tbuckley/cabot-search huggingface dataset:
Androgen Receptor Pathway in Rats with Autosomal Dominant Polycystic Kidney Disease
Authors: Shizuko Nagao, Masatomo Kusaka, Kazuhiro Nishii, Tohru Marunouchi, Hiroki Kurahashi, Hisahide Takahashi, Jared Grantham
Journal: Journal of the American Society of Nephrology (2005)

Androgens have been implicated in mediating disease escalation in autosomal dominant polycystic kidney disease (ADPKD). Dihydrotestosterone (DHT), an agonist, and flutamide (FLT), an antagonist, were administered to Han:SPRD rats with ADPKD, and the role of androgen receptor (AR) abundance and activation on the enlargement and function of cystic kidneys was evaluated. Renal AR abundance determined by immunoblots in 8- to 10-wk-old Cy/+ male rats was naturally increased four-fold above that of littermate +/+ controls. In male Cy/+, castration decreased AR abundance below control +/+ by -89.4%, and AR expression within cyst mural epithelial cells was strikingly decreased. Castration of Cy/+ male rats also reduced the usual increases in kidney weight by -49.7%, kidney cyst area by -34.0%, and serum urea nitrogen by -72.8%; these indices were restored to precastration levels by DHT. In Cy/+ male rats, FLT administration reduced the increase in kidney weight by -27.6% and serum urea nitrogen by -53.7% and decreased the increment in AR expression by -84.2% in comparison with untreated +/+ controls. There was no effect of FLT in female rats. Immunoblot expression of phospho-extracellular signal-regulated kinase 1/2 (P-ERK) and B-Raf, key intermediates in the mitogen-activated protein kinase pathway that are abnormally elevated in Cy/+, was unaffected by castration and/or administration of DHT or FLT. AR was not expressed in renal epithelial cell nuclei of androgen-deficient rats but was displayed in most tubule and mural cyst cell nuclei of androgen-replete rats. In androgen-deficient Cy/+, 80.6% of renal epithelial cells that had entered the cell cycle (proliferating cell nuclear antigen positive) also expressed P-ERK. In androgen-replete rats, proliferating cell nuclear antigen-positive cells co-expressed AR (12.7%), P-ERK (36.4%), and P-ERK + AR (45.0%); 5.9% were probably stimulated by other mitogenic mechanisms. It is concluded that androgens potentiate renal cell proliferation and cyst enlargement through ERK1/2-dependent and ERK1/2-independent signaling mechanisms in Han:SPRD. It is suggested that the basal rate of cell proliferation is determined by ERK1/2 signaling to a major extent and that androgens have additive effects.
Cardiomyocyte GATA4 functions as a stress-responsive regulator of angiogenesis in the murine heart
Authors: Joerg Heineke, Mannix Auger-Messier, Jian Xu, Toru Oka, Michelle A. Sargent, Allen York, Raisa Klevitsky, Sachin Vaikunth, Stephen A. Duncan, Bruce J. Aronow, Jeffrey Robbins, Timothy M. Cromblehol, Jeffery D. Molkentin
Journal: Journal of Clinical Investigation (2007)

