tbuckley/cabot-search huggingface dataset:
Smad Signaling Is Required to Maintain Epigenetic Silencing during Breast Cancer Progression
Authors: Panagiotis Papageorgis, Arthur W. Lambert, Sait Ozturk, Fangming Gao, Hongjie Pan, Upender Manne, Yuriy O. Alekseyev, Arunthathi Thiagalingam, Hamid M. Abdolmaleky, Marc Lenburg, Sam Thiagalingam
Journal: Cancer Research (2010)

Breast cancer progression is associated with aberrant DNA methylation and expression of genes that control the epithelial-mesenchymal transition (EMT), a critical step in malignant conversion. Although the genes affected have been studied, there is little understanding of how aberrant activation of the DNA methylation machinery itself occurs. Using a breast cancer cell-based model system, we found that cells that underwent EMT exhibited overactive transforming growth factor beta (TGFbeta) signaling and loss of expression of the CDH1, CGN, CLDN4, and KLK10 genes as a result of hypermethylation of their corresponding promoter regions. Based on these observations, we hypothesized that activated TGFbeta-Smad signaling provides an "epigenetic memory" to maintain silencing of critical genes. In support of this hypothesis, disrupting Smad signaling in mesenchymal breast cancer cells resulted in DNA demethylation and reexpression of the genes identified. This epigenetic reversal was accompanied by an acquisition of epithelial morphology and a suppression of invasive properties. Notably, disrupting TGFbeta signaling decreased the DNA binding activity of DNA methyltransferase DNMT1, suggesting that failure to maintain methylation of newly synthesized DNA was the likely cause of DNA demethylation. Together, our findings reveal a hyperactive TGFbeta-TGFbetaR-Smad2 signaling axis needed to maintain epigenetic silencing of critical EMT genes and breast cancer progression.
Textbook of adult emergency medicine, 2nd edition
Authors: P McCrory
Journal: British Journal of Sports Medicine (2005)

Edited by P Cameron et al. Published by Churchill Livingstone, 2004, pp 952, £45.99, softcover. ISBN 0443072892

Interested in emergency medicine? Then this is the book for you. This book summarises the literature in this field concisely and provides both an Australian and UK perspective on how these various issues may be dealt with. Apart from trauma, the book details a systematic approach …
Rhinitis: a complication to asthma
Authors: J. W. Hansen, S. F. Thomsen, H. Nolte, V. Backer
Journal: Allergy (2010)

Asthma and rhinitis often co-occur, and this potentially increases the disease severity and impacts negatively on the quality of life. We studied disease severity, airway responsiveness, atopy, quality of life and treatment in subjects with both asthma and rhinitis compared to patients with asthma or rhinitis alone.We examined 878 patients: 182 with asthma, 362 with rhinitis and 334 with both asthma and rhinitis. All had a clinical interview concerning severity of symptoms, treatment, and quality of life, a skin prick test, a lung function test and a bronchial provocation with methacholine.Patients with both asthma and rhinitis had less severe asthma based on the frequency of respiratory symptoms compared to patients with asthma alone (55%vs 66%P = 0.01). On the contrary, they were more airway responsive (P < 0.05) and had more perennial allergy (P < 0.001). Asthmatics had poor perception of the general health, independent of rhinitis (P < 0.001). No differences were found in asthma-specific quality of life, whereas rhinitis-specific quality of life was worse in those with both asthma and rhinitis compared to those with rhinitis alone (P < 0.01). Subjects with both diseases were undertreated in 85% of the cases.We encourage that these observations be used in the evaluation and treatment of patients with asthma and rhinitis and that they contribute to the understanding of asthma and rhinitis as a uniform airways disease.
Brisk walking and serum lipid and lipoprotein variables in previously sedentary women--effect of 12 weeks of regular brisk walking followed by 12 weeks of detraining.
Authors: A E Hardman, A Hudson
Journal: British Journal of Sports Medicine (1994)

