tbuckley/cabot-search huggingface dataset:
Use of high-density tiling microarrays to identify mutations globally and elucidate mechanisms of drug resistance in Plasmodium falciparum
Authors: Neekesh V Dharia, Amar Sidhu, María Cassera, Scott J Westenberger, Selina ER Bopp, Rich T Eastman, David Plouffe, Serge Batalov, Daniel J Park, Sarah K Volkman, Dyann F Wirth, Yingyao Zhou, David A Fidock, Elizabeth A Winzeler
Journal: Genome biology (2009)

The identification of genetic changes that confer drug resistance or other phenotypic changes in pathogens can help optimize treatment strategies, support the development of new therapeutic agents, and provide information about the likely function of genes. Elucidating mechanisms of phenotypic drug resistance can also assist in identifying the mode of action of uncharacterized but potent antimalarial compounds identified in high-throughput chemical screening campaigns against Plasmodium falciparum.Here we show that tiling microarrays can detect de novo a large proportion of the genetic changes that differentiate one genome from another. We show that we detect most single nucleotide polymorphisms or small insertion deletion events and all known copy number variations that distinguish three laboratory isolates using readily accessible methods. We used the approach to discover mutations that occur during the selection process after transfection. We also elucidated a mechanism by which parasites acquire resistance to the antimalarial fosmidomycin, which targets the parasite isoprenoid synthesis pathway. Our microarray-based approach allowed us to attribute in vitro derived fosmidomycin resistance to a copy number variation event in the pfdxr gene, which enables the parasite to overcome fosmidomycin-mediated inhibition of isoprenoid biosynthesis.We show that newly emerged single nucleotide polymorphisms can readily be detected and that malaria parasites can rapidly acquire gene amplifications in response to in vitro drug pressure. The ability to define comprehensively genetic variability in P. falciparum with a single overnight hybridization creates new opportunities to study parasite evolution and improve the treatment and control of malaria.
Empirical evidence of bias in treatment effect estimates in controlled trials with different interventions and outcomes: meta-epidemiological study
Authors: Lesley Wood, Matthias Egger, Lise Lotte Gluud, Kenneth F Schulz, Peter Jüni, Douglas G Altman, Christian Gluud, Richard M Martin, Anthony J G Wood, Jonathan A C Sterne
Journal: BMJ (2008)

<b>Objective</b> To examine whether the association of inadequate or unclear allocation concealment and lack of blinding with biased estimates of intervention effects varies with the nature of the intervention or outcome. <b>Design</b> Combined analysis of data from three meta-epidemiological studies based on collections of meta-analyses. <b>Data sources</b> 146 meta-analyses including 1346 trials examining a wide range of interventions and outcomes. <b>Main outcome measures</b> Ratios of odds ratios quantifying the degree of bias associated with inadequate or unclear allocation concealment, and lack of blinding, for trials with different types of intervention and outcome. A ratio of odds ratios &lt;1 implies that inadequately concealed or non-blinded trials exaggerate intervention effect estimates. <b>Results</b> In trials with subjective outcomes effect estimates were exaggerated when there was inadequate or unclear allocation concealment (ratio of odds ratios 0.69 (95% CI 0.59 to 0.82)) or lack of blinding (0.75 (0.61 to 0.93)). In contrast, there was little evidence of bias in trials with objective outcomes: ratios of odds ratios 0.91 (0.80 to 1.03) for inadequate or unclear allocation concealment and 1.01 (0.92 to 1.10) for lack of blinding. There was little evidence for a difference between trials of drug and non-drug interventions. Except for trials with all cause mortality as the outcome, the magnitude of bias varied between meta-analyses. <b>Conclusions</b> The average bias associated with defects in the conduct of randomised trials varies with the type of outcome. Systematic reviewers should routinely assess the risk of bias in the results of trials, and should report meta-analyses restricted to trials at low risk of bias either as the primary analysis or in conjunction with less restrictive analyses.
Remarks on the Effects of Anhelonium Lewinii (the Mescal Button)
Authors: S. W. Mitchell
Journal: BMJ (1896)