The transcription factor GATA4 is a critical regulator of cardiac gene expression, modulating cardiomyocyte differentiation and adaptive responses of the adult heart. We report what we believe to be a novel function for GATA4 in murine cardiomyocytes as a nodal regulator of cardiac angiogenesis. Conditional overexpression of GATA4 within adult cardiomyocytes increased myocardial capillary and small conducting vessel densities and increased coronary flow reserve and perfusion-dependent cardiac contractility. Coculture of HUVECs with either GATA4-expressing cardiomyocytes or with myocytes expressing a dominant-negative form of GATA4 enhanced or reduced HUVEC tube formation, respectively. Expression of GATA4 in skeletal muscle by adenoviral gene transfer enhanced capillary densities and hindlimb perfusion following femoral artery ablation. Deletion of Gata4 specifically from cardiomyocytes reduced myocardial capillary density and prevented pressure overload-augmented angiogenesis in vivo. GATA4 induced the angiogenic factor VEGF-A, directly binding the Vegf-A promoter and enhancing transcription. GATA4-overexpressing mice showed increased levels of cardiac VEGF-A, while Gata4-deleted mice demonstrated decreased VEGF-A levels. The induction of HUVEC tube formation in GATA4-overexpressing cocultured myocytes was blocked with a VEGF receptor antagonist. Pressure overload-induced dysfunction in Gata4-deleted hearts was partially rescued by adenoviral gene delivery of VEGF and angiopoietin-1. To our knowledge, these results demonstrate [corrected] a previously unrecognized function for GATA4 as a regulator of cardiac angiogenesis through a nonhypoxic, load, and/or disease-responsive mechanism.
Genomic-scale analysis of psoriatic skin reveals differentially expressed insulin-like growth factor-binding protein-7 after phototherapy
Authors: M. Hochberg, S. Zeligson, N. Amariglio, G. Rechavi, A. Ingber, C.D. Enk
Journal: British Journal of Dermatology (2006)

Phototherapy is an effective therapy for psoriasis. The molecular mechanisms underlying its efficacy are not yet understood.To compare the expression profiles of psoriatic epidermis in patients before and after undergoing phototherapy with the purpose of expounding the molecular mechanisms underlying the efficacy of this therapeutic modality.Patients with psoriasis were investigated before and after full courses of phototherapy: three patients completed 3 weeks of heliotherapy at the Dead Sea; three patients received narrowband ultraviolet B (NB-UVB) for a total of 20-27 treatments. Epidermal samples were analysed using oligonucleotide microarrays. Our microarray results led us to explore further and to quantify a specific gene, insulin-like growth factor-binding protein-7 (IGFBP7), using real-time quantitative reverse transcriptase-polymerase chain reaction assays and immunohistochemical protein expression.We identified 315 genes modulated by phototherapy: the expressions of 248 genes (142 up; 106 down) were changed by Dead Sea treatment, 116 (71 up; 45 down) by NB-UVB and 49 (37 up; 12 down) were modulated regardless of treatment. The differentially changed genes include S100 calcium-binding proteins, dendritic cell markers, tumour necrosis factor-alpha target genes, matrix metalloproteinases and NFkappaB target genes. We also found that IGFBP7 mRNA and protein were significantly underexpressed in psoriatic compared with normal epidermis, and that phototherapy significantly increased their expression.IGFBP7 is underexpressed in psoriatic epidermis but is inducible by UVB.
Interactions of surfactant protein D with bacterial lipopolysaccharides. Surfactant protein D is an Escherichia coli-binding protein in bronchoalveolar lavage.
Authors: S F Kuan, K Rust, E Crouch
Journal: Journal of Clinical Investigation (1992)