The purpose of this study was to examine the effectiveness of brisk walking as a means of improving endurance fitness and influencing serum lipid and lipoprotein variables in previously sedentary women. Walkers (n = 10, mean (s.e.m.) age 47.3(2.0) years) followed a programme of brisk walking (mean(s.e.m.) speed 1.76(0.03) m s-1) for 12 weeks, after which the training stimulus was withdrawn. Controls (n = 10, mean(s.e.m.) age 41.6(1.2) years) maintained their habitual sedentary lifestyle throughout. Endurance fitness was determined using laboratory measures of responses to treadmill walking. Serum lipid and lipoprotein variables were determined in venous blood (12-h fasted). Body fatness was assessed by anthropometry and dietary practice using the 7-day weighed food intake technique. Measurements were repeated after 12 and 24 weeks. Brisk walking resulted in a decrease in heart rate and blood lactate concentration during exercise, while detraining was accompanied by a reversal of these changes. Changes in body mass and the ratio of circumferences at the waist and hip did not differ between groups but the sum of four skinfolds decreased with brisk walking and increased with detraining. High density lipoprotein (HDL) and HDL2 cholesterol increased with walking and decreased with detraining but no between group changes (analysis of variance, P < 0.05) were found in other lipid and lipoprotein variables. These findings suggest that regular brisk walking can improve endurance fitness and increase HDL cholesterol concentration in sedentary women.
Antitumor Immunity in the Shope Papilloma-Carcinoma Complex of Rabbits, I. Papilloma Regression Induced by Homologous and Autologous Tissue Vaccines&lt;xref ref-type="fn" rid="fn1"&gt;2&lt;/xref&gt;
Authors: C. A. Evans, L. R. Gorman, Y. Ito, R. S. Weiser
Journal: JNCI Journal of the National Cancer Institute (1962)

A substantial increase in frequency of regression of Shope papillomas occurred in rabbits inoculated with a vaccine made of freshly removed homologous tumor tissue. Spontaneous regression rates in unvaccinated littermate controls were approximately 25 percent; the regression rate in groups of vaccinated animals was usually between 50 and 90 percent. In most experiments Bordetella pertussis cells were included in the vaccine, but vaccines without B. pertussis were equally effective. An autologous tissue vaccine was as effective as homologous tissue vaccine, though that made from homologous tissue stored in glycerine had little activity. The available evidence favors the concept that the regression of papillomas in the system studied is a consequence of a specific immunological reaction against the tumor.
A randomized phase III study comparing adjuvant 5-fluorouracil/folinic acid with FOLFIRI in patients following complete resection of liver metastases from colorectal cancer
Authors: M. Ychou, W. Hohenberger, S. Thezenas, M. Navarro, J. Maurel, C. Bokemeyer, E. Shacham-Shmueli, F. Rivera, C. Kwok-Keung Choi, A. Santoro
Journal: Annals of Oncology (2009)
Heterograft aortic valve replacement: initial follow-up studies
Authors: M. F. O'Brien, J. K. Clarebrough, I. G. McDonald, G. S. Hale, H. S. Bray, J. F. Cade
Journal: Thorax (1967)

