tbuckley/cabot-search huggingface dataset:
Symmetrical Dimethylarginine
Authors: Stefanie M. Bode-Bo[Combining Diaeresis]ger, Fortunato Scalera, Jan T. Kielstein, Jens Martens-Lobenhoffer, Gu[Combining Diaeresis]nter Breithardt, Manfred Fobker, Holger Reinecke
Journal: Journal of the American Society of Nephrology (2006)

Symmetrical dimethylarginine (SDMA) is the structural isomer of the endogenous nitric oxide synthase (NOS) inhibitor asymmetric dimethylarginine. Whereas the major route of asymmetric dimethylarginine elimination is the hydrolytic degradation by dimethylarginine dimethylaminohydrolase, SDMA is eliminated by renal excretion. SDMA does not directly inhibit NOS but is a competitor of arginine transport. This study showed for the first time that measurement of SDMA can be a marker of estimated GFR and extent of coronary artery disease (CAD). In 97 patients with CAD, SDMA was a marker of estimated GFR. On multiple regression analysis of the CAD parameter stenosis score, SDMA was the only parameter retained. In addition, endothelial cells from the third passage were cultured in medium that contained 70 micromol/L arginine and was incubated for 24 h in the presence of various concentration of SDMA (0, 2, 5, 10, and 100 micromol/L). The levels of nitrate and nitrite in conditioned media, the protein expression of NOS, and the content of reactive oxygen species in endothelial cells were determined. SDMA inhibited dose dependently the NO synthesis in intact endothelial cells, whereas it had no effect on protein expression of NOS. This effect was associated with an increase in reactive oxygen species. Co-incubation with L-arginine but not D-arginine reversed the effect of SDMA on NOS pathway. Our data suggest that SDMA reduced the endothelial NO synthesis, probably by limiting L-arginine supply to NOS. It is concluded that SDMA might be a useful parameter for detecting patients in very early stages of chronic kidney disease and for determining their risk for developing cardiovascular disease.
Molecular Distinctions between Stasis and Telomere Attrition Senescence Barriers Shown by Long-term Culture of Normal Human Mammary Epithelial Cells
Authors: James C. Garbe, Sanchita Bhattacharya, Batul Merchant, Ekaterina Bassett, Karen Swisshelm, Heidi S. Feiler, Andrew J. Wyrobek, Martha R. Stampfer
Journal: Cancer Research (2009)

Normal human epithelial cells in culture have generally shown a limited proliferative potential of approximately 10 to 40 population doublings before encountering a stress-associated senescence barrier (stasis) associated with elevated levels of cyclin-dependent kinase inhibitors p16 and/or p21. We now show that simple changes in medium composition can expand the proliferative potential of human mammary epithelial cells (HMEC) initiated as primary cultures to 50 to 60 population doublings followed by p16-positive, senescence-associated beta-galactosidase-positive stasis. We compared the properties of growing and senescent pre-stasis HMEC with growing and senescent post-selection HMEC, that is, cells grown in a serum-free medium that overcame stasis via silencing of p16 expression and that display senescence associated with telomere dysfunction. Cultured pre-stasis populations contained cells expressing markers associated with luminal and myoepithelial HMEC lineages in vivo in contrast to the basal-like phenotype of the post-selection HMEC. Gene transcript and protein expression, DNA damage-associated markers, mean telomere restriction fragment length, and genomic stability differed significantly between HMEC populations at the stasis versus telomere dysfunction senescence barriers. Senescent isogenic fibroblasts showed greater similarity to HMEC at stasis than at telomere dysfunction, although their gene transcript profile was distinct from HMEC at both senescence barriers. These studies support our model of the senescence barriers encountered by cultured HMEC in which the first barrier, stasis, is retinoblastoma-mediated and independent of telomere length, whereas a second barrier (agonescence or crisis) results from telomere attrition leading to telomere dysfunction. Additionally, the ability to maintain long-term growth of genomically stable multilineage pre-stasis HMEC populations can greatly enhance experimentation with normal HMEC.
Glucocorticoid Therapy for Immune-Mediated Diseases: Basic and Clinical Correlates
Authors: Dimitrios T. Boumpas
Journal: Annals of Internal Medicine (1993)

