tbuckley/cabot-search huggingface dataset:
Swelling-Activated Chloride Current Is Persistently Activated in Ventricular Myocytes From Dogs With Tachycardia-Induced Congestive Heart Failure
Authors: Henry F. Clemo, Bruce S. Stambler, Clive M. Baumgarten
Journal: Circulation Research (1999)

Abstract —The hypothesis that cellular hypertrophy in congestive heart failure (CHF) modulates mechanosensitive (ie, swelling- or stretch-activated) anion channels was tested. Digital video microscopy and amphotericin-perforated-patch voltage clamp were used to measure cell volume and ion currents in ventricular myocytes isolated from normal dogs and dogs with rapid ventricular pacing-induced CHF. In normal myocytes, osmotic swelling in 0.9T to 0.6T solution (T, relative osmolarity; isosmotic solution, 296 mOsmol/L) was required to elicit I Cl,swell , an outwardly rectifying swelling-activated Cl – current that reversed near –33 mV and was inhibited by 1 mmol/L 9-anthracene carboxylic acid (9AC), an anion channel blocker. Block of I Cl,swell by 9AC simultaneously increased the volume of normal cells in hyposmotic solutions by up to 7%, but 9AC had no effect on volume in isosmotic or hyperosmotic solutions. In contrast, I Cl,swell was persistently activated under isosmotic conditions in CHF myocytes, and 9AC increased cell volume by 9%. Osmotic shrinkage in 1.1T to 1.5T solution inhibited both I Cl,swell and 9AC-induced cell swelling in CHF cells, whereas osmotic swelling only slightly increased I Cl,swell . The current density for fully activated 9AC-sensitive I Cl,swell was 40% greater in CHF than normal myocytes. In both groups, 9AC-sensitive current and 9AC-induced cell swelling were proportional with changes in osmolarity and 9AC concentration, and the effects of 9AC on current and volume were blocked by replacing bath Cl – with methanesulfonate. CHF thus altered the set point and magnitude of I Cl,swell and resulted in its persistent activation. We previously observed analogous regulation of mechanosensitive cation channels in the same CHF model. Mechanosensitive anion and cation channels may contribute to the electrophysiological and contractile derangements in CHF and may be novel targets for therapy.
DNA Copy Number Aberrations in Breast Cancer by Array Comparative Genomic Hybridization
Authors: Jian Li, Kai Wang, Shengting Li, Vera Timmermans-Wielenga, Fritz Rank, Carsten Wiuf, Xiuqing Zhang, Huanming Yang, Lars Bolund
Journal: Genomics Proteomics & Bioinformatics (2009)

Abstract Array comparative genomic hybridization (CGH) has been popularly used for analyzing DNA copy number variations in diseases like cancer. In this study, we investigated 82 sporadic samples from 49 breast cancer patients using 1-Mb resolution bacterial artificial chromosome CGH arrays. A number of highly frequent genomic aberrations were discovered, which may act as “drivers” of tumor progression. Meanwhile, the genomic profiles of four “normal” breast tissue samples taken at least 2 cm away from the primary tumor sites were also found to have some genomic aberrations that recurred with high frequency in the primary tumors, which may have important implications for clinical therapy. Additionally, we performed class comparison and class prediction for various clinicopathological parameters, and a list of characteristic genomic aberrations associated with different clinicopathological phenotypes was compiled. Our study provides clues for further investigations of the underlying mechanisms of breast carcinogenesis.
Impact of COPD diagnosis in the face of multi-morbidity: Patients' perspectives
Authors: Sameera Ansari, Hassan Hosseinzadeh, Sarah Dennis, Nicholas Zwar
Journal: European Respiratory Journal (2014)

