tbuckley/cabot-search huggingface dataset:
Impact of DNA ligase IV on nonhomologous end joining pathways during class switch recombination in human cells
Authors: Qiang Pan-Hammarström, Anne-Marie Jones, Aleksi Lähdesmäki, Wei Zhou, Richard A. Gatti, Lennart Hammarström, Andrew R. Gennery, Michael R. Ehrenstein
Journal: The Journal of Experimental Medicine (2005)

Class switch recombination (CSR) is a region-specific, transcriptionally regulated, nonhomologous recombinational process that is initiated by activation-induced cytidine deaminase (AID). The initial lesions in the switch (S) regions are subsequently processed and resolved, leading to recombination of the two targeted S regions. The mechanisms by which repair and ligation of the broken DNA ends occurs is still elusive. Recently, a small number of patients lacking DNA ligase IV, a critical component of the nonhomologous end joining (NHEJ) machinery, have been identified. We show that these patients display a considerably increased donor/acceptor homology at Sμ–Sα junctions compared with healthy controls. In contrast, Sμ–Sγ junctions show an increased frequency of insertions but no increase in junctional homology. These altered patterns of junctional resolution may be related to differences in the homology between the Sμ and the downstream isotype S regions, and could reflect different modes of switch junction resolution when NHEJ is impaired. These findings link DNA ligase IV, and thus NHEJ, to CSR.
Surgery in early NSCLC and co-morbidity
Authors: D Sortini, E Pozza, K Maravegias, A Liboni, A Sortini
Journal: Thorax (2005)

We would like to congratulate Janssen-Heijnen et al 1 on their well performed study and on their significant contribution to resolving the problem of treatment in patients with non-small cell lung cancer (NSCLC) and co-morbidity. However, we could not find a description of the surgical approach used and would like to ask the authors to provide details of the surgical procedures adopted and the accompanying survival rates. We think,2 in agreement with other authors3 that, for patients with early stage NSCLC and co-morbidity, a less invasive surgical approach should be used. This view is supported by studies in elderly patients or in patients with co-morbidity showing that a less invasive approach does not influence survival rates. Only the recurrence …
Role of DNA methylation in renal cell carcinoma
Authors: Niraj Shenoy, Nishanth Vallumsetla, Yiyu Zou, Jose Nahun Galeas, Makardhwaj Shrivastava, Caroline Hu, Katalin Susztak, Amit Verma
Journal: Journal of Hematology & Oncology (2015)

Alterations in DNA methylation are seen in cancers and have also been examined in clear cell renal cell carcinoma (ccRCC). Numerous tumor suppressor genes have been reported to be partially or completely silenced due to hypermethylation of their promoters in single-locus studies, and the use of hypomethylating agents has been shown to restore the expression of many of these genes in vitro. In particular, members of the Wnt and TGF-beta pathways, pro-apoptotic genes such as APAF-1 and negative cell-cycle regulators such as KILLIN have been shown to be epigenetically silenced in numerous studies in ccRCC. Recently, TCGA analysis of a large cohort of ccRCC samples demonstrated that aberrant hypermethylation correlated with the stage and grade in kidney cancer. Our genome-wide studies also revealed aberrant widespread hypermethylation that affected regulatory regions of the kidney genome in ccRCC. We also observed that aberrant enhancer hypermethylation was predictive of adverse prognosis in ccRCC. Recent discovery of mutations affecting epigenetic regulators reinforces the importance of these changes in the pathophysiology of ccRCC and points to the potential of epigenetic modulators in the treatment of this malignancy.
Genomic linkage map of the human blood fluke Schistosoma mansoni
Authors: Charles D Criscione, Claudia LL Valentim, Hirohisa Hirai, Philip T LoVerde, Timothy JC Anderson
Journal: Genome biology (2009)