Glucocorticoids are pleiotropic hormones that at pharmacologic doses prevent or suppress inflammation and other immunologically mediated processes. At the molecular level, glucocorticoids form complexes with specific receptors that migrate to the nucleus where they interact with selective regulatory sites within DNA; this results in positive and negative modulation of several genes involved in inflammatory and immune responses. At the cellular level, glucocorticoids inhibit the access of leukocytes to inflammatory sites; interfere with the functions of leukocytes, endothelial cells, and fibroblasts; and suppress the production and the effects of humoral factors involved in the inflammatory response. Clinically, several modes of glucocorticoid administration are used, depending on the disease process, the organ involved, and the extent of involvement. High doses of daily glucocorticoids are usually required in patients with severe diseases involving major organs, whereas alternate-day regimens may be used in patients with less aggressive diseases. Intravenous glucocorticoids (pulse therapy) are frequently used to initiate therapy in patients with rapidly progressive, immunologically mediated diseases. The benefits of glucocorticoid therapy can easily be offset by severe side effects; even with the greatest care, side effects may occur. Moreover, for certain complications (for example, infection diathesis, peptic ulcer, osteoporosis, avascular necrosis, and atherosclerosis), other drug toxicities and pathogenic factors overlap with glucocorticoid effects. Minimizing the incidence and severity of glucocorticoid-related side effects requires carefully decreasing the dose; using adjunctive disease-modifying immunosuppressive and anti-inflammatory agents; and taking general preventive measures.
Phase II, Open-Label Study of Brivanib as Second-Line Therapy in Patients with Advanced Hepatocellular Carcinoma
Authors: Richard S. Finn, Yoon-Koo Kang, Mary Mulcahy, Blase N. Polite, Ho Yeong Lim, Ian Walters, Christine Baudelet, Demetrios Manekas, Joong-Won Park
Journal: Clinical Cancer Research (2012)

Brivanib, a selective dual inhibitor of fibroblast growth factor and VEGF signaling, has recently been shown to have activity as first-line treatment for patients with advanced hepatocellular carcinoma (HCC). This phase II open-label study assessed brivanib as second-line therapy in patients with advanced HCC who had failed prior antiangiogenic treatment.Brivanib was administered orally at a dose of 800 mg once daily. The primary objectives were tumor response rate, time to response, duration of response, progression-free survival, overall survival (OS), disease control rate, time to progression (TTP), and safety and tolerability.Forty-six patients were treated. Best responses to treatment with brivanib (N = 46 patients) using modified World Health Organization criteria were partial responses for two patients (4.3%), stable disease for 19 patients (41.3%), and progressive disease for 19 patients (41.3%). The tumor response rate was 4.3%; the disease control rate was 45.7%. Median OS was 9.79 months. Median TTP as assessed by study investigators following second-line treatment with brivanib was 2.7 months. The most common adverse events were fatigue, decreased appetite, nausea, diarrhea, and hypertension.Brivanib had a manageable safety profile and is one of the first agents to show promising antitumor activity in advanced HCC patients treated with prior sorafenib.
Development of a Multimarker Assay for Early Detection of Ovarian Cancer
Authors: Zoya Yurkovetsky, Steven Skates, Aleksey Lomakin, Brian Nolen, Trenton Pulsipher, Francesmary Modugno, Jeffrey Marks, Andrew Godwin, Elieser Gorelik, Ian Jacobs, Usha Menon, Karen Lu, Donna Badgwell, Robert C. Bast, Anna E. Lokshin
Journal: Journal of Clinical Oncology (2010)

Purpose Early detection of ovarian cancer has great promise to improve clinical outcome. Patients and Methods Ninety-six serum biomarkers were analyzed in sera from healthy women and from patients with ovarian cancer, benign pelvic tumors, and breast, colorectal, and lung cancers, using multiplex xMAP bead-based immunoassays. A Metropolis algorithm with Monte Carlo simulation (MMC) was used for analysis of the data. Results A training set, including sera from 139 patients with early-stage ovarian cancer, 149 patients with late-stage ovarian cancer, and 1,102 healthy women, was analyzed with MMC algorithm and cross validation to identify an optimal biomarker panel discriminating early-stage cancer from healthy controls. The four-biomarker panel providing the highest diagnostic power of 86% sensitivity (SN) for early-stage and 93% SN for late-stage ovarian cancer at 98% specificity (SP) was comprised of CA-125, HE4, CEA, and VCAM-1. This model was applied to an independent blinded validation set consisting of sera from 44 patients with early-stage ovarian cancer, 124 patients with late-stage ovarian cancer, and 929 healthy women, providing unbiased estimates of 86% SN for stage I and II and 95% SN for stage III and IV disease at 98% SP. This panel was selective for ovarian cancer showing SN of 33% for benign pelvic disease, SN of 6% for breast cancer, SN of 0% for colorectal cancer, and SN of 36% for lung cancer. Conclusion A panel of CA-125, HE4, CEA, and VCAM-1, after additional validation, could serve as an initial stage in a screening strategy for epithelial ovarian cancer.
FANTOM4 EdgeExpressDB: an integrated database of promoters, genes, microRNAs, expression dynamics and regulatory interactions
Authors: Jessica Severin, Andrew M Waterhouse, Hideya Kawaji, Timo Lassmann, Erik van Nimwegen, Piotr J Balwierz, Michiel JL de Hoon, David A Hume, Piero Carninci, Yoshihide Hayashizaki, Harukazu Suzuki, Carsten O Daub, Alistair RR Forrest
Journal: Genome biology (2009)

