tbuckley/cabot-search huggingface dataset:
Pathway analysis of kidney cancer using proteomics and metabolic profiling
Authors: Bertrand Perroud, Jinoo Lee, Nelly Valkova, Amy Dhirapong, Pei-Yin Lin, Oliver Fiehn, Dietmar Kültz, Robert H Weiss
Journal: Molecular Cancer (2006)

Abstract Background Renal cell carcinoma (RCC) is the sixth leading cause of cancer death and is responsible for 11,000 deaths per year in the US. Approximately one-third of patients present with disease which is already metastatic and for which there is currently no adequate treatment, and no biofluid screening tests exist for RCC. In this study, we have undertaken a comprehensive proteomic analysis and subsequently a pathway and network approach to identify biological processes involved in clear cell RCC (ccRCC). We have used these data to investigate urinary markers of RCC which could be applied to high-risk patients, or to those being followed for recurrence, for early diagnosis and treatment, thereby substantially reducing mortality of this disease. Results Using 2-dimensional electrophoresis and mass spectrometric analysis, we identified 31 proteins which were differentially expressed with a high degree of significance in ccRCC as compared to adjacent non-malignant tissue, and we confirmed some of these by immunoblotting, immunohistochemistry, and comparison to published transcriptomic data. When evaluated by several pathway and biological process analysis programs, these proteins are demonstrated to be involved with a high degree of confidence (p values &lt; 2.0 E-05) in glycolysis, propanoate metabolism, pyruvate metabolism, urea cycle and arginine/proline metabolism, as well as in the non-metabolic p53 and FAS pathways. In a pilot study using random urine samples from both ccRCC and control patients, we performed metabolic profiling and found that only sorbitol, a component of an alternative glycolysis pathway, is significantly elevated at 5.4-fold in RCC patients as compared to controls. Conclusion Extensive pathway and network analysis allowed for the discovery of highly significant pathways from a set of clear cell RCC samples. Knowledge of activation of these processes will lead to novel assays identifying their proteomic and/or metabolomic signatures in biofluids of patient at high risk for this disease; we provide pilot data for such a urinary bioassay. Furthermore, we demonstrate how the knowledge of networks, processes, and pathways altered in kidney cancer may be used to influence the choice of optimal therapy.
Epithelial-mesenchymal transition: focus on metastatic cascade, alternative splicing, non-coding RNAs and modulating compounds
Authors: Timur R Samatov, Alexander G Tonevitsky, Udo Schumacher
Journal: Molecular Cancer (2013)

Epithelial-mesenchymal transition (EMT) is a key process in embryonic development and metastases formation during malignant progression. This review focuses on transcriptional regulation, non-coding RNAs, alternative splicing events and cell adhesion molecules regulation during EMT. Additionally, we summarize the knowledge with regard to the small potentially druggable molecules capable of modulating EMT for cancer therapy.
Endomyocardial nitric oxide synthase and the hemodynamic phenotypes of human dilated cardiomyopathy and of athlete's heart
Authors: Jean G.F Bronzwaer, Christopher Zeitz, Cees A Visser, Walter J Paulus
Journal: Cardiovascular Research (2002)

In dilated cardiomyopathy and in athlete's heart, progressive LV dilatation is accompanied by rightward displacement of the diastolic LV pressure-volume relation. In dilated cardiomyopathy, an increase in diastolic LV stiffness can limit this rightward displacement thereby decreasing LV systolic performance. Because nitric oxide (NO) reduces diastolic LV stiffness, the present study relates diastolic LV stiffness and LV systolic performance to intensity of endomyocardial NO synthase (NOS) gene expression in dilated cardiomyopathy and in athlete's heart.Microtip LV pressures, conductance-catheter or angiographic LV volumes, echocardiographic LV wall thicknesses and snap-frozen LV endomyocardial biopsies were obtained in 33 patients with dilated cardiomyopathy and in three professional cyclists referred for sustained ventricular tachycardia. Intensity of LV endomyocardial inducible NOS (NOS2) and constitutive NOS (NOS3) gene expression was determined using quantitative reverse transcription-polymerase chain reaction (RT-PCR).Dilated cardiomyopathy patients with higher diastolic LV stiffness-modulus and lower LV stroke work had lower NOS2 and NOS3 gene expression at any given level of LV end-diastolic wall stress. The intensity of NOS2 and NOS3 gene expression observed in athlete's heart was similar to dilated cardiomyopathy with low LV diastolic stiffness-modulus and preserved LV stroke work.High LV endomyocardial NOS gene expression is observed in athlete's heart and in dilated cardiomyopathy with low diastolic LV stiffness and preserved LV stroke work. Favourable effects on the hemodynamic phenotype of high LV endomyocardial NOS gene expression could result from a NO-mediated decrease in diastolic LV stiffness and a concomitant rise in LV preload reserve.
The interleukin 2 receptor. Functional consequences of its bimolecular structure.
Authors: H M Wang, K A Smith
Journal: The Journal of Experimental Medicine (1987)

