tbuckley/cabot-search huggingface dataset:
Telomere Shortening and Chromosomal Abnormalities in Intestinal Metaplasia of the Urinary Bladder
Authors: Michael J. Morton, Shaobo Zhang, Antonio Lopez-Beltran, Gregory T. MacLennan, John N. Eble, Rodolfo Montironi, Ming-Tse Sung, Puay-Hoon Tan, Suqin Zheng, Honghong Zhou, Liang Cheng
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Although intestinal metaplasia is often found in association with adenocarcinoma of the urinary bladder, it is unclear whether intestinal metaplasia of the bladder is a premalignant lesion. Telomere shortening has recently been implicated in epithelial carcinogenesis. We used quantitative fluorescent in situ hybridization (FISH) to measure telomere length and UroVysion FISH to detect cytogenetic abnormalities in urinary bladder specimens with intestinal metaplasia. Experimental Design: Paraffin-embedded tissue blocks from 34 patients with intestinal metaplasia of the urinary bladder were evaluated. Twelve of the 34 patients had coexistent cystitis glandularis, and telomere length was measured in these lesions for comparison. Tissue sections were prepared and hybridized with a telomere-specific peptide nucleic acid probe. Quantitative FISH on interphase nuclei was used to assess telomere signal intensity. Additional sections were hybridized with centromeric probes for chromosomes 3, 7, and 17 and a locus-specific probe 9p21. Multicolor FISH was used to analyze for cytogenic abnormalities in the interphase nuclei of intestinal metaplasia. Results: In all 34 cases, reduced average telomere signal intensity was observed in the nuclei of intestinal metaplasia cells compared with adjacent control nuclei to produce a mean relative intensity of 48.5% (P &amp;lt; 0.0001). When cystitis glandularis was present, significant differences in the telomere-specific signal intensity existed between cystitis glandularis and normal cells (P = 0.0005) and between cystitis glandularis and intestinal metaplasia cells (P = 0.0015). Three of the 34 cases showed chromosomal gains in the UroVysion FISH assay. Conclusions: Our findings indicate that intestinal metaplasia in the urinary bladder is associated with significant telomere shortening relative to telomere length in adjacent normal urothelial cells. These lesions also occasionally showed cytogenetic abnormalities associated with telomere shortening. Our findings support the hypothesis that intestinal metaplasia of the urinary bladder is a precursor lesion to and could be a marker in the development of adenocarcinoma of the urinary bladder.
Vascular Progenitor Cells Isolated From Human Embryonic Stem Cells Give Rise to Endothelial and Smooth Muscle–Like Cells and Form Vascular Networks In Vivo
Authors: Lino S. Ferreira, Sharon Gerecht, Hester F. Shieh, Nicki Watson, Maria A. Rupnick, Susan M. Dallabrida, Gordana Vunjak-Novakovic, Robert Langer
Journal: Circulation Research (2007)

We report that human embryonic stem cells contain a population of vascular progenitor cells that have the ability to differentiate into endothelial-like and smooth muscle (SM)-like cells. Vascular progenitor cells were isolated from EBs grown in suspension for 10 days and were characterized by expression of the endothelial/hematopoietic marker CD34 (CD34+ cells). When these cells are subsequently cultured in EGM-2 (endothelial growth medium) supplemented with vascular endothelial growth factor-165 (50 ng/mL), they give rise to endothelial-like cells characterized by a cobblestone cell morphology, expression of endothelial markers (platelet endothelial cell-adhesion molecule-1, CD34, KDR/Flk-1, vascular endothelial cadherin, von Willebrand factor), incorporation of acetylated low-density lipoprotein, and formation of capillary-like structures when placed in Matrigel. In contrast, when CD34+ cells are cultured in EGM-2 supplemented with platelet-derived growth factor-BB (50 ng/mL), they give rise to SM-like cells characterized by spindle-shape morphology, expression of SM cell markers (alpha-SM actin, SM myosin heavy chain, calponin, caldesmon, SM alpha-22), and the ability to contract and relax in response to common pharmacological agents such as carbachol and atropine but rarely form capillary-like structures when placed in Matrigel. Implantation studies in nude mice show that both cell types contribute to the formation of human microvasculature. Some microvessels contained mouse blood cells, which indicates functional integration with host vasculature. Therefore, the vascular progenitors isolated from human embryonic stem cells using methods established in the present study could provide a means to examine the mechanisms of endothelial and SM cell development, and they could also provide a potential source of cells for vascular tissue engineering.
Long-Term Results of First-Line Sequential High-Dose Etoposide, Ifosfamide, and Cisplatin Chemotherapy Plus Autologous Stem Cell Support for Patients With Advanced Metastatic Germ Cell Cancer: An Extended Phase I/II Study of the German Testicular Cancer Study Group
Authors: H.-J. Schmoll, C. Kollmannsberger, B. Metzner, J.T. Hartmann, N. Schleucher, P. Schöffski, J. Schleicher, O. Rick, J. Beyer, D. Hossfeld, L. Kanz, W.E. Berdel, R. Andreesen, C. Bokemeyer
Journal: Journal of Clinical Oncology (2003)