A 22-year-old man with a five-year history of drug and alcohol abuse presented with a left hemiparesis preceded by three transient ischaemic attacks, two of which occurred whilst smoking cannabis. Substance abuse was the only identifiable risk factor for cerebrovascular disease.
Point mutation E1099K in MMSET/NSD2 enhances its methyltranferase activity and leads to altered global chromatin methylation in lymphoid malignancies
Authors: J A Oyer, X Huang, Y Zheng, J Shim, T Ezponda, Z Carpenter, M Allegretta, C I Okot-Kotber, J P Patel, A Melnick, R L Levine, A Ferrando, A D MacKerell, N L Kelleher, J D Licht, R Popovic
Journal: Leukemia (2013)
Phase III Study Comparing Second- and Third-Generation Regimens With Concurrent Thoracic Radiotherapy in Patients With Unresectable Stage III Non–Small-Cell Lung Cancer: West Japan Thoracic Oncology Group WJTOG0105
Authors: Nobuyuki Yamamoto, Kazuhiko Nakagawa, Yasumasa Nishimura, Kayoko Tsujino, Miyako Satouchi, Shinzoh Kudo, Toyoaki Hida, Masaaki Kawahara, Koji Takeda, Nobuyuki Katakami, Toshiyuki Sawa, Soichiro Yokota, Takashi Seto, Fumio Imamura, Hideo Saka, Yasuo Iwamoto, Hiroshi Semba, Yasutaka Chiba, Hisao Uejima, Masahiro Fukuoka
Journal: Journal of Clinical Oncology (2010)

This phase III trial of concurrent thoracic radiotherapy (TRT) was conducted to compare third-generation chemotherapy with second-generation chemotherapy in patients with unresectable stage III non-small-cell lung cancer (NSCLC).Eligible patients received the following treatments: A (control), four cycles of mitomycin (8 mg/m(2) on day 1)/vindesine (3 mg/m(2) on days 1, 8)/cisplatin (80 mg/m(2) on day 1) plus TRT 60 Gy (treatment break for 1 week); B, weekly irinotecan (20 mg/m(2))/carboplatin (area under the plasma concentration-time curve [AUC] 2) for 6 weeks plus TRT 60 Gy, followed by two courses of irinotecan (50 mg/m(2) on days 1, 8)/carboplatin (AUC 5 on day 1); C, weekly paclitaxel (40 mg/m(2))/carboplatin (AUC 2) for 6 weeks plus TRT 60 Gy, followed by two courses of paclitaxel (200 mg/m(2) on day 1)/carboplatin (AUC 5 on day 1).The median survival time and 5-year survival rates were 20.5, 19.8, and 22.0 months and 17.5%, 17.8%, and 19.8% in arms A, B, and C, respectively. Although no significant differences in overall survival were apparent among the treatment arms, noninferiority of the experimental arms was not achieved. The incidences of grade 3 to 4 neutropenia, febrile neutropenia, and gastrointestinal disorder were significantly higher in arm A than in arm B or C (P < .001). Chemotherapy interruptions were more common in arm B than in arm A or C.Arm C was equally efficacious and exhibited a more favorable toxicity profile among three arms. Arm C should be considered a standard regimen in the management of locally advanced unresectable NSCLC.
Identification of 491 proteins in the tear fluid proteome reveals a large number of proteases and protease inhibitors.
Authors: Gustavo A de Souza, Lyris MF de Godoy, Matthias Mann
Journal: Genome biology (2006)

The tear film is a thin layer of fluid that covers the ocular surface and is involved in lubrication and protection of the eye. Little is known about the protein composition of tear fluid but its deregulation is associated with disease states, such as diabetic dry eyes. This makes this body fluid an interesting candidate for in-depth proteomic analysis.In this study, we employ state-of-the-art mass spectrometric identification, using both a hybrid linear ion trap-Fourier transform (LTQ-FT) and a linear ion trap-Orbitrap (LTQ-Orbitrap) mass spectrometer, and high confidence identification by two consecutive stages of peptide fragmentation (MS/MS/MS or MS3), to characterize the protein content of the tear fluid. Low microliter amounts of tear fluid samples were either pre-fractionated with one-dimensional SDS-PAGE and digested in situ with trypsin, or digested in solution. Five times more proteins were detected after gel electrophoresis compared to in solution digestion (320 versus 63 proteins). Ontology classification revealed that 64 of the identified proteins are proteases or protease inhibitors. Of these, only 24 have previously been described as components of the tear fluid. We also identified 18 anti-oxidant enzymes, which protect the eye from harmful consequences of its exposure to oxygen. Only two proteins with this activity have been previously described in the literature.Interplay between proteases and protease inhibitors, and between oxidative reactions, is an important feature of the ocular environment. Identification of a large set of proteins participating in these reactions may allow discovery of molecular markers of disease conditions of the eye.
Performance of p16/Ki-67 Immunostaining to Detect Cervical Cancer Precursors in a Colposcopy Referral Population
Authors: Nicolas Wentzensen, Lauren Schwartz, Rosemary E. Zuna, Katie Smith, Cara Mathews, Michael A. Gold, R. Andy Allen, Roy Zhang, S. Terence Dunn, Joan L. Walker, Mark Schiffman
Journal: Clinical Cancer Research (2012)