High-affinity IL-2-R binding results from an exceptional type of cooperative interaction between two IL-2-binding proteins termed alpha and beta. When expressed together on the cell surface, these two distinct chains form a noncovalent kinetic hybrid receptor complex that exploits a rapid association rate contributed by the p55 beta chain and a slow dissociation rate characteristic for the p75 alpha chain. The p75 alpha chains signal cell growth, whereas the p55 beta chains only facilitate IL-2 binding by serving as helper binding sites, having no discernible signaling role themselves. The unique functional implications of this structural organization indicate that this cooperative bimolecular arrangement reflects a general mechanism by which the efficiency of surface receptors can be enhanced markedly.
Deficiency of Protein Kinase Cα in Mice Results in Impairment of Epidermal Hyperplasia and Enhancement of Tumor Formation in Two-Stage Skin Carcinogenesis
Authors: Takeshi Hara, Yuriko Saito, Takaaki Hirai, Kenji Nakamura, Kazuki Nakao, Motoya Katsuki, Kazuhiro Chida
Journal: Cancer Research (2005)

Abstract We generated a mouse strain lacking protein kinase Cα (PKCα) and evaluated the significance of the enzyme in epithelial hyperplasia and tumor formation. PKCα-deficient mice exhibited increased susceptibility to tumor formation in two-stage skin carcinogenesis by single application of 7,12-dimethylbenz(a)anthracene (DMBA) for tumor initiation and repeated applications of 12-O-tetradecanoylphorbol-13-acetate (TPA) for tumor promotion. Tumor formation was not enhanced by DMBA or TPA treatment alone, suggesting that PKCα suppresses tumor promotion. However, the severity of epidermal hyperplasia induced by topical TPA treatment was markedly reduced. In mutant mice, the number of 5-bromo-2′-deoxyuridine–labeled epidermal basal keratinocytes increased 16 to 24 hours after topical TPA treatment as in the case of wild-type mice, but significantly decreased at 36 and 48 hours. Furthermore, the regenerating epithelium induced by skin wound significantly decreased in thickness but was not structurally impaired. The enhanced tumor formation may not be associated with epidermal hyperplasia. The induction levels of epidermal growth factor (EGF) receptor ligands, tumor growth factor α (TGF-α), and heparin-binding EGF-like growth factor, in the skin of mutant mice by TPA treatment were significantly lower than those in the skin of wild-type mice. PKCα may regulate the supply of these EGF receptor ligands in basal keratinocytes, resulting in a reduced epidermal hyperplasia severity in the mutant mice. We propose that PKCα positively regulates epidermal hyperplasia but negatively regulates tumor formation in two-stage skin carcinogenesis.
Changes in procoagulant and fibrinolytic gene expression during bleomycin-induced lung injury in the mouse.
Authors: M A Olman, N Mackman, C L Gladson, K M Moser, D J Loskutoff
Journal: Journal of Clinical Investigation (1995)

Bleomycin-induced lung injury is an established murine model of human pulmonary fibrosis. Although procoagulant molecules (e.g., tissue factor [TF]) and fibrinolytic components (e.g., urokinase [u-PA] and type 1 plasminogen activator inhibitor [PAI-1]) have been detected in alveolar fluid from injured lungs, the origin of these molecules remains unknown. We therefore examined the expression of procoagulant and fibrinolytic components in relation to the distribution of parenchymal fibrin in bleomycin-injured lungs. Extravascular fibrin localized to the alveolar and extracellular matrix in injured lung tissue. Injured lung tissue extracts contained elevated levels of PAI-1 activity and decreased levels of u-PA activity. Whole lung PAI-1 and TF mRNAs were dramatically induced by lung injury. In situ hybridization of injured lungs revealed that PAI-1, u-PA, and TF mRNAs were induced within the fibrin-rich fibroproliferative lesions, primarily in fibroblast-like and macrophagelike cells, respectively, while TF mRNA was also induced in perilesional alveolar cells. Taken together, these observations suggest that the induction of PAI-1 and TF gene expression plays and important role in the formation and persistence of extracellular fibrin in bleomycin injured murine lungs.
Increased KIT Inhibition Enhances Therapeutic Efficacy in Gastrointestinal Stromal Tumor
Authors: Teresa S. Kim, Michael J. Cavnar, Noah A. Cohen, Eric C. Sorenson, Jonathan B. Greer, Adrian M. Seifert, Megan H. Crawley, Benjamin L. Green, Rachel Popow, Nagavarakishore Pillarsetty, Darren R. Veach, Anson T. Ku, Ferdinand Rossi, Peter Besmer, Cristina R. Antonescu, Shan Zeng, Ronald P. DeMatteo
Journal: Clinical Cancer Research (2014)

