tbuckley/cabot-search huggingface dataset:
Randomized Intervention Studies in Human Polycystic Kidney and Liver Disease
Authors: Robert W. Schrier
Journal: Journal of the American Society of Nephrology (2010)

Autosomal dominant polycystic disease (ADPKD) is the most common life-threatening genetic disease in the United States. ADPKD is more common than Huntington disease, hemophilia, cystic fibrosis, sickle cell disease, Down syndrome, and myotonic dystrophy combined .1 The increase in kidney cyst volume over time correlates with hypertension and progressive renal dysfunction, yet, to date, there is no established intervention to slow or prevent the renal cyst growth. Increased proliferation accompanies renal cyst growth, and recent research in nonorthologous experimental animals and patients with ADPKD suggests aberrant activation of the Ser/Thr kinase mammalian target of rapamycin (mTOR), which modulates cell growth and proliferation.2–5 Recently, rapamycin was shown to have dramatic effects on liver cyst volumes in humans6 and in an orthologous rodent model with conditional inactivation of the PKD1 gene.7 The results demonstrate that mTOR inhibition with rapamycin decreases cyst growth, fibrosis, and proliferation and improves renal function. Of interest, there was regression of cyst burden, which may have been due to increased apoptosis among the cystic epithelium.

Perico et al. 8 in this issue of JASN performed a renal safety and efficacy study to examine further this potential pathogenetic ADPKD pathway in humans. This randomized crossover study examined the effect of sirolimus (rapamycin) over 6 months on progression of ADPKD compared with conventional therapy. The main efficacy variable was the effect on total kidney volume, but renal cyst and parenchymal volumes were also measured. The effect of sirolimus on GFR was also examined relative to kidney volume and structure …
Vascular Smooth Muscle Cell Calcification Is Mediated by Regulated Exosome Secretion
Authors: Alexander N. Kapustin, Martijn L.L. Chatrou, Ignat Drozdov, Ying Zheng, Sean M. Davidson, Daniel Soong, Malgorzata Furmanik, Pilar Sanchis, Rafael Torres Martin De Rosales, Daniel Alvarez-Hernandez, Rukshana Shroff, Xiaoke Yin, Karin Muller, Jeremy N. Skepper, Manuel Mayr, Chris P. Reutelingsperger, Adrian Chester, Sergio Bertazzo, Leon J. Schurgers, Catherine M. Shanahan
Journal: Circulation Research (2015)

Rationale: Matrix vesicles (MVs), secreted by vascular smooth muscle cells (VSMCs), form the first nidus for mineralization and fetuin-A, a potent circulating inhibitor of calcification, is specifically loaded into MVs. However, the processes of fetuin-A intracellular trafficking and MV biogenesis are poorly understood. Objective: The objective of this study is to investigate the regulation, and role, of MV biogenesis in VSMC calcification. Methods and Results: Alexa488-labeled fetuin-A was internalized by human VSMCs, trafficked via the endosomal system, and exocytosed from multivesicular bodies via exosome release. VSMC-derived exosomes were enriched with the tetraspanins CD9, CD63, and CD81, and their release was regulated by sphingomyelin phosphodiesterase 3. Comparative proteomics showed that VSMC-derived exosomes were compositionally similar to exosomes from other cell sources but also shared components with osteoblast-derived MVs including calcium-binding and extracellular matrix proteins. Elevated extracellular calcium was found to induce sphingomyelin phosphodiesterase 3 expression and the secretion of calcifying exosomes from VSMCs in vitro, and chemical inhibition of sphingomyelin phosphodiesterase 3 prevented VSMC calcification. In vivo, multivesicular bodies containing exosomes were observed in vessels from chronic kidney disease patients on dialysis, and CD63 was found to colocalize with calcification. Importantly, factors such as tumor necrosis factor-α and platelet derived growth factor-BB were also found to increase exosome production, leading to increased calcification of VSMCs in response to calcifying conditions. Conclusions: This study identifies MVs as exosomes and shows that factors that can increase exosome release can promote vascular calcification in response to environmental calcium stress. Modulation of the exosome release pathway may be as a novel therapeutic target for prevention.
Impact of professionalism on injuries in rugby union
Authors: W M Garraway, A J Lee, S J Hutton, E B A W Russell, D A D Macleod
Journal: British Journal of Sports Medicine (2000)