COPD, a major cause of morbidity and mortality worldwide, often occurs in the presence of co-morbidities which may influence experience and management of the disease. No prior study seemed to have gained perspectives of newly-diagnosed primary care COPD patients, particularly in relation to co-morbidities. This qualitative study aimed to explore the biopsychosocial impact of a new diagnosis of COPD in the context of multi-morbidity and to gain an understanding of how patients react to the diagnosis and incorporate it into their lives.  Participants were identified from a cohort of primary care patients with multi-morbidity recently diagnosed with COPD.  Data was collected via semi-structured interviews from 9 male and 8 female participants aged between 40 and 85. Thematic analysis revealed that most participants had difficulty recognising the importance of COPD and its long-term implications. In many cases, the salience of another chronic condition outweighed COPD. Self-management capacity and utilisation of healthcare services were challenged by limited understanding of the disease.  This study is thought to be a first in providing an insight into how primary care patients feel about being diagnosed with COPD, as well as their prioritisation of the disease in the context of multi-morbidity. It highlights the need for tailored education and personalised management plans incorporating COPD patients9 perspectives in primary care.
MDM2 Promoter SNP309 Is Associated with the Risk of Hepatocellular Carcinoma in Patients with Chronic Hepatitis C
Authors: Narayan Dharel, Naoya Kato, Ryosuke Muroyama, Masaru Moriyama, Run-Xuan Shao, Takao Kawabe, Masao Omata
Journal: Clinical Cancer Research (2006)

Abstract Purpose: A single nucleotide polymorphism (SNP) in the promoter region of MDM2 gene, SNP309, has recently been shown to be associated with accelerated tumor formation in both hereditary and sporadic cancers in humans. However, the association of SNP309 with hepatocellular carcinoma is unknown. We evaluated the association of SNP309 with the risk of hepatocellular carcinoma development among Japanese patients with chronic hepatitis C virus infection. Experimental Design: We genotyped the SNP309 at the MDM2 promoter in 435 Japanese patients with chronic hepatitis C virus infection, including 187 patients with hepatocellular carcinoma and 48 healthy subjects, using a fluorogenic PCR. Presence of SNP was also confirmed by direct sequencing of the MDM2 promoter region. Results: The proportion of G/G genotype of the SNP309 in patients with hepatocellular carcinoma (33%) was significantly higher than that in patients without hepatocellular carcinoma (23%), with an odds ratio (95% confidence interval) of 2.28 (1.30-3.98). A multivariate analysis revealed that MDM2 SNP309 (G/G versus T/T), age &amp;gt;60 years, male gender, presence of cirrhosis, serum α-fetoprotein &amp;gt;20 μg/L, and serum albumin &amp;lt;3.2 g/dL were independently associated with the hepatocellular carcinoma development at odds ratio of 2.27, 2.46, 3.08, 4.15, 4.87, and 6.33, respectively. Conclusions: The MDM2 promoter SNP309 is associated with the presence of hepatocellular carcinoma in Japanese patients with chronic hepatitis C.
Absorption behavior of riociguat (BAY 63-2521): Bioavailability, food effects, and dose-proportionality
Authors: Corina Becker, Reiner Frey, Christiane Hesse, Sigrun Unger, Michael Reber, Wolfgang Mueck
Journal: European Respiratory Journal (2012)

Introduction  Riociguat, an oral soluble guanylate cyclase (sGC) stimulator, is currently investigated in the treatment of PH. Riociguat increases cGMP production through a novel dual mode of action: direct NO-independent sGC stimulation and increasing sGC sensitivity to low NO levels.   Aim  To characterize the biopharmaceutic properties of riociguat including absolute bioavailability (BA), interaction with food, and dose-proportionality.   Methods  Pharmacokinetics (PK) following IV and oral administration of immediate release tablets were characterized in 3 open-label, randomized, crossover studies in healthy male subjects: absolute BA (n=22), food effect at 2.5 mg (n=24), and dose-proportionality over 0.5–2.5 mg (n=24). Safety and tolerability were also assessed.   Results  Absolute BA was 94% (90% CI: 83–107). A high-fat breakfast delayed absorption with little effect on the extent of riociguat absorption (ratio AUC fed /AUC fasted  88% CI: 82–95). PK were dose-proportional over 0.5–2.5 mg (common slope of AUC 1.09 [90%CI: 1.04–1.14]; C max  0.98 [90% CI: 0.93–1.04]). Intra-individual variability was low (G-CV AUC, C max   max  G-CV 65%). Riociguat was well tolerated in all studies. Adverse events were as expected from the mode of action.   Conclusion  Riociguat shows complete oral absorption, and no clinically relevant food effect. At 0.5–2.5 mg, riociguat systemic exposure increased dose-proportionately with moderate-to-high inter-individual and low intra-individual variability. Results support the suitability of the individualized dose titration concept investigated in Phase 3 PAH and CTEPH studies.
Epigenetic CRBP downregulation appears to be an evolutionarily conserved (human and mouse) and oncogene-specific phenomenon in breast cancer.
Authors: Alice Arapshian, Silvina Bertran, Yuvarani S Kuppumbatti, Shigeo Nakajo, Rafael Mira-y-Lopez
Journal: Molecular Cancer (2004)

