tbuckley/cabot-search huggingface dataset:
RhoA Activation Mediates Phosphatidylinositol 3-Kinase–Dependent Proliferation of Human Vascular Endothelial Cells
Authors: Ste[Combining Acute Accent]phanie Coupel, Fabrice Leboeuf, Gwe[Combining Acute Accent]nola Boulday, Jean-Paul Soulillou, Be[Combining Acute Accent]atrice Charreau
Journal: Journal of the American Society of Nephrology (2004)

ABSTRACT. HLA class I ligation on graft endothelial cells (EC) has been shown to promote graft arteriosclerosis and chronic allograft nephropathy. This study investigated transcriptional and functional changes mediated by anti-HLA antibodies (Ab), developed by transplant recipient, on vascular renal EC. For mimicking interactions that occur between alloantibodies and graft endothelium, HLA-typed primary cultures of human EC were incubated in vitro in the presence of monomorphic or polymorphic anti-HLA class I Ab. Gene expression analysis identified the upregulation of several molecules involved in cell signaling and proliferation, including the GTP-binding protein RhoA. It was demonstrated further that HLA class I ligation on EC induced a rapid translocation of RhoA to the cell membrane associated with F-actin stress fiber formation and cytoskeleton reorganization. Western blot analysis showed that anti-HLA class I Ab induced, in addition to RhoA, the activation of phosphatidylinositol 3-kinase, reflected by the phosphorylation of Akt (Ser473) and GSK3β (Ser9), in EC. C3 exoenzyme, an inhibitor of RhoA, inhibited RhoA translocation in response to HLA class I ligation and reduced phosphatidylinositol 3-kinase activation. EC proliferation and cell cycle progression, examined by 5,6-carboxyfluorescein diacetate succinimidyl ester staining, demonstrated that anti-HLA-induced EC proliferation was efficiently prevented by the 3-hydroxy-3-methylglutaryl CoA reductase inhibitor simvastatin (0.1 μmol/L) through inhibition of RhoA geranylgeranylation. Taken together, these findings support the conclusion that RhoA is a key mediator of signaling pathways that lead to cytoskeletal reorganization and EC proliferation in response to alloantibodies that bind to HLA class I and demonstrate the specific and potent inhibitory effect of simvastatin on allostimulated EC growth.
High Parathyroid Hormone Level and Osteoporosis Predict Progression of Coronary Artery Calcification in Patients on Dialysis
Authors: Hartmut H. Malluche, Gustav Blomquist, Marie-Claude Monier-Faugere, Thomas L. Cantor, Daniel L. Davenport
Journal: Journal of the American Society of Nephrology (2015)

Coronary artery calcifications (CACs) are observed in most patients with CKD on dialysis (CKD-5D). CACs frequently progress and are associated with increased risk for cardiovascular events, the major cause of death in these patients. A link between bone and vascular calcification has been shown. This prospective study was designed to identify noninvasive tests for predicting CAC progression, including measurements of bone mineral density (BMD) and novel bone markers in adult patients with CKD-5D. At baseline and after 1 year, patients underwent routine blood tests and measurement of CAC, BMD, and novel serum bone markers. A total of 213 patients received baseline measurements, of whom about 80% had measurable CAC and almost 50% had CAC Agatston scores>400, conferring high risk for cardiovascular events. Independent positive predictors of baseline CAC included coronary artery disease, diabetes, dialysis vintage, fibroblast growth factor-23 concentration, and age, whereas BMD of the spine measured by quantitative computed tomography was an inverse predictor. Hypertension, HDL level, and smoking were not baseline predictors in these patients. Three quarters of 122 patients completing the study had CAC increases at 1 year. Independent risk factors for CAC progression were age, baseline total or whole parathyroid hormone level greater than nine times the normal value, and osteoporosis by t scores. Our results confirm a role for bone in CKD-associated CAC prevalence and progression.
Abstract 3945: HIFs regulate alternative splicing of HIF target genes
Authors: Johnny Sena, Liyi Wang, Cheng-jun Hu
Journal: Cancer Research (2012)