EdgeExpressDB is a novel database and set of interfaces for interpreting biological networks and comparing large high-throughput expression datasets that requires minimal development for new data types and search patterns. The FANTOM4 EdgeExpress database http://fantom.gsc.riken.jp/4/edgeexpress summarizes gene expression patterns in the context of alternative promoter structures and regulatory transcription factors and microRNAs using intuitive gene-centric and sub-network views. This is an important resource for gene regulation in acute myeloid leukemia, monocyte/macrophage differentiation and human transcriptional networks.
Prostate Cancer Immunology: Biology, Therapeutics, and Challenges
Authors: W. Scott Webster, Eric J. Small, Brian I. Rini, Eugene D. Kwon
Journal: Journal of Clinical Oncology (2005)

A number of recently developed and promising approaches to antitumoral immunotherapy are being investigated as potential treatments for advanced prostate cancer. These approaches largely revolve around strategies to increase antigen-specific T-cell activation against prostate tumors as well as precise manipulations of critical co-regulatory receptors that help to maintain and prolong the activity of antigen-presenting cells and T cells that are capable of mediating tumor regression. Herein, we describe the experience with the most recent and promising approaches pertaining to prostate cancer immunotherapy. Additionally, we discuss the mechanistic basis for these approaches as well as current limitations that must still be addressed in order to propel immunotherapy into the forefront of prostate cancer treatment.
Assembly of the Candida albicans genome into sixteen supercontigs aligned on the eight chromosomes
Authors: Marco van het Hoog, Timothy J Rast, Mikhail Martchenko, Suzanne Grindle, Daniel Dignard, Hervé Hogues, Christine Cuomo, Matthew Berriman, Stewart Scherer, BB Magee, Malcolm Whiteway, Hiroji Chibana, André Nantel, PT Magee
Journal: Genome biology (2007)

Abstract Background The 10.9× genomic sequence of Candida albicans , the most important human fungal pathogen, was published in 2004. Assembly 19 consisted of 412 supercontigs, of which 266 were a haploid set, since this fungus is diploid and contains an extensive degree of heterozygosity but lacks a complete sexual cycle. However, sequences of specific chromosomes were not determined. Results Supercontigs from Assembly 19 (183, representing 98.4% of the sequence) were assigned to individual chromosomes purified by pulse-field gel electrophoresis and hybridized to DNA microarrays. Nine Assembly 19 supercontigs were found to contain markers from two different chromosomes. Assembly 21 contains the sequence of each of the eight chromosomes and was determined using a synteny analysis with preliminary versions of the Candida dubliniensis genome assembly, bioinformatics, a sequence tagged site (STS) map of overlapping fosmid clones, and an optical map. The orientation and order of the contigs on each chromosome, repeat regions too large to be covered by a sequence run, such as the ribosomal DNA cluster and the major repeat sequence, and telomere placement were determined using the STS map. Sequence gaps were closed by PCR and sequencing of the products. The overall assembly was compared to an optical map; this identified some misassembled contigs and gave a size estimate for each chromosome. Conclusion Assembly 21 reveals an ancient chromosome fusion, a number of small internal duplications followed by inversions, and a subtelomeric arrangement, including a new gene family, the TLO genes. Correlations of position with relatedness of gene families imply a novel method of dispersion. The sequence of the individual chromosomes of C. albicans raises interesting biological questions about gene family creation and dispersion, subtelomere organization, and chromosome evolution.
Human C-reactive protein exacerbates metabolic disorders in association with adipose tissue remodelling
Authors: Hidehiro Kaneko, Toshihisa Anzai, Toshiyuki Nagai, Atsushi Anzai, Toshiyuki Takahashi, Yoshinori Mano, Kohkichi Morimoto, Yuichiro Maekawa, Hiroshi Itoh, Tsutomu Yoshikawa, Satoshi Ogawa, Keiichi Fukuda
Journal: Cardiovascular Research (2011)

