tbuckley/cabot-search huggingface dataset:
Altered Localization of p120 Catenin During Epithelial to Mesenchymal Transition of Colon Carcinoma Is Prognostic for Aggressive Disease
Authors: David I. Bellovin, Richard C. Bates, Alona Muzikansky, David L. Rimm, Arthur M. Mercurio
Journal: Cancer Research (2005)

Abstract We examined the expression and localization of p120 catenin (p120ctn) as a consequence of the epithelial to mesenchymal transition (EMT) of highly differentiated colon carcinoma cells (LIM1863 cells). This unique line grows in suspension as spheroids and undergoes an EMT within 24 hours following stimulation with transforming growth factor-β and tumor necrosis factor-α. Although p120ctn expression remains stable during the EMT, its localization shifts from cell-cell junctions to the cytoplasm. Interestingly, a marked decrease in RhoA activation coincident with E-cadherin loss occurs during the EMT and correlates with the formation of a p120ctn/RhoA complex. Use of RNA interference showed that p120ctn reduction results in increased RhoA activity and a significant decrease in the motility of post-EMT cells. To determine the relevance of these findings to colorectal cancer progression, we assessed p120ctn expression by immunohistochemistry in 557 primary tumors. Of note, we observed that 53% of tumors presented cytoplasmic staining for p120ctn, and statistical analysis revealed that this localization is predictive of poor patient outcome. Cytoplasmic p120ctn correlated with later-stage tumors, significantly reduced 5- and 10-year survival times and a greater propensity for metastasis to lymph nodes compared with junctional p120ctn. We also confirmed that altered localization of p120ctn corresponded with loss or cytoplasmic localization of E-cadherin. These alterations in E-cadherin are also associated with a significant reduction in patient survival time and an increase in tumor stage and lymph node metastasis. These data provide a compelling argument for the importance of both p120ctn and the EMT itself in the progression of colorectal carcinoma.
Statistics in Clinical Practice: David Coggon. 2nd edition. London: BMJ Books, 2002. 14.95, 120 pp. ISBN 0727916092
Authors: T Seemungal
Journal: Thorax (2003)

This is a very clearly written introduction to statistics, suitable for medical students and doctors who need a quick update in order to understand the current literature. Professor Coggon moves rapidly through types of data (continuous, ordinal or univariate and multivariate) to methods of …
Allelic Variants in Long-QT Disease Genes in Patients With Drug-Associated Torsades de Pointes
Authors: Ping Yang, Hideaki Kanki, Benoit Drolet, Tao Yang, Jian Wei, Prakash C. Viswanathan, Stefan H. Hohnloser, Wataru Shimizu, Peter J. Schwartz, Marshall Stanton, Katherine T. Murray, Kris Norris, Alfred L. George, Dan M. Roden
Journal: Circulation (2002)

Background — DNA variants appearing to predispose to drug-associated “acquired” long-QT syndrome (aLQTS) have been reported in congenital long-QT disease genes. However, the incidence of these genetic risk factors has not been systematically evaluated in a large set of patients with aLQTS. We have previously identified functionally important DNA variants in genes encoding K + channel ancillary subunits in 11% of an aLQTS cohort. Methods and Results — The coding regions of the genes encoding the pore-forming channel proteins KvLQT1, HERG, and SCN5A were screened in (1) the same aLQTS cohort (n=92) and (2) controls, drawn from patients tolerating QT-prolonging drugs (n=67) and cross sections of the Middle Tennessee (n=71) and US populations (n=90). The frequency of three common nonsynonymous coding region polymorphisms was no different between aLQTS and control subjects, as follows: 24% versus 19% for H558R (SCN5A), 3% versus 3% for R34C (SCN5A), and 14% versus 14% for K897T (HERG). Missense mutations (absent in controls) were identified in 5 of 92 patients. KvLQT1 and HERG mutations (one each) reduced K + currents in vitro, consistent with the idea that they augment risk for aLQTS. However, three SCN5A variants did not alter I Na , which argues that they played no role in the aLQTS phenotype. Conclusions — DNA variants in the coding regions of congenital long-QT disease genes predisposing to aLQTS can be identified in ≈10% to 15% of affected subjects, predominantly in genes encoding ancillary subunits.
Pathogenesis of Atherosclerosis in Diabetes Mellitus
Authors: John A Colwell, Maria Lopes-Virella, Perry V Halushka
Journal: Diabetes Care (1981)

