tbuckley/cabot-search huggingface dataset:
Hepatitis C, Acute Humoral Rejection, and Renal Allograft Survival
Authors: John P. Forman, Nina Tolkoff-Rubin, Manuel Pascual, Julie Lin
Journal: Journal of the American Society of Nephrology (2004)

The effect of recipient hepatitis C virus (HCV) infection on renal allograft loss and acute rejection in kidney transplantation remains controversial. We studied 354 renal allograft recipients transplanted during 1996 to 2001 who had HCV antibodies (Ab) measured before transplantation. The primary outcome was death-censored allograft loss and the secondary outcome was acute humoral rejection (AHR). Compared with HCV Ab-negative patients, those with positive HCV Ab had longer time on dialysis before transplantation, higher percentage of panel-reactive antibodies (PRA), were more likely to receive a cadaveric transplant, and were more likely to develop delayed graft function (DGF). In univariate analyses, predictors of renal allograft loss included HCV, cadaveric graft, PRA >20%, HLA mismatch ≥5, retransplantation, DGF, induction therapy, and AHR. When adjusted for PRA >20%, HLA mismatch ≥5, and multiple transplant status, HCV was not a statistically significant predictor of allograft loss. HCV was also associated with AHR but lost significance when adjusted for PRA >20%. HCV Ab-positive patients were more likely to have longer duration of dialysis before transplantation prior to kidney transplants, higher PRA, and to receive cadaveric transplants. These characteristics likely resulted in more DGF and AHR after transplantation. After adjusting for these confounding factors, the association between HCV Ab positivity and renal allograft loss was notably attenuated and no longer statistically significant.
Benefit from adjuvant tamoxifen therapy in primary breast cancer patients according oestrogen receptor, progesterone receptor, EGF receptor and HER2 status
Authors: M. Dowsett, J. Houghton, C. Iden, J. Salter, J. Farndon, R. A'Hern, R. Sainsbury, M. Baum
Journal: Annals of Oncology (2006)
Endocrine functions of bone in mineral metabolism regulation
Authors: L. Darryl Quarles
Journal: Journal of Clinical Investigation (2008)

Given the dramatic increase in skeletal size during growth, the need to preserve skeletal mass during adulthood, and the large capacity of bone to store calcium and phosphate, juxtaposed with the essential role of phosphate in energy metabolism and the adverse effects of hyperphosphatemia, it is not surprising that a complex systems biology has evolved that permits cross-talk between bone and other organs to adjust phosphate balance and bone mineralization in response to changing physiological requirements. This review examines the newly discovered signaling pathways involved in the endocrine functions of bone, such as those mediated by the phosphaturic and 1,25(OH)2D-regulating hormone FGF23, and the broader systemic effects associated with abnormalities of calcium and phosphate homeostasis.
Increased Association of ZO-1 With Connexin43 During Remodeling of Cardiac Gap Junctions
Authors: Ralph J. Barker, Robert L. Price, Robert G. Gourdie
Journal: Circulation Research (2002)

The intercellular geometry of connexin43 (Cx43) gap junctional coupling is key to coordinated spread of electrical activation through the ventricle of the mammalian heart. A progressive redistribution of electrical and mechanical junctions into intercalated discs occurs during postnatal development. Breakdown of disc-localized pattern in the adult heart, to recapitulate immature distributions, is thought to be key to the genesis of conduction disturbance and arrhythmia. Recently, ZO-1 (a PDZ-MAGUK protein), has been suggested to have a role in generating coupling geometries between myocytes. We therefore investigated the codistribution of ZO-1 with Cx43 and N-cadherin in the adult rat ventricle using quantitative immunoconfocal and immunoelectron microscopy. These analyses indicated that, whereas ZO-1 and Cx43 codistribute within discs, only low to moderate point-by-point colocalization of Cx43 and ZO-1 is found within these domains compared with the relatively high level of colocalization between N-cadherin and ZO-1. By contrast, levels of association between Cx43 and ZO-1 increased rapidly and significantly ( P &lt;0.001) after partial or complete enzymatic dissociation of myocytes from intact ventricle—a treatment known to induce gap junction endocytosis. Coimmunoprecipitation using Cx43- and ZO-1-specific antibodies confirmed that significantly ( P &lt;0.03) increased ZO-1 is precipitated relative to Cx43 in freshly dissociated myocytes as compared with intact ventricle. On immunoblots, decreases in Cx43 relative mobility, consistent with increased phosphorylation, were observed following myocyte dissociation. The increased ZO-1-Cx43 association that occurs after remodeling of myocyte intercellular contacts indicates the possibility of unanticipated roles for ZO-1 in gap junction turnover during cardiac development and disease processes.
Hypertension exacerbates the effect of hypercholesterolemia on the myocardial microvasculature
Authors: M RODRIGUEZPORCEL, A LERMAN, J HERRMANN, R SCHWARTZ, T SAWAMURA, M CONDORELLI, C NAPOLI, L LERMAN
Journal: Cardiovascular Research (2003)

