tbuckley/cabot-search huggingface dataset:
Promoter Hypomethylation of EpCAM-Regulated <i>Bone Morphogenetic Protein</i> Gene Family in Recurrent Endometrial Cancer
Authors: Ya-Ting Hsu, Fei Gu, Yi-Wen Huang, Joseph Liu, Jianhua Ruan, Rui-Lan Huang, Chiou-Miin Wang, Chun-Liang Chen, Rohit R. Jadhav, Hung-Cheng Lai, David G. Mutch, Paul J. Goodfellow, Ian M. Thompson, Nameer B. Kirma, Tim Hui-Ming Huang
Journal: Clinical Cancer Research (2013)

Epigenetic regulation by promoter methylation plays a key role in tumorigenesis. Our goal was to investigate whether altered DNA methylation signatures associated with oncogenic signaling delineate biomarkers predictive of endometrial cancer recurrence.Methyl-CpG-capture sequencing was used for global screening of aberrant DNA methylation in our endometrial cancer cohort, followed by validation in an independent The Cancer Genome Atlas (TCGA) cohort. Bioinformatics as well as functional analyses in vitro, using RNA interference (RNAi) knockdown, were performed to examine regulatory mechanisms of candidate gene expression and contribution to aggressive phenotype, such as epithelial-mesenchymal transition (EMT).We identified 2,302 hypermethylated loci in endometrial tumors compared with control samples. Bone morphogenetic protein (BMP) family genes, including BMP1, 2, 3, 4, and 7, were among the frequently hypermethylated loci. Interestingly, BMP2, 3, 4, and 7 were less methylated in primary tumors with subsequent recurrence and in patients with shorter disease-free interval compared with nonrecurrent tumors, which was validated and associated with poor survival in the TCGA cohort (BMP4, P = 0.009; BMP7, P = 0.007). Stimulation of endometrial cancer cells with epidermal growth factor (EGF) induced EMT and transcriptional activation of these genes, which was mediated by the epithelial cell adhesion molecule (EpCAM). EGF signaling was implicated in maintaining the promoters of candidate BMP genes in an active chromatin configuration and thus subject to transcriptional activation.Hypomethylation signatures of candidate BMP genes associated with EpCAM-mediated expression present putative biomarkers predictive of poor survival in endometrial cancer.
Angiopep-conjugated poly(ethylene glycol)-co-poly(ε-caprolactone) nanoparticles as dual-targeting drug delivery system for brain glioma
Authors: Hongliang Xin, Xinyi Jiang, Jijin Gu, Xianyi Sha, Liangcen Chen, Kitki Law, Yanzuo Chen, Xiao Wang, Ye Jiang, Xiaoling Fang
Journal: Biomaterials (2011)
Expert opinion on the cough hypersensitivity syndrome in respiratory medicine
Authors: Alyn H. Morice, Eva Millqvist, Maria G. Belvisi, Kristina Bieksiene, Surinder S. Birring, Kian Fan Chung, Roberto W. Dal Negro, Peter Dicpinigaitis, Ahmad Kantar, Lorcan P. McGarvey, Adalberto Pacheco, Raimundas Sakalauskas, Jaclyn A. Smith
Journal: European Respiratory Journal (2014)

In 2011, a European Respiratory Society Task Force embarked on a process to determine the position and clinical relevance of the cough hypersensitivity syndrome, a disorder characterised by troublesome coughing often triggered by low levels of thermal, mechanical or chemical exposure, in the management of patients with chronic cough. A 21-component questionnaire was developed by an iterative process supported by a literature review. 44 key opinion leaders in respiratory medicine were selected and interviewed as to their opinions. There was a high degree of unanimity in the responses obtained, with all opinion leaders supporting the concept of cough hypersensitivity as a clinically useful paradigm. The classic stratification of cough into asthmatic, rhinitic and reflux-related phenotypes was supported. Significant disparity of opinion was seen in the response to two questions concerning the therapy of chronic cough. First, the role of acid suppression in reflux cough was questioned. Secondly, the opinion leaders were split as to whether a trial of oral steroids was indicated to establish a diagnosis of eosinophilic cough. The cough hypersensitivity syndrome was clearly endorsed by the opinion leaders as a valid and useful concept. They considered that support of patients with chronic cough was inadequate and the Task Force recommends that further work is urgently required in this neglected area.
Phase II Study of Weekly Docetaxel and Trastuzumab for Patients With HER-2–Overexpressing Metastatic Breast Cancer
Authors: Francisco J. Esteva, Vicente Valero, Daniel Booser, Laura T. Guerra, James L. Murray, Lajos Pusztai, Massimo Cristofanilli, Banu Arun, Bita Esmaeli, Herbert A. Fritsche, Nour Sneige, Terry L. Smith, Gabriel N. Hortobagyi
Journal: Journal of Clinical Oncology (2002)