Patients with disseminated germ cell cancer and poor prognosis (International Germ Cell Cancer Collaborative Group [IGCCCG] classification) achieve only a 45% to 50% long-term survival by standard chemotherapy. First-line high-dose chemotherapy might be able to improve the result. This analysis reports toxicity and long-term results of a large phase I/II study of sequential high-dose etoposide, ifosfamide, and cisplatin (VIP) in patients with advanced germ cell tumors.Between July 1993 and November 1999, 221 patients with either Indiana "advanced disease" (n = 39) or IGCCCG "poor prognosis" criteria (n = 182) received one cycle of VIP followed by three to four sequential cycles of high-dose VIP chemotherapy plus stem cell support, every 3 weeks, at six consecutive dose levels.Dose limiting toxicity occurred at level 8 (100 mg/m2 cisplatinum, 1750 mg/m2 etoposide, 12 g/m2 ifosfamide) with grade 4 mucositis (three of eight patients), grade 3 CNS toxicity (one of eight patients), grade 4 renal toxicity (one of eight patients), and prolonged granulocytopenia (one of eight patients). After 4-year median follow-up, progression-free survival and disease-specific survival rates in the poor prognosis subgroup were 69% and 79% at 2 years and 68% and 73% at 5 years, with 76% for gonadal/retroperitoneal versus 67% for mediastinal primaries. Severe toxicity included treatment related death (4%), treatment-related acute myeloid leukemia (1%), long-term impared renal function (3%), chronic renal failure (1%), and persistent grade 2-3 neuropathy (5%).Repetitive cycles of high-dose VIP with peripheral stem cell support can be successfully applied in a multicenter setting. Dose level 6 with cisplatin 100 mg/m2, etoposide 1500 mg/m2, and ifosfamide 10 g/m2 is recommended for further investigation in randomized trials. An ongoing randomized trial within the European Organization for Research and Treatment of Cancer evaluates this protocol against four cycles of standard cisplatin, etoposide, and bleomycin.
Integrated Profiling Reveals a Global Correlation between Epigenetic and Genetic Alterations in Mesothelioma
Authors: Brock C. Christensen, E. Andres Houseman, Graham M. Poage, John J. Godleski, Raphael Bueno, David J. Sugarbaker, John K. Wiencke, Heather H. Nelson, Carmen J. Marsit, Karl T. Kelsey
Journal: Cancer Research (2010)

Abstract Development of mesothelioma is linked mainly to asbestos exposure, but the combined contributions of genetic and epigenetic alterations are unclear. We investigated the potential relationships between gene copy number (CN) alterations and DNA methylation profiles in a case series of pleural mesotheliomas (n = 23). There were no instances of significantly correlated CN alteration and methylation at probed loci, whereas averaging loci over their associated genes revealed only two genes with significantly correlated CN and methylation alterations. In contrast to the lack of discrete correlations, the overall extent of tumor CN alteration was significantly associated with DNA methylation profile when comparing CN alteration extent among methylation profile classes. Further, there was evidence that this association was partially attributable to prevalent allele loss at the DNA methyltransferase gene DNMT1. Our findings define a strong association between global genetic and global epigenetic dysregulation in mesothelioma, rather than a discrete, local coordination of gene inactivation. Cancer Res; 70(14); 5686–94. ©2010 AACR.
Frequency and significance of antibody to double-stranded DNA in chronic active hepatitis
Authors: James R. Wood, Albert J. Czaja, Sandra J. Beaver, Stephen Hall, William W. Ginsburg, David K. Kaufman, Harold Markowitz
Journal: Hepatology (1986)