Schistosoma mansoni is a blood fluke that infects approximately 90 million people. The complete life cycle of this parasite can be maintained in the laboratory, making this one of the few experimentally tractable human helminth infections, and a rich literature reveals heritable variation in important biomedical traits such as virulence, host-specificity, transmission and drug resistance. However, there is a current lack of tools needed to study S. mansoni's molecular, quantitative, and population genetics. Our goal was to construct a genetic linkage map for S. mansoni, and thus provide a new resource that will help stimulate research on this neglected pathogen.We genotyped grandparents, parents and 88 progeny to construct a 5.6 cM linkage map containing 243 microsatellites positioned on 203 of the largest scaffolds in the genome sequence. The map allows 70% of the estimated 300 Mb genome to be ordered on chromosomes, and highlights where scaffolds have been incorrectly assembled. The markers fall into eight main linkage groups, consistent with seven pairs of autosomes and one pair of sex chromosomes, and we were able to anchor linkage groups to chromosomes using fluorescent in situ hybridization. The genome measures 1,228.6 cM. Marker segregation reveals higher female recombination, confirms ZW inheritance patterns, and identifies recombination hotspots and regions of segregation distortion.The genetic linkage map presented here is the first for S. mansoni and the first for a species in the phylum Platyhelminthes. The map provides the critical tool necessary for quantitative genetic analysis, aids genome assembly, and furnishes a framework for comparative flatworm genomics and field-based molecular epidemiological studies.
Identifying problems with data collection at a local level: survey of NHS maternity units in England
Authors: N. Kenney, A. Macfarlane
Journal: BMJ (1999)

<h3>Abstract</h3> <b>Objectives:</b> To document the extent to which maternity data are collected and how they are recorded, and to identify problems that may affect their availability throughout the NHS. <b>Methods:</b> Postal survey in September 1997 with structured questionnaires. <b>Setting:</b> 207 NHS trusts with maternity units in England. <b>Participants:</b> Heads of midwifery in maternity units. <b>Main outcome measures:</b> Extent to which maternity data were routinely recorded, how they were recorded and evaluated, and to whom they were made available. <b>Results:</b> 167 (81%) of questionnaires were returned, representing 166 trusts. Of these trusts, 165 collected ≥17 of the 19 data items in HES maternity tail, and 158 collected ≥40 of the 45 items selected from Körner dataset. Only 18 collected all five items selected from the "indicators of success," and 17 did not collect any. In 58 of trusts data were primarily recorded on paper. A computerised maternity information system was used by 106 (63%) of trusts, but many recorded data on paper first. Thirty four did not audit data for accuracy. Most trusts analysed data not routinely collected at national level, but 18 did not analyse HES maternity tail and 17 did not analyse Körner data. <b>Conclusions:</b> Improvement is needed in quality, completeness, and availability of maternity data at a national level, particularly if the NHS information strategy is to be successfully implemented. Although most of the data items in national datasets are recorded locally, variations in the way data are defined, recorded, and analysed and lack of linkage between computer systems restrict their access, availability, and use at local, district, and national levels. <h3>Key messages</h3> Most NHS maternity data missing at a national level are collected at a local level Variations in the way in which maternity data are defined, recorded, audited, and analysed can affect the quality, completeness, and availability of this information throughout the NHS Considerable work and investment will be required to implement the plans set out in the NHS information strategy <i>Information for Health</i>
Opioid Peptide Gene Expression Primes Cardiogenesis in Embryonal Pluripotent Stem Cells
Authors: Carlo Ventura, Margherita Maioli
Journal: Circulation Research (2000)

Zinc finger-containing transcription factor GATA-4 and homeodomain Nkx-2.5 govern crucial developmental fates and have been found to promote cardiogenesis in embryonic cells exposed to the differentiating agent DMSO. Nevertheless, intracellular activators of these transcription factors are largely unknown. In this study, pluripotent P19 cells expressed the prodynorphin gene, an opioid gene encoding for the dynorphin family of opioid peptides. P19 cells were also able to synthesize and secrete dynorphin B, a biologically active end product of the prodynorphin gene. DMSO-primed GATA-4 and Nkx-2.5 gene expression was preceded by a marked increase in prodynorphin gene expression and dynorphin B synthesis and secretion. The DMSO effect occurred at the transcriptional level. In the absence of DMSO, dynorphin B triggered GATA-4 and Nkx-2.5 gene expression and led to the appearance of both alpha-myosin heavy chain and myosin light chain-2V transcripts, two markers of cardiac differentiation. Moreover, dynorphin B-exposed cells were positively stained in the presence of MF 20, a mouse monoclonal antibody raised against the alpha-myosin heavy chain. Opioid receptor antagonism and inhibition of opioid gene expression by a prodynorphin antisense phosphorothioate oligonucleotide blocked DMSO-induced cardiogenesis, suggesting an autocrine role of an opioid gene in developmental decisions.
Topoisomerase IIα Amplification Does Not Predict Benefit From Dose-Intense Cyclophosphamide, Doxorubicin, and Fluorouracil Therapy in <i>HER2</i>-Amplified Early Breast Cancer: Results of CALGB 8541/150013
Authors: Lyndsay N. Harris, Gloria Broadwater, Maysa Abu-Khalaf, David Cowan, Ann D. Thor, Daniel Budman, Constance T. Cirrincione, Donald A. Berry, Eric P. Winer, Clifford A. Hudis, Daniel F. Hayes, Paula Friedman, Matthew Ellis, Lynn Dressler
Journal: Journal of Clinical Oncology (2009)