Abstract Purpose: Cytology-based screening has limited sensitivity to detect prevalent cervical precancers. Human papilloma virus (HPV) DNA testing is highly sensitive and provides a high, long-term reassurance of low risk of cervical cancer. However, the specificity of HPV DNA testing is limited, requiring additional, more disease-specific markers for efficient screening approaches. Experimental Design: Liquid-based cytology samples were collected from 625 women referred to colposcopy. A slide was stained using the CINtec plus cytology assay. Pap cytology and HPV genotyping were conducted from the same vial. Clinical performance characteristics were calculated for all women, stratified by age, and for women referred with a low-grade squamous intraepithelial lesion (LSIL) Pap. Results: p16/Ki-67 positivity increased with histologic severity, from 26.8% in normal histology, 46.5% in CIN1, 82.8% in CIN2 to 92.8% in CIN3. Among women with CIN3, p16/Ki-67 positivity increased from 77.8% for women younger than 30 years without HPV16 to 100% for women 30 years and older with HPV16. The sensitivity and specificity to detect CIN3+ were 93.2% and 46.1%, respectively, and increased to 97.2% and 60.0% among women 30 years and older. In women with high-risk (HR)-HPV–positive atypical squamous cells of undetermined significance (ASC-US) and LSIL, sensitivity and specificity for detection of CIN3 were 90.6% and 48.6%, respectively. Conclusions: p16/Ki-67 testing could reduce referral to colposcopy by almost half while detecting the most severe cases of CIN3. The high sensitivity of p16/Ki-67 with significantly improved specificity compared with HPV testing makes p16/Ki-67 a viable option for LSIL triage. Further studies are required to evaluate p16/Ki-67 as triage marker in HPV-based screening strategies. Clin Cancer Res; 18(15); 4154–62. ©2012 AACR.
Enhanced Natural Killer Cell Binding and Activation by Low-Fucose IgG1 Antibody Results in Potent Antibody-Dependent Cellular Cytotoxicity Induction at Lower Antigen Density
Authors: Rinpei Niwa, Mikiko Sakurada, Yukari Kobayashi, Aya Uehara, Kouji Matsushima, Ryuzo Ueda, Kazuyasu Nakamura, Kenya Shitara
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Recent studies have revealed that fucose removal from the oligosaccharides of human IgG1 antibodies results in a significant enhancement of antibody-dependent cellular cytotoxicity (ADCC) via improved IgG1 binding to FcγRIIIa. In this report, we investigated the relationship between enhanced ADCC and antigen density on target cells using IgG1 antibodies with reduced fucose. Experimental Design: Using EL4 cell-derived transfectants with differential expression levels of exogenous human CC chemokine receptor 4 or human CD20 as target cells, ADCC of fucose variants of chimeric IgG1 antibodies specific for these antigens were measured. We further investigated IgG1 binding to natural killer (NK) cells and NK cell activation during ADCC induction to elucidate the mechanism by which low-fucose IgG1 induces ADCC upon target cells with low antigen expression. Results: Low-fucose IgG1s showed potent ADCC at low antigen densities at which their corresponding high-fucose counterparts could not induce measurable ADCC. The quantitative analysis revealed that fucose depletion could reduce the antigen amount on target cells required for constant degrees of ADCC induction by 10-fold for CC chemokine receptor 4 and 3-fold for CD20. IgG1 binding to NK cells was increased by ligating IgG1 with clustered antigen, especially for low-fucose IgG1. Up-regulation of an activation marker, CD69, on NK cells, particularly the CD56dim subset, in the presence of both the antibody and target cells was much greater for the low-fucose antibodies. Conclusions: Our data showed that fucose removal from IgG1 could reduce the antigen amount required for ADCC induction via efficient recruitment and activation of NK cells.
Seizure characteristics and outcomes in 508 Chinese adult patients undergoing primary resection of low-grade gliomas: a clinicopathological study
Authors: G. You, Z.-Y. Sha, W. Yan, W. Zhang, Y.-Z. Wang, S.-W. Li, L. Sang, Z. Wang, G.-L. Li, S.-W. Li, Y.-J. Song, C.-S. Kang, T. Jiang
Journal: Neuro-Oncology (2011)

