tbuckley/cabot-search huggingface dataset:
Cloning and functional characteristics of murine large granular lymphocyte-1: a member of the Ly-49 gene family (Ly-49G2)
Authors: L H Mason, J R Ortaldo, H A Young, V Kumar, M Bennett, S K Anderson
Journal: The Journal of Experimental Medicine (1995)

Large granular lymphocyte (LGL) 1 is a cell surface glycoprotein expressed on a subset (50%) of C57BL/6 natural killer (NK) cells. Immunoprecipitation experiments reveal that the LGL-1 protein exists as a disulfide-linked 40-kD homodimer. Functional studies of LGL-1+ cells indicate that selected H-2d target cells are not lysed efficiently by these interleukin (IL)-2-cultured NK cells. These findings suggested that LGL-1 may be a member of the Ly-49 gene family. Here we report the molecular cloning of the LGL-1 cDNA from a severe combined immunodeficient-adherent lymphokine-activated killer cell library transfected into Cos-7 cells and find LGL-1 to be homologous to the Ly-49 gene at both the nucleotide (85%) and amino acid levels (73%). Sequencing of our LGL-1 cDNA has revealed it to be nearly identical to the Ly-49G2 cDNA recently isolated by cross-hybridization with an Ly-49 probe. LGL-1 represents a type II transmembrane protein of 267 amino acids with its carboxyl end exposed extracellularly. The LGL-1 protein contains 11 highly conserved cysteine residues and a 25-amino acid transmembrane region. Southern blot analysis demonstrates that there are a number of homologous genes in mouse DNA that hybridize strongly to LGL-1. Northern analyses using poly A+ RNA from LGL-1+ NK cells indicate that LGL-1 is expressed as a 1.4 kb mRNA. Two-color flow cytometry analysis (FCA) of C57BL/6 splenic NK cells demonstrates that LGL-1 and Ly-49 label overlapping subsets of cells. FCA identifies four subsets of NK cells as defined by LGL-1 versus Ly-49 staining. We have sorted these individual subsets, expanded them in IL-2, and performed cytotoxicity experiments to determine their target cell profiles in relation to class I expression. Results of these studies are complex, but indicate that Ly-49 may not be the only molecule that recognizes class I as an inhibitory signal for cytotoxicity. LGL-1+ cells also fail to lyse several H-2d-expressing tumor targets and concanavalin A lymphoblasts from BALB/c but not C57BL/6 mice. This inhibition of lysis by LGL-1+ NK cells is negated by addition of monoclonal antibody (mAb) 4D11 that recognizes the LGL-1 protein. When mAbs to the class I molecules H-2Dd and H-2Ld (alpha 1 alpha 2 domains only) are added to cytotoxicity assays, LGL-1+ cells lyse H-2d targets very effectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Survival Advantage of Hispanic Patients Initiating Dialysis in the United States Is Modified by Race
Authors: Bhamidipati V.R. Murthy, Donald A. Molony, Austin G. Stack
Journal: Journal of the American Society of Nephrology (2005)

Differences in survival have been reported among ethnic groups in the general population. Whether these extend to patients with ESRD is unclear. Using national data, mortality risks of ethnic groups who began dialysis treatment in the United States between May 1, 1995, and July 31, 1997, were compared over 2 yr. Patients were classified as Hispanic or non-Hispanic and then subclassified by race forming six race-specific subgroups: Hispanic white, black, and other and non-Hispanic white, black, and other. Mortality rates for Hispanics compared with non-Hispanics were 19.2 versus 26 per 100 patient-years at risk for those with diabetes and were 14.7 versus 22.7 per 100 patient-years at risk for those without diabetes. For those with diabetes, adjusted mortality risks for Hispanics versus non-Hispanics were 30% lower (95% confidence interval [CI], 26 to 34%). In subgroup analysis, mortality risks for Hispanic whites and Hispanic blacks were 35% (95% CI, 31 to 39%) and 33% (95% CI, 12 to 48%) lower than non-Hispanic whites and were similar in magnitude to those of non-Hispanic blacks (32% lower; 95% CI, 29 to 35%) and non-Hispanic other (33% lower; 95% CI, 28 to 39%). Interestingly, mortality risks for Hispanic others were not significantly different from non-Hispanic whites. For those without diabetes, adjusted mortality risks for Hispanics versus non-Hispanics were 17% lower (95% CI, 9 to 23%), and subgroup analysis yielded similar patterns to those of individuals with diabetes. The survival advantage of Hispanic over non-Hispanic patients who receive chronic dialysis treatment in the United States is not consistent across subgroups and is modified by race. Cultural and genetic differences as well as variation in the access and delivery of care before and while on dialysis may account for these differences.
AT-03 * ATYPICAL TERATOID/RHABDOID TUMOUR IS A GENETICALLY HOMOGENEOUS BUT EPIGENETICALLY HETEROGENEOUS DISEASE THAT IS DEFINED BY SUBGROUP SPECIFIC SUPER-ENHANCERS
Authors: P. Johann, S. Erkek, M. Zapatka, K. Kerl, I. Buchhalter, V. Hovestadt, A. Korshunov, M. Rhyzova, D. T. W. Jones, P. A. Northcott, M. C. Fruhwald, M. Hasselblatt, A. Gajjar, S. M. Pfister, M. Kool
Journal: Neuro-Oncology (2015)