The cellular retinol binding protein I gene (CRBP) is downregulated in a subset of human breast cancers and in MMTV-Myc induced mouse mammary tumors. Functional studies suggest that CRBP downregulation contributes to breast tumor progression. What is the mechanism underlying CRBP downregulation in cancer? Here we investigated the hypothesis that CRBP is epigenetically silenced through DNA hypermethylation in human and mouse breast cancer. Bisulfite sequencing of CRBP in a panel of 6 human breast cancer cell lines demonstrated that, as a rule, CRBP hypermethylation is closely and inversely related to CRBP expression and identified one exception to this rule. Treatment with 5-azacytidine, a DNA methyltransferase inhibitor, led to CRBP reexpression, supporting the hypothesis that CRBP hypermethylation is a proximal cause of CRBP silencing. In some cells CRBP reexpression was potentiated by co-treatment with retinoic acid, an inducer of CRBP, and trichostatin A, a histone deacetylase inhibitor. Southern blot analysis of a small panel of human breast cancer specimens identified one case characterized by extensive CRBP hypermethylation, in association with undetectable CRBP mRNA and protein. Bisulfite sequencing of CRBP in MMTV-Myc and MMTV-Neu/NT mammary tumor cell lines extended the rule of CRBP hypermethylation and silencing (both seen in MMTV-Myc but not MMTV-Neu/NT cells) from human to mouse breast cancer and suggested that CRBP hypermethylation is an oncogene-specific event. CRBP hypermethylation appears to be an evolutionarily conserved and principal mechanism of CRBP silencing in breast cancer. Based on the analysis of transgenic mouse mammary tumor cells, we hypothesize that CRBP silencing in human breast cancer may be associated with a specific oncogenic signature.
Selective renal angiography in Wegener's granulomatosis
Authors: H. M. Moutsopoulos, P. C. Avgerinos, C. G. Tsampoulas, P. A. Katsiotis
Journal: Annals of the Rheumatic Diseases (1983)

Two patients whose illnesses meet the criteria of Wegener's granulomatosis are presented. Selective renal angiography performed in both revealed multiple arterial aneurysms similar to those classically found in polyarteritis nodosa.
Mutant V599EB-Raf Regulates Growth and Vascular Development of Malignant Melanoma Tumors
Authors: Arati Sharma, Nishit R. Trivedi, Melissa A. Zimmerman, David A. Tuveson, Charles D. Smith, Gavin P. Robertson
Journal: Cancer Research (2005)

Abstract Activating mutations of the B-RAF gene are observed in &amp;gt;60% of human melanomas. Approximately 90% of these mutations occur in the activation segment of the kinase domain as a single-base substitution that converts a valine to glutamic acid at codon 599 (V599E) in exon 15. This mutation causes activation of the kinase as well as downstream effectors of the mitogen-activated protein kinase–signaling cascade, leading to melanoma tumor development by an as yet unknown mechanism. In this study, we have identified the role of V599EB-Raf in melanoma tumor development by characterizing the mechanism by which this mutant protein promotes melanoma tumorigenesis. Small interfering RNA targeted against B-Raf or a Raf kinase inhibitor (BAY 43-9006) was used to reduce expression and/or activity of V599EB-Raf in melanoma tumors. This inhibition led to reduced activity of the mitogen-activated protein kinase–signaling cascade and inhibited tumor development in animals. Targeted reduction of mutant V599EB-Raf expression (activity) in melanoma cells before tumor formation inhibited tumorigenesis by reducing the growth potential of melanoma cells. In contrast, reduction of mutant V599EB-Raf activity in preexisting tumors prevented further vascular development mediated through decreased vascular endothelial growth factor secretion, subsequently increasing apoptosis in tumors. These effects in combination with reduced proliferative capacity halted growth, but did not shrink the size of preexisting melanoma tumors. Thus, these studies identify the mechanistic underpinnings by which mutant V599EB-RAF promotes melanoma development and show the effectiveness of targeting this protein to inhibit melanoma tumor growth.
Increased ERK and JNK activities correlate with disease activity in patients with systemic lupus erythematosus
Authors: Y Molad, M Amit-Vasina, O Bloch, E Yona, M J Rapoport
Journal: Annals of the Rheumatic Diseases (2009)