To assess the frequency and significance of immunoglobulin G antibody to double-stranded DNA in chronic active hepatitis, 99 patients with severe disease were tested for the antibody by an enzyme-linked immunosorbent assay of established sensitivity and specificity. Antibody was detected in 56 patients (57%) and occurred with similar frequency in patients with autoimmune (64%), idiopathic (46%) and type B (43%) disease. The mean serum level of antibody was higher in autoimmune disease but it was not significantly different from that in the other diagnostic categories. Patients with and without the antibody could not be distinguished by clinical, laboratory or histologic findings. Responses to corticosteroid therapy and mortality were unrelated to antibody status. In five patients, the antibody disappeared after corticosteroid treatment and induction of histologic remission. We conclude that immunoglobulin G antibody to double-stranded DNA is frequently present in patients with severe chronic active hepatitis. Patients with autoimmune disease may have higher antibody levels than others, but the presence of antibody does not connote a disease of specific etiology, unique presentation or different behavior. The prevalence of the finding and its disappearance after corticosteroid therapy suggest that it is a nonspecific manifestation of inflammatory activity.
Prostaglandin protects against bile salt induced increases in proton permeation of duodenal brush border membrane.
Authors: D Zhao, B H Hirst
Journal: Gut (1991)

A direct protective action of prostaglandin on luminal cell membranes was investigated by preincubating rabbit duodenal brush border membrane vesicles with prostaglandin E2 (PGE2) before incubation with bile salts. Membrane perturbation was assessed by measuring the net proton permeability (Pnet). Bile salts (deoxycholate, glycodeoxycholate, and taurodeoxycholate; 0.1-1.0 mmol/l) resulted in concentration dependent increases in Pnet: from (mean (SE] 5.42 (0.17) (n = 20) to 8.44 (0.24) x 10(-4) (n = 13) cm/s with 0.5 mmol/l deoxycholate. PGE2, 10(-8)-10(-6) mol/l, when added alone had no effect on Pnet: 5.41 (0.21) x 10(-4) (n = 14) cm/s with 10(-6) M PGE2. When duodenal brush border membranes were preincubated with PGE2, 10(-7)-10(-6) mol/l, however, the bile salt induced increase in Pnet was significantly reduced: 7.22 (0.18) x 10(-4) (n = 13) cm/s with 10(-7) mol/l PGE2 and 0.5 mmol/l deoxycholate. These findings indicate that PGE2 exerts a direct protective action on duodenal luminal membranes.
THE PEPTOLYTIC POWER OF LIVER, SPLEEN, AND KIDNEYS IN POISONING BY PHOSPHORUS AND CHLOROFORM
Authors: J. P. Simonds
Journal: The Journal of Experimental Medicine (1918)

1. Glycerol extracts of liver, spleen, and kidney contain an ereptic ferment capable of splitting peptone into amino-acids. 2. Poisoning by phosphorus appears to reduce the ereptic power of the liver, and to a less extent that of the kidneys. 3. Poisoning by chloroform appears to have no appreciable effect upon the ereptase content of the liver, spleen, or kidneys. 4. Feeding of sugar to normal animals has little or no effect upon the ereptic power of the liver, spleen, or kidneys. 5. Feeding of sugar before and after poisoning with phosphorus appears to prevent the reduction of ereptic power of the liver.
Serum and Urinary Nitrites and Nitrates and Doppler Sonography in Children With Diabetes
Authors: Alessandra Savino, Piernicola Pelliccia, Cosima Schiavone, Alessandra Primavera, Stefano Tumini, Angelika Mohn, Francesco Chiarelli
Journal: Diabetes Care (2006)