Atypical Teratoid/Rhabdoid Tumours (AT/RT) represent a quantitatively important type of pediatric brain tumours with a poor outcome. They are most common in infants and young children and all characterized by SMARCB1/SMARCA4 mutations as the sole, recurrent genetic lesions. However, by transcriptome and methylation analyses we identified three distinct subgroups with a deregulation of cancer associated pathways such as the Sonic Hedgehog pathway- and proteins implicated into melanoma biology (such as the transcription factor MITF). As whole genome DNA- and RNA-sequencing did not reveal any other recurrent mutations or gene fusions, we investigated whether epigenetic mechanisms define the three subgroups and may contribute to the highly variable clinical response to treatment. Therefore, we performed whole genome bisulfite DNA sequencing for 24 AT/RTs. These data demonstrated that DNA in these tumors is generally hypermethylated. In addition, 15 tumors were subjected to ChIP-sequencing for 6 histone marks (H3K27ac, H3K9me3, H3K4me1, H3K27me3, H3K4me3, H3K36me3). The integrative analyses of these multiple layers of data revealed subgroup specific (super)enhancers that account for the observed overexpression in particular cancer specific pathways. These enhancers drive genes previously implicated in AT/RT (such as BMP4 and CyclinD1) but also novel targets (such as TYR and GLI2).Transcription factor binding site analyses within the enhancer elements, revealed regulatory circuits that converge on a small number of subgroup specific factors (such as the melanoma related transcription factor MITF). Additional ChIP experiments for these factors are currently being conducted to delineate the targets of these central hubs. Employing this approach we identified crucial differences in the histone code that do not only account for the transcriptomic heterogeneity in this disease, but possibly also for the variable response to current treatments.
Sex moderates circadian chemotherapy effects on survival of patients with metastatic colorectal cancer: a meta-analysis
Authors: S. Giacchetti, P.A. Dugué, P.F. Innominato, G.A. Bjarnason, C. Focan, C. Garufi, S. Tumolo, B. Coudert, S. Iacobelli, R. Smaaland, M. Tampellini, R. Adam, T. Moreau, F. Lévi
Journal: Annals of Oncology (2012)
COPD and chronic bronchitis risk of indoor air pollution from solid fuel: a systematic review and meta-analysis
Authors: O. P Kurmi, S. Semple, P. Simkhada, W C. S Smith, J. G Ayres
Journal: Thorax (2010)

