti-PD-1/PD-L1) provide significant survival benefits in many cancers, but the efficacy of these treatments varies considerably across different cancer types. Identifying the underlying variables associated with this cancer type-specific response remains an important open research challenge.To evaluate systematically a multitude of neoantigen-, checkpoint-, and immune response-related variables to determine the key variables that accurately predict the response to anti-PD-1/PD-L1 therapy across different cancer types.This analysis of a broad range of data used whole-exome and RNA sequencing of 7187 patients from the publicly available Cancer Genome Atlas and the objective response rate (ORR) data of 21 cancer types obtained from a collection of clinical trials. Thirty-six variables of 3 distinct classes considered were associated with (1) tumor neoantigens, (2) tumor microenvironment and inflammation, and (3) the checkpoint targets. The performance of each class of variables and their combinations in predicting the ORR to anti-PD-1/PD-L1 therapy was evaluated. Accuracy of predictions was quantified with Spearman correlation measured using a standard leave-one-out cross-validation, a statistical method of evaluating a statistical model by dividing data into 2 segments: one to train the model and the other to validate the model. Data were collected from October 19 through 31, 2018, and were analyzed from November 1 through December 14, 2018.Response to anti-PD-1/PD-1 therapy.Among the 36 variables, estimated CD8+ T-cell abundance was the most predictive of the response to anti-PD-1/PD-L1 therapy across cancer types (Spearman R = 0.72; P < 2.3 × 10-4), followed by the tumor mutational burden (Spearman R = 0.68; P < 6.2 × 10-4), and the fraction of samples with high PD1 gene expression (Spearman R = 0.68; P < 6.9 × 10-4). Notably these top 3 variables cover the 3 classes considered, and their combination is highly correlated with response (Spearman R = 0.90; P < 4.1 × 10-8), explaining more than 80% of the ORR variance observed across different tumor types.That we know of, this is the first systematic evaluation of the different variables associated with anti-PD-1/PD-L1 therapy response across different tumor types. The findings suggest that the 3 key variables can explain most of the observed cross-cancer response variability, but their relative explanatory roles may vary in specific cancer types.
Glomerular Immunodeposits of Patients with IgA Nephropathy Are Enriched for IgG Autoantibodies Specific for Galactose-Deficient IgA1
Authors: Dana V. Rizk, Manish K. Saha, Stacy Hall, Lea Novak, Rhubell Brown, Zhi-Qiang Huang, Huma Fatima, Bruce A. Julian, Jan Novak
Journal: Journal of the American Society of Nephrology (2019)

IgA nephropathy (IgAN) is the leading primary GN worldwide. The disease is thought to result from glomerular deposition of circulating immune complexes of IgG bound to galactose-deficient IgA1 (Gd-IgA1). However, routine immunofluorescence microscopy fails to detect IgG in many kidney biopsies from patients with IgAN and the specificity of IgG in immunodeposits has not been tested.We used remnant frozen kidney-biopsy specimens from 34 patients with IgAN; 14 were IgG-positive and 20 were IgG-negative by routine immunofluorescence microscopy. Six patients with primary membranous nephropathy (MN) and eight with lupus nephritis (LN) served as controls. IgG in the kidney tissue was extracted and its amount determined by ELISA. IgG molecular integrity was assessed by SDS-PAGE immunoblotting. Antigenic specificity of extracted IgG was determined by ELISA using phospholipase A2 receptor (PLA2R) or Gd-IgA1 as antigen. In addition, ten other IgAN cases, six IgG-positive and four IgG-negative by routine immunofluorescence, were used for colocalization studies by confocal microscopy.IgG extracted from MN but not IgAN immunodeposits reacted with PLA2R. Conversely, IgG extracted from IgAN but not MN or LN immunodeposits reacted with Gd-IgA1. Even IgAN kidney-biopsy specimens without IgG by routine immunofluorescence microscopy had IgG specific for Gd-IgA1. Confocal microscopy confirmed the presence of IgG in the IgAN biopsies with colocalization of glomerular IgA and IgG.These results reveal for the first time that IgAN kidney biopsies, with or without IgG by routine immunofluorescence, contain Gd-IgA1-specific IgG autoantibodies. These findings support the importance of these autoantibodies in the pathogenesis of IgAN.
Long non-coding RNA NEAT1 targeting impairs the DNA repair machinery and triggers anti-tumor activity in multiple myeloma
Authors: Elisa Taiana, Vanessa Favasuli, Domenica Ronchetti, Katia Todoerti, Francesca Pelizzoni, Martina Manzoni, Marzia Barbieri, Sonia Fabris, Ilaria Silvestris, Maria Eugenia Gallo Cantafio, Natalia Platonova, Valeria Zuccalà, Lorenza Maltese, Debora Soncini, Samantha Ruberti, Michele Cea, Raffaella Chiaramonte, Nicola Amodio, Pierfrancesco Tassone, Luca Agnelli, Antonino Neri
Journal: Leukemia (2019)
Chromosomal Abnormalities and Prognosis in <i>NPM1</i>-Mutated Acute Myeloid Leukemia: A Pooled Analysis of Individual Patient Data From Nine International Cohorts
Authors: Linus Angenendt, Christoph Röllig, Pau Montesinos, David Martínez-Cuadrón, Eva Barragan, Raimundo García, Carmen Botella, Pilar Martínez, Farhad Ravandi, Tapan Kadia, Hagop M. Kantarjian, Jorge Cortes, Gunnar Juliusson, Vladimir Lazarevic, Martin Höglund, Sören Lehmann, Christian Recher, Arnaud Pigneux, Sarah Bertoli, Pierre-Yves Dumas, Hervé Dombret, Claude Preudhomme, Jean-Baptiste Micol, Christine Terré, Zdeněk Ráčil, Jan Novák, Pavel Žák, Andrew H. Wei, Ing S. Tiong, Meaghan Wall, Elihu Estey, Carole Shaw, Rita Exeler, Lisa Wagenführ, Friedrich Stölzel, Christian Thiede, Matthias Stelljes, Georg Lenz, Jan-Henrik Mikesch, Hubert Serve, Gerhard Ehninger, Wolfgang E. Berdel, Michael Kramer, Utz Krug, Christoph Schliemann
Journal: Journal of Clinical Oncology (2019)