Objectives —To measure the frequency and nature of injuries occurring in competitive matches since professionalism was introduced in rugby union. Methods —The cohort study previously conducted in players from senior rugby clubs in the Scottish Borders in 1993–1994 when rugby union was an entirely amateur sport was repeated in 1997–1998. The same injury definition, outcome criteria, and method of calculating playing hours were used. In total, 803 (84%) of 960 eligible players participated, including all 30 adult players who played professionally for the Scottish Rugby Union or Border Reivers District. The 576 injury episodes in 381 of these players in competitive matches were compared with the 373 injuries in 266 players out of 975 (94 %) who were eligible and registered with the same senior rugby clubs in 1993–1994. Outcomes were the occurrence of injury episodes, days away from playing or training for rugby, and time lost to employment or attendance at school/college as a consequence of being injured. Results —The proportion of players who were injured almost doubled from 1993–1994 to 1997–1998, despite an overall reduction of 7% of the playing strength of participating clubs. Period prevalence injury rates rose in all age specific groups, particularly in younger players. This translated into an injury episode every 3.4 matches in 1993–94, rising to one in every 2.0 matches in 1997–1998. An injury episode occurred in a professional team for every 59 minutes of competitive play. Professional players sustained a higher proportion of recurrent injuries, particularly in the early part of the season. Some 56% of all their days lost to the game were caused by injuries to the muscles, ligaments, and joints of the knee, hip, and thigh. Conclusions —The introduction of professionalism in rugby union has coincided with an increase in injuries to both professional and amateur players. To reduce this, attention should be focused on the tackle, where many injuries occur. The International Rugby Board should place a moratorium on the use of protective equipment in competitive matches until its contribution to player morbidity has been fully assessed.
Decontextualised data IN, decontextualised theory OUT
Authors: Benjamin Roberts, Mike Kalish, Kathryn Hird, Kim Kirsner
Journal: Behavioral and Brain Sciences (1999)

We discuss our concerns associated with three assumptions upon which the model of Levelt, Roelofs &amp; Meyer is based: assumed generalisability of decontextualised experimental programs, assumed highly modular architecture of the language production systems, and assumed symbolic computations within the language production system. We suggest that these assumptions are problematic and require further justification.
Investigation of variants of the aromatase gene (CYP19A1) in female pattern hair loss
Authors: S. Redler, M.P. Birch, D. Drichel, K. Dobson, F.F. Brockschmidt, R. Tazi-Ahnini, K.A. Giehl, N. Kluck, R. Kruse, G. Lutz, H. Wolff, T. Becker, M.M. Nöthen, A.G. Messenger, R.C. Betz
Journal: British Journal of Dermatology (2011)

Funding sources S.R. was a recipient of a BONFOR Gerok fellowship from the Medical Faculty of the University of Bonn. M.M.N. is recipient of a grant from the Alfried Krupp von Bohlen und Halbach‐Stiftung. R.C.B. is recipient of a Heisenberg Professorship from the German Research Foundation (DFG). This study was also funded by the British Skin Foundation (A.G.M. and R.T.‐A., 2005). Conflicts of interest: none declared. A.G.M. and R.C.B. have contributed equally to this work. Madam, Female pattern hair loss (FPHL) is a common disorder which affects around 12% of women by the age of 30 years, and 30–40% of women by the age of 70 years.1 2–3 Although its precise aetiopathogenesis is unknown, reports of familial occurrence strongly implicate genetic factors.4 5–6 Yip et al.7 recently performed a gene‐wide study of association between FPHL and the aromatase gene encoding CYP19A1, which is known to convert androgens to oestrogens in scalp hair follicles.8 They examined 61 tagging single nucleotide polymorphisms (SNPs) of CYP19A1 in an Australian sample of 484 caucasian women with grade 3–5 FPHL (according to the Sinclair scale9) and 471 controls.7 While no significant association was obtained at the allelic level, the CC genotype of rs4646 was significantly more frequent in cases (58·1%) than controls (48·9%) when compared with collapsed AC and AA groups (P =0·006), suggesting a recessive genetic effect. Although this result did not withstand experiment‐wide correction for multiple testing, its validity was supported by the following lines of evidence: (i) the highest frequency of the CC genotype (68·2%) occurred in women < 40 years, which is consistent with the hypothesis that genetic predisposition is more evident among early‐onset cases; and (ii) the rs4646 CC genotype has been associated with higher oestrogen levels than the AA genotype, which is consistent with reports that oestrogen has inhibitory effects on hair growth. Given the lack of experiment‐wide significance, the authors were cautious in their interpretation, and stressed the need for replication in independent samples. To our knowledge, the present study is the first to attempt replication of this finding.
Population level survival of patients with chronic myelocytic leukemia in Germany compared to the US in the early 21st century
Authors: Dianne Pulte, Benjamin Barnes, Lina Jansen, Nora Eisemann, Katharina Emrich, Adam Gondos, Stefan Hentschel, Bernd Holleczek, Klaus Kraywinkel, Hermann Brenner
Journal: Journal of Hematology & Oncology (2013)