Twenty-three patients have had calf or pig heterograft aortic valve replacements. Eight of these patients have required Starr-Edwards mitral ball-valve prostheses for associated mitral valve disease. There have been two hospital deaths and one late death. The 20 surviving patients have shown symptomatic improvement. Clinical evidence of incompetence is present in one patient. Pre-operative and post-operative ciné-aortograms show valve mobility with a wide central orifice. Heterografts have the advantages of homografts in being free from thromboembolism and from the need for anticoagulants; they exhibit some resistance to infection as compared with prosthetic valves. We think that heterografts, because of their wider range of size, can offer a better haemodynamic result with little clinical aortic incompetence. The long-term fate of aortic valve heterografts is not known with certainty, although the durability of homografts is better known. There is a possibility of late degeneration or rupture. If the valve continues to function normally, then it would be justifiable to recommend operation at an earlier stage in the progression of the patient9s disease. At present, despite encouraging early results, we think the use of heterografts should be limited, like that of other prostheses, to those patients who show severe cardiac disability.
THE EFFECTS OF PHARMACOLOGIC AGENTS ON THE PULMO-NARY CIRCULATION IN THE DOG. STUDIES ON EPINEPHRINE, NOR-EPINEPHRINE, 5-HYDROXYTRYPTAMINE, ACETYLCHOLINE, HISTAMINE AND AMINOPHYLLINE 1
Authors: Hans G. Borst, Erik Berglund, Maurice McGregor, Philip E. Waithe
Journal: Journal of Clinical Investigation (1957)
The effects of calcium antagonists on renal hemodynamics, urinary protein excretion, and glomerular morphology in diabetic states.
Authors: G L Bakris
Journal: Journal of the American Society of Nephrology (1991)

Numerous animal studies have been performed in the early stages of diabetic renal disease documenting beneficial effects of angiotensin converting enzyme inhibitors. Over the past 5 yr, a number of animal and human studies show similar results with certain calcium antagonists. However, the data with calcium antagonists are not as consistent as that with angiotensin converting enzyme inhibitors. This article will review all of the pertinent clinical and laboratory studies involving these classes of agents in the course of diabetic nephropathy. Emphasis is placed on explaining divergent results between animal and human studies with regard to renal hemodynamic, histologic, and antiproteinic effects.
Alterations to Bone Mineral Composition as an Early Indication of Osteomyelitis in the Diabetic Foot
Authors: Karen A. Esmonde-White, Francis W.L. Esmonde-White, Crystal M. Holmes, Michael D. Morris, Blake J. Roessler
Journal: Diabetes Care (2013)

OBJECTIVE Osteomyelitis in the diabetic foot is a major risk factor for amputation, but there is a limited understanding of early-stage infection, impeding limb-preserving diagnoses. We hypothesized that bone composition measurements provide insight into the early pathophysiology of diabetic osteomyelitis. RESEARCH DESIGN AND METHODS Compositional analysis by Raman spectroscopy was performed on bone specimens from patients with a clinical diagnosis of osteomyelitis in the foot requiring surgical intervention as either a biopsy (n = 6) or an amputation (n = 11). RESULTS An unexpected result was the discovery of pathological calcium phosphate minerals in addition to normal bone mineral. Dicalcium phosphate dihydrate, also called brushite, and uncarbonated apatite were found to be exclusively associated with infected bone. CONCLUSIONS Compositional measurements provided a unique insight into the pathophysiology of osteomyelitis in diabetic foot ulcers. At-patient identification of pathological minerals by Raman spectroscopy may serve as an early-stage diagnostic approach.
Molecular Phenotypes of Acute Kidney Injury in Kidney Transplants
Authors: Konrad S. Famulski, Declan G. de Freitas, Chatchai Kreepala, Jessica Chang, Joana Sellares, Banu Sis, Gunilla Einecke, Michael Mengel, Jeff Reeve, Philip F. Halloran
Journal: Journal of the American Society of Nephrology (2012)

Little is known regarding the molecular phenotype of kidneys with AKI because biopsies are performed infrequently. However, all kidney transplants experience acute injury, making early kidney transplants an excellent model of acute injury, provided the absence of rejection, because donor kidneys should not have CKD, post-transplant biopsies occur relatively frequently, and follow-up is excellent typically. Here, we used histopathology and microarrays to compare indication biopsies from 26 transplants with acute injury with 11 pristine protocol biopsies of stable transplants. Kidneys with acute injury showed increased expression of 394 transcripts associated with the repair response to injury, including many epithelium-like injury molecules tissue, remodeling molecules, and inflammation molecules. Many other genes also predicted the phenotype, including the acute injury biomarkers HAVCR1 and IL18. Pathway analysis of the injury-repair transcripts revealed similarities to cancer, development, and cell movement. The injury-repair transcript score in kidneys with acute injury correlated with reduced graft function, future renal recovery, brain death, and need for dialysis, but not with future graft loss. In contrast, histologic features of acute tubular injury did not correlate with function or with the molecular changes. Thus, the transcripts associated with repair of injury suggest a massive coordinated response of the kidney parenchyma to acute injury, providing both an objective measure for assessing the severity of injury in kidney biopsies and validation for many biomarkers of AKI.
Enlarged Jugular Foramen
Authors: A. Everette James
Journal: JAMA (1968)