Background: Aberrant signalling along the p21ras/MAP kinase pathway has been demonstrated in systemic lupus erythematosus (SLE). Objective: To determine whether expression and activity of the MAP kinases ERK and JNK reflect disease activity in patients with SLE. Methods: Blood samples of 42 outpatients with SLE were prospectively collected during four consecutive visits. The control group included 20 healthy subjects. Disease activity was assessed using the SLE Disease Activity Index (SLEDAI). Expression of total ERK and JNK kinases and their active forms (pERK and pJNK) was determined in whole protein lysates of peripheral blood mononuclear cells. Results: The mean levels of the active kinases pERK and pJNK were significantly increased in patients with active disease (SLEDAI 4–20) as compared with patients with inactive disease (SLEDAI 0–3), p = 0.04, as well as with healthy controls, p = 0.03 and p = 0.003 for pERK and pJNK, respectively. The percentage of activated forms of ERK and JNK of the total expression of these MAP kinases was also gradually increased, reaching 50% for pERK and &gt;40% for pJNK in patients with SLE with moderate-to-severe disease (SLEDAI 7–20), p = 0.005, p = 0.005 and p = 0.02, p = 0.05 as compared with controls and inactive patients, respectively. A decrease of more than three SLEDAI points was associated with a significant reduction in the expression of both total and activated forms of ERK and JNK, p = 0.03, p = 0.01, respectively. Conclusions: The results show that ERK and JNK activity reflects disease activity in patients with SLE. These MAP kinases may serve as additional tools for the evaluation of disease activity and management of these patients.
Prognostic Significance of BACH2 Expression in Diffuse Large B-Cell Lymphoma: A Study of the Osaka Lymphoma Study Group
Authors: Emiko Sakane-Ishikawa, Shin-ichi Nakatsuka, Yasuhiko Tomita, Shigeki Fujita, Itsuko Nakamichi, Tetsuya Takakuwa, Haruo Sugiyama, Shirou Fukuhara, Masayuki Hino, Akihisa Kanamaru, Toshihiro Soma, Machiko Tsukaguchi, Kazuhiko Igarashi, Yuzuru Kanakura, Katsuyuki Aozasa
Journal: Journal of Clinical Oncology (2005)

BACH2, a B-cell-specific transcription repressor, is abundantly expressed in lymphocytes of B-cell lineage as well as B-cell lymphoma cell lines. BACH2 possesses an inhibitory effect on proliferation of Raji cell lines derived from Burkitt's lymphoma. In this study, the prognostic significance of BACH2 expression was examined in diffuse large B-cell lymphoma (DLBCL).BACH2 expression was immunohistochemically examined on the paraffin-embedded sections obtained by biopsy from 108 patients (62 males and 46 females; age range, 23 to 85 years) with DLBCL. Staining intensity in the cytoplasm of the tumor cells was categorized as equal to or stronger (level 1) or weaker (level 2) than that in the endothelial cells in the same specimens.Level 1 and 2 expression of BACH2 was found in 32.4% and 67.6% of patients, respectively. Patients with level 1 expression showed significantly better disease-free and overall survival rate than those with level 2 expression (both P < .05). Multivariate analysis revealed BACH2 expression level together with performance status, elevated serum level of lactate dehydrogenase, and treatment response to be independent factors for prognosis of the patients.BACH2 expression level is a useful marker to predict disease-free and overall survival of patients with DLBCL.
Overexpression of the <i>CD155</i> gene in human colorectal carcinoma
Authors: D Masson, A Jarry, B Baury, P Blanchardie, C Laboisse, P Lustenberger, M G Denis
Journal: Gut (2001)