Numerous studies have shown that patients with diabetes mellitus have accelerated atherosclerotic vascular disease, and major advances in understanding its pathogenesis have been made. Current suggestions are that endothelial injury may be the initial event in the genesis of atherosclerosis, followed by platelet adhesion and aggregation at the site of injury. In diabetes, evidence of endothelial dysfunction is present. Smooth muscle cell proliferation is an important pathologic finding in atherosclerosis. This process is stimulated by a platelet mitogen, which has been partially characterized. The mitogen has not been studied in diabetes. Lipid accumulation in the area of the atherosclerotic lesion is primarily in the form of intracellular and extracellular esterified cholesterol. In uncontrolled diabetes, elevated plasma low density lipoprotein levels and decreased plasma high density lipoprotein levels favor lipid deposition in large vessels. There is evidence of a thrombotic state in certain diabetic patients. Collectively, these abnormalities of endothelial, platelet, smooth muscle, lipoprotein, and coagulation behavior may be viewed as contributing to the problem of accelerated atherosclerosis in diabetes. A thorough understanding of the pathogenesis of this process aids in designing appropriate preventive therapeutic approaches.
Myelodysplastic syndrome with chromosome 5 abnormalities: a nationwide survey in Japan
Authors: T Tasaka, K Tohyama, M Kishimoto, K Ohyashiki, K Mitani, T Hotta, A Kanamaru, S Okamoto, M Karasawa, A Kimura, M Tomonaga, T Uchiyama, K Ozawa
Journal: Leukemia (2008)
Staging of the mediastinum: value of positron emission tomography imaging in non-small cell lung cancer
Authors: T Bury, P Paulus, A Dowlati, JL Corhay, T Weber, B Ghaye, J Schoffers, R Limet, A Albert, P Rigo, M Radermecker
Journal: European Respiratory Journal (1996)

Recent studies have shown limitations of morphological imaging in staging mediastinal lymph node involvement in lung cancer. In contrast to computed tomography (CT), which depends primarily on anatomical imaging features, positron emission tomography (PET) with 18-fluorodeoxyglucose (FDG) depends mainly on the metabolic characteristics of a tissue for the diagnosis of disease. We have performed a prospective study comparing FDG-PET and CT of the thorax in the presurgical assessment of the mediastinum in 50 patients with newly diagnosed non-small cell lung cancer (NSCLC). CT and PET scans were interpreted separately, and results were compared to pathological staging obtained during thoracotomy. Hilar or mediastinal lymph node involvement was present in 58%. In staging for lymph node involvement, CT had a sensitivity of 72% and specificity of 81%, whereas PET had a sensitivity and specificity of 90% and 86%, respectively. When the PET study was compared to histological results, there were four cases showing more advanced mediastinal involvement with PET and four cases showing less involvement with PET. From our preliminary results, we conclude that positron emission tomography with 18-fluorodeoxyglucose is significantly more accurate than computed tomography in the mediastinal staging of non-small cell lung cancer.
Delay in Diagnosis of Diabetes Is Not the Patient's Fault
Authors: Lisa-Ann Fraser, Jennifer Twombly, Ming Zhu, Qi Long, John J. Hanfelt, K.M. Venkat Narayan, Peter W.F. Wilson, Lawrence S. Phillips
Journal: Diabetes Care (2009)

Previous reports have suggested that onset of diabetes occurs 4–7 years before clinical diagnosis (1). However, it is not known whether delay in diagnosis reflects patient factors, such as lack of medical visits or glucose measurements, or provider factors, such as clinical inertia (2).

We reviewed the charts of 50 patients selected for delayed diagnosis at the Atlanta Veterans Affairs (VA) Medical Center. Date of first diabetes range hyperglycemia (D1) was defined by outpatient fasting plasma glucose (0630–1000 h) ≥126 mg/dl, random glucose (1001–1800 h) ≥200 mg/dl, 2-h post–oral glucose tolerance test (OGTT) glucose ≥200 mg/dl, or A1C ≥6.5%. Date of second diabetes range hyperglycemia (D2) was defined by having any two of these values or any value twice. The date …
Functional Diversity of Signaling Pathways through G Protein–Coupled Receptor Heterodimerization with a Species-Specific Orphan Receptor Subtype
Authors: Tsubasa Sakai, Masato Aoyama, Takehiro Kusakabe, Motoyuki Tsuda, Honoo Satake
Journal: Molecular Biology and Evolution (2009)