PURPOSE: To evaluate the safety and efficacy of weekly docetaxel plus trastuzumab in women with HER-2–overexpressing metastatic breast cancer. Efficacy was correlated with serum HER-2 extracellular domain (ECD) levels. PATIENTS AND METHODS: Thirty women with metastatic breast cancer were treated with weekly docetaxel and trastuzumab as first- or second-line therapy. Both docetaxel 35 mg/m 2 /wk and trastuzumab 2 mg/kg/wk were delivered in 4-week cycles consisting of three weekly treatments followed by 1 week of rest. A loading dose of trastuzumab 4 mg/kg was administered 1 day before the start of the first cycle. RESULTS: The median delivered dose-intensity of docetaxel was 24 mg/m 2 /wk (range, 18 to 27 mg/m 2 /wk). The intent-to-treat overall response rate (ORR) was 63% (95% confidence interval [CI], 44% to 80%). The ORR in patients whose tumors were HER-2–positive by fluorescence in situ hybridization was 67% (16 of 24 patients; 95% CI, 45% to 84%). In patients with elevated serum HER-2 ECD at baseline, the ORR was 76% (95% CI, 53% to 92%), compared with 33% (95% CI, 7% to 70%) in patients with low HER-2 ECD levels (P = .04). Variations in HER-2 ECD concentrations during treatment correlated with response to treatment. Median time to progression was 9 months. Acute toxicity, including myelosuppression, was mild. Fatigue, fluid retention, and excessive tearing became more common with repetitive dosing. CONCLUSION: Weekly docetaxel and trastuzumab is an active combination for treating patients with HER-2–overexpressing metastatic breast cancer. Serum HER-2 ECD testing may be a promising method for monitoring patients on trastuzumab-based therapy.
Vasoconstriction to Endogenous Endothelin-1 Is Increased in the Peripheral Circulation of Patients With Essential Hypertension
Authors: Stefano Taddei, Agostino Virdis, Lorenzo Ghiadoni, Isabella Sudano, Massimo Notari, Antonio Salvetti
Journal: Circulation (1999)

In humans, endothelin (ET)-1 could be implicated in the pathophysiology of several cardiovascular diseases, including essential hypertension. We therefore evaluated the role of ET-1 in control of vascular tone in essential hypertension.We used strain-gauge venous plethysmography to test changes in forearm blood flow induced by intrabrachial infusion of TAK-044 (10, 30, and 100 microgram. 100 mL(-1). min(-1)), an ET(A)/ET(B) receptor antagonist, or sodium nitroprusside (1 and 2 microgram. 100 mL(-1). min(-1)), a vasodilator that acts on smooth muscle cells, in hypertensive patients and healthy controls (n=10 in each group). The NO pathway was also evaluated by infusion of N(G)-monomethyl-L-arginine, (L-NMMA; 10, 30, and 100 microgram. 100 mL(-1). min(-1)), an NO synthase inhibitor, and norepinephrine (3, 9, and 30 ng. 100 mL(-1). min(-1)) as control. Immunoreactive plasma ET-1 was measured by radioimmunoassay. In hypertensive patients, TAK-044 caused a vasodilation that was significantly (P<0.01) increased compared with normotensive subjects. Moreover, vasoconstriction to L-NMMA was significantly (P<0.01) decreased in hypertensive patients compared with controls. In contrast, the vascular responses to sodium nitroprusside and norepinephrine, as well as levels of immunoreactive plasma ET-1, were similar in hypertensive patients and controls. In the study population, vasodilation to TAK-044 and vasoconstriction to L-NMMA showed an inverse correlation (r=-0.56, P<0.05).These results indicate that TAK-044 caused a greater degree of vasodilation in the forearm vessels of essential hypertensive patients compared with normotensive subjects, an alteration associated with decreased tonic NO release.
Duct destructive chronic pancreatitis. A new insight into the pathology of idiopathic non-alcoholic chronic pancreatitis
Authors: WLADIMIR V BOGOMOLETZ
Journal: Gut (1997)

Duct destructive chronic pancreatitis.A new insight into the pathology of idiopathic non-alcoholic chronic pancreatitisIn a leading article published in Gut in 1990, Sarles et al made the opening comment that "there have been few eVorts to classify diseases of the pancreas by their specific pathological features and causes... ". 1 Indeed, the classification of pancreatitis is fraught with a major diYculty, that of developing a comprehensive system which embodies aetiology, pathogenesis, clinical features, and pathological findings.The 1984 Marseille-Rome classification included three types: acute pancreatitis, chronic pancreatitis and obstructive pancreatitis. 2The 1992 Atlanta classification dealt almost exclusively with acute pancreatitis. 3
Bacterial communication and group behavior
Authors: E. Peter Greenberg
Journal: Journal of Clinical Investigation (2003)