Seizure is a common presenting manifestation and plays an important role in the clinical presentation and quality of life for patients with low-grade gliomas (LGGs). The authors set out to identify factors that influence preoperative seizure characteristics and postoperative seizure control. Cases involving adult patients who had undergone initial surgery for LGGs in a single institution between 2005 and 2009 were retrospectively reviewed. Univariate and multivariate logistic regression analyses were used to identify factors associated with preoperative seizures and postoperative seizure control. Of the 508 patients in the series, 350 (68.9%) presented with seizures. Age less than 38 years and cortical involvement of tumor were more likely to be associated with seizures (P = .003 and .001, respectively, multivariate logistic analysis). For the cohort of 350 patients with seizures, Engel classification was used to evaluate 6- and 12-month outcome after surgery: completely seizure free (Engel class I), 65.3% and 62.5%; not seizure free (Engel classes II, III, IV), 34.7% and 37.5%. After multivariate logistic analysis, favorable seizure prognosis was more common in patients with secondary generalized seizure (P = .006) and with calcification on MRI (.031). With respect to treatment-related variables, patients achieved much better seizure control after gross total resection than after subtotal resection (P < .0001). Ki67 was an independent molecular marker predicting poor seizure control in the patients with a history of seizure if overexpressed but was not a predictor for those without preoperative seizures. These factors may provide insight into developing effective treatment strategies aimed at prolonging patients' survival.
A novel tumor-promoting role for nuclear factor IA in glioblastomas is mediated through negative regulation of p53, p21, and PAI1
Authors: Jun Sung Lee, Jiping Xiao, Parita Patel, Jake Schade, Jinhua Wang, Benjamin Deneen, Anat Erdreich-Epstein, Hae-Ri Song
Journal: Neuro-Oncology (2013)

Nuclear factor IA (NFIA), a transcription factor and essential regulator in embryonic glial development, is highly expressed in human glioblastoma (GBM) compared with normal brain, but its contribution to GBM and cancer pathogenesis is unknown. Here we demonstrate a novel role for NFIA in promoting growth and migration of GBM and establish the molecular mechanisms mediating these functions. To determine the role of NFIA in glioma, we examined the effects of NFIA in growth, proliferation, apoptosis, and migration. We used gain-of-function (overexpression) and loss-of-function (shRNA knockdown) of NFIA in primary patient-derived GBM cells and established glioma cell lines in culture and in intracranial xenografts in mouse brains. Knockdown of native NFIA blocked tumor growth and induced cell death and apoptosis. Complementing this, NFIA overexpression accelerated growth, proliferation, and migration of GBM in cell culture and in mouse brains. These NFIA tumor-promoting effects were mediated via transcriptional repression of p53, p21, and plasminogen activator inhibitor 1 (PAI1) through specific NFIA-recognition sequences in their promoters. Importantly, the effects of NFIA on proliferation and apoptosis were independent of TP53 mutation status, a finding especially relevant for GBM, in which TP53 is frequently mutated. NFIA is a modulator of GBM growth and migration, and functions by distinct regulation of critical oncogenic pathways that govern the malignant behavior of GBM.
Sex Differences in the Effects of Alcohol on Brain Structure
Authors: Adolf Pfefferbaum, Margaret Rosenbloom, Anjali Deshmukh, Edith V. Sullivan
Journal: American Journal of Psychiatry (2001)