Dr. Robert F. Rider: A 25-year-old white woman noted a mass in the right side of her neck that had increased in size for three years. The patient stated that she experienced diminished hearing and later deafness, pain over the right mastoid, serous discharge from the right ear, and, most recently, hoarseness and difficulty in swallowing. Her husband had noted facial asymmetry and also that her right pupil was smaller than the left. She described a feeling of "tiredness" of the entire right side of her face. The feeling had persisted for the past five months. Physical examination revealed a Horner's syndrome on the right, negative vestibular response, auditory nerve deafness on the right, deviation of the palate and tongue to the right, and paralysis of the right facial nerve. A firm, immobile, nontender 10 × 6-cm mass was palpable from the mastoid process to the right mandibular angle. On
Calcium/Calmodulin-Dependent Protein Kinase II and Its Endogenous Inhibitor α in Medullary Thyroid Cancer
Authors: Eleonora Russo, Marcella Salzano, Valentina De Falco, Caterina Mian, Susi Barollo, Agnese Secondo, Maurizio Bifulco, Mario Vitale
Journal: Clinical Cancer Research (2014)

Calcium/calmodulin-dependent kinase II (CaMKII) is involved in the regulation of cell proliferation. Its endogenous inhibitor (hCaKIINα) is expressed in some cell types. We determined the role of CaMKII in RET-stimulated proliferation and hCaMKIINα in medullary thyroid carcinoma (MTC).We analyzed the role of RET mutants on CaMKII activation in NIH3T3 and in MTC cell lines, and determined the effect of CaMKII inhibition on RET/ERK pathway and cell proliferation. Then the expression of hCaKIINα mRNA was determined by real-time PCR in primary MTC and it was correlated with some clinicopathologic parameters.RET(C634Y) and RET(M918T) mutants expressed in NIH3T3 cells induced CaMKII activation. CaMKII was activated in unstimulated MTC cells carrying the same RET mutants and it was inhibited by RET inhibition. Inhibition of CaMKII in these cells induced a reduction of Raf-1, MEK, and ERK phosphorylation, cyclin D expression, and cell proliferation. hCaKIINα mRNA expression in primary MTC was very variable and did not correlate with gender and age at diagnosis. Serum calcitonin, (R(2) = 0.032; P = 0.017), tumor volume (P = 0.0079), lymph node metastasis (P = 0.033), and staging (P = 0.0652) were negatively correlated with the hCaKIINα mRNA expression.CaMKII is activated by RET mutants and is activated at baseline in MTC cells where it mediates the oncogenic pathway leading to cell proliferation. The mRNA expression of its endogenous inhibitor hCaKIINα inversely correlates with the severity of MTC. CaMKII might represent a new target for MTC therapy and hCaKIINα is a marker of disease extension.
Prognostic Significance of <b> <i>c-kit</i> </b> Mutation in Localized Gastrointestinal Stromal Tumors
Authors: Tae Won Kim, Hyoungnam Lee, Yoon-Koo Kang, Mi Sun Choe, Min-Hee Ryu, Heung Moon Chang, Jung Sun Kim, Jeong Hwan Yook, Byung Sik Kim, Jung Shin Lee
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Constitutive mutational activation of c-kit has been found to be associated with the pathogenesis of gastrointestinal stromal tumors (GISTs). The prognostic significance of c-kit mutations, however, is still controversial. Experimental Design: We examined 86 patients curatively resected for localized GIST. Genomic DNA was extracted from paraffin-embedded tumor tissues. Exons 9, 11, 13, and 17 of the c-kit gene were amplified by PCR and sequenced. Results: Mutations in exon 11 were detected in 61 tumors, and