Abstract Alternative splicing is the process in which identical pre-mRNA molecules are spliced in different ways, allowing individual gene to express multiple mRNAs or isoforms that encode proteins with diverse and even antagonistic functions. Alternative splicing occurs in over 70% of human genes, is important in normal development and many diseases including cancer. It is well known that most solid-tumors are hypoxic and the hypoxic microenvironment is a driving force for tumor progression and metastasis by hypoxia-inducible-factor (HIF)-mediated transcriptional programs that increase genes involved in tumor growth, angiogenesis, and metastasis. Here, we report a novel finding that transcriptional factor HIF not only activates gene expression, also regulates RNA splicing of its target genes, generating isoforms that favor tumor growth. Using an Exon Microarray we found that approximately 1000 genes are predicted to undergo hypoxia-mediated AS in Hep3B cells, 100 of those genes are hypoxia inducible genes. Using RT-PCR, RT-qPCR and WB we validated that the first 10 HIF target genes, CA9, ANGPTL4, WNK1, PLOD2, ADM, DUOX2, ENO2, P4HA2, EGLN3, and PDK1 undergo hypoxia-mediate AS, as predicted by exon array. Interestingly, AS of these genes is regulated by HIFs, not by hypoxia since: 1) siRNA knockdown of ARNT, HIF1, or HIF2 inhibits hypoxic induction of HIF target genes as well as inhibits hypoxia-mediated splicing changes; and 2) Normoxic HIF activity by deleting VHL, inhibiting PHD, or expressing normoxic-stable HIF protein led to hypoxic splicing patterns of HIF target genes, demonstrating HIF activity is sufficient to induce alternative splicing of HIF target genes. However, AS of HIF target genes cannot be explained by increased transcription of these genes since no splicing changes were observed when these genes were activated by hybrid protein with HIF transactivation domains replaced by VP16, E2F1, or SP1 transactivation domain. Further experiments indicated that the N-terminal transactivation domains (N-TAD) of HIF1α or HIF2α are responsible for splicing changes of these HIF-target genes. In summary, we have uncovered a novel function of HIFs in the regulation of target gene splicing. The discovery of HIF's role in mRNA splicing of its target genes will change the dogma concerning the role of HIF in cancer progression. We propose that HIFs promote cancer progression not only through transcription activation but also through alteration of mRNA splicing of HIF targets. RO1 CA134687 NIH/NCI (Hu) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3945. doi:1538-7445.AM2012-3945
Apical effect of diosmectite on damage to the intestinal barrier induced by basal tumour necrosis factor-alpha.
Authors: L Mahraoui, M Heyman, O Plique, M T Droy-Lefaix, J F Desjeux
Journal: Gut (1997)

BACKGROUND: In many digestive diseases the intestinal barrier is weakened by the release of proinflammatory cytokines, including tumour necrosis factor-alpha (TNF alpha). AIM: To investigate the protective effect of apical diosmectite on the intestinal dysfunction induced by the proinflammatory cytokine TNF alpha. METHODS: Filter grown monolayers of the intestinal cell line HT29-19A were incubated for 48 hours in basal medium containing 10 ng/ml TNF alpha and 5 U/ml interferon-gamma (IFN gamma). Next, 1, 10, or 100 mg/ml diosmectite was placed in the apical medium for one hour. Intestinal function was then assessed in Ussing chambers by measuring ionic conductance (G) and apicobasal fluxes of 14C-mannitol (Jman), and intact horseradish peroxidase. In control intestinal monolayers, diosmectite did not significantly modify G, Jman, or intact horseradish peroxidase. RESULTS: After incubation with TNF alpha and IFN gamma, intestinal function altered, as shown by the increases compared with control values for G (22.8 (3.7) v (9.6 (0.5) mS/cm2), Jman (33.8 (7.5) v 7.56 (0.67) micrograms/h x cm2), and intact horseradish peroxidase (1.95 (1.12) v 0.14 (0.04) micrograms/h x cm2). G and Jman were closely correlated, suggesting that the increase in permeability was paracellular. Treatment with diosmectite restored al the variables to control values. CONCLUSIONS: Basal TNF alpha disrupts the intestinal barrier through the tight junctions, and apical diosmectite counteracts this disruption.
Diabetes increases mortality after myocardial infarction by oxidizing CaMKII
Authors: Min Luo, Xiaoqun Guan, Elizabeth D. Luczak, Di Lang, William Kutschke, Zhan Gao, Jinying Yang, Patric Glynn, Samuel Sossalla, Paari D. Swaminathan, Robert M. Weiss, Baoli Yang, Adam G. Rokita, Lars S. Maier, Igor R. Efimov, Thomas J. Hund, Mark E. Anderson
Journal: Journal of Clinical Investigation (2013)