The existence of species-specific and interspecies bacterial cell-cell communication and group organization was only recently accepted. Researchers are now realizing that the ability of these microbial teams to communicate and form structures, known as biofilms, at key times during the establishment of infection significantly increases their ability to evade both host defenses and antibiotics. This Perspective series discusses the known signaling mechanisms, the roles they play in both chronic Gram-positive and Gram-negative infections, and promising therapeutic avenues of investigation.
The self-organizing consciousness
Authors: Pierre Perruchet, Annie Vinter
Journal: Behavioral and Brain Sciences (2002)

We propose that the isomorphism generally observed between the representations composing our momentary phenomenal experience and the structure of the world is the end-product of a progressive organization that emerges thanks to elementary associative processes that take our conscious representations themselves as the stuff on which they operate, a thesis that we summarize in the concept of Self-Organizing Consciousness (SOC).
Lipid Peroxidation and Platelet Activation in Murine Atherosclerosis
Authors: Tillmann Cyrus, Lina X. Tang, Joshua Rokach, Garret A. FitzGerald, Domenico Praticò
Journal: Circulation (2001)

Background Lipid peroxidation and platelet activation are thought to be important contributors to the pathogenesis of atherosclerosis. The relevance of their interaction in vivo, however, is unknown. Methods and Results LDL receptor–deficient (LDLR −/− ) mice on a high-fat diet developed extensive atherosclerosis and had increased urinary levels of 8,12- iso -isoprostane (iP) F 2α -VI and 2,3-dinor-thromboxane (Tx) B 2 , markers of in vivo lipid peroxidation and platelet activation, respectively. Vitamin E supplementation suppressed 8,12- iso -iPF 2α -VI biosynthesis and reduced atherosclerosis (65%) without having a significant effect on lipid levels or TxB 2 biosynthesis. Addition of the platelet inhibitor indomethacin to vitamin E simultaneously suppressed 8,12- iso -iPF 2α -VI and TxB 2 , significantly reduced soluble intercellular adhesion molecule-1 and monocyte chemoattractant protein-1, and remarkably, further reduced atherosclerosis (80%). Conclusions These results indicate that in vivo lipid peroxidation and platelet activation coexist in murine atherosclerosis and that lipid peroxidation does not contribute to platelet activation and reflects the oxidant component of the inflammatory response. Our findings suggest that oxidant stress and platelet activation represent 2 distinct therapeutic targets in atherogenesis. We propose that a combination of antioxidants and platelet inhibitors might be rationally evaluated in the prevention of progression of human atherosclerosis.
The AKT–mTOR axis regulates de novo differentiation of CD4+Foxp3+ cells
Authors: Sokol Haxhinasto, Diane Mathis, Christophe Benoist
Journal: The Journal of Experimental Medicine (2008)

CD4+Foxp3+ regulatory T (T reg) cells play an essential role in maintaining immunological tolerance via their suppressive function on conventional CD4+ T (Tconv) cells. Repertoire studies suggest that distinct T cell receptor signaling pathways lead to T reg differentiation, but the signals that regulate T reg specification are largely unknown. We identify AKT as a strong repressor of entry into the T reg phenotype in vitro and in vivo. A constitutively active allele of AKT substantially diminished TGF-β–induced Foxp3 expression in a kinase-dependent manner and via a rapamycin-sensitive pathway, implicating the AKT–mammalian target of rapamycin axis. The observed impairment in Foxp3 induction was part of a broad dampening of the typical T reg transcriptional signature. Expression of active AKT at a stage before Foxp3 turn on during normal T reg differentiation in the thymus selectively impaired differentiation of CD4+Foxp3+ cells without any alteration in the positive selection of Tconv. Activated AKT, in contrast, did not affect established Foxp3 expression in T reg cells. These results place AKT at a nexus of signaling pathways whose proper activation has a strong and broad impact on the onset of T reg specification.
The Calcineurin Homologous Protein-1 Increases Na+/H+-Exchanger 3 Trafficking via Ezrin Phosphorylation
Authors: Francesca Di Sole, Victor Babich, Orson W. Moe
Journal: Journal of the American Society of Nephrology (2009)