mutations in exon 9 were observed in three tumors, whereas no mutations were detected in exons 13 or 17. The overall c-kit mutation frequency was 74%. Amino acid alterations in the 61 tumors with exon 11 mutations were deletion in 33 tumors, substitution in 20, both deletion and substitution in 4, insertion in 1, and duplication in 3. Histologically, tumors with c-kit mutations showed higher mitotic counts and higher cellularity. The 5-year relapse-free survival (RFS) in patients having GISTs with c-kit mutations was 21%, compared with 60% in those without c-kit mutations. Significantly higher RFS rates were observed in patients with tumors having mitotic counts &amp;lt; 5 mitoses/50 high power field, spindle-cell histology, tumor size &amp;lt; 5 cm, or gastric GISTs. Multivariate analyses indicated association of poorer RFS with a higher mitotic count [≥5 of 50 high power fields; odds ratio (OR) = 3.0], presence of c-kit mutations (OR = 5.6), and a larger tumor size (≥5 cm; OR = 4.2). Conclusions: The presence of c-kit mutation, along with high mitotic count and larger tumor size, was an independent factor for poor prognosis in patients with localized GISTs.
SNAPIN: an endogenous toll-like receptor ligand in rheumatoid arthritis
Authors: Bo Shi, QiQuan Huang, Paul Peter Tak, Margriet J Vervoordeldonk, Chiang-Ching Huang, Andrea Dorfleutner, Christian Stehlik, Richard M Pope
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Objective</h3> The mechanisms contributing to the persistent activation of macrophages in rheumatoid arthritis (RA) are not fully understood. Some studies suggest that endogenous toll-like receptor (TLR) ligands promote the chronic inflammation observed in RA. The objective of this study was to identify endogenous TLR ligands expressed in RA synovial tissue (ST) based on their ability to bind the extracellular domains of TLR2 or TLR4. <h3>Methods</h3> A yeast two-hybrid cDNA library was constructed from ST obtained by arthroscopy from patients with RA and screened using the extracellular domains of TLR2 and TLR4 as the bait. Interactions between TLRs and Snapin were demonstrated by reciprocal co-immunoprecipitation. ST was examined by histology, and single- and two-colour immunohistochemistry and quantitative reverse transcriptase PCR. Snapin (SNAP – associated protein) expression in macrophages was examined by Western Blot analysis and confocal microscopy. The ability of Snapin to activate through TLR2 was examined. <h3>Results</h3> Employing a yeast two-hybrid system, Snapin was the most frequently identified molecule that interacted with TLR2. These results were confirmed by pull-down of in vitro-expressed Snapin together with TLR2. By immunohistochemistry and quantitative reverse transcriptase PCR, Snapin was highly expressed in RA ST, and it was readily detected in macrophages, where it co-localised in the late endosomes. ST Snapin expression correlated with inflammation and was not disease specific. Finally, Snapin was capable of activating through TLR2. <h3>Conclusion</h3> These observations identify Snapin as a novel endogenous TLR2 ligand in RA, and thus support a role for persistent TLR2 signalling in the pathogenesis of RA.
ZEB1 sensitizes lung adenocarcinoma to metastasis suppression by PI3K antagonism
Authors: Yanan Yang, Young-Ho Ahn, Yulong Chen, Xiaochao Tan, Lixia Guo, Don L. Gibbons, Christin Ungewiss, David H. Peng, Xin Liu, Steven H. Lin, Nishan Thilaganathan, Ignacio I. Wistuba, Jaime Rodriguez-Canales, Georgia McLendon, Chad J. Creighton, Jonathan M. Kurie
Journal: Journal of Clinical Investigation (2014)