Surfactant protein D (SP-D) is a collagenous glycoprotein that is secreted into the pulmonary airspaces by alveolar type II and nonciliated bronchiolar cells. SP-D exhibits Ca(++)-dependent carbohydrate binding in vitro and is structurally related to the collagenous C-type lectins, including serum conglutinin, serum mannose-binding proteins, and surfactant protein A. Preliminary studies showed calcium- and saccharide-dependent binding of fluorescein-conjugated or radioiodinated SP-D to a variety of microorganisms, including Gram-negative bacteria and fungi. A laboratory strain of Escherichia coli (Y1088) was chosen to further examine the mechanism(s) of binding. Binding of SP-D to Y1088 was time dependent, saturable, and inhibited by cold SP-D or competing saccharides; Scatchard analysis gave a Kd of 2 x 10(-11) M. At higher concentrations, SP-D also caused Ca(++)-dependent agglutination of Y1088 that was inhibited by alpha-glucosyl-containing saccharides, antisera to the carbohydrate-binding domain of SP-D, or Y1088 LPS. Lectin blots showed specific binding of 125I-SP-D to Y1088 LPS, as well as LPS from other several strains of enteric Gram-negative bacteria. Immunogold studies demonstrated strong and uniform surface labeling of the bacteria. Rat and human bronchoalveolar lavage (BAL) caused Ca(++)-dependent agglutination of E. coli that was dose dependent and inhibited by competing saccharides or anti-SP-D. SP-D was selectively and efficiently adsorbed from rat BAL by incubation with E. coli, and incubation of E. coli with radiolabeled rat type II cell medium revealed that SP-D is the major E. coli-binding protein secreted by freshly isolated cells in culture. We suggest that SP-D plays important roles in the lung's defense against Gram-negative bacteria.
TCT-328 Clinical Outcomes Based Upon Classification Using Appropriateness Use Criteria
Authors: David Arboleda, Regina M. Hardison, Oscar C. Marroquin, Faith Selzer, Maria M. Brooks, Catalin Toma, Sameer J. Khandhar, Joon S. Lee, A. J. Conrad Smith, John T. Schindler, Sun K. Scolieri, Suresh Mulukutla
Journal: Journal of the American College of Cardiology (2013)
Congenital sick sinus syndrome caused by recessive mutations in the cardiac sodium channel gene (SCN5A)
Authors: D. Woodrow Benson, Dao W. Wang, Macaira Dyment, Timothy K. Knilans, Frank A. Fish, Margaret J. Strieper, Thomas H. Rhodes, Alfred L. George
Journal: Journal of Clinical Investigation (2003)

Sick sinus syndrome (SSS) describes an arrhythmia phenotype attributed to sinus node dysfunction and diagnosed by electrocardiographic demonstration of sinus bradycardia or sinus arrest. Although frequently associated with underlying heart disease and seen most often in the elderly, SSS may occur in the fetus, infant, and child without apparent cause. In this setting, SSS is presumed to be congenital. Based on prior associations with disorders of cardiac rhythm and conduction, we screened the α subunit of the cardiac sodium channel (SCN5A) as a candidate gene in ten pediatric patients from seven families who were diagnosed with congenital SSS during the first decade of life. Probands from three kindreds exhibited compound heterozygosity for six distinct SCN5A alleles, including two mutations previously associated with dominant disorders of cardiac excitability. Biophysical characterization of the mutants using heterologously expressed recombinant human heart sodium channels demonstrate loss of function or significant impairments in channel gating (inactivation) that predict reduced myocardial excitability. Our findings reveal a molecular basis for some forms of congenital SSS and define a recessive disorder of a human heart voltage-gated sodium channel.
Administration of a Soluble Recombinant Complement C3 Inhibitor Protects Against Renal Disease in MRL/lpr Mice
Authors: Lihua Bao, Mark Haas, Damian M. Kraus, Bradley K. Hack, Jonathan K. Rakstang, V. Michael Holers, Richard J. Quigg
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. Complement receptor 1-related gene/protein y (Crry) in rodents is a potent membrane complement regulator that inhibits complement C3 activation by both classical and alternative pathways. To clarify the role of complement in lupus nephritis, MRL/<i>lpr</i> mice were given Crry as a recombinant protein (Crry-Ig) from 12 to 24 wk of age. Control groups were given saline or normal mouse IgG. Sera and urine were collected biweekly. Only 1 of 20 (5%) Crry-Ig-treated mice developed renal failure (BUN &gt; 50 mg/dl) compared with 18 of 38 (47.4%) mice in control groups (<i>P</i> = 0.001). BUN levels at 24 wk were reduced from 68.8 ± 9.7 mg/dl in control groups to 38.5 ± 3.9 mg/dl in the Crry-Ig-treated group (<i>P</i> &lt; 0.01). Urinary albumin excretion at 24 wk was also significantly reduced from 5.3 ± 1.4 mg/mg creatinine in the control groups to 0.5 ± 0.2 mg/mg creatinine in the Crry-Ig-treated group (<i>P</i> &lt; 0.05). Of the histologic data at 24 wk, there was a significant reduction in scores for glomerulosclerosis and C3d, IgG, IgG3, and IgA staining intensity in glomeruli in complement-inhibited animals. Crry-Ig-treated animals were also protected from vasculitic lesions. Although there was no effect on relevant autoimmune manifestations such as anti-double stranded DNA titers or cryoglobulin IgG3 levels, circulating immune complex levels were markedly higher in complement-inhibited animals. Thus, inhibition of complement activation with Crry-Ig significantly reduces renal disease in MRL/<i>lpr</i> lupus mice. The data support the strategy of using recombinant complement C3 inhibitors to treat human lupus nephritis. E-mail: rquigg@medicine.uchicago.edu
Hypertrophic obstructive cardiomyopathy, a histological, histochemical, and ultrastructural study of biopsy material
Authors: S. V. Noorden, E. G. J. Olsen, A. G. E. Pearse
Journal: Cardiovascular Research (1971)