Over half the world is exposed daily to the smoke from combustion of solid fuels. Chronic obstructive pulmonary disease (COPD) is one of the main contributors to the global burden of disease and can be caused by biomass smoke exposure. However, studies of biomass exposure and COPD show a wide range of effect sizes. The aim of this systematic review was to quantify the impact of biomass smoke on the development of COPD and define reasons for differences in the reported effect sizes.A systematic review was conducted of studies with sufficient statistical power to calculate the health risk of COPD from the use of solid fuel, which followed standardised criteria for the diagnosis of COPD and which dealt with confounding factors. The results were pooled by fuel type and country to produce summary estimates using a random effects model. Publication bias was also estimated.There were positive associations between the use of solid fuels and COPD (OR=2.80, 95% CI 1.85 to 4.0) and chronic bronchitis (OR=2.32, 95% CI 1.92 to 2.80). Pooled estimates for different types of fuel show that exposure to wood smoke while performing domestic work presents a greater risk of development of COPD and chronic bronchitis than other fuels.Despite heterogeneity across the selected studies, exposure to solid fuel smoke is consistently associated with COPD and chronic bronchitis. Efforts should be made to reduce exposure to solid fuel by using either cleaner fuel or relatively cleaner technology while performing domestic work.
Type III Transforming Growth Factor-β (TGF-β) Receptor Mediates Apoptosis in Renal Cell Carcinoma Independent of the Canonical TGF-β Signaling Pathway
Authors: Vitaly Margulis, Tapati Maity, Xiu-Ying Zhang, Simon J. Cooper, John A. Copland, Christopher G. Wood
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Alterations in transforming growth factor-β (TGF-β) signaling occur early during malignant transformation of renal epithelial cells and are associated with loss of type III TGF-β receptor (TβRIII) expression. We evaluated the role of TβRIII in mediation of apoptosis using in vitro cell culture and in vivo animal models of clear cell renal cell carcinoma. Experimental Design: TβR3 expression was manipulated with adenoviral gene vector delivery system in vitro and in vivo. Induction of apoptosis and signaling through the Smad and mitogen-activated protein kinase (MAPK) pathways were examined at various time points after infection. To study viral oncolysis in vivo, human renal cell carcinoma cells were implanted s.c. in the flanks of nude mice and treated with intratumoral injections of adenovirus. Results: Restoring TβRIII expression in clear cell renal cell carcinoma resulted in a marked induction of apoptosis using in vitro cell culture and in vivo animal models. The expression of the cytoplasmic domain, but not the extracellular domain, of TβRIII mimicked the induction of apoptosis by full-length TβRIII in cell culture and the growth inhibition of tumors in athymic nude mice. TβRIII-associated apoptosis was not dependent on signaling through the canonical TGF-β/Smad pathway but was mediated through p38 MAPK. Conclusion: These findings indicate a novel mechanistic antitumor function for TβRIII and further support its role as an important tumor suppressor in clear cell renal cell carcinoma.
Tiotropium and olodaterol fixed-dose combination<i>versus</i>mono-components in COPD (GOLD 2–4)
Authors: Roland Buhl, François Maltais, Roger Abrahams, Leif Bjermer, Eric Derom, Gary Ferguson, Matjaž Fležar, Jacques Hébert, Lorcan McGarvey, Emilio Pizzichini, Jim Reid, Antony Veale, Lars Grönke, Alan Hamilton, Lawrence Korducki, Kay Tetzlaff, Stella Waitere-Wijker, Henrik Watz, Eric Bateman
Journal: European Respiratory Journal (2015)

Efficacy and safety of tiotropium+olodaterol fixed-dose combination (FDC) compared with the mono-components was evaluated in patients with moderate to very severe chronic obstructive pulmonary disease (COPD) in two replicate, randomised, double-blind, parallel-group, multicentre, phase III trials. Patients received tiotropium+olodaterol FDC 2.5/5 μg or 5/5 μg, tiotropium 2.5 μg or 5 μg, or olodaterol 5 μg delivered once-daily via Respimat inhaler over 52 weeks. Primary end points were forced expiratory volume in 1 s (FEV1) area under the curve from 0 to 3 h (AUC0-3) response, trough FEV1 response and St George's Respiratory Questionnaire (SGRQ) total score at 24 weeks. In total, 5162 patients (2624 in Study 1237.5 and 2538 in Study 1237.6) received treatment. Both FDCs significantly improved FEV1 AUC0-3 and trough FEV1 response versus the mono-components in both studies. Statistically significant improvements in SGRQ total score versus the mono-components were only seen for tiotropium+olodaterol FDC 5/5 μg. Incidence of adverse events was comparable between the FDCs and the mono-components. These studies demonstrated significant improvements in lung function and health-related quality of life with once-daily tiotropium+olodaterol FDC versus mono-components over 1 year in patients with moderate to very severe COPD.
Optimized <i>Clostridium</i>-Directed Enzyme Prodrug Therapy Improves the Antitumor Activity of the Novel DNA Cross-Linking Agent PR-104
Authors: Shie-Chau Liu, G-One Ahn, Mitomu Kioi, Mary-Jo Dorie, Adam V. Patterson, J. Martin Brown
Journal: Cancer Research (2008)