Gonadotropin-releasing hormones (GnRHs) play pivotal roles in control of reproduction via a hypothalamic–pituitary–periphery endocrine system and nervous systems of not only vertebrates but also invertebrates. GnRHs trigger several signal transduction cascades via GnRH receptors (GnRHRs), members of the G protein–coupled receptor (GPCR) family. Recently, six GnRHs (tunicate GnRH [tGnRH]-3 to tGnRH-8) and four GnRHRs (Ciona intestinalis [Ci]-GnRHR1 to GnRHR-4), including a species-specific paralog, Ci-GnRHR4 (R4) regarded as an orphan receptor or nonfunctional receptor, were identified in the protochordate, C. intestinalis, which lacks the hypothalamic–pituitary system. Here, we show novel functional modulation of GnRH signaling pathways via GPCR heterodimerization. Immunohistochemical analysis showed colocalization of R1 and R4 in test cells of the ascidian ovary. The native R1–R4 heterodimerization was detected in the Ciona ovary by coimmunoprecipitation analysis. The heterodimerization in HEK293 cells cotransfected with R1 and R4 was also observed by coimmunoprecipitation and fluorescent energy transfer analyses. Binding assay revealed that R4 had no affinity for tGnRHs, and the heterodimerization did not alter the binding affinity of R1 to the ligands. The R1–R4 elicited 10-fold more potent Ca2+ mobilization than R1 exclusively by tGnRH-6, although R1-mediated cyclic AMP production was not affected by any of tGnRHs via the R1–R4 heterodimer. Moreover, the R1–R4 heterodimer potentiated translocation of both Ca2+-dependent protein kinase C-α (PKCα) by tGnRH-6 and Ca2+-independent PKCζ by tGnRH-5 and tGnRH-6, eventually leading to the upregulation of extracellular signal-regulated kinase (ERK) phosphorylation compared with R1 alone. These results provide evidence that the species-specific GnRHR orphan paralog, R4, serves as an endogenous modulator for the fine-tuning of activation of PKC subtype–selective signal transduction via heterodimerization with R1 and that the species-specific GPCR heterodimerization, in concert with multiplication of tGnRHs and Ci-GnRHRs, participates in functional evolution of neuropeptidergic GnRH signaling pathways highly conserved throughout the animal kingdom.
50-Year Trends in Smoking-Related Mortality in the United States
Authors: Michael J. Thun, Brian D. Carter, Diane Feskanich, Neal D. Freedman, Ross Prentice, Alan D. Lopez, Patricia Hartge, Susan M. Gapstur
Journal: New England Journal of Medicine (2013)

The disease risks from cigarette smoking increased in the United States over most of the 20th century, first among male smokers and later among female smokers. Whether these risks have continued to increase during the past 20 years is unclear.
Efficacy and tolerability of eplerenone and losartan in hypertensive black and white patients
Authors: John M Flack, Suzanne Oparil, J.Howard Pratt, Barbara Roniker, Susan Garthwaite, Jay H Kleiman, Yonghong Yang, Scott L Krause, Diane Workman, Elijah Saunders
Journal: Journal of the American College of Cardiology (2003)
The murine MHC class I genes, H-2Dq and H-2Lq, are strikingly homologous to each other, H-2Ld, and two genes reported to encode tumor-specific antigens.
Authors: D R Lee, R J Rubocki, W R Lie, T H Hansen
Journal: The Journal of Experimental Medicine (1988)