Comparison of myocardial biopsies from cases of hypertrophic obstructive cardiomyopathy and other conditions shows that a diagnosis can often be made on histological grounds. Histochemistry and electron microscopy add supporting evidence but no lesion specific to hypertrophic obstructive cardiomyopathy has been found.
Predicting the development of gastric cancer from combining Helicobacter pylori antibodies and serum pepsinogen status: a prospective endoscopic cohort study
Authors: H Watabe
Journal: Gut (2005)

<b>Background and aim:</b><i>Helicobacter pylori</i> infection and gastric atrophy are both risk factors for gastric cancer. We aimed to elucidate the natural history of gastric cancer development according to <i>H pylori</i> infection and gastric atrophy status. <b>Subjects and methods:</b> A total of 9293 participants in a mass health appraisal programme were candidates for inclusion in the present prospective cohort study: 6983 subjects revisited the follow up programme. Subjects were classified into four groups according to serological status at initial endoscopy. Group A (n = 3324) had "normal" pepsinogen and were negative for <i>H pylori</i> antibody; group B (n = 2134) had "normal" pepsinogen and were positive for <i>H pylori</i> antibody; group C (n = 1082) had "atrophic" pepsinogen and were positive for <i>H pylori</i> antibody; and group D (n = 443) had "atrophic" pepsinogen and were negative for <i>H pylori</i> antibody. Incidence of gastric cancer was determined by annual endoscopic examination. <b>Results:</b> Mean duration of follow up was 4.7 years and the average number of endoscopic examinations was 5.1. The annual incidence of gastric cancer was 0.04% (95% confidence interval (CI) 0.02–0.09), 0.06% (0.03–0.13), 0.35% (0.23–0.57), and 0.60% (0.34–1.05) in groups A, B, C, and D, respectively. Hazard ratios compared with group A were 1.1 (95% CI 0.4–3.4), 6.0 (2.4–14.5), and 8.2 (3.2–21.5) in groups B, C, and D, respectively. Age, sex, and "group" significantly served as independent valuables by multivariate analysis. <b>Conclusions:</b> The combination of serum pepsinogen and anti-<i>H pylori</i> antibody provides a good predictive marker for the development of gastric cancer.
Improved Endpoints for Cancer Immunotherapy Trials
Authors: A. Hoos, A. M. M. Eggermont, S. Janetzki, F. S. Hodi, R. Ibrahim, A. Anderson, R. Humphrey, B. Blumenstein, L. Old, J. Wolchok
Journal: JNCI Journal of the National Cancer Institute (2010)