PURPOSE Nucleophosmin 1 ( NPM1) mutations are associated with a favorable prognosis in acute myeloid leukemia (AML) when an internal tandem duplication (ITD) in the fms-related tyrosine kinase 3 gene ( FLT3) is absent ( FLT3-ITD neg ) or present with a low allelic ratio ( FLT3-ITD low ). The 2017 European LeukemiaNet guidelines assume this is true regardless of accompanying cytogenetic abnormalities. We investigated the validity of this assumption. METHODS We analyzed associations between karyotype and outcome in intensively treated patients with NPM1 mut / FLT3-ITD neg/low AML who were prospectively enrolled in registry databases from nine international study groups or treatment centers. RESULTS Among 2,426 patients with NPM1 mut / FLT3-ITD neg/low AML, 2,000 (82.4%) had a normal and 426 (17.6%) had an abnormal karyotype, including 329 patients (13.6%) with intermediate and 83 patients (3.4%) with adverse-risk chromosomal abnormalities. In patients with NPM1 mut / FLT3-ITD neg/low AML, adverse cytogenetics were associated with lower complete remission rates (87.7%, 86.0%, and 66.3% for normal, aberrant intermediate, and adverse karyotype, respectively; P &lt; .001), inferior 5-year overall (52.4%, 44.8%, 19.5%, respectively; P &lt; .001) and event-free survival (40.6%, 36.0%, 18.1%, respectively; P &lt; .001), and a higher 5-year cumulative incidence of relapse (43.6%, 44.2%, 51.9%, respectively; P = .0012). These associations remained in multivariable mixed-effects regression analyses adjusted for known clinicopathologic risk factors ( P &lt; .001 for all end points). In patients with adverse-risk chromosomal aberrations, we found no significant influence of the NPM1 mutational status on outcome. CONCLUSION Karyotype abnormalities are significantly associated with outcome in NPM1 mut / FLT3-ITD neg/low AML. When adverse-risk cytogenetics are present, patients with NPM1 mut share the same unfavorable prognosis as patients with NPM1 wild type and should be classified and treated accordingly. Thus, cytogenetic risk predominates over molecular risk in NPM1 mut / FLT3-ITD neg/low AML.
Urinary defense begins in the kidney
Authors: Tian Shen, Abraham Levitman, Yuanji Li, Mendel Jacobs, Katherine Xu, Jonathan Barasch
Journal: Kidney International (2019)

Urinary defense begins in the kidney, quite literally! In the inaugural volume of the Journal of Urology published in 1917, Shohl and Janney demonstrated that urine pH 4.6 to 5.0 was lethal for several strains of Escherichia coli. 1 Shohl A.T. Janney J.H. The growth of Bacillus coli in urine at varying hydrogen ion concentrations. J Urol. 1917; 1: 211-212 Google Scholar Even to this day, therapeutic acidification of the urine is often recommended for suppression of urinary tract infections (UTI).
Perception about prostate cancer among African-American men: Focus group analysis
Authors: Ivis T. Forrester-Anderson
Journal: Cancer Research (2004)

4732  Focus groups are an effective strategy for obtaining information about the health beliefs and practices of African-American men. Fourteen (14) focus groups were conducted in three counties in the Baltimore Metropolitan Area (Baltimore City, Baltimore County, Harford County) to determine factors that impact the low participation rate of African American men in annual screening for prostate cancer. Focus group participants ranging in age from 19–81 years were recruited from churches, clinics, work sites, and social clubs. The discussions, which were audiotaped and subsequently transcribed, were moderated by African Americans who utilized a 13-item open-ended questionnaire. Themes identified using the cut-and-paste method included the following barri ers: lack of knowledge and awareness, fears, and misconceptions, limited access and availability of screening services, embarrassment, and distrust for medical professionals and government. Positive belief, hope and experience with prostate cancer were enabling factors for prostate cancer screening. Outcomes from the groups will be used in planning and developing a culturally sensitive health education program for African American men. Lack of education and awareness about prostate cancer among African-American men, necessitates increased funding for educational and screening programs within this hard to reach population.