The aim of the present study was to evaluate serum and urinary nitric oxide (NO) concentrations in children and adolescents with diabetes compared with age-matched healthy control subjects to find out whether Doppler ultrasonography could be used to detect changes in renal resistive indexes (RIs) in children with diabetes and to assess whether there are correlations between these parameters and NO excretion.We studied 42 children with type 1 diabetes and 41 matched healthy control subjects, both divided into prepubertal or pubertal children. Serum and urinary nitrite and nitrate (NO2-+NO3-) concentrations were evaluated as an index of NO production. Doppler ultrasonographic registration of intrarenal RI was performed.Compared with healthy control subjects, children with diabetes had significantly increased concentrations of serum (30.26 +/- 6.52 vs. 24.47 +/- 7.27 mmol/l, P = 0.001) and urinary NO2-+NO3- (345.07 +/- 151.35 vs. 245.86 +/- 80.25 mmol/l, P = 0.002); the same was true for Doppler RI values (0.64 +/- 0.03 vs. 0.60 +/- 0.04, P = 0.035). This occurs in both prepubertal and the pubertal children. A significant positive correlation was found between serum and urinary NO2-+NO3- levels (P = 0.002, r = 0.374). Serum NO2-+NO3- concentrations also correlated positively with Doppler RI (P = 0.032, r = 0.262) and HbA1c (A1C) (P = 0.004, r = 0.329); urinary NO2-+NO3- concentrations correlated positively with A1C (P = 0.001, r = 0.394). Doppler RI correlated positively with A1C (P = 0.000, r = 0.424).This study demonstrates that in children with diabetes, chronic hyperglycemia may act through a mechanism that involves increased NO production and/or action and contributes to generating intrarenal hemodynamic abnormalities, which are detectable by Doppler ultrasonography even in early diabetic nephropathy.
Meta-Analysis of Randomized Clinical Trials Comparing Cisplatin to Carboplatin in Patients With Advanced Non–Small-Cell Lung Cancer
Authors: Katsuyuki Hotta, Keitaro Matsuo, Hiroshi Ueoka, Katsuyuki Kiura, Masahiro Tabata, Mitsune Tanimoto
Journal: Journal of Clinical Oncology (2004)

It remains undetermined whether cisplatin and carboplatin are equally effective for advanced non-small-cell lung cancer (NSCLC). We therefore did a meta-analysis of trials that compared cisplatin-based chemotherapy with carboplatin-based chemotherapy.We performed a literature search to identify trials that had investigated the substitution of carboplatin for cisplatin in the treatment of advanced NSCLC. We evaluated these trials for inclusion, rated methodologic quality, and abstracted relevant data.Of 1,191 reports, eight trials (2,948 patients) were identified, five of which investigated drug regimens containing platinum plus a new agent. Cisplatin-based chemotherapy produced a higher response rate, but the survival advantage was not significant (hazard ratio = 1.050; 95% CI, 0.907 to 1.216; P =.515). Subgroup analysis revealed that combination chemotherapy consisting of cisplatin plus a new agent yields 11% longer survival than carboplatin plus the same new agent (hazard ratio = 1.106; 95% CI, 1.005 to 1.218; P =.039). Patients on cisplatin-based chemotherapy frequently developed nausea and vomiting; thrombocytopenia was more frequent during carboplatin-based chemotherapy. No significant difference in treatment-related mortality was observed.We found that combination chemotherapy consisting of cisplatin plus a new agent yields a substantial survival advantage compared with carboplatin plus a new agent in patients with advanced NSCLC, although we failed to find any survival difference in an analysis that included both new and old agents. The strength of our conclusion is limited because we used abstracted data, and careful interpretation is thus required. Nevertheless, our results raise a critical point that needs to be evaluated in future studies.
Systemic analysis of the response of Aspergillus niger to ambient pH
Authors: Mikael R Andersen, Linda Lehmann, Jens Nielsen
Journal: Genome biology (2009)