Objective: Hypercholesterolemia (HC) and hypertension (HT) are both major risk factors for the development and progression of atherosclerotic heart disease, and their co-existence has been associated with an increased incidence of cardiac events in clinical studies. HC and HT are individually associated with abnormal myocardial vascular function, but whether HT exacerbates the HC-induced myocardial vascular dysfunction remains unclear. Methods: We studied in pigs the effect of renovascular HT superimposed on diet-induced HC (HC+HT) on myocardial perfusion and microvascular permeability in vivo (using electron-beam computed tomography) in response to cardiac challenge (i.v. adenosine and dobutamine). The involvement of systemic and myocardial tissue oxidative stress in vitro was assessed by oxidizability of LDL, levels of endogenous antioxidants, and tissue activities of radical–scavenger systems. Results: While in normal animals myocardial perfusion increased in response to i.v. adenosine (+36±13%, P<0.05), in HC and HT alone the increase was blunted. In HC+HT myocardial perfusion response was further attenuated and significantly lower than normal, and myocardial vascular resistance failed to decrease (+7.6±8.8 vs. −21.0±5.8%, P = 0.02 versus normal). HC+HT also showed blunted response to dobutamine, and augmented increases in microvascular permeability in vivo. These functional abnormalities were associated with increased systemic and myocardial tissue oxidative stress compared to HC or HT alone, and a synergistic decrease in endogenous antioxidant defenses in myocardial tissue. Furthermore, chronic antioxidant vitamin supplementation in combined HC and HT improved myocardial vascular responses. Conclusion: HT amplifies the HC-induced myocardial microvascular dysfunction in vivo and increased oxidative stress in vitro. These alterations may potentially play a role in the increased incidence of cardiac events observed when HC and HT co-exist.
Properdin- and nephritic factor-dependent C3 convertases: requirement of native C3 for enzyme formation and the function of bound C3b as properdin receptor.
Authors: R D Schreiber, R G Medicus, O Gïtze, H J Müller-Eberhard
Journal: The Journal of Experimental Medicine (1975)

Two complex enzymes were assembled that both converted C3 to C3b, one consisting of activated properdin (P), native C3, proactivator (PA) and proactivator convertase (PAase), and the other of nephritic factor (NF) and the same three cofactors. By maintaining a critical concentration of PAase, the P-C3 convertase and the NF-C3 convertase were shown to function efficiently without formation of the C3b-feedback enzyme. The former two enzymes are distinct from the C3b-dependent C3 convertase in that they utilize native C3 instead of C3b and PA in an apparently uncleaved form. The P- and NF-C3 convertase express maximal activity within approximately 10 min at 37 degrees C and decay with a half-life of 35 min at 37 degrees C, which is in contradistinction to the reported lability of the C3b-feedback enzyme. P- and NF-C3 convertases are inhibited by their product C3b, which may constitute a heretofore unknown control of the alternative pathway. A direct physical interaction of P with native C3 and C3b was demonstrated by agglutination of C3b-bearing erythrocytes and by agglutination inhibition. Bound C3b thus constitutes the only known receptor of P and may fulfill an important localizing function for P and the P-C3 convertase in vivo. Although P and NF form functionally similar enzymes, they act independently of each other and are apparently immunochemically unrelated proteins.
Phosphorylation and Activation of Cell Division Cycle Associated 8 by Aurora Kinase B Plays a Significant Role in Human Lung Carcinogenesis
Authors: Satoshi Hayama, Yataro Daigo, Takumi Yamabuki, Daizaburo Hirata, Tatsuya Kato, Masaki Miyamoto, Tomoo Ito, Eiju Tsuchiya, Satoshi Kondo, Yusuke Nakamura
Journal: Cancer Research (2007)