Gastrointestinal stromal tumor (GIST) is the most common human sarcoma and a model of targeted molecular therapy. GIST depends on oncogenic KIT signaling and responds to the tyrosine kinase inhibitor imatinib. However, imatinib is rarely curative. We hypothesized that PLX3397, which inhibits KIT and colony-stimulating-factor-1 receptor (CSF1R), would be more efficacious than imatinib in GIST by also depleting tumor-associated macrophages, which are generally thought to support tumor growth.We treated Kit(V558del/+) mice that develop GIST or mice with subcutaneous human GIST xenografts with imatinib or PLX3397 and analyzed tumor weight, cellular composition, histology, molecular signaling, and fibrosis. In vitro assays on human GIST cell lines were also performed.PLX3397 was more effective than imatinib in reducing tumor weight and cellularity in both Kit(V558del)(/+) murine GIST and human GIST xenografts. The superiority of PLX3397 did not depend on depletion of tumor-associated macrophages, because adding CSF1R inhibition did not improve the effects of imatinib. Instead, PLX3397 was a more potent KIT inhibitor than imatinib in vitro. PLX3397 therapy also induced substantial intratumoral fibrosis, which impaired the subsequent delivery of small molecules.PLX3397 therapy has greater efficacy than imatinib in preclinical GIST models and warrants study in patients with GIST. The resultant intratumoral fibrosis may represent one of the barriers to achieving complete tumor eradication.
Cardiac Angiography in Renally Impaired Patients (CARE) Study
Authors: Richard J. Solomon, Madhu K. Natarajan, Serge Doucet, Samin K. Sharma, Cezar S. Staniloae, Richard E. Katholi, Joseph L. Gelormini, Marino Labinaz, Abel E. Moreyra
Journal: Circulation (2007)

Background— No direct comparisons exist of the renal tolerability of the low-osmolality contrast medium iopamidol with that of the iso-osmolality contrast medium iodixanol in high-risk patients. Methods and Results— The present study is a multicenter, randomized, double-blind comparison of iopamidol and iodixanol in patients with chronic kidney disease (estimated glomerular filtration rate, 20 to 59 mL/min) who underwent cardiac angiography or percutaneous coronary interventions. Serum creatinine (SCr) levels and estimated glomerular filtration rate were assessed at baseline and 2 to 5 days after receiving medications. The primary outcome was a postdose SCr increase ≥0.5 mg/dL (44.2 μmol/L) over baseline. Secondary outcomes were a postdose SCr increase ≥25%, a postdose estimated glomerular filtration rate decrease of ≥25%, and the mean peak change in SCr. In 414 patients, contrast volume, presence of diabetes mellitus, use of N-acetylcysteine, mean baseline SCr, and estimated glomerular filtration rate were comparable in the 2 groups. SCr increases ≥0.5 mg/dL occurred in 4.4% (9 of 204 patients) after iopamidol and 6.7% (14 of 210 patients) after iodixanol ( P =0.39), whereas rates of SCr increases ≥25% were 9.8% and 12.4%, respectively ( P =0.44). In patients with diabetes, SCr increases ≥0.5 mg/dL were 5.1% (4 of 78 patients) with iopamidol and 13.0% (12 of 92 patients) with iodixanol ( P =0.11), whereas SCr increases ≥25% were 10.3% and 15.2%, respectively ( P =0.37). Mean post-SCr increases were significantly less with iopamidol (all patients: 0.07 versus 0.12 mg/dL, 6.2 versus 10.6 μmol/L, P =0.03; patients with diabetes: 0.07 versus 0.16 mg/dL, 6.2 versus 14.1 μmol/L, P =0.01). Conclusions— The rate of contrast-induced nephropathy, defined by multiple end points, is not statistically different after the intraarterial administration of iopamidol or iodixanol to high-risk patients, with or without diabetes mellitus. Any true difference between the agents is small and not likely to be clinically significant.
The incidence of exercise-associated hyponatraemia in the London marathon
Authors: Courtney Kipps, Sanjay Sharma, Dan Tunstall Pedoe
Journal: British Journal of Sports Medicine (2009)