Unlike chemotherapy, which acts directly on the tumor, cancer immunotherapies exert their effects on the immune system and demonstrate new kinetics that involve building a cellular immune response, followed by changes in tumor burden or patient survival. Thus, adequate design and evaluation of some immunotherapy clinical trials require a new development paradigm that includes reconsideration of established endpoints. Between 2004 and 2009, several initiatives facilitated by the Cancer Immunotherapy Consortium of the Cancer Research Institute and partner organizations systematically evaluated an immunotherapy-focused clinical development paradigm and created the principles for redefining trial endpoints. On this basis, a body of clinical and laboratory data was generated that supports three novel endpoint recommendations. First, cellular immune response assays generate highly variable results. Assay harmonization in multicenter trials may minimize variability and help to establish cellular immune response as a reproducible biomarker, thus allowing investigation of its relationship with clinical outcomes. Second, immunotherapy may induce novel patterns of antitumor response not captured by Response Evaluation Criteria in Solid Tumors or World Health Organization criteria. New immune-related response criteria were defined to more comprehensively capture all response patterns. Third, delayed separation of Kaplan-Meier curves in randomized immunotherapy trials can affect results. Altered statistical models describing hazard ratios as a function of time and recognizing differences before and after separation of curves may allow improved planning of phase III trials. These recommendations may improve our tools for cancer immunotherapy trials and may offer a more realistic and useful model for clinical investigation.
Signal Transducers and Activators of Transcription 5a–Dependent Cross-talk between Follicular Lymphoma Cells and Tumor Microenvironment Characterizes a Group of Patients with Improved Outcome after R-CHOP
Authors: Minna Taskinen, Erkka Valo, Marja-Liisa Karjalainen-Lindsberg, Sampsa Hautaniemi, Seppo Meri, Sirpa Leppä
Journal: Clinical Cancer Research (2010)

Abstract Purpose: Tumor microenvironment has a strong effect on the survival of follicular lymphoma (FL) patients. The aim of this study was to determine what are the signaling pathways that mediate the cross-talk between lymphoma cells and tumor-infiltrating inflammatory cells and contribute to the clinical outcome of FL patients. Experimental Design: Gene expression profiling and pathway impact analyses were done from pretreatment lymphoma tissue of 24 patients. The findings were validated immunohistochemically in an independent cohort of 81 patients. All patients were treated with the combination of rituximab and cyclophoshamide-doxorubicin-vincristine-prednisone chemotherapy. In addition, microarray was used to screen the genes differentially expressed between control and rituximab-stimulated B-cell lymphoma cells in culture. Results: Among the transcripts differentially expressed in the FL tissues between the patients with favorable or adverse outcomes, an overrepresentation of genes associated with the signal transducers and activators of transcription (STAT)5a pathway was observed. In a validation set, a better progression-free survival was observed among the patients with high STAT5a protein expression. In the FL tissue, STAT5a positivity was barely detectable in the neoplastic B cells, but a subpopulation of follicular dendritic cells and T lymphocytes showed prominent STAT5a expression. Rituximab was found to induce the expression of STAT5a-associated interleukin-15 in B-lymphoma cells in culture, thereby providing a possible explanation for the cross-talk between rituximab-stimulated FL cells and their microenvironment. Conclusion: The findings suggest that STAT5a activity in immunologically active nonmalignant cells acts as molecular predictor for rituximab and cyclophoshamide-doxorubicin-vincristine-prednisone–treated FL patients. Clin Cancer Res; 16(9); 2615–23. ©2010 AACR.
OncomiRs: the discovery and progress of microRNAs in cancers
Authors: William CS Cho
Journal: Molecular Cancer (2007)