Abstract Through genome-wide gene expression analysis of lung carcinomas, we detected in the great majority of lung cancer samples cotransactivation of cell division cycle associated 8 (CDCA8) and aurora kinase B (AURKB), which were considered to be components of the vertebrate chromosomal passenger complex. Immunohistochemical analysis of lung cancer tissue microarrays showed that overexpression of CDCA8 and AURKB was significantly associated with poor prognosis of lung cancer patients. AURKB directly phosphorylated CDCA8 at Ser154, Ser219, Ser275, and Thr278 and seemed to stabilize CDCA8 protein in cancer cells. Suppression of CDCA8 expression with small interfering RNA against CDCA8 significantly suppressed the growth of lung cancer cells. In addition, functional inhibition of interaction between CDCA8 and AURKB by a cell-permeable peptide corresponding to 20-amino acid sequence of a part of CDCA8 (11R-CDCA8261–280), which included two phosphorylation sites by AURKB, significantly reduced phosphorylation of CDCA8 and resulted in growth suppression of lung cancer cells. Our data imply that selective suppression of the CDCA8-AURKB pathway could be a promising therapeutic strategy for treatment of lung cancer patients. [Cancer Res 2007;67(9):4113–22]
Ascidian Larva Reveals Ancient Origin of Vertebrate-Skeletal-Muscle Troponin I Characteristics in Chordate Locomotory Muscle
Authors: C. L. Cleto
Journal: Molecular Biology and Evolution (2003)

Ascidians are protochordates related to vertebrate ancestors. The ascidian larval tail, with its notochord, dorsal nerve cord, and flanking rows of sarcomeric muscle cells, exhibits the basic chordate body plan. Molecular characterization of ascidian larval tail muscle may provide insight into molecular aspects of vertebrate skeletal muscle evolution. We report studies of the Ci-TnI gene of the ascidian Ciona intestinalis, which encodes the muscle contractile regulatory protein troponin I (TnI). Previous studies of a distantly related ascidian, Halocynthia roretzi, showed that different TnI genes were expressed in larval and adult muscles, the larval TnI isoforms having an unusual C-terminal truncation not seen in any vertebrate TnI. Here we show that, in contrast with Halocynthia, Ciona does not have a specialized larval TnI; the same TnI gene that is expressed in the heart and body-wall muscle of the sessile adult is also expressed in embryonic/larval tail muscle cells. Moreover the TnI isoform produced in embryonic/larval muscle is identical to that produced in adult body-wall muscle, i.e., a 182-residue protein with the characteristic chain length and overall structure of vertebrate skeletal muscle TnI isoforms. Phylogenetic analyses indicate that the unique features of Halocynthia larval TnI likely represent derived features, and hence that the vertebrate-skeletal-muscle -like TnI of Ciona is a closer reflection of the ancestral ascidian larval TnI. Our results indicate that characteristics of vertebrate skeletal muscle TnI emerged early in the evolution of chordate locomotory muscle, before the ascidian/vertebrate divergence. These features could be related to a basal chordate locomotory innovation—e.g., swimming by oscillation of an internal notochord skeleton—or they may be of even greater antiquity within the deuterostomes.
Regulation of Phosphoglucose Isomerase/Autocrine Motility Factor Activities by the Poly(ADP-Ribose) Polymerase Family-14
Authors: Takashi Yanagawa, Tatsuyoshi Funasaka, Soichi Tsutsumi, Huankai Hu, Hideomi Watanabe, Avraham Raz
Journal: Cancer Research (2007)

Abstract Phosphoglucose isomerase (PGI; EC 5.3.1.9) is a ubiquitous cytosolic enzyme essential for glycolysis and gluconeogenesis. PGI is a multifunctional dimeric protein that extracellularly acts as a cytokine [autocrine motility factor (AMF)] eliciting mitogenic, motogenic, and differentiation functions through binding to its cell surface receptor gp78/AMF receptor (AMFR). AMFR contains a seven-transmembrane domain with RING-H2 and leucine zipper motifs showing ubiquitin protein ligase (E3) activity and is exposed on the endoplasmic reticulum surface. Augmented expressions of both PGI/AMF and AMFR have been implicated in tumor progression and metastasis, and an intracellular binding partner of PGI/AMF is expected to regulate in part its diverse biological functions. Thus, we screened a cDNA library using a yeast two-hybrid system to search for interacting protein(s) and report on the finding of poly(ADP-ribose) polymerase-14 (PARP-14) to be a binding partner with PGI/AMF. PARP-14–PGI/AMF interaction was confirmed by coimmunoprecipitation and immunolocalization. We also report that PGI/AMF degradation is mainly regulated by the ubiquitin-lysosome system and RNA interference experiments revealed that PARP-14 inhibits PGI/AMF ubiquitination, thus contributing to its stabilization and secretion. This newly characterized PARP-14 protein should assist in understanding the regulation of PGI/AMF intracellular function(s) and may provide a new therapeutic target for inhibition of PGI/AMF inducing tumor cell migration and invasion during metastasis. [Cancer Res 2007;67(18):8682–9]
Pericardial involvement in systemic sclerosis
Authors: R J Byers, D A S Marshall, A J Freemont
Journal: Annals of the Rheumatic Diseases (1997)