Diabetes increases oxidant stress and doubles the risk of dying after myocardial infarction, but the mechanisms underlying increased mortality are unknown. Mice with streptozotocin-induced diabetes developed profound heart rate slowing and doubled mortality compared with controls after myocardial infarction. Oxidized Ca2+/calmodulin-dependent protein kinase II (ox-CaMKII) was significantly increased in pacemaker tissues from diabetic patients compared with that in nondiabetic patients after myocardial infarction. Streptozotocin-treated mice had increased pacemaker cell ox-CaMKII and apoptosis, which were further enhanced by myocardial infarction. We developed a knockin mouse model of oxidation-resistant CaMKIIδ (MM-VV), the isoform associated with cardiovascular disease. Streptozotocin-treated MM-VV mice and WT mice infused with MitoTEMPO, a mitochondrial targeted antioxidant, expressed significantly less ox-CaMKII, exhibited increased pacemaker cell survival, maintained normal heart rates, and were resistant to diabetes-attributable mortality after myocardial infarction. Our findings suggest that activation of a mitochondrial/ox-CaMKII pathway contributes to increased sudden death in diabetic patients after myocardial infarction.
Defect in Insulin-Like Growth Factor-1 Survival Mechanism in Atherosclerotic Plaque–Derived Vascular Smooth Muscle Cells Is Mediated by Reduced Surface Binding and Signaling
Authors: V. A. Patel, Q.-J. Zhang, K. Siddle, M. A. Soos, M. Goddard, P. L. Weissberg, M. R. Bennett
Journal: Circulation Research (2001)

Abstract —Apoptosis of vascular smooth muscle cells (VSMCs) is increased in atherosclerosis compared with normal vessels, where it may contribute to plaque rupture. We have previously found that human plaque–derived VSMCs (pVSMCs) are intrinsically sensitive to apoptosis and not responsive to the protective effects of insulin-like growth factor-1 (IGF-1). We therefore examined the mechanism underlying this defect. Human pVSMCs showed &lt;25% 125 I–IGF-1 surface binding, &lt;20% IGF-1 receptor (IGF-1R) expression than that of normal medial VSMCs, and &lt;40% Akt kinase activity in response to IGF-1. pVSMCs expressed and secreted high levels of IGF-1 binding proteins (IGFBPs), and the IGF-1 analogues, long R3 and Des 1,3 IGF-1, which do not bind to IGFBPs, were able to increase pVSMC survival to normal medial VSMC levels. The long R3 survival effect was phosphatidylinositol 3-kinase–mediated, but it was not dependent on Akt activity alone. Intimal pVSMCs in vivo showed reduced IGF-1R expression compared with medial VSMCs, in particular at the shoulder regions of plaques. We conclude that human pVSMCs show an intrinsic sensitivity to apoptosis caused in part by defective expression of IGF-1R, impaired IGF-1–mediated survival signaling and increased IGFBP secretion. This impaired IGF-1 protection against apoptosis may promote VSMC loss and plaque instability in atherosclerosis.
Tiotropium in the management of chronic obstructive pulmonary disease
Authors: P.J. Rees
Journal: European Respiratory Journal (2002)