Epithelial tumor cells that have undergone epithelial-to-mesenchymal transition (EMT) are typically prone to metastasis and drug resistance and contribute to a poor clinical outcome. The transcription factor ZEB1 is a known driver of EMT, and mediators of ZEB1 represent potential therapeutic targets for metastasis suppression. Here, we have shown that phosphatidylinositol 3-kinase-targeted (PI3K-targeted) therapy suppresses metastasis in a mouse model of Kras/Tp53-mutant lung adenocarcinoma that develops metastatic disease due to high expression of ZEB1. In lung adenocarcinoma cells from Kras/Tp53-mutant animals and human lung cancer cell lines, ZEB1 activated PI3K by derepressing miR-200 targets, including amphiregulin (AREG), betacellulin (BTC), and the transcription factor GATA6, which stimulated an EGFR/ERBB2 autocrine loop. Additionally, ZEB1-dependent derepression of the miR-200 and miR-183 target friend of GATA 2 (FOG2) enhanced GATA3-induced expression of the p110α catalytic subunit of PI3K. Knockdown of FOG2, p110α, and RHEB ameliorated invasive and metastatic propensities of tumor cells. Surprisingly, FOG2 was not required for mesenchymal differentiation, suggesting that mesenchymal differentiation and invasion are distinct and separable processes. Together, these results indicate that ZEB1 sensitizes lung adenocarcinoma cells to metastasis suppression by PI3K-targeted therapy and suggest that treatments to selectively modify the metastatic behavior of mesenchymal tumor cells are feasible and may be of clinical value.
E2F1 is a novel fibrogenic gene that regulates cholestatic liver fibrosis through the Egr-1/SHP/EID1 network
Authors: Yuxia Zhang, Ningyi Xu, Jun Xu, Bo Kong, Bryan Copple, Grace L. Guo, Li Wang
Journal: Hepatology (2014)

E2F transcription factor 1 (E2F1) is an important regulator of metabolic diseases; however, its role in liver function remains elusive. This study unraveled a regulatory cascade involving E2F1, early growth response-1 (Egr-1), nuclear receptor small heterodimer partner (SHP, NR0B2), and EIA-like inhibitor of differentiation 1 (EID1) in cholestatic liver fibrosis. Liver E2F1 messenger RNA (mRNA) and protein expression was strongly up-regulated in human nonalcoholic steatohepatitis (NASH) and alcohol cirrhosis; the latter was inversely correlated with diminished SHP expression. E2F1 was also highly induced by 3,5-diethoxycarbonyl-1, 4-dihydrocollidine (DDC) feeding and bile-duct ligation (BDL) in mice. E2F1−/− mice exhibited reduced biliary fibrosis by DDC as determined by Masson Trichrome and Picro Sirius red staining, and decreased serum bile acid (BA), BA pool size, and fecal BA excretion. In addition, cholestatic liver fibrosis induced by BDL, as determined by immunohistochemistry analysis of a1 collagen expression, was increased in SHP−/− mice but attenuated in hepatocyte SHP -overexpressed transgenic (STG) mice. Egr-1 exhibited marked induction in livers of SHP−/− mice compared to the wild-type mice in both sham and BDL groups, and reduction in STG livers. Egr-1 promoter was activated by E2F1, and the activation was abrogated by expression of SHP and its co-repressor EID1 in hepatoma cells Huh7, Hepa1, and stellate cells LX2. Chromatin immunoprecipitation assays further confirmed the association of E2F1, SHP, and EID1 proteins with the Egr-1 promoter, and their direct protein interactions were determined by glutathione S-transferase pull-down assays. Interestingly, E2F1 activated Egr-1 expression in a biphasic fashion as described in both human and mouse hepatocytes. Conclusion : E2F1 is a fibrogenic gene and could serve as a potential new diagnostic marker for nonalcoholic and alcoholic liver fibrosis/cirrhosis. (Hepatology 2014;60:919–930)