<h3>OBJECTIVE</h3> To determine the frequency and histological characteristics of pericardial involvement in systemic sclerosis. <h3>METHOD</h3> Necropsy sections of pericardium from 44 patients with systemic sclerosis were studied, together with sections from 19 age/sex matched controls. Sections were stained with haematoxylin and eosin, acid toluidine blue, and elastic van Gieson. Mast cells were counted in 10 random high power fields and the degree of fibrosis was quantified using a Chalkley count. <h3>RESULTS</h3> Chronic pericarditis was seen in 31 (77.5%) of the systemic sclerosis cases, but in only one of the controls. The characteristic changes of uraemic pericarditis were not seen. The degree of fibrosis was greater in those with systemic sclerosis, though numbers of mast cells, thought to be important in fibrogenesis, were similar in both groups. Myocardial fibrosis was seen in 15 (37.5%) of systemic sclerosis cases but in none of the controls. <h3>CONCLUSION</h3> The incidence of pericarditis and myocardial fibrosis is much greater than in controls. The results indicate that pericarditis is a primary disease (rather than secondary to uraemia).
Salivary Cortisol in Panic Attacks
Authors: B Bandelow, D Wedekind, J Pauls, A Broocks, G Hajak, E Rüther
Journal: American Journal of Psychiatry (2000)

OBJECTIVE: Documentation of hypothalamic-pituitary-adrenal (HPA) axis disturbance in panic disorder has been inconsistent. Increased cortisol levels have been associated with altered HPA function due to stress. The authors examined salivary cortisol levels in spontaneously occurring, unprovoked panic attacks. METHOD: Patients with panic disorder (N=25) collected saliva samples when panic attacks occurred. Levels of cortisol in the saliva samples were determined and were compared with levels in comparison samples of saliva obtained 24 hours after the panic attack occurred. RESULTS: During spontaneous panic attacks there was a subtle but significant elevation of cortisol levels, compared with levels obtained 24 hours later. No significant correlations were found between the cortisol elevations during panic attacks and the severity of the attack as measured by using the Acute Panic Inventory or the severity of illness as measured by using the Panic and Agoraphobia Scale. CONCLUSIONS: Saliva sampling may be a useful method for investigating neuroendocrine parameters during spontaneously occurring panic attacks.
Lactate production and exercise-induced metabolic acidosis: guilty or not guilty?
Authors: A. van Meerhaeghe, B. Velkeniers
Journal: European Respiratory Journal (2005)

To the Editors: 

In the excellent and very interesting chapter concerning clinical exercise testing published in the European Respiratory Monograph on lung function testing, Roca and Rabinovitch 1 wrote the following. “Increased lactate production is responsible for the fall in muscle pH, which in turn may play a role in determining exercise intolerance in these patients (COPD patients). Premature lactic acidosis during exercise in COPD patients has been associated with reduced oxidative enzyme concentrations …
Lipoprotein Accumulation in Macrophages via Toll-Like Receptor-4–Dependent Fluid Phase Uptake
Authors: Soo-Ho Choi, Richard Harkewicz, Jee Hyun Lee, Agnès Boullier, Felicidad Almazan, Andrew C. Li, Joseph L. Witztum, Yun Soo Bae, Yury I. Miller
Journal: Circulation Research (2009)

Toll-like receptor (TLR)4 recognizes microbial pathogens, such as lipopolysaccharide, and mediates lipopolysaccharide-induced proinflammatory cytokine secretion, as well as microbial uptake by macrophages. In addition to exogenous pathogens, TLR4 recognizes modified self, such as minimally oxidized low-density lipoprotein (mmLDL). Here we report that mmLDL and its active components, cholesteryl ester hydroperoxides, induce TLR4-dependent fluid phase uptake typical of macropinocytosis. We show that mmLDL induced recruitment of spleen tyrosine kinase (Syk) to a TLR4 signaling complex, TLR4 phosphorylation, activation of a Vav1-Ras-Raf-MEK-ERK1/2 signaling cascade, phosphorylation of paxillin, and activation of Rac, Cdc42, and Rho. These mmLDL-induced and TLR4- and Syk-dependent signaling events and cytoskeletal rearrangements lead to enhanced uptake of small molecules, dextran, and, most importantly, both native and oxidized LDL, resulting in intracellular lipid accumulation. An intravenous injection of fluorescently labeled mmLDL in wild-type mice resulted in its rapid accumulation in circulating monocytes, which was significantly attenuated in TLR4-deficient mice. These data describe a novel mechanism leading to enhanced lipoprotein uptake in macrophages that would contribute to foam cell formation and atherosclerosis. These data also suggest that cholesteryl ester hydroperoxides are an endogenous ligand for TLR4. Because TLR4 is highly expressed on the surface of circulating monocytes in patients with chronic inflammatory conditions, and cholesteryl ester hydroperoxides are present in plasma, lipid uptake by monocytes in circulation may contribute to the pathological roles of monocytes in chronic inflammatory diseases.
<i>MGMT</i> Promoter Methylation Is Prognostic but Not Predictive for Outcome to Adjuvant PCV Chemotherapy in Anaplastic Oligodendroglial Tumors: A Report From EORTC Brain Tumor Group Study 26951
Authors: Martin J. van den Bent, Hendrikus J. Dubbink, Marc Sanson, Cathleen R. van der Lee-Haarloo, Monika Hegi, Judith W.M. Jeuken, Ahmed Ibdaih, Alba A. Brandes, Martin J.B. Taphoorn, Marc Frenay, Denis Lacombe, Thierry Gorlia, Winand N.M. Dinjens, Johan M. Kros
Journal: Journal of Clinical Oncology (2009)