Abstract We have previously shown that spores of the nonpathogenic clostridial strain C. sporogenes genetically engineered to express the E. coli–derived cytosine deaminase gene are effective in converting systemically injected nontoxic 5-fluorocytosine into the toxic anticancer drug 5-fluorouracil, thereby producing tumor-specific antitumor activity. To improve the expression of E. coli–derived genes with this system, we first replaced the original fdP promoter in the vector with one of two powerful endogenous clostridial promoters: that of the thiolase gene (thlP) and that for the clostridial transcription factor abrB310 (abrBP). These substitutions improved protein expression levels of the prodrug-activating genes by 2- to 3-fold in comparison with fdP-driven expression. However, despite these strong promoters, we found much higher expression of the nitroreductase (NTR) protein in the E. coli host compared with the clostridial host, which we hypothesized could be the result of different codon use between the two organisms. To test this, we constructed new expression vectors with an artificially synthesized NTR gene using optimized clostridial codons (sNTR). Results from both enzymatic assays and Western blots of cell extracts from clostridial transformants harboring plasmid constructs of thlP-sNTR and abrBP-sNTR showed that the expression and activity of the NTR gene product was increased by ∼20-fold compared with the original construct. In vivo studies with i.v. administered sNTR-expressing C. sporogenes spores in SiHa tumor–bearing mice showed significantly improved antitumor efficacy when combined with either 5-aziridinyl-2,4-dinitrobenzamide (CB1954) or the novel dinitrobenzamide mustard prodrug, PR-104. [Cancer Res 2008;68(19):7995–8003]
Origin of Primate Orphan Genes: A Comparative Genomics Approach
Authors: M. Toll-Riera, N. Bosch, N. Bellora, R. Castelo, L. Armengol, X. Estivill, M. Mar Alba
Journal: Molecular Biology and Evolution (2008)

Genomes contain a large number of genes that do not have recognizable homologues in other species and that are likely to be involved in important species-specific adaptive processes. The origin of many such "orphan" genes remains unknown. Here we present the first systematic study of the characteristics and mechanisms of formation of primate-specific orphan genes. We determine that codon usage values for most orphan genes fall within the bulk of the codon usage distribution of bona fide human proteins, supporting their current protein-coding annotation. We also show that primate orphan genes display distinctive features in relation to genes of wider phylogenetic distribution: higher tissue specificity, more rapid evolution, and shorter peptide size. We estimate that around 24% are highly divergent members of mammalian protein families. Interestingly, around 53% of the orphan genes contain sequences derived from transposable elements (TEs) and are mostly located in primate-specific genomic regions. This indicates frequent recruitment of TEs as part of novel genes. Finally, we also obtain evidence that a small fraction of primate orphan genes, around 5.5%, might have originated de novo from mammalian noncoding genomic regions.
CS1, a Potential New Therapeutic Antibody Target for the Treatment of Multiple Myeloma
Authors: Eric D. Hsi, Roxanne Steinle, Balaji Balasa, Susann Szmania, Aparna Draksharapu, Benny P. Shum, Mahrukh Huseni, David Powers, Amulya Nanisetti, Yin Zhang, Audie G. Rice, Anne van Abbema, Melanie Wong, Gao Liu, Fenghuang Zhan, Myles Dillon, Shihao Chen, Susan Rhodes, Franklin Fuh, Naoya Tsurushita, Shankar Kumar, Vladimir Vexler, John D. Shaughnessy, Bart Barlogie, Frits van Rhee, Mohamad Hussein, Daniel E.H. Afar, Marna B. Williams
Journal: Clinical Cancer Research (2008)