C-reactive protein (CRP) expression is increased with metabolic alterations. We sought to clarify the effect of CRP on the development of obesity-induced metabolic disorders using human CRP-overexpressing transgenic mice (CRPTG). CRPTG and their non-transgenic littermates (CON) were fed a standard diet (STD) or a high-fat diet (HFD) from 6 weeks of age. Oral glucose tolerance and intraperitoneal insulin tolerance tests 12 weeks after starting the diets showed deterioration of glucose tolerance and insulin sensitivity in HFD/CRPTG compared with HFD/CON. Hepatocellular ballooning, oil droplets, and peri-sinusoidal fibrosis were more prominent in HFD/CRPTG than in HFD/CON. In HFD/CRPTG, hepatic triglyceride content was higher and serum adiponectin levels lower than in HFD/CON. Epididymal adipose tissue mRNA expression of mucin-like, hormone receptor-like 1, monocyte chemotactic protein-1, and tumour necrosis factor-α in HFD/CRPTG was up-regulated compared with that in HFD/CON. Immunohistochemical staining of epididymal adipose tissue showed that the number of Mac-3+ macrophages was higher in HFD/CRPTG than in HFD/CON. Human CRP overexpression facilitated the development of insulin resistance and hepatosteatosis with HFD in association with adiponectin down-regulation and enhancement of macrophage infiltration and expression of pro-inflammatory cytokines in epididymal adipose tissue, suggesting its pathogenic role in the development of obesity-induced metabolic disorders.
Loss of Tsc1/Tsc2 activates mTOR and disrupts PI3K-Akt signaling through downregulation of PDGFR
Authors: Hongbing Zhang, Gregor Cicchetti, Hiroaki Onda, Henry B. Koon, Kirsten Asrican, Natalia Bajraszewski, Francisca Vazquez, Christopher L. Carpenter, David J. Kwiatkowski
Journal: Journal of Clinical Investigation (2003)

Tuberous sclerosis (TSC) is a familial tumor syndrome due to mutations in TSC1 or TSC2, in which progression to malignancy is rare. Primary Tsc2(-/-) murine embryo fibroblast cultures display early senescence with overexpression of p21CIP1/WAF1 that is rescued by loss of TP53. Tsc2(-/-)TP53(-/-) cells, as well as tumors from Tsc2(+/-) mice, display an mTOR-activation signature with constitutive activation of S6K, which is reverted by treatment with rapamycin. Rapamycin also reverts a growth advantage of Tsc2(-/-)TP53(-/-) cells. Tsc1/Tsc2 does not bind directly to mTOR, however, nor does it directly influence mTOR kinase activity or cellular phosphatase activity. There is a marked reduction in Akt activation in Tsc2(-/-)TP53(-/-) and Tsc1(-/-) cells in response to serum and PDGF, along with a reduction in cell ruffling. PDGFRalpha and PDGFRbeta expression is markedly reduced in both the cell lines and Tsc mouse renal cystadenomas, and ectopic expression of PDGFRbeta in Tsc2-null cells restores Akt phosphorylation in response to serum, PDGF, EGF, and insulin. This activation of mTOR along with downregulation of PDGFR PI3K-Akt signaling in cells lacking Tsc1 or Tsc2 may explain why these genes are rarely involved in human cancer. This is in contrast to PTEN, which is a negative upstream regulator of this pathway.
Regulation of protumorigenic pathways by Insulin like growth factor binding protein2 and its association along with β-catenin in breast cancer lymph node metastasis
Authors: Priyanka Sehgal, Neeraj Kumar, Varuvar Rajesh Praveen Kumar, Shilpa Patil, Animesh Bhattacharya, Manavalan Vijaya Kumar, Geetashree Mukherjee, Paturu Kondaiah
Journal: Molecular Cancer (2013)

Abstract Background Insulin like growth factor binding proteins modulate the mitogenic and pro survival effects of IGF. Elevated expression of IGFBP2 is associated with progression of tumors that include prostate, ovarian, glioma among others. Though implicated in the progression of breast cancer, the molecular mechanisms involved in IGFBP2 actions are not well defined. This study investigates the molecular targets and biological pathways targeted by IGFBP2 in breast cancer. Methods Transcriptome analysis of breast tumor cells (BT474) with stable knockdown of IGFBP2 and breast tumors having differential expression of IGFBP2 by immunohistochemistry was performed using microarray. Differential gene expression was established using R-Bioconductor package. For validation, gene expression was determined by qPCR. Inhibitors of IGF1R and integrin pathway were utilized to study the mechanism of regulation of β-catenin. Immunohistochemical and immunocytochemical staining was performed on breast tumors and experimental cells, respectively for β-catenin and IGFBP2 expression. Results Knockdown of IGFBP2 resulted in differential expression of 2067 up regulated and 2002 down regulated genes in breast cancer cells. Down regulated genes principally belong to cell cycle, DNA replication, repair, p53 signaling, oxidative phosphorylation, Wnt signaling. Whole genome expression analysis of breast tumors with or without IGFBP2 expression indicated changes in genes belonging to Focal adhesion, Map kinase and Wnt signaling pathways. Interestingly, IGFBP2 knockdown clones showed reduced expression of β- catenin compared to control cells which was restored upon IGFBP2 re-expression. The regulation of β-catenin by IGFBP2 was found to be IGF1R and integrin pathway dependent. Furthermore, IGFBP2 and β-catenin are co-ordinately overexpressed in breast tumors and correlate with lymph node metastasis. Conclusion This study highlights regulation of β-catenin by IGFBP2 in breast cancer cells and most importantly, combined expression of IGFBP2 and β-catenin is associated with lymph node metastasis of breast tumors.
Functional specialization does not require a one-to-one mapping between brain regions and emotions
Authors: Andrea Scarantino
Journal: Behavioral and Brain Sciences (2012)