Purpose O6-methylguanine-methyltransferase (MGMT) promoter methylation has been shown to predict survival of patients with glioblastomas if temozolomide is added to radiotherapy (RT). It is unknown if MGMT promoter methylation is also predictive to outcome to RT followed by adjuvant procarbazine, lomustine, and vincristine (PCV) chemotherapy in patients with anaplastic oligodendroglial tumors (AOT). Patients and Methods In the European Organisation for the Research and Treatment of Cancer study 26951, 368 patients with AOT were randomly assigned to either RT alone or to RT followed by adjuvant PCV. From 165 patients of this study, formalin-fixed, paraffin-embedded tumor tissue was available for MGMT promoter methylation analysis. This was investigated with methylation specific multiplex ligation-dependent probe amplification. Results In 152 cases, an MGMT result was obtained, in 121 (80%) cases MGMT promoter methylation was observed. Methylation strongly correlated with combined loss of chromosome 1p and 19q loss (P = .00043). In multivariate analysis, MGMT promoter methylation, 1p/19q codeletion, tumor necrosis, and extent of resection were independent prognostic factors. The prognostic significance of MGMT promoter methylation was equally strong in the RT arm and the RT/PCV arm for both progression-free survival and overall survival. In tumors diagnosed at central pathology review as glioblastoma, no prognostic effect of MGMT promoter methylation was observed. Conclusion In this study, on patients with AOT MGMT promoter methylation was of prognostic significance and did not have predictive significance for outcome to adjuvant PCV chemotherapy. The biologic effect of MGMT promoter methylation or pathogenetic features associated with MGMT promoter methylation may be different for AOT compared with glioblastoma.
Work stress and risk of cancer: meta-analysis of 5700 incident cancer events in 116 000 European men and women
Authors: K. Heikkila, S. T. Nyberg, T. Theorell, E. I. Fransson, L. Alfredsson, J. B. Bjorner, S. Bonenfant, M. Borritz, K. Bouillon, H. Burr, N. Dragano, G. A. Geuskens, M. Goldberg, M. Hamer, W. E. Hooftman, I. L. Houtman, M. Joensuu, A. Knutsson, M. Koskenvuo, A. Koskinen, A. Kouvonen, I. E. H. Madsen, L. L. Magnusson Hanson, M. G. Marmot, M. L. Nielsen, M. Nordin, T. Oksanen, J. Pentti, P. Salo, R. Rugulies, A. Steptoe, S. Suominen, J. Vahtera, M. Virtanen, A. Vaananen, P. Westerholm, H. Westerlund, M. Zins, J. E. Ferrie, A. Singh-Manoux, G. D. Batty, M. Kivimaki
Journal: BMJ (2013)

An empirical assessment of drug release from amorphous systems of celecoxib (CEL), poly(vinyl pyrrolidone) (PVP), and meglumine (MEG) was performed and compared with that for its crystalline form. CEL–PVP (4:1 w/w) binary and CEL–PVP–MEG (7:2:1 w/w) ternary amorphous systems provided higher drug dissolution. Mathematical modeling of drug release data was found to best fit the Hixson-Crowell release model. The biphasic drug release during a 6-h duration exhibited higher release kinetics in the first phase due to the presence of drug in amorphous form. The release kinetics subdued in the latter phase due to ongoing devitrification process in amorphous systems. A comprehensive understanding of drug release from amorphous systems will accentuate the rationalized design of amorphous drug delivery systems.