BACKGROUND AND AIMS The Tage4 gene (tumour associated glycoprotein E4) is overexpressed in rat colon tumours and Min mouse intestinal adenomas. The rat Tage4 protein has approximately 40% identity with human CD155, a member of the immunoglobulin superfamily coding for a transmembrane protein capable of serving as an entry receptor for poliovirus, porcine pseudorabies virus, and bovine herpesvirus 1. Analysis of the rat Tage4 gene has revealed structural and functional similarities with the human CD155 gene. We therefore investigated expression of the CD155 gene in human colorectal carcinomas. METHODS Overall CD155 expression was assessed by semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemical analysis using tissue specimens from patients with colorectal adenomas and adenocarcinomas. We also used a qualitative RT-PCR assay to determine relative expression of different splicing variants in each sample. RESULTS mRNA levels of CD155 were increased in six of six colorectal cancer tissues compared with the tumour free colon mucosa. Immunohistochemical analysis revealed an increased level of CD155 protein in 12 of 12 samples. The qualitative RT-PCR assay revealed that relative expression of the different CD155 variant transcripts was similar in the different normal and cancer samples tested, indicating that this overexpression is not associated with a particular mRNA variant generated by alternative splicing of the CD155 gene. CONCLUSION We have shown for the first time that the CD155 gene is overexpressed in colorectal carcinoma and that this overexpression begins at an early stage in tumorigenesis and continues to late stages.
Co-delivery of Doxorubicin and Bmi1 siRNA by Folate Receptor Targeted Liposomes Exhibits Enhanced Anti-Tumor Effects <i>in vitro</i> and <i>in vivo</i>
Authors: Tan Yang, Bin Li, ShiBo Qi, Yong Liu, Yongkang Gai, Peng Ye, Guang Yang, Wendian Zhang, Peng Zhang, Xingxing He, Weijie Li, Zhiping Zhang, Guangya Xiang, Chuanrui Xu
Journal: Theranostics (2014)

Bmi1 gene overexpression is found in various human tumors and has been shown as a potential target for gene treatment.However, siRNA-based treatments targeting Bmi1 gene have been restricted to limited delivery, low bioavailability and hence relatively reduced efficacy.To overcome these barriers, we developed a folate receptor targeted co-delivery system folate-doxorubicin/Bmi1 siRNA liposome (FA-DOX/siRNA-L).The FA-DOX/siRNA-L was prepared through electrostatic interaction between folate doxorubicin liposome (FA-DOX-L) and Bmi1 siRNA.In vitro and in vivo studies showed that FA-DOX/siRNA-L inhibited tumor growth by combinatory role of Bmi1 siRNA and doxorubicin (DOX).Co-delivery of Bmi1 siRNA and DOX by FA-DOX/siRNA-L showed significantly higher efficacy than sole delivery of either DOX or Bmi1 siRNA.Real-time PCR and western blot analysis showed that FA-DOX/siRNA-L silenced the expression of Bmi1 gene.In addition, higher accumulation of the siRNA and DOX in tumor cells indicated that folate ligand displayed tumor targeting effect.These results suggest that Bmi1 is an effective therapeutic target for siRNA based cancer treatment that can be further improved by co-delivery of DOX through targeted liposomes.
Innervation of Human Atrioventricular and Arterial Valves
Authors: Kevin Marron, Magdi H. Yacoub, Julia M. Polak, Mary N. Sheppard, David Fagan, Bruce F. Whitehead, Marc R. de Leval, Robert H. Anderson, John Wharton
Journal: Circulation (1996)

Limited information exists on the innervation of human cardiac valves and the relationship of nerve fibers and terminals with functional elements within leaflets.We examined human AV and arterial valves, obtained postmortem and at surgery, using quantitative immunohistochemical, histochemical, and confocal microscopic techniques. Significant differences in nerve density and distribution were found both between and within cardiac valves. Nerve density within the anterior leaflet of the mitral valve, for example, was twofold greater than that in the posterior leaflet (P < .001). Nerves within the AV valves were situated in the atrial layer and extended over the proximal and medial portions of the leaflets, whereas those in the arterial valves were situated in the ventricular layer. No nerves reached either the free edge or the fibrous core of the leaflets. The arterial valves displayed a similar density of innervation, except for the noncoronary leaflet of the aortic valve in which the innervation was attenuated (P < .01). The innervation of aortic valvar leaflets was age dependent. Nerve terminal arborizations, arising from myelinated nerves and exhibiting variable morphology, were detected in all four cardiac valves and in some tendinous cords. Nerve terminals exhibited either acetylcholinesterase activity or tyrosine hydroxylase and neuropeptide Y immunoreactivity. Varicose nerve fibers occurred in close physical proximity to valvar endothelial, smooth muscle, and fibroblast cells.Human cardiac valves have distinct patterns of innervation that comprise both primary sensory and autonomic components. The presence of distinct nerve terminals and the close association of varicose nerve fibers with endothelial, smooth muscle, and fibroblast cells suggest a possible neural involvement in the control of valvar function.