The Na(+)/H(+)-exchanger 3 (NHE3) is essential for regulation of Na(+) transport in the renal and intestinal epithelium. Although changes in cell surface abundance control NHE3 function, the molecular signals that regulate NHE3 surface expression are not well defined. We found that overexpression of the calcineurin homologous protein-1 (CHP1) in opossum kidney cells increased NHE3 transport activity, surface protein abundance, and ezrin phosphorylation. CHP1 knockdown by small interfering RNA had the opposite effects. Overexpression of wild-type ezrin increased both NHE3 transport activity and surface protein abundance, confirming that NHE3 is downstream of ezrin. Expression of a pseudophosphorylated ezrin enhanced these effects, whereas expression of an ezrin variant that could not be phosphorylated prevented the downstream effects on NHE3. Furthermore, CHP1 knockdown reversed the activation of NHE3 by wild-type ezrin but not by the pseudophosphorylated ezrin. Taken together, these results demonstrate that CHP1 increases NHE3 abundance and constitutive function in a manner dependent on ezrin phosphorylation.
Compound Heterozygosity for Mutations (W156X and R225W) in <i>SCN5A</i> Associated With Severe Cardiac Conduction Disturbances and Degenerative Changes in the Conduction System
Authors: Connie R. Bezzina, Martin B. Rook, W.Antoinette Groenewegen, Lucas J. Herfst, Allard C. van der Wal, Jan Lam, Habo J. Jongsma, Arthur A.M. Wilde, Marcel M.A.M. Mannens
Journal: Circulation Research (2003)

Cardiac conduction defects associate with mutations in SCN5A , the gene encoding the cardiac Na + channel. In the present study, we characterized a family in which the proband was born in severe distress with irregular wide complex tachycardia. His older sister died at 1 year of age from severe conduction disease with similarly widened QRS-complexes. Mutational analysis of SCN5A in the proband demonstrated compound heterozygosity for a nonsense mutation (W156X), inherited from the father, and a missense mutation (R225W), inherited from the mother. Genotyping on DNA extracted from tissue from the deceased sibling revealed the same SCN5A genotype. Injection of cRNA encoding the W156X mutation in Xenopus oocytes did not produce any current. The R225W substitution neutralizes the third Arg residue within the voltage-sensing segment of domain I. Expression studies showed that this mutation leads to a severe reduction in I Na and is also associated with gating changes. Histological examination of the heart from the deceased sibling revealed changes consistent with a dilated type of cardiomyopathy and severe degenerative abnormalities of the specialized conduction system. The occurrence of compound heterozygosity for these two mutations implies that the proband carries solely severely dysfunctional cardiac Na + channels. This explains his severe phenotype and that of his deceased sister who had been a carrier of the same genotype. The morphological changes within the heart of the deceased sibling may have occurred secondary to the Na + channel abnormality and contributed to the severity of the disorder in this individual.
Relationship of Asymmetric Dimethylarginine With Penile Doppler Ultrasound Parameters in Men with Vasculogenic Erectile Dysfunction
Authors: Nikolaos Ioakeimidis, Charalambos Vlachopoulos, Konstantinos Rokkas, Athanasios Aggelis, Dimitrios Terentes-Printzios, Alexios Samentzas, Nikolaos Alexopoulos, Christodoulos Stefanadis
Journal: European Urology (2011)
Interleukin 6 is not a crucial regulator in an animal model of tumour necrosis factor-mediated bilateral sacroiliitis
Authors: S. Hayer, B. Niederreiter, I. Nagelreiter, J. Smolen, K. Redlich
Journal: Annals of the Rheumatic Diseases (2010)

<h3>Objective</h3> To evaluate the role of interleukin 6 (IL-6) in the pathogenesis of bilateral erosive sacroiliitis in human tumour necrosis factor transgenic (hTNFtg) mice, an animal model of ankylosing spondylitis (AS). <h3>Methods</h3> Histological sections of the sacroiliac joints from hTNFtg and <i>IL-6</i><sup>−/−</sup>hTNFtg mice were evaluated, and wild type and <i>IL-6</i><sup>−/−</sup>mice served as controls. mRNA levels of inflammation and tissue degradation related genes isolated from sacroiliac joints were also evaluated by quantitative PCR. <h3>Results</h3> Severe, erosive bilateral sacroiliitis in 14-week-old hTNFtg animals was accompanied by an upregulation of mRNAs related to tissue inflammation such as matrix metalloproteinase 3 (MMP3), MMP9 and MMP13 or osteoclast activation such as cathepsin K and tartrate-resistant acid phosphatase. In addition, IL-6 was increased in the sera and in the sacroiliac joints of hTNFtg animals. However, high expression of these marker genes in sacroiliac joints from <i>IL-6</i><sup>−/−</sup>hTNFtg mice was also found. Moreover, absence of IL-6 in these animals did not alter bilateral, erosive sacroiliitis when compared to hTNFtg littermates. <h3>Conclusions</h3> IL-6 is not a crucial regulator in an animal model of TNF-mediated bilateral, erosive sacroiliitis. This finding questions the potential of IL-6 blockade as a new treatment in patients with AS.
Plasma Homocysteine Concentration, Statin Therapy, and the Risk of First Acute Coronary Events
Authors: Paul M. Ridker, Jessie Shih, Thomas J. Cook, Michael Clearfield, John R. Downs, Aruna D. Pradhan, Stephan E. Weis, Antonio M. Gotto
Journal: Circulation (2002)