This study investigated whether alcoholic women manifest deficits in cortical gray and white matter volumes and ventricular enlargement similar to those seen in alcoholic men.Volumetric measures of intracranium, cortical gray matter, white matter and sulci, and lateral and third ventricles were obtained from magnetic resonance images of 42 women and 44 men with DSM-III-R alcoholism and age-matched healthy comparison groups (37 women and 48 men). Groups of alcoholic men and women were matched on age and length of sobriety, but men had a 2.5 times higher lifetime alcohol consumption than women.Women, regardless of diagnosis, had less cortical gray and white matter and smaller third ventricles than men, consistent with sex-related differences in intracranial volume. Alcoholics had larger volumes of cortical sulci and lateral and third ventricles than comparison subjects. Diagnosis-by-sex interactions for cortical white matter and sulcal volumes were due to abnormalities in alcoholic men but not alcoholic women, relative to same-sex comparison subjects. This interaction persisted for cortical sulci after covarying for lifetime alcohol consumption. Slopes relating cortical gray matter and sulcal volumes to age were steeper in alcoholic than in comparison men. Slopes relating lateral ventricle volume to age were steeper in alcoholic than in comparison women. In alcoholic women, longer sobriety was associated with larger white matter volumes.Alcoholic men and women show different brain morphological deficits, relative to same-sex comparison subjects. However, age and alcoholism interact in both sexes, which puts all older alcoholics at particular risk for the negative sequelae of alcoholism.
Effects of immunosuppressive treatment on interleukin-15 and interleukin-15 receptor α expression in muscle tissue of patients with polymyositis or dermatomyositis
Authors: Mei Zong, Ingela Loell, Eva Lindroos, Gustavo A Nader, Helene Alexanderson, Christina Ståhl Hallengren, Kristian Borg, Snjolaug Arnardottir, Iain B McInnes, Ingrid E Lundberg
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Objectives</h3> To investigate the expression of interleukin (IL)-15 and IL-15 receptor α (IL-15Rα) in muscle tissue from patients with polymyositis or dermatomyositis before and after conventional immunosuppressive (IS) treatment. <h3>Methods</h3> Muscle biopsies from 17 patients before and after conventional IS treatment and seven healthy individuals were investigated by immunohistochemistry using antibodies against IL-15 and IL-15Rα. Quantification was performed by computerised image analysis. Cellular localisation of IL-15 was determined by double immunofluorescence. Clinical outcome was measured by the functional index and serum creatine kinase. Human myotubes were cultured and IL-15 staining was performed by immunocytochemistry. <h3>Results</h3> IL-15 was observed in mononuclear inflammatory cells of muscle tissue while IL-15Rα was localised to mononuclear inflammatory cells, capillaries and large vessels. Double staining showed localisation of IL-15 to CD163+ macrophages. A significantly larger number of IL-15 and IL-15Rα-positive cells were seen in muscle tissue of patients compared with healthy individuals. Baseline IL-15 expression correlated negatively with improvement in muscle function. After conventional IS treatment, a significantly lower number of IL-15 and IL-15Rα-positive cells was found. However, compared with controls, eight of 17 patients still had more IL-15-positive cells and less muscle function improvement was shown in this group of patients, both in short-term and long-term observations. Human differentiated myotubes were negative for IL-15 staining. <h3>Conclusions</h3> IL-15 and its receptor are expressed in the muscle tissue of patients with myositis and IL-15 expression is correlated with improvement in muscle function. IL-15 may play a role in the pathogenesis of myositis and could be a biological treatment target, at least in a subgroup of patients with polymyositis or dermatomyositis.
KRAS/NRAS and BRAF Mutations in the 20050181 Study of Panitumumab + FOLFIRI for the 2ND-Line Treatment of Metastatic Colorectal Cancer: Updated Analysis
Authors: M. Peeters, K. Oliner, T. Price, A. Cervantes, A. Sobrero, M. Ducreux, Y. Hotko, T. André, E. Chan, F. Lordick, C. Punt, A. Strickland, G. Wilson, T. Ciuleanu, L. Roman, E. Van Cutsem, H. Yu, A.S. Jung, R. Sidhu, S. Patterson
Journal: Annals of Oncology (2014)
Small-conductance calcium-activated potassium (SK) channels contribute to action potential repolarization in human atria
Authors: Lasse Skibsbye, Claire Poulet, Jonas Goldin Diness, Bo Hjorth Bentzen, Lei Yuan, Utz Kappert, Klaus Matschke, Erich Wettwer, Ursula Ravens, Morten Grunnet, Torsten Christ, Thomas Jespersen
Journal: Cardiovascular Research (2014)

AimsSmall-conductance calcium-activated potassium (SK) channels are expressed in the heart of various species, including humans. The aim of the present study was to address whether SK channels play a functional role in human atria.