Bronchodilators play an important role in the treatment of chronic obstructive pulmonary disease (COPD) and anticholinergics have a long history as an effective and safe treatment. Two papers in this issue extend the information available on tiotropium, through large studies lasting a year. The study by Vincken et al. 1, on behalf of the Dutch/Belgian tiotropium study group, shows better results with the long-acting anticholinergic tiotropium than with ipratropium in COPD. A number of previous publications have shown that the prolonged bronchodilator action of tiotropium, found in single dose studies, is maintained with continued use 2–4. This publication extends shorter studies from the same group 2 and shows that the benefits in spirometry, symptoms, health status and exacerbations were maintained over 12 months of the study. A multicentre study from Casaburi et al. 5, comparing tiotropium with placebo, also confirms the continued effect over 12 months. In addition, tiotropium, compared with placebo, improved health status on COPD-specific measures such as the St George's Respiratory Questionnaire, and general measures, such as the Short Form (SF)-36 5.

Such larger and longer studies are needed for alternative end points, such as exacerbations. The baseline forced expiratory volume in one second of ∼40% predicted in these groups of patients, puts them in …
Amphiregulin Is a Promising Prognostic Marker for Liver Metastases of Colorectal Cancer
Authors: Michiyo Yamada, Yasushi Ichikawa, Shigeru Yamagishi, Nobuyoshi Momiyama, Mitsuyoshi Ota, Syoichi Fujii, Kuniya Tanaka, Shinji Togo, Shigeo Ohki, Hiroshi Shimada
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Aberrant activation of epidermal growth factor receptors (EGFR/HER1) by ligand stimulation or heterodimerization with human epidermal growth factor 2 (HER2) is considered to play an important role in the development of colorectal carcinoma. Amphiregulin (AR) is a ligand of EGFR that might be related to the development and progression of gastrointestinal tumors. The aim of this study was to determine the AR, EGFR, and HER2 protein expression levels and to evaluate their prognostic relevance to the clinical course of colorectal cancer. Experimental Design: The AR, EGFR, and HER2 protein levels in primary tumors of colorectal cancer (n = 106) were examined using immunohistochemistry. Metastatic sites in liver specimens (n = 16) were also analyzed in the same manner. Results: Thirteen (81.6%) metastatic lesions of the liver stained positive for AR. Among the primary lesions of colorectal cancer, 58 (54.7%) stained positive for AR, 13 (12.3%) stained positive for EGFR, and 5 (4.7%) stained positive for HER2. When the relationships between each protein expression level and the clinicopathologic factors were examined, only the AR expression level was significantly related to liver metastasis (P = 0.0296). A multivariate analysis of liver metastasis proved that AR expression was an independent prognostic factor of liver metastasis from colorectal cancer (P = 0.0217). Conclusions: AR expression in primary lesions of colorectal cancer is an important predictive marker of liver metastasis.
Splicing for survival
Authors: Heather L. Van Epps
Journal: The Journal of Experimental Medicine (2005)

The oncogene BCR–ABL1 hijacks a B cell signaling protein by inducing the synthesis of a linker protein, according to Feldhahn and colleagues on page 1837. This study helps explain how BCR–ABL1 causes B cell leukemias in humans and identifies a potential new target for drug development.






Figure 

The oncogene BCR–ABL1 induces the synthesis of a splice variant of Bruton's tyrosine kinase (BTKp52) that hijacks full-length BTK and transforms B cells.




Translocation events that combine unrelated chromosomal sequences are found in up to 65% of human acute leukemias. One such translocation event creates a chimeric protein between the signaling protein BCR and the tyrosine kinase ABL1. The BCR–ABL1 fusion allows precursor B cells to bypass survival signals from the pre-B cell receptor that are normally required for B cell survival. But exactly how BCR–ABL1 ensures B cell survival in the absence of pre-B cell receptor signals was not completely clear.