Background Exercise-associated hyponatraemia (EAH) is a potentially fatal cause of collapse in endurance exercise. It is understood to be a dilutional hyponatraemia caused by an increase of total body water relative to the amount of exchangeable sodium stores. Fourteen runners presented to one London hospital with symptomatic EAH several hours after finishing the 2003 London Marathon, and more recently, a young male runner died from the complications of severe EAH after crossing the finish line of the London Marathon. Objectives To determine the incidence of EAH in runners in the London Marathon. Methods Volunteers were recruited at race registration where they were weighed, had blood tests and completed a demographic and experience questionnaire. Weights, blood tests and a fluid intake questionnaire were repeated after the finish. Blood was analysed on-site using hand-held i-STAT blood analysers. Results Of the 88 volunteers, 11 (12.5%) developed asymptomatic hyponatraemia (serum sodium 128–134 mmol/l). They consumed more fluid (p&lt;0.001) and gained more weight (p&lt;0.001) than did those without hyponatraemia. Conclusions A significant proportion (12.5%) of healthy volunteers developed asymptomatic hyponatraemia running a marathon in cool conditions. On average, these runners consumed more fluid and gained more weight than did non-hyponatraemic runners, although fluid intake was not related to weight gain in this study. Four of the 11 hyponatraemic runners lost weight over the course of the marathon, strengthening the case for an additional factor, such as inappropriate antidiuretic hormone release during exercise, in the development of EAH.
Alternative End Points to Evaluate a Therapeutic Strategy in Advanced Colorectal Cancer: Evaluation of Progression-Free Survival, Duration of Disease Control, and Time to Failure of Strategy—An Aide et Recherche en Cancérologie Digestive Group Study
Authors: Benoist Chibaudel, Franck Bonnetain, Qian Shi, Marc Buyse, Christophe Tournigand, Daniel J. Sargent, Carmen J. Allegra, Richard M. Goldberg, Aimery de Gramont
Journal: Journal of Clinical Oncology (2011)

Progression-free survival (PFS) is not an optimal end point to evaluate therapeutic strategies in advanced colorectal cancer (ACRC). Therefore, composite end points have been proposed to evaluate a chemotherapy strategy when sequential treatments are available: duration of disease control (DDC) and time to failure of strategy (TFS). The goal of this study was to evaluate these alternative end points and their potential surrogacy for overall survival (OS).We pooled individual patient data from three randomized trials evaluating chemotherapy strategy, which accrued 1,042 patients with previously untreated ACRC. In these trials, first-line treatment was either oxaliplatin- or irinotecan-based chemotherapy. Compared with TFS, DDC included neither time interval between progression and next sequence of treatment nor time to progression if the best result of the next sequence of treatment was progression.There was good correlation between DDC and OS (correlation of median: r, 0.62; correlation of hazard ratio [HR]: adjusted copula R(2), 0.72) and between TFS and OS (correlation of median: r, 0.59; correlation of HR: adjusted copula R(2), 0.67). There was no correlation between PFS and OS (correlation of median: r, 0.45; correlation of HR: adjusted copula R(2), 0.47).DDC and TFS roughly achieved the same results. Both are acceptable new end points to evaluate a therapeutic strategy in ACRC. Although TFS achieved a pragmatic evaluation of a multiline strategy, DDC captured the effect of a specific sequence in a therapeutic strategy.
Abstract P6-04-12: Novel selective estrogen receptors degraders regress tumors in pre-clinical models of endocrine-resistant breast cancer
Authors: JH Hager, B Darimont, J Joseph, S Govek, K Grillot, A Aparicio, E Bischoff, M Kahraman, J Kaufman, A Lai, K-J Lee, N Lu, J Nagasawa, R Prudente, J Qian, J Sensintaffar, G Shao, R Heyman, P Rix, ND Smith
Journal: Cancer Research (2012)