The advent of tyrosine kinase inhibitors has produced 5-year survival of 90 + % for chronic myelocytic leukemia (CML) patients in clinical trials. However, population level survival has been lower, especially in older patients. Here, we examine survival of patients with CML in Germany and compare it to survival of patients in the United States (US). Data were extracted from the Surveillance, Epidemiology, and End Results database in the US and 11 cancer registries in Germany. Patients 15–69 years old diagnosed with CML were included in the analysis. Period analysis for 2002–2006 was used to provide the most up-to-date possible estimates of five-year relative survival. Five-year relative survival was 68.7% overall in Germany and 72.7% in the US. Survival was higher in the US for all age groups except for ages 15–39 years, but the difference was only statistically significant for ages 50–59 years (at 67.5% vs 77.7% in Germany and the US, respectively). Survival decreased with age, ranging from 83.1% and 81.9%, respectively, in Germany and the US for patients 15–39 years old to 54.2% and 54.5%, respectively, in patients 65–69 years old. Survival increased between 2002 and 2006 by 12.0% points in Germany and 17.1% points in the US. Five-year survival estimates were higher in the US than in Germany overall, but the difference was only significant for ages 50–59 years. Survival did not equal that seen in clinical trials for either country, but strong improvement in survival was seen between 2002 and 2006.
Fruit and vegetable consumption and mortality from all causes, cardiovascular disease, and cancer: systematic review and dose-response meta-analysis of prospective cohort studies
Authors: X. Wang, Y. Ouyang, J. Liu, M. Zhu, G. Zhao, W. Bao, F. B. Hu
Journal: BMJ (2014)

<h3>Abstract</h3> Gene expression states influence the three-dimensional conformation of the genome through poorly understood mechanisms. Here, we investigate the conformation of the murine <i>HoxB</i> locus, a gene-dense genomic region containing closely spaced genes with distinct activation states in mouse embryonic stem (ES) cells. To predict possible folding scenarios, we performed computer simulations of polymer models informed with different chromatin occupancy features, which define promoter activation states or CTCF binding sites. Single cell imaging of the locus folding was performed to test model predictions. While CTCF occupancy alone fails to predict the in vivo folding at genomic length scale of 10 kb, we found that homotypic interactions between active and Polycomb-repressed promoters co-occurring in the same DNA fibre fully explain the HoxB folding patterns imaged in single cells. We identify state-dependent promoter interactions as major drivers of chromatin folding in gene-dense regions.
Clearance of Giardia muris infection requires helper/inducer T lymphocytes.
Authors: M F Heyworth, J R Carlson, T H Ermak
Journal: The Journal of Experimental Medicine (1987)

The aim of this work was to identify the T cell subset (helper/inducer or cytotoxic/suppressor) that plays a major part in the clearance of Giardia muris infection. BALB/c mice were selectively depleted of helper/inducer (Th/i) or cytotoxic/suppressor (Tc/s) T cells, by treatment with rat IgG monoclonal antibodies directed against the Th/i cell surface antigen L3T4, or against the Tc/s cell surface antigen Ly-2, and were infected with G. muris cysts. While mice depleted of Tc/s cells cleared G. muris infection at a normal rate, mice depleted of Th/i cells did not clear the infection. Depletion of the relevant T cell subset was confirmed by flow cytometry and by immunohistochemistry. The data indicate that helper/inducer T cells, but not cytotoxic T cells, are of major importance for elimination of G. muris from the mouse intestine.
Differences in Brain Chemistry in Children and Adolescents With Attention Deficit Hyperactivity Disorder With and Without Comorbid Bipolar Disorder: A Proton Magnetic Resonance Spectroscopy Study
Authors: Constance M. Moore, Joseph Biederman, Janet Wozniak, Eric Mick, Megan Aleardi, Megan Wardrop, Meghan Dougherty, Terri Harpold, Paul Hammerness, Edin Randall, Perry F. Renshaw
Journal: American Journal of Psychiatry (2006)