microRNAs (miRNAs) are evolutionarily conserved, endogenous, small, noncoding RNA molecules of about 22 nucleotides in length that function as posttranscriptional gene regulators. They are deemed to play a crucial role in the initiation and progression of human cancer, and those with a role in cancer are designated as oncogenic miRNAs (oncomiRs). For example, miR-15 and miR-16 induce apoptosis by targeting Bcl2. miRNAs from the miR-17-92 cluster modulate tumor formation and function as oncogenes by influencing the translation of E2F1 mRNA. miR-21 modulates gemcitabine-induced apoptosis by phosphatase and tensin homolog deleted on chromosome 10-dependent activation of PI 3-kinase signaling. miR-34a acts as a suppressor of neuroblastoma tumorigenesis by targeting the mRNA encoding E2F3 and reducing E2F3 protein levels. The chromosomal translocations associating with human tumors disrupt the repression of High mobility group A2 by let-7 miRNA. In addition, the oncomiRs expression profiling of human malignancies has also identified a number of diagnostic and prognostic cancer signatures. This article introduces the roles of oncomiRs in neoplasm development, progression, diagnosis, prognostication, as well as their mechanism of actions on target mRNAs and the functional outcomes of their actions on mRNAs. The paper ends with a brief perspective to the future of oncomiRs.
Combination antibiotic susceptibility testing to treat exacerbations of cystic fibrosis associated with multiresistant bacteria: a randomised, double-blind, controlled clinical trial
Authors: Shawn D Aaron, Katherine L Vandemheen, Wendy Ferris, Dean Fergusson, Elizabeth Tullis, David Haase, Yves Berthiaume, Neil Brown, Pearce Wilcox, Veronica Yozghatlian, Peter Bye, Scott Bell, Francis Chan, Barbara Rose, Alphonse Jeanneret, Anne Stephenson, Mary Noseworthy, Andreas Freitag, Nigel Paterson, Steve Doucette, Colin Harbour, Michel Ruel, Noni MacDonald
Journal: The Lancet (2005)
Differences in atherosclerosis according to area level socioeconomic deprivation: cross sectional, population based study
Authors: K. A Deans, V. Bezlyak, I. Ford, G D. Batty, H. Burns, J. Cavanagh, E. d. Groot, A. McGinty, K. Millar, P. G Shiels, C. Tannahill, Y. N Velupillai, N. Sattar, C. J Packard
Journal: BMJ (2009)

To examine the relation between area level social deprivation and ultrasound markers of atherosclerosis (common carotid intima-media thickness and plaque score), and to determine whether any differences can be explained by "classic" (currently recognised) or "emerging" (novel) cardiovascular risk factors.Cross sectional, population based study.NHS Greater Glasgow Health Board area.666 participants were selected on the basis of how their area ranked in the Scottish Index of Multiple Deprivation 2004. Approximately equal numbers of participants from the most deprived areas and the least deprived areas were included, as well as equal numbers of men and women and equal numbers of participants from each age group studied (35-44, 45-54, and 55-64 years).Carotid intima-media thickness and plaque score, as detected by ultrasound.The mean age and sex adjusted intima-media thickness was significantly higher in participants from the most deprived areas than in those from the least deprived areas (0.70 mm (standard deviation (SD) 0.16 mm) v 0.68 mm (SD 0.12 mm); P=0.015). On subgroup analysis, however, this difference was only apparent in the highest age tertile in men (56.3-66.5 years). The difference in unadjusted mean plaque score between participants from the most deprived and those from the least deprived areas was more striking than the difference in intima-media thickness (least deprived 1.0 (SD 1.5) v most deprived 1.7 (SD 2.0); P<0.0001). In addition, a significant difference in plaque score was apparent in the two highest age tertiles in men (46.8-56.2 years and 56.3-66.5 years; P=0.0073 and P<0.001) and the highest age tertile in women (56.3-66.5 years; P<0.001). The difference in intima-media thickness between most deprived and least deprived males remained significant after adjustment for classic risk factors, emerging risk factors, and individual level markers of socioeconomic status (P=0.010). Adjustment for classic risk factors and emerging cardiovascular risk factors, either alone or in combination, did not abolish the deprivation based difference in plaque presence (as a binary measure; adjusted odds ratio of 1.73, 95% confidence interval 1.07 to 2.82). However, adjustment for classic risk factors and individual level markers of early life socioeconomic status abolished the difference in plaque presence between the most deprived and the least deprived individuals (adjusted odds ratio 0.94, 95% CI 0.54 to 1.65; P=0.84).Deprivation is associated with increased carotid plaque score and intima-media thickness. The association of deprivation with atherosclerosis is multifactorial and not adequately explained by classic or emerging risk factors.