Abstract Purpose: We generated a humanized antibody, HuLuc63, which specifically targets CS1 (CCND3 subset 1, CRACC, and SLAMF7), a cell surface glycoprotein not previously associated with multiple myeloma. To explore the therapeutic potential of HuLuc63 in multiple myeloma, we examined in detail the expression profile of CS1, the binding properties of HuLuc63 to normal and malignant cells, and the antimyeloma activity of HuLuc63 in preclinical models. Experimental Design: CS1 was analyzed by gene expression profiling and immunohistochemistry of multiple myeloma samples and numerous normal tissues. HuLuc63-mediated antimyeloma activity was tested in vitro in antibody-dependent cellular cytotoxicity (ADCC) assays and in vivo using the human OPM2 xenograft model in mice. Results: CS1 mRNA was expressed in &amp;gt;90% of 532 multiple myeloma cases, regardless of cytogenetic abnormalities. Anti-CS1 antibody staining of tissues showed strong staining of myeloma cells in all plasmacytomas and bone marrow biopsies. Flow cytometric analysis of patient samples using HuLuc63 showed specific staining of CD138+ myeloma cells, natural killer (NK), NK-like T cells, and CD8+ T cells, with no binding detected on hematopoietic CD34+ stem cells. HuLuc63 exhibited significant in vitro ADCC using primary myeloma cells as targets and both allogeneic and autologous NK cells as effectors. HuLuc63 exerted significant in vivo antitumor activity, which depended on efficient Fc-CD16 interaction as well as the presence of NK cells in the mice. Conclusions: These results suggest that HuLuc63 eliminates myeloma cells, at least in part, via NK-mediated ADCC and shows the therapeutic potential of targeting CS1 with HuLuc63 for the treatment of multiple myeloma.
Premature apoptosis of keratinocytes and the dysregulation of keratinization in porokeratosis
Authors: C-S. Shen, K. Tabata, M. Matsuki, T. Goto, T. Yokochi, K. Yamanishi
Journal: British Journal of Dermatology (2002)

Porokeratosis is a dyskeratotic disorder of the skin characterized by cornoid lamella with parakeratosis, hyperkeratosis and loss of granular layers. The pathogenesis of porokeratosis and the mechanism(s) of its abnormal keratinization are still unknown.To elucidate the mechanism(s) of abnormal keratinization that leads to the formation of cornoid lamellae in porokeratosis.Apoptosis of keratinocytes was assessed in the skin of seven patients by an in situ apoptosis assay based on the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labelling (TUNEL) reaction. Patterns of loricrin and involucrin expression were examined by immunohistochemistry.TUNEL-positive keratinocytes were observed in the epidermis underlying the cornoid lamella in all cases examined. Furthermore, loricrin expression was interrupted there, in contrast to involucrin, which was expressed diffusely in the lesional epidermis.These results suggest that an abnormal early keratinocyte apoptosis accompanied by dysregulation of terminal differentiation of those cells may be involved in the pathogenesis of porokeratosis.
Population-Based Assessment of Surgical Treatment Trends for Patients With Melanoma in the Era of Sentinel Lymph Node Biopsy
Authors: Janice N. Cormier, Yan Xing, Meichun Ding, Jeffrey E. Lee, Paul F. Mansfield, Jeffrey E. Gershenwald, Merrick I. Ross, Xianglin L. Du
Journal: Journal of Clinical Oncology (2005)

Purpose The surgical staging of melanoma dramatically changed with the introduction of sentinel lymph node (SLN) biopsy. In this study, Surveillance, Epidemiology, and End Results (SEER) data were examined to determine how surgical treatment is being carried out and whether SLN biopsy is being performed in melanoma patients in conformance with National Comprehensive Cancer Network (NCCN) guidelines. Patients and Methods The SEER database (1998 to 2001) was searched for all patients with invasive melanoma. NCCN guidelines were used to define optimal stage-specific surgical treatment. Treatment trends in patients with stages I to III disease were summarized, and multivariate analyses were performed to identify factors associated with nonadherence with treatment guidelines. Results A total of 21,867 melanoma patients were identified; 18,499 of these patients met the inclusion criteria. The number of patients diagnosed with stage III melanoma increased by 55.7% over the study period, and this corresponded to a 53% increase in the number of SLN biopsies performed annually. The odds ratios for nonadherence were 2.32, 2.27, and 1.54 for stages IB, II, and III disease, respectively, compared with stage IA melanoma. Multivariate analyses revealed that age more than 65 years, marital status, minority populations, and primary tumor location were associated with nonadherence with guidelines. Treatment patterns among tumor registries also varied significantly. Conclusion Stage migration is evident in the SEER registries in consort with increasing use of SLN biopsy. Although treatment trends are improving, SLN biopsy continues to be underused, particularly in the elderly and minority populations, in patients with truncal and head/neck melanomas, and also in some geographic regions of the United States.