Two phenomena appear to distinguish the D region class I genes from those in the K region in the murine MHC: (a) haplotype disparity in the number of expressed D region class I molecules has been observed; and (b) clines of closely related D region class I molecules among and within mice of different H-2 haplotypes can be defined. Both of these observations have been based on serological and peptide mapping analyses of these molecules. Recent reports using molecular biological approaches have corroborated these findings. Since the mouse strain B10.AKM expresses multiple D region class I antigens, all of which are closely related to the prototypic Ld molecule, we investigated the Dq region of B10.AKM using molecular approaches. Three D region class I genes were isolated from genomic B10.AKM bacteriophage and cosmid libraries. Based on alignment of those genes with the BALB/c D region class I genes by analogous restriction endonuclease sites and by hybridization of one of those genes with a D4d gene-derived oligonucleotide probe, we have designated these genes as Dq, Lq, and D4q. As determined by DNA-mediated gene transfer to mouse L cells followed by serological analyses, the Dq and Lq genes encode previously characterized Dq region class I antigens. The nucleic acid sequence comparisons of the Dq and Lq genes demonstrated a higher level of homology with the Ld and Db genes than with other D region class I genes. In addition, CTL stimulated with a Dq, Lq, or Ld gene transfectant showed strong crossreactions with the other transfectants as targets, suggesting that the products of these genes are also functionally related. Thus, these studies suggest that the L molecule represents a prototypic structure shared by several D region gene products, and furthermore, the duplication of an Ld-like progenitor gene resulted in two Dq region class I genes, Dq and Lq. Unexpectedly, the sequences determined for the Dq and Lq genes are nearly identical to the sequences of two genes, A166 and A149, respectively, which were reported to encode the tumor-specific antigens; these novel class I genes were isolated from an H-2k fibrosarcoma, 1591. This raises the distinct possibility that these purported tumor-specific class I genes were introduced into this tumor by contamination.
Genome-wide association study of lung function decline in adults with and without asthma
Authors: Medea Imboden, Emmanuelle Bouzigon, Ivan Curjuric, Adaikalavan Ramasamy, Ashish Kumar, Dana B. Hancock, Jemma B. Wilk, Judith M. Vonk, Gian A. Thun, Valerie Siroux, Rachel Nadif, Florent Monier, Juan R. Gonzalez, Matthias Wjst, Joachim Heinrich, Laura R. Loehr, Nora Franceschini, Kari E. North, Janine Altmüller, Gerard H. Koppelman, Stefano Guerra, Florian Kronenberg, Mark Lathrop, Miriam F. Moffatt, George T. O’Connor, David P. Strachan, Dirkje S. Postma, Stephanie J. London, Christian Schindler, Manolis Kogevinas, Francine Kauffmann, Debbie L. Jarvis, Florence Demenais, Nicole M. Probst-Hensch
Journal: Journal of Allergy and Clinical Immunology (2012)
Epidermal growth factor receptor signalling contributes to house dust mite-induced epithelial barrier dysfunction
Authors: I.H. Heijink, A. van Oosterhout, A. Kapus
Journal: European Respiratory Journal (2010)

Impaired airway epithelial barrier function has emerged as a key factor in the pathogenesis of allergic asthma. We aimed to discern the involvement of the epidermal growth factor receptor (EGFR) in allergen-induced epithelial barrier impairment, as we previously observed that house dust mite (HDM) signals through EGFR. We investigated the junctional integrity of human bronchial epithelial cells using electric cell-substrate impedance sensing and immunofluorescent staining. HDM induced a rapid, transient fall in epithelial resistance, concomitant with delocalisation of E-cadherin and zona occludens (ZO)-1, and proteolytic cleavage of the latter. EGFR inhibition by AG1478 reduced the HDM-triggered decrease in epithelial resistance and improved restoration of epithelial junctions. Similarly, AG1478 increased epithelial barrier recovery upon electroporation-induced injury, although it delayed the migration phase of the wound healing response. HDM-promoted redistribution of E-cadherin was mediated via EGFR-dependent activation of protease-activated receptor (PAR)-2, while the concomitant ZO-1 degradation was PAR-2/EGFR-independent. Importantly, the fibrogenic cytokine transforming growth factor (TGF)-β prolonged HDM-induced EGFR phosphorylation and inhibited ligand-induced EGFR internalisation/degradation, which resulted in sustained E-cadherin and ZO-1 redistribution. Thus, allergen-induced, PAR-2/EGFR-mediated signalling decreases epithelial resistance and promotes junction disassembly. The TGF-β-enhanced EGFR signalling may be an important contributor to barrier dysfunction and increased epithelial vulnerability in response to HDM.
Effects of Angiotensin-Converting Enzyme Inhibition on the Development of the Atrial Fibrillation Substrate in Dogs With Ventricular Tachypacing–Induced Congestive Heart Failure
Authors: Danshi Li, Kaori Shinagawa, Li Pang, Tack Ki Leung, Sophie Cardin, Zhiguo Wang, Stanley Nattel
Journal: Circulation (2001)