PURPOSE We have demonstrated that patients with HER2-amplified tumors derive more benefit from higher doses of doxorubicin-containing chemotherapy (cyclophosphamide, doxorubicin, and fluorouracil [CAF]). Because topoisomerase IIalpha (Topo-IIalpha) is a target for doxorubicin and is coamplified in 20% to 50% of HER2-amplified tumors, we postulated that Topo-IIalpha copy number might account for the benefit from CAF dose escalation in HER2-positive tumors. To address this hypothesis, we examined Topo-IIalpha and HER2 copy number, CAF dose, and clinical outcomes in Cancer and Leukemia Group B (CALGB) 8541. PATIENTS AND METHODS Topo-IIalpha and HER2 copy number were measured by fluorescent in situ hybridization (FISH) using a triple-probe system, which includes Topo-IIalpha, HER2, and chromosome 17 (CEP17). Topo-IIalpha and/or HER2 were classified as amplified (> or = two copies/CEP17, deleted (< or = 0.67 copies/CEP17) and normal copy number (> .67 to < 2.0 copies/CEP17). Results Topo-IIalpha/HER2/CEP17 measurement was successful in 624 of 687 cases. HER2 was amplified in 117 cases (19%). Topo-IIalpha was amplified in 41 cases (7%) and deleted in 69 cases (11%). Topo-IIalpha amplification was highly correlated with HER2 amplification (39 of 41; P < .0001), HER2 by immunohistochemistry, and by dual-probe FISH. Topo-IIalpha was deleted in both the HER2-amplified (30 of 69; 43%), normal (22 of 69; 32%) and HER2-deleted tumors (17 of 69; 25%). Although Topo-IIalpha-amplified tumors were nearly always HER2 amplified, these tumors did not receive benefit from increasing the dose of CAF (P = .15). CONCLUSION The correlative companion study CALGB 8541-150013 does not support the hypothesis that Topo-IIalpha amplification is the mechanism behind benefit from increased dose of anthracyclines in HER2-positive breast cancer.
Evidence of Skeletal Muscle Metabolic Reserve During Whole Body Exercise in Patients with Chronic Obstructive Pulmonary Disease
Authors: R. S. RICHARDSON, J. SHELDON, D. C. POOLE, S. R. HOPKINS, A. L. RIES, P. D. WAGNER
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

When freed from central cardiorespiratory limitations, healthy human skeletal muscle has exhibited a significant metabolic reserve. We studied the existence of this reserve in 10 severely compromised (FEV1 = 0.97 ± SE 0.01) patients with chronic obstructive pulmonary disease (COPD). To manipulate O2 supply and O2 demand in locomotor and respiratory muscles, subjects performed both maximal conventional two-legged cycle ergometry (large muscle mass) and single-leg knee extensor exercise (KE, small muscle mass) while breathing room air (RA), 100% O2, and 79% helium + 21% O2 (HeO2). With each gas mixture, peak ventilation, peak heart rate, and perceived breathlessness were lower in KE than cycle exercise (p < 0.05). Arterial O2 saturation and maximal work capacity increased in both exercise modalities while subjects breathed 100% O2 (work: + 10% bike, + 25% KE, p < 0.05). HeO2 increased maximal work capacity on the cycle ( + 14%, p < 0.05) but had no effect on KE. HeO2 resulted in the greatest maximum minute ventilation in both bike and KE (p < 0.05) but had no effect on arterial O2 saturation. Thus, a skeletal muscle metabolic reserve in these patients with COPD is evidenced by: (1) greater muscle mass specific work in KE; (2) greater work rates with higher fraction of inspired oxygen (Fi O2 ); (3) an even greater effect of Fi O2 during KE (i.e., when the lungs are less challenged); and (4) the positive effect of HeO2 on bicycle work rate. This skeletal muscle metabolic reserve suggests that reduced whole body exercise capacity in COPD is the result of central restraints rather than peripheral skeletal muscle dysfunction, while the beneficial effect of 100% O2 (with no change in maximum ventilation) suggests that the respiratory system is not the sole constraint to oxygen consumption.
Rule change incidence on physiological characteristics of elite basketball players: a 10-year-period investigation
Authors: B Cormery, M Marcil, M Bouvard
Journal: British Journal of Sports Medicine (2007)