Abstract Background The filamentous fungus Aspergillus niger is an exceptionally efficient producer of organic acids, which is one of the reasons for its relevance to industrial processes and commercial importance. While it is known that the mechanisms regulating this production are tied to the levels of ambient pH, the reasons and mechanisms for this are poorly understood. Methods To cast light on the connection between extracellular pH and acid production, we integrate results from two genome-based strategies: A novel method of genome-scale modeling of the response, and transcriptome analysis across three levels of pH. Results With genome scale modeling with an optimization for extracellular proton-production, it was possible to reproduce the preferred pH levels for citrate and oxalate. Transcriptome analysis and clustering expanded upon these results and allowed the identification of 162 clusters with distinct transcription patterns across the different pH-levels examined. New and previously described pH-dependent cis -acting promoter elements were identified. Combining transcriptome data with genomic coordinates identified four pH-regulated secondary metabolite gene clusters. Integration of regulatory profiles with functional genomics led to the identification of candidate genes for all steps of the pal/pacC pH signalling pathway. Conclusions The combination of genome-scale modeling with comparative genomics and transcriptome analysis has provided systems-wide insights into the evolution of highly efficient acidification as well as production process applicable knowledge on the transcriptional regulation of pH response in the industrially important A. niger . It has also made clear that filamentous fungi have evolved to employ several offensive strategies for out-competing rival organisms.
What factors are associated with physical activity in older people, assessed objectively by accelerometry?
Authors: T J Harris, C G Owen, C R Victor, R Adams, D G Cook
Journal: British Journal of Sports Medicine (2008)

Objectives: To assess physical activity (PA) levels measured objectively using accelerometers in community-dwelling older people and to examine the associations with health, disability, anthropometric measures and psychosocial factors. Design: Cross-sectional survey. Setting: Single general practice (primary care centre), United Kingdom. Participants: Random selection of 560 community-dwelling older people at least 65 years old, registered with the practice. 43% (238/560) participated. Assessment of risk factors: Participants completed a questionnaire assessing health, disability, psychosocial factors and PA levels; underwent anthropometric assessment; and wore an accelerometer (Actigraph) for 7 days. Main outcome measures: Average daily accelerometer step-counts and time spent in different PA levels. Associations between step-counts and other factors were examined using linear regression. Results: Average daily step-count was 6443 (95% CI 6032 to 6853). Men achieved 754 (84 to 1424) more steps daily than women. Step-count declined steadily with age. Independent predictors of average daily step-count were: age; general health; disability; diabetes; body mass index; exercise self-efficacy; and perceived exercise control. Activities associated independently with higher step-counts included number of long walks and dog-walking. Only 2.5% (6/238) of participants achieved the recommended 150 minutes weekly of at least moderate-intensity activity in ⩾10 minute bouts; 62% (147/238) achieved none. Conclusions: This is the first population-based sample of older people with objective PA and anthropometric measures. PA levels in older people are well below recommended levels, emphasising the need to increase PA in this age group, particularly in those who are overweight/obese or have diabetes. The independent effects of exercise self-efficacy and exercise control on PA levels highlight their role as potential mediators for intervention studies.
New treatments for multiple sclerosis
Authors: W I McDonald
Journal: BMJ (1995)

Encouraging progress has been made in the development of treatments that reduce disease activity in multiple sclerosis. The relation between disability and such activity (as reflected in the relapse rate or the appearance of new lesions on magnetic resonance imaging) is complex, but recent evidence suggests that it may be possible to delay, though not yet abolish, the progress of irrecoverable neurological deficit.

The results of three large randomised controlled trials in ambulant patients with little or moderate disability have been announced during the past 18 months. Only one has been fully reported in the medical literature,1 but two others were widely discussed at a joint meeting of the American Neurological Association and the Association of British Neurologists held last October. Because much uncertainty exists about the potential role of these very expensive treatments it is important that the present position is clearly understood. In the review that follows, the figures for the two recent reports have been derived from information provided by the sponsors of the trials2 3; the data on which the conclusions of these two studies are based have yet to be subjected to peer review.

In a trial of interferon beta-1b 372 patients with relapsing and remitting disease were allocated to placebo or a low dose (1.6 MIU) or high dose (8 MIU) of the drug, which was given by subcutaneous injection on alternate days. After two years the relapse rate (the primary end point) was significantly lower in patients receiving the high dose than in those receiving placebo (1.27/year …