Feldhahn et al. now show that Bruton's tyrosine kinase (BTK)—a key component of the pre-B cell receptor signaling pathway—is perpetually phosphorylated (and thus activated) in BCR–ABL1-expressing leukemia cells. Downstream signals, including calcium flux and expression of the pro-survival protein Bcl-xL, were also activated in these cells. BTK phosphorylation depended on the kinase activity of BCR–ABL1, as inhibiting this kinase decreased BTK phosphorylation. But the mechanism was mysterious, as previous studies had ruled out a direct interaction between BCR–ABL1 and BTK.

The authors had noted that several kinase-deficient splice variants of BTK accumulated in leukemia cells. One of these variants (BTKp52) bound to both BCL–ABL1 and full-length BTK, providing a bridge that allowed BCR–ABL1 to phosphorylate full-length BTK. BTKp52 was needed to maintain cell survival, as removal of this protein drove the cells into apoptosis. Remarkably, the BCR–ABL1 protein itself triggered the production of the BTK splice variants, a finding consistent with previous studies showing that BCR–ABL1 induces the expression of proteins involved in RNA splicing.
Targeting pathophysiological rhythms: prednisone chronotherapy shows sustained efficacy in rheumatoid arthritis
Authors: F. Buttgereit, G. Doering, A. Schaeffler, S. Witte, S. Sierakowski, E. Gromnica-Ihle, S. Jeka, K. Krueger, J. Szechinski, R. Alten
Journal: Annals of the Rheumatic Diseases (2010)

This 9-month open-label extension of the Circadian Administration of Prednisone in Rheumatoid Arthritis Study (CAPRA 1) investigated the long-term safety and efficacy of prednisone chronotherapy with a novel modified-release (MR) prednisone for up to 12 months.Of 288 patients with rheumatoid arthritis originally randomised to MR or immediate-release (IR) prednisone, 249 continued with prednisone chronotherapy (2-10 mg/day) in the 9-month open-label extension. Duration of morning stiffness of the joints (MS), disease activity scores (DAS28), American College of Rheumatology (ACR20) responses and plasma levels of interleukin 6 (IL-6) were assessed. Safety was analysed from adverse event reports and laboratory investigations.During the 3-month double-blind phase, patients in the MR group achieved a reduction in MS of 33.1% while no change was observed in the IR group. After 6 months of treatment, MS was reduced in the IR/MR group by 54% and in the MR/MR group by 56%. MS reduction after 12 months was 45% (IR/MR group) and 55% (MR/MR group). Plasma levels of IL-6 declined on MR treatment. DAS28 was reduced from 5.8 to 4.8 (MR/MR group) and 4.9 (IR/MR group), respectively. 37% of the 219 patients who completed the 12-month study achieved improvement according to the ACR20 criteria. Adverse events did not differ from the known profile of low-dose prednisone.Prednisone chronotherapy with the MR tablet was safe and well tolerated and provided a sustained improvement which resulted in a better benefit to risk ratio of low-dose glucocorticoid treatment for at least 12 months.
Thrombolytic Therapy in Acute Myocardial Infarction
Authors: M L Simoons
Journal: Annual Review of Medicine (1989)