Objective: To evaluate, by examining data collected on professional basketball players during a 10-year period, the differences in aerobic capacity in function of the playing position and the impact on these parameters of the change in time regulation of 2000, which shortened the time allowed to attempt a field goal by 6 s and divided the duration of play in four quarters. Methods: Twice a year between 1994 and 2004, professional basketball players (n = 68) were studied for anthropometric characteristics and were submitted to an incremental exercise test on a cycle ergometer. Statistical analyses were carried out to determine the interaction between the playing position and the effect of the change in time regulation on the physiological characteristics of the players. Results: Anthropometric measurements were different in function of the playing position, the centres being taller and heavier than the forwards and the guards. Guards exhibited the highest V̇ o 2 max (54.0 (SE 1.6) ml/min/kg) and were the most affected by the change in time regulation of 2000 with a 19.5% increase. Significant main effects of “before” versus “after” rule changes were found for maximal and submaximal O 2 consumption, which were increased by 12.8% at ventilatory threshold, 7.3% at respiratory compensation point and 7.8% at V̇ o 2 max. Conclusion: While anthropometric characteristics remained constant during the last decade, the change in rule of 2000 may have contributed in modifying the physiological profile of basketball players, by generally increasing their level of fitness.
T cell regulation of immunoglobulin class expression in the antibody response to trinitrophenyl-ficoll. Evidence for T cell enhancement of the immunoglobulin class switch.
Authors: P K Mongini, W E Paul, E S Metcalf
Journal: The Journal of Experimental Medicine (1982)

In the absence of T cells, B cells were found to respond to the type 2 T-independent (TI-2) antigen, trinitrophenyl (TNP)-Ficoll, with a characteristic hierarchy of IgM and IgG subclass Ab production which directly correlated with 5' to 3' Igh-C gene order, i.e., IgM greater tha IgG3 greater than IgG1 greater than IgG2b greater than IgG2a. This was evident when immune serum Ab titers were analyzed, when in vitro secretion of antibody from immune cells was measured and when TNP-Ficoll-stimulated clones in a splenic focus assay were analyzed for isotype production. T cells were found to cause a preferential relative increase in the amount of IgG2a antibody produced to TNP-Ficoll. The T cell responsible was present in anti-IgM neonatally suppressed mice and was needed early in the response, i.e., on the day of immunization or earlier. T cells were found to increase the frequency of TNP-Ficoll-responsive B cell clones that produced IgG2a in the splenic focus assay. The great majority of these IgG2a-positive clones also produced IgM and all or nearly all of the IgG isotypes whose genes are encoded 5' to the Igh-gamma 2a gene. The data are discussed in terms to T cell enhancement of IgG2a Ab synthesis being mediated through T cell enhancement of the Igh-C gene switching mechanism within TNP-Ficoll-responsive B cell clones. Thus, isotypes encoded by genes on the 3' end of the Igh-gamma gene complex, which in the absence of T cells have a low probability of being switched to, are the most influenced by T cell help.
Analysis of Cause-Specific Mortality in the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Study
Authors: Jonathan S. Steinberg, Ara Sadaniantz, Jack Kron, Andrew Krahn, D. Marty Denny, James Daubert, W. Barton Campbell, Edward Havranek, Katherine Murray, Brian Olshansky, Gearoid O’Neill, Magdi Sami, Stanley Schmidt, Randle Storm, Miguel Zabalgoitia, John Miller, Mary Chandler, Elaine M. Nasco, H. Leon Greene
Journal: Circulation (2004)