Lindquist et al. have assumed that functional specialization requires a one-to-one mapping between brain regions and discrete emotions. This assumption is in tension with the fact that regions can have multiple functions in the context of different, possibly distributed, networks. Once we open the door to other forms of functional specialization, neuroimaging data no longer favor constructionist models over natural kind models.
Delayed lupus nephritis
Authors: D-C Varela, G Quintana, E C Somers, A Rojas-Villarraga, G Espinosa, M-E Hincapie, W J McCune, R Cervera, J-M Anaya
Journal: Annals of the Rheumatic Diseases (2008)

To describe and analyse the clinical and immunological characteristics of a large series of patients with delayed lupus nephritis (LN).A cross-sectional study was carried out. Patients with systemic lupus erythematosus (SLE) who developed renal involvement >or=5 years after the first manifestation(s) of the disease (delayed LN, n = 48) were compared with patients with SLE in whom LN developed within 5 years or less after SLE appeared (early-onset LN, n = 187). A control group, the no LN (NLN) group, comprised patients with longstanding SLE (duration of disease >10 years) who had never shown signs of renal involvement (n = 164).The group with delayed LN was positively associated with Sjögren's syndrome, lung involvement and antiphospholipid syndrome as compared with early LN. However, its renal clinical expression and histopathological patterns were similar to those of early-onset LN. The frequency of anti-dsDNA, anti-Sm and anti-RNP antibodies was higher in patients with LN than in the NLN group, as was the frequency of low complement levels. Jaccoud's arthropathy was a protective factor for nephritis.Delayed LN is not uncommon in patients with SLE. The identified risk factors might aid in its diagnosis and enhance the ability to identify patients at risk for this complication of SLE.
Differential Actions of Cardioprotective Agents on the Mitochondrial Death Pathway
Authors: Masaharu Akao, Brian O’Rourke, Hideo Kusuoka, Yasushi Teshima, Steven P. Jones, Eduardo Marbán
Journal: Circulation Research (2003)

We examined the effect of cardioprotective agents on three distinct phases of the H 2 O 2 -induced response that leads to loss of mitochondrial membrane potential (ΔΨ m ) and cell death in cultured cardiac myocytes: (1) priming, consisting of calcium-dependent morphological changes in mitochondria (swelling and loss of cristae), with preserved ΔΨ m , (2) depolarization, the rapid ΔΨ m depolarization caused by mitochondrial permeability transition pore (PTP) opening, and (3) cell fragmentation. The mitochondrial ATP-sensitive potassium (mitoK ATP ) channel opener diazoxide markedly decreased the likelihood that cells would undergo priming: many mitochondria remained fully polarized and morphologically intact. Diazoxide not only decreased the number of cells undergoing ΔΨ m depolarization but also delayed the onset of ΔΨ m loss, whereas it did not change the duration of depolarization in unprotected cells. The adenine nucleotide translocase inhibitor bongkrekic acid mimicked the effect of diazoxide to suppress priming, except that its effects were not blocked by the mitoK ATP channel blocker 5-hydroxydecanoate. In contrast, the PTP inhibitor cyclosporin A (CsA) did not prevent priming: neither latency for ΔΨ m depolarization nor mitochondrial morphological changes were affected. However, CsA slowed the process of depolarization and blunted its severity. Importantly, coapplication of diazoxide and CsA exhibited additive effects, improving the efficacy of protection. Activation of mitoK ATP channels suppresses the cell death process at its earliest stage, by preserving mitochondrial integrity during oxidative stress. By virtue of its pharmacology and its phenotypic consequences, this mode of action is distinguishable from that of other cardioprotective interventions.