OBJECTIVE: The authors’ goal was to investigate phosphatidylinositol and glutamatergic metabolism in the anterior cingulate cortex of children and adolescents with attention deficit hyperactivity disorder (ADHD) alone, children with ADHD plus bipolar disorder, and children with no axis I diagnosis. METHOD: Proton spectra were acquired from a 4.8-ml voxel placed in the anterior cingulate cortex of 30 subjects who were 6 to 13 years old. Fifteen subjects had ADHD and no comorbid disorder, eight had ADHD plus bipolar disorder, and seven were healthy comparison subjects. RESULTS: Children with ADHD had a significantly higher ratio of glutamate plus glutamine to myo-inositol-containing compounds than children with ADHD plus bipolar disorder and healthy children. CONCLUSIONS: myo-Inositol-containing compounds may provide information on the action of antimanic treatments such as lithium, valproate, and carbamazepine. Glutamate and glutamine are measures of glutamatergic neurotransmission and thus may also reflect changes in serotonin and dopamine pathways.
Activation of Na+/H+ exchanger by hepatocyte growth factor in hepatocytes
Authors: Akira Kaneko, Norio Hayashi, Yuji Tanaka, Masayoshi Horimoto, Toshifumi Ito, Yutaka Sasaki, Hideyuki Fusamoto, Takenobu Kamada
Journal: Hepatology (1995)

The effect of the hepatocyte growth factor (HGF) on the Na+/H+ exchanger was studied using primary cultured hepatocytes. HGF induced intracellular pH (pHi) elevation of 0.10 pH units in hepatocytes cultured for 4 to 7 hours; the response was lower after other culture periods. Even with the same culture period, intercellular heterogeneity was found in the responsiveness to HGF. This heterogeneity may be partially accounted for by the weak but significant correlation observed between the basal pHi level and the degree of pHi elevation caused by HGF in hepatocytes. The pHi elevation caused by HGF was blocked on pretreatment of the hepatocytes with amiloride, suggesting that HGF activates the Na+/H+ exchanger. This hypothesis was confirmed by the fact that HGF increased the initial rapid rate of cell alkalization of acid-loaded hepatocytes. The tyrosine kinase inhibitor, genistein, also blocked the elevation, consistent with the fact that HGF receptor/c-met has a tyrosine kinase domain. To clarify the signal transduction pathway from tyrosine kinase to the Na+/H+ exchanger, we examined the effects of inhibitors of other kinases (H-7, H-8, and W-7) on the HGF-induced pHi elevation and found that only W-7 blocked it. This pHi elevation was also prevented on preincubation of the hepatocytes with thapsigargin, which blocks the calcium response caused by HGF. These results suggest that HGF activates the Na+/H+ exchanger in hepatocytes through a tyrosine kinase-calcium/calmodulin-dependent pathway.
Whole-body 18FDG positron emission tomography in the staging of non-small cell lung cancer
Authors: T Bury, A Dowlati, P Paulus, JL Corhay, R Hustinx, B Ghaye, M Radermecker, P Rigo
Journal: European Respiratory Journal (1997)

Despite advances in morphological imaging, some patients with lung cancer are found to have nonresectable disease at surgery or die of recurrence within yr of surgery. We performed a prospective study in 109 patients to compare the accuracy of whole-body positron emission tomography (PET) using fluorine-18 deoxyglucose (18FDG) and conventional imaging (CI) methods for the staging of non-small cell lung cancer (NSCLC). When CI or PET study suggested metastatic disease, confirmation was obtained by biopsy or follow-up information. As compared to CI, 18FDG-PET correctly changed the N stage in 22 patients (33%) and the M stage in 15 patients (14%). For the detection of distant metastases, PET study showed five false-positive sites and no false-negative cases. Currently, the accuracy of PET in the detection of M stage is 96%. Our study shows that visual interpretation of whole-body fluorine-18 deoxyglucose-positron emission tomography images can improve the diagnostic accuracy in the staging of non-small cell lung cancer. Further experience is needed to establish if metabolic imaging would be a cost-effective tool in the future management of lung cancer.
Inpatient Interdisciplinary Care
Authors: Hilary J. Mosher, Peter J. Kaboli
Journal: JAMA Internal Medicine (2015)