Background Atrial structural remodeling creates a substrate for atrial fibrillation (AF), but the underlying signal transduction mechanisms are unknown. This study assessed the effects of ACE inhibition on arrhythmogenic atrial remodeling and associated mitogen-activated protein kinase (MAPK) changes in a dog model of congestive heart failure (CHF). Methods and Results Dogs were subjected to various durations of ventricular tachypacing (VTP, 220 to 240 bpm) in the presence or absence of oral enalapril 2 mg · kg −1 · d −1 . VTP for 5 weeks induced CHF, local atrial conduction slowing, and interstitial fibrosis and prolonged atrial burst pacing–induced AF. Atrial angiotensin II concentrations and MAPK expression were increased by tachypacing, with substantial changes in phosphorylated forms of c-Jun N-terminal kinase (JNK), extracellular signal–regulated kinase (ERK), and p38-kinase. Enalapril significantly reduced tachypacing-induced changes in atrial angiotensin II concentrations and ERK expression. Enalapril also attenuated the effects of CHF on atrial conduction (conduction heterogeneity index reduced from 3.1±0.4 to 1.9±0.2 ms/mm, P &lt;0.05), atrial fibrosis (from 11.9±1.1% to 7.5±0.4%, P &lt;0.01), and mean AF duration (from 651±164 to 218±75 seconds, P &lt;0.05). Vasodilator therapy of a separate group of VTP dogs with hydralazine and isosorbide mononitrate did not alter CHF-induced fibrosis or AF promotion. Conclusions CHF-induced increases in angiotensin II content and MAPK activation contribute to arrhythmogenic atrial structural remodeling. ACE inhibition interferes with signal transduction leading to the AF substrate in CHF and may represent a useful new component to AF therapy.
Defective Epidermal Innate Immunity and Resultant Superficial Dermatophytosis in Adult T-cell Leukemia/Lymphoma
Authors: Yu Sawada, Motonobu Nakamura, Rieko Kabashima-Kubo, Takatoshi Shimauchi, Miwa Kobayashi, Yoshiki Tokura
Journal: Clinical Cancer Research (2012)

Abstract Purpose: Superficial dermatophytosis is quite commonly seen in patients with adult T-cell leukemia/lymphoma (ATLL), as approximately 50% of the patients develop cutaneous mycotic infections. Because superficially infected fungi in the stratum corneum of the epidermis cannot directly contact with T cells infiltrating in the upper dermis, some perturbation of epidermal innate immunity has been postulated. Interleukin (IL)-17–producing helper T cells (Th17) can induce the keratinocyte production of antimicrobial peptides such as human β defensin (HBD)-2 and LL-37, which play an essential role in cutaneous innate immunity. Experimental Design: We investigated the frequency of circulating Th17 cells, serum levels of cytokines, and epidermal expression of HBD-1, 2, 3, and LL-37 in ATLL patients with or without superficial dermatophytosis. Results: The frequency of peripheral Th17 cells and the serum level of IL-17 was significantly decreased in ATLL patients, whereas the serum IL-10 and TGF-β1 levels were increased as compared with healthy controls. Furthermore, ATLL patients with dermatophytosis had higher IL-10 and TGF-β1 levels and lower IL-17 levels than did those without dermatophytosis. Immunohistochemical study revealed that the epidermal expression of both HBD-2 and LL-37 were significantly lower in ATLL patients with dermatophytosis than in non-ATLL patients with dermatophytosis. Conclusions: Taken together, these results suggest that the keratinocyte production of antimicrobial peptides promoted by Th17 cells is reduced in ATLL patients, leading to the perturbed innate immunity and the frequent occurrence of superficial dermatophytosis. Clin Cancer Res; 18(14); 3772–9. ©2012 AACR.
The bronchoprotective effect of inhaled salmeterol in preschool children: a dose-ranging study
Authors: RA Primhak, CM Smith, SC Yong, R Wach, M Kurian, R Brown, J Efthimiou
Journal: European Respiratory Journal (1999)

The optimal dose of salmeterol in infants and preschool children is not known. The aim of this study was to assess the bronchoprotective effect of different doses of salmeterol using methacholine-induced wheeze in children aged &lt;4 yrs. Children &lt;4 yrs old with a history of recurrent wheeze underwent two methacholine challenges within 7 days. One hour before each challenge they were pretreated in double-blind fashion using a metered-dose inhaler and Babyhaler spacer. Placebo was given before one challenge, and either 25, 50 or 100 microg of salmeterol before the other. Both the dose and treatment order were random. The provocative concentration of methacholine causing wheeze (PCwheeze) was measured on each occasion. Studies were terminated when wheeze occurred or arterial oxygen saturation (Sa,o2) fell below 91%. Of the 42 children enrolled, 33 completed the study. Two subjects refused the challenge test, two failed to return and five developed upper respiratory tract infections or wheeze between the two tests. The mean (range) age of the population was 27 (8-46) months. Ratios of PCwheeze between treatment and placebo challenges were calculated for each dosage group. The treatment/placebo ratios (95% confidence intervals) were 1.2 (0.6-2.4) for 25 microg, 2.5 (1.4-4.6) for 50 microg (p&lt;0.01), and 4.0 (2.1-7.4) (p&lt;0.001) for 100 microg doses. In recurrently wheezy children aged &lt;4 yrs a single dose of salmeterol between 25 and 100 microg has a dose-dependent effect on methacholine-induced wheeze, and this is significantly different from placebo at 50 and 100 microg. This study suggests that the Babyhaler effectively delivers salmeterol to children &lt;4 yrs of age and that doses between 50-100 microg are efficacious.