Abstract 80% of all breast cancers express the estrogen receptor alpha (ERα) and thus are treated with anti-hormonal therapies that directly block ER function (e.g. Tamoxifen) or hormone synthesis (Aromatase Inhibitors). While these therapies are initially effective, acquired resistance invariably emerges. Importantly, the majority of these tumors continue to depend on ERα for growth and survival. The emerging evidence that ERα can signal in both a ligand-dependent and ligand-independent manner supports the development of agents that are not only competitive ERα antagonists but also reduce steady state levels of the receptor and thus limit both modes of signaling. We have identified novel, non-steroidal ERα antagonists that induce degradation of ERα in breast cancer cell lines at picomolar concentrations resulting in significant reduction in steady state ERα protein levels. Using peptide-based conformational profiling, we show that these Selective Estrogen Receptor Degraders (SERDs) induce estrogen receptor conformations that are distinct from both fulvestrant and tamoxifen indicating a unique mechanism of action. This unique biological profile coupled with good oral pharmacokinetics produces tumor regressions in both tamoxifen-sensitive and -resistant models of breast cancer in vivo. Recent pre-clinical and clinical data indicate that PI3K pathway signaling can contribute to the endocrine resistant state. In a preclinical model of tamoxifen resistant breast cancer in which SERD monotherapy only produces tumor growth inhibition, SERD therapy in combination with torc1/2 inhibition results in frank tumor regressions. These orally bioavailable SERDs hold promise as a next generation therapy for the treatment of ER+ breast cancer as monotherapy, as well as in combination with agents that target other pathways involved in both intrinsic and acquired endocrine resistance. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-04-12.
Serum Ammonia Level for the Evaluation of Hepatic Encephalopathy
Authors: Phillip S. Ge, Bruce A. Runyon
Journal: JAMA (2014)

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Dose-finding study of weekly docetaxel, anthracyclines plus fluoropyrimidines as first-line treatment in advanced breast cancer
Authors: O. Pagani, C. Sessa, F. Nolè, E. Munzone, D. Crivellari, D. Lombardi, B. Thürlimann, D. Hess, R. Graffeo, M. Ruggeri, S. Longhi, A. Goldhirsch
Journal: Annals of Oncology (2005)
Experimental Uremia Affects Hypothalamic Amino Acid Neurotransmitter Milieu
Authors: FRANZ SCHAEFER, MARCEL VOGEL, GUIDO KERKHOFF, JOHANNES WOITZIK, MARKUS DASCHNER, OTTO MEHLS
Journal: Journal of the American Society of Nephrology (2001)

Abstract. Chronic renal failure is associated with delayed puberty and hypogonadism. To investigate the mechanisms subserving the reported reduced pulsatile release of gonadotropin-releasing hormone (GnRH) in chronic renal failure, this study examined the amino acid neurotransmitter milieu in the medial preoptic area (MPOA), the hypothalamic region where the GnRH-secreting neurons reside, in 5/6-nephrectomized male rats and in ad libitum-fed or pair-fed controls. All rats were castrated and received either a testosterone or a vehicle implant to evaluate additional effects of the prevailing sex steroid milieu. Local excitatory (essential amino acids: aspartate, glutamate) and inhibitory (γ-aminobutyric acid [GABA], taurine) amino acid transmitter outflow in the MPOA was measured by microdialysis via stereotactically implanted cannulae in the awake, freely moving rats. In addition to basal extracellular concentrations, the neurosecretory capacity was assessed by the addition of 100 mM KCl to the dialysis fluid. The mechanisms of neurosecretion were evaluated further by inhibition of vesicular release with the use of Ca2+-free, Mg2+-enriched dialysis fluid and by local perfusion with inhibitors of voltage-dependent synaptic release (1 μM tetrodotoxin) and of GABA reuptake (0.5 mM nipecotic acid). In the uremic rats, basal outflow of GABA, glutamate and aspartate, and K+-stimulated aspartate outflow were increased. K+-stimulated GABA and glutamate release was less sensitive to Ca2+ depletion in the uremic than in the control rats. The elevated basal GABA and essential amino acid outflow in the uremic rats was due to a voltage- and Ca2+-independent mechanism. GABA reuptake was inhibited proportionately by nipecotic acid in uremic and pair-fed control rats. Testosterone supplementation had no independent effects on neurotransmitter outflow. In summary, the amino acid neurotransmitter milieu is altered in the MPOA of uremic rats by a nonsynaptic, nonvesicular mechanism. These abnormalities may contribute to the impaired function of the GnRH pulse generator.