Expectations that reestablishing and maintaining sinus rhythm in patients with atrial fibrillation might improve survival were disproved in the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study. This report describes the cause-specific modes of death in the AFFIRM treatment groups.All deaths in patients enrolled in AFFIRM underwent blinded review by the AFFIRM Events Committee, and a mode of death was assigned. In AFFIRM, 2033 patients were randomized to a rhythm-control strategy and 2027 patients to a rate-control strategy. During a mean follow-up of 3.5 years, there were 356 deaths in the rhythm-control patients and 310 deaths in the rate-control patients (P=0.07). In the rhythm-control group, 129 patients (9%) died of a cardiac cause, and in the rate-control group, 130 patients (10%) died (P=0.95). Both groups had similar rates of arrhythmic and nonarrhythmic cardiac deaths. The numbers of vascular deaths were similar in the 2 groups: 35 (3%) in the rhythm-control group and 37 (3%) in the rate-control group (P=0.82). There were no differences in the rates of ischemic stroke and central nervous system hemorrhage. In the rhythm-control group, there were 169 noncardiovascular deaths (47.5% of the total number of deaths), whereas in the rate-control arm, there were 113 noncardiovascular deaths (36.5% of the total number of deaths) (P=0.0008). Differences in noncardiovascular death rates were due to pulmonary and cancer-related deaths.Management of atrial fibrillation with a rhythm-control strategy conferred no advantage over a rate-control strategy in cardiac or vascular mortality and may be associated with an increased noncardiovascular death rate.
The Effect of Discharge Voltage on Renal Injury and Impairment Caused by Lithotripsy in the Pig
Authors: BRET A. CONNORS, ANDREW P. EVAN, LYNN R. WILLIS, PHILIP M. BLOMGREN, JAMES E. LINGEMAN, NAOMI S. FINEBERG
Journal: Journal of the American Society of Nephrology (2000)

The present study was designed to determine the effects of shock wave voltage (kV) on lesion size and renal function induced by shock wave lithotripsy (SWL) in the 6- to 8-wk-old pig. Each SWL-treated pig received 2000 shock waves at 12, 18, or 24 kV to the lower pole calyx of one kidney. A group of sham SWL pigs served as time controls. Bilateral GFR, renal plasma flow (RPF), and para-aminohippurate (PAH) extraction were measured 1 h before and 1 and 4 h after SWL in all treated and sham animals. The kidneys were removed at the end of each experiment for morphometric analysis. The SWL-induced lesion increased significantly in size as shock wave energy was increased from 12 to 24 kV. PAH extraction, a measure of tubular function, was not significantly affected at 12 kV, was transiently reduced at 18 kV, and was reduced for the duration of the experiment at 24 kV. GFR and RPF, however, were significantly and similarly reduced at the 1 h post-SWL period at all three kilovolt levels. At the 4-h post-SWL period, both GFR and RPF had returned to baseline levels. Lesion size and tubular injury were correlated with changes in kilovoltage, while changes in renal hemodynamics were already maximal at the lowest discharge voltage. These findings suggest that renal microvessels are highly sensitive to shock waves and that frank injury to tubules and vessels may be more closely related to discharge energy than is renal blood flow.
Tumor Marker Utility Grading System: a Framework to Evaluate Clinical Utility of Tumor Markers
Authors: D. F. Hayes, R. C. Bast, C. E. Desch, H. Fritsche, N. E. Kemeny, J. M. Jessup, G. Y. Locker, J. S. Macdonald, R. G. Mennel, L. Norton, P. Ravdin, S. Taube, R. J. Winn
Journal: JNCI Journal of the National Cancer Institute (1996)

Introduction of tumor markers into routine clinical practice has been poorly controlled, with few criteria or guidelines as to how such markers should be used. We propose a Tumor Marker Utility Grading System (TMUGS) to evaluate the clinical utility of tumor markers and to establish and investigational agenda for evaluation of new tumor markers. A Tumor Marker Utility Grading Worksheet has been designed. The initial portion of this worksheet is used to clarify the precise characteristics of the marker in question. These characteristics include the marker designation, the molecule and/or substance and the relevant alteration from normalcy, the assay format and reagents, the specimen type, and the neoplastic disease for which the marker is being evaluated. To determine the clinical utility of each marker, one of several potential uses must be designated, including risk assessment, screening, differential diagnosis, prognosis, and monitoring clinical course. For each of these uses, associations between marker assay results and expected biologic process and end points must be determined. However, knowledge of tumor marker data should contribute to a decision in practice that results in a more favorable clinical outcome for the patient, including increased overall survival, increased disease-free survival, improvement in quality of life, or reduction in cost of care. Semiquantitative utility scales have been developed for each end point. The only markers recommended for use in routine clinical practice are those that are assigned utility scores of "++" or "+++" on a 6-point scale (ranging from 0 to +++) in the categories relative to more favorable clinical outcomes. Each utility score assignment should be supported by documentation of the level of evidence used to evaluate the marker. TMUGS will establish a standardized analytic technique to evaluate clinical utility of known and future tumor markers. It should result in improved patient outcomes and more cost-efficient investigation and application of tumor markers.