Elevated homocysteine levels are associated with increased coronary risk, and it has been suggested that homocysteine screening may provide a method to identify high-risk patients for aggressive primary prevention.Homocysteine was measured at baseline and after 1 year among 5569 participants in the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS), a randomized trial of lovastatin in the primary prevention of acute coronary events. The effects of homocysteine, LDL cholesterol, and lovastatin on risk were assessed over 5.2 years of trial follow-up. Median baseline homocysteine levels were significantly higher among study participants who subsequently had acute coronary events compared with those who did not (12.1 versus 10.9 micro;mol/L, P<0.001). The relative risks of future events from lowest (referent) to highest quartile of homocysteine were 1.0, 1.6, 1.6, and 2.2 (P<0.001). These effects were similar among those allocated to lovastatin and those allocated to placebo and were modestly attenuated after adjustment for other traditional risk factors. As predicted, the subgroup of participants with elevated LDL cholesterol and elevated homocysteine levels were at high risk and benefited greatly from statin therapy (relative risk, 0.46; 95% CI, 0.29 to 0.75; number needed to treat=26). However, in contrast to findings in this trial for C-reactive protein, homocysteine evaluation did not help to define low LDL subgroups with different responses to lovastatin therapy.Although homocysteine predicted future coronary events in AFCAPS/TexCAPS, we found little evidence that homocysteine evaluation provided an improved method to target statin therapy among those with low-to-normal LDL cholesterol levels.
A natural autoantibody is encoded by germline heavy and lambda light chain variable region genes without somatic mutation.
Authors: K A Siminovitch, V Misener, P C Kwong, Q L Song, P P Chen
Journal: Journal of Clinical Investigation (1989)

While nonmutated germline variable region (V) genes have been found to encode heavy or light chains of various human autoantibodies, the use of germline V genes by both chains of a given autoantibody has not been documented. Recently, we reported that the heavy chain V gene (designated Humha346) of the Kim4.6 anti-DNA antibody is identical to a germline VH gene, 1.9III. To investigate whether this autoantibody was entirely germline encoded, we searched for the germline counterpart to the Kim4.6 V lambda segment (designated Humla146) and isolated a V lambda I gene designated Humlv117, which was identical to Humla146. Together with the sequence identity of the Kim4.6/Humha346 and 1.9III VH genes, the current data provide the first direct proof that an autoantibody can be encoded entirely by germline V genes without any somatic change. In addition, Humlv117 is the first V lambda I germline gene that has been isolated, and is highly homologous to the V lambda genes expressed in two lymphomas. Thus, this V lambda I gene should provide a useful tool for investigating the expression of the human V lambda gene repertoire, particularly with regard to autoimmune and/or lymphoproliferative diseases.
A developmental model for the evolution of language and intelligence in early hominids
Authors: Sue Taylor Parker, Kathleen Rita Gibson
Journal: Behavioral and Brain Sciences (1979)

Abstract This paper presents a model for the nature and adaptive significance of intelligence and language in early hominids based on comparative developmental, ecological, and neurological data. We propose that the common ancestor of the great apes and man displayed rudimentary forms of late sensorimotor and early preoperational intelligence similar to that of one- to four-year-old children. These abilities arose as adaptations for extractive foraging with tools, which requires a long postweaning apprenticeship. They were elaborated in the first hominids with the shift to primary dependence on this feeding strategy. These first hominids evolved a protolanguage, similar to that of two-year-old human children, with which they could describe the nature and location of food and request help in obtaining it. The descendents of the first hominids displayed intuitive intelligence, similar to that of four- to seven-year-old children, which arose as an adaptation for complex hunting involving aimed-missile throwing, stone-tool manufacture, animal butchery, food division, and shelter construction. The comparative developmental and paleontological data are consistent with the hypothesis that the stages of development of intelligence and language and their neural substrates in our species recapitulate the stages of their evolution.