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A Three-Gene Expression Signature Model for Risk Stratification of Patients with Neuroblastoma
Authors: Idoia Garcia, Gemma Mayol, José Ríos, Gema Domenech, Nai-Kong V. Cheung, André Oberthuer, Matthias Fischer, John M. Maris, Garrett M. Brodeur, Barbara Hero, Eva Rodríguez, Mariona Suñol, Patricia Galvan, Carmen de Torres, Jaume Mora, Cinzia Lavarino
Journal: Clinical Cancer Research (2012)

Neuroblastoma is an embryonal tumor with contrasting clinical courses. Despite elaborate stratification strategies, precise clinical risk assessment still remains a challenge. The purpose of this study was to develop a PCR-based predictor model to improve clinical risk assessment of patients with neuroblastoma.The model was developed using real-time PCR gene expression data from 96 samples and tested on separate expression data sets obtained from real-time PCR and microarray studies comprising 362 patients.On the basis of our prior study of differentially expressed genes in favorable and unfavorable neuroblastoma subgroups, we identified three genes, CHD5, PAFAH1B1, and NME1, strongly associated with patient outcome. The expression pattern of these genes was used to develop a PCR-based single-score predictor model. The model discriminated patients into two groups with significantly different clinical outcome [set 1: 5-year overall survival (OS): 0.93 ± 0.03 vs. 0.53 ± 0.06, 5-year event-free survival (EFS): 0.85 ± 0.04 vs. 0.042 ± 0.06, both P < 0.001; set 2 OS: 0.97 ± 0.02 vs. 0.61 ± 0.1, P = 0.005, EFS: 0.91 ± 0.8 vs. 0.56 ± 0.1, P = 0.005; and set 3 OS: 0.99 ± 0.01 vs. 0.56 ± 0.06, EFS: 0.96 ± 0.02 vs. 0.43 ± 0.05, both P < 0.001]. Multivariate analysis showed that the model was an independent marker for survival (P < 0.001, for all). In comparison with accepted risk stratification systems, the model robustly classified patients in the total cohort and in different clinically relevant risk subgroups.We propose for the first time in neuroblastoma, a technically simple PCR-based predictor model that could help refine current risk stratification systems.
A Concentrated Aglycone Isoflavone Preparation (GCP) That Demonstrates Potent Anti-Prostate Cancer Activity <b> <i>In vitro</i> </b> and <b> <i>In vivo</i> </b>
Authors: Debra L. Bemis, Jillian L. Capodice, Manisha Desai, Ralph Buttyan, Aaron E. Katz
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Isoflavones have anticancer activities, but naturally occurring isoflavones are predominantly glycosylated and poorly absorbed. Genistein combined polysaccharide (GCP; Amino Up Chemical Co., Sapporo, Japan), is a fermentation product of soy extract and basidiomycetes mycillae that is enriched in biologically active aglycone isoflavones. This study analyzes GCP in vitro and in vivo for potential utility as a prostate cancer chemopreventative agent. Experimental Design: Androgen-sensitive LNCaP and androgen-independent PC-3 cells were grown with various concentrations of GCP. In vitro cell growth was analyzed by the WST-1 assay, and apoptosis was assessed by fluorescence-activated cell sorting and detection of poly(ADP-ribose) polymerase cleavage using Western blot techniques. Effects of GCP on expression of cell cycle-regulatory proteins p53 (LNCaP only), p21, and p27 and the protein kinase Akt were considered using Western blot techniques. An in vivo LNCaP xenograft model was used to study the effects of a 2% GCP-supplemented diet on tumor growth in comparison with a control diet. Results: GCP significantly suppressed LNCaP and PC-3 cell growth over 72 h (89% and 78% in LNCaP and PC-3, respectively, at 10 μg/ml; P &amp;lt; 0.0001). This reduction was associated with apoptosis in LNCaP cells, but not in PC-3 cells. GCP induced p27 and p53 (LNCaP only) protein expression within 6 h and suppressed phosphorylated Akt in both cell lines. The 2% GCP-supplemented diet significantly slowed LNCaP tumor growth, increasing apoptosis (P &amp;lt; 0.001), and decreasing proliferation (P &amp;lt; 0.001) over 4 weeks. Conclusions: GCP has potent growth-inhibitory effects against prostate cancer cell lines in vitro and in vivo. These data suggest GCP has potential as an effective chemopreventive agent against prostate cancer cell growth.