CD40 is a cell-surface member of the TNF (tumor necrosis factor) receptor superfamily. Upon activation, CD40 can license dendritic cells to promote antitumor T cell activation and re-educate macrophages to destroy tumor stroma. Numerous agonist CD40 ...Read More
Analysis of Aberrant DNA Methylation and Human Papillomavirus DNA in Cervicovaginal Specimens to Detect Invasive Cervical Cancer and Its Precursors
Authors: Andreas Widschwendter, Conny Gattringer, Lennart Ivarsson, Heidi Fiegl, Alois Schneitter, Angela Ramoni, Hannes M. Müller, Annemarie Wiedemair, Susanne Jerabek, Elisabeth Müller-Holzner, Georg Goebel, Christian Marth, Martin Widschwendter
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Cancer of the uterine cervix is an important cause of death in women worldwide. Pap smears as a tool for screening decreased the incidence and mortality of cervical cancer dramatically. This proof of principle study aimed to develop a potential tool for cervical screening using a test that can be applied by patients without visiting a physician and to increase the coverage rate, especially of the high-risk population with low socioeconomic status. Experimental Design: Human papillomavirus (HPV) DNA testing and methylation analysis of DNA obtained from cervicovaginal specimens of 13, 31, and 11 patients with no dysplasia/low-grade squamous intraepithelial lesion (SIL), high-grade SIL, and invasive cervical cancer, respectively, collected on a tampon, was performed using PCR-based methods to detect invasive cervical cancer and study whether these changes are already present in the precursor lesions. Results: High-risk HPV DNA was present in 68 and 82% of patients with high-grade SIL and invasive cervical cancer. DNA methylation of the 11 genes tested increased with severity of the cervical lesion. Unsupervised hierarchical cluster analysis using solely information on DNA methylation of the 11 genes was able to predict the presence of invasive cervical cancers: one of the two clusters formed contained 9 of 11 invasive cervical cancers, as well as two high-grade SILs. Conclusions: HPV DNA and DNA methylation analyzed in cervicovaginal specimens are able to predict invasive cervical cancers. To detect all high-grade SILs when applying this test, genes that become methylated earlier throughout cervical carcinogenesis have to be defined.
Estrogens potentiate the synthesis and release of mediators of allergy from mast cells by increasing intracellular calcium
Authors: T. Midoro-Horiuti, M. Zaitsu, K.C. Lambert, J.J. Grady, D.M. Estes, E.M. Curran, E.G. Brooks, C.S. Watson, R.M. Goldblum
Journal: Journal of Allergy and Clinical Immunology (2005)
The Role of the Renal Ammonia Transporter Rhcg in Metabolic Responses to Dietary Protein
Authors: Lisa Bounoure, Davide Ruffoni, Ralph Müller, Gisela Anna Kuhn, Soline Bourgeois, Olivier Devuyst, Carsten A. Wagner
Journal: Journal of the American Society of Nephrology (2014)

High dietary protein imposes a metabolic acid load requiring excretion and buffering by the kidney. Impaired acid excretion in CKD, with potential metabolic acidosis, may contribute to the progression of CKD. Here, we investigated the renal adaptive response of acid excretory pathways in mice to high-protein diets containing normal or low amounts of acid-producing sulfur amino acids (SAA) and examined how this adaption requires the RhCG ammonia transporter. Diets rich in SAA stimulated expression of enzymes and transporters involved in mediating NH4 (+) reabsorption in the thick ascending limb of the loop of Henle. The SAA-rich diet increased diuresis paralleled by downregulation of aquaporin-2 (AQP2) water channels. The absence of Rhcg transiently reduced NH4 (+) excretion, stimulated the ammoniagenic pathway more strongly, and further enhanced diuresis by exacerbating the downregulation of the Na(+)/K(+)/2Cl(-) cotransporter (NKCC2) and AQP2, with less phosphorylation of AQP2 at serine 256. The high protein acid load affected bone turnover, as indicated by higher Ca(2+) and deoxypyridinoline excretion, phenomena exaggerated in the absence of Rhcg. In animals receiving a high-protein diet with low SAA content, the kidney excreted alkaline urine, with low levels of NH4 (+) and no change in bone metabolism. Thus, the acid load associated with high-protein diets causes a concerted response of various nephron segments to excrete acid, mostly in the form of NH4 (+), that requires Rhcg. Furthermore, bone metabolism is altered by a high-protein acidogenic diet, presumably to buffer the acid load.