tbuckley/cabot-search huggingface dataset:
Histone deacetylase inhibition suppresses the transforming growth factor β1-induced epithelial-to-mesenchymal transition in hepatocytes
Authors: Aki Kaimori, James J. Potter, Michael Choti, Zhen Ding, Esteban Mezey, Ayman A. Koteish
Journal: Hepatology (2010)

Abstract Transforming growth factor β1 (TGFβ1) plays a crucial role in the induction of the epithelial-to-mesenchymal transition (EMT) in hepatocytes, which contributes to the pathogenesis of liver fibrosis. The inhibition of the TGFβ1 cascade suppresses EMT and the resultant fibrosis. In this study, we focus on EMT-induced fibrosis in hepatocytes and the epigenetic regulation of the type I collagen gene. Histone acetylation is an important, major epigenetic mechanism that modulates gene transcription. We evaluated the epigenetic regulation of type I collagen in alpha mouse liver 12 hepatocytes (an untransformed mouse cell line) that had undergone EMT after treatment with TGFβ1. The histone deacetylase inhibitor trichostatin A (TSA) inhibited EMT; this was reflected by the preservation of epithelial markers and function (E-cadherin and albumin). Fibrosis, the ultimate outcome of EMT, was abolished by TSA; this was indicated by the inhibition of type I collagen deposition. TSA exerted its anti-EMT effects by deactivating the mothers against decapentaplegic homolog 3 (Smad3)/Smad4 transcription complex and by interfering with p300, a coactivator of the type I collagen promoter, and preventing its binding to Smad3. TSA also restored Friend leukemia virus integration 1, an inhibitor of the type I collagen gene. TGFβ1-induced EMT and its inhibition by TSA were replicated in human primary hepatocytes. Conclusion: Histone deacetylase inhibition abrogates TGFβ1-induced EMT in hepatocytes and reverses EMT-induced fibrosis by epigenetic modulation of type I collagen.
Dual Degradation of Aurora A and B Kinases by the Histone Deacetylase Inhibitor LBH589 Induces G2-M Arrest and Apoptosis of Renal Cancer Cells
Authors: Tai-Lung Cha, Mei-Jen Chuang, Sheng-Tang Wu, Guang-Huan Sun, Sun-Yran Chang, Dah-Shyong Yu, Shih-Ming Huang, Steven Kuan-Hua Huan, Tse-Chou Cheng, Tzu-Ting Chen, Pao-Luo Fan, Pei-Wen Hsiao
Journal: Clinical Cancer Research (2009)

This study is aimed at investigating antineoplastic efficacy of histone deacetylase inhibitor (HDACI) LBH589 on renal cell carcinoma (RCC) and elucidating the novel molecular mechanisms involved in growth arrest and apoptosis by targeting the important nonhistone molecules.We analyzed the growth-inhibitory effect of LBH589 on RCC by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay in vitro and antitumor efficacy by xenograft experiments in vivo. To verify the associated molecular mechanisms involved in LBH589-mediated cell death and cell cycle progression by Western blotting and fluorescence-activated cell sorting analysis.HDACI LBH589 induced degradation of both Aurora A and B kinases through a proteasome-mediated pathway by targeting HDAC3 and HDAC6. The dual degradation of Aurora A and B kinases mediated by LBH589 resulted in inducing G2-M arrest and apoptosis of renal cancer cell lines and our results also showed that LBH589 potently inhibited renal cancer cell growth in vitro and suppressed tumor formation in vivo. The Aurora A and B kinases and HDAC3 are overexpressed in the human RCC tumor tissues examined, which make them perfect targets for HDACI LBH589 treatment.Our in vitro and in vivo data showed that LBH589 has potent anticancer effect of renal cancer cells. LBH589 and other HDACI treatment resulted in inducing G2-M arrest and apoptosis of renal cancer cells through degradation of Aurora A and B kinases by inhibition of HDAC3 and HDAC6. The clinical efficacy of LBH589 in the treatment of patients with metastatic RCC, especially those with high Aurora kinase and HDAC expression, is worthy of further investigation.
Functional Divergence and Horizontal Transfer of Type IV Secretion Systems
Authors: A. Carolin Frank, Cecilia M. Alsmark, Mikael Thollesson, Siv G. E. Andersson
Journal: Molecular Biology and Evolution (2005)

The type IV secretion system (TFSSs) is a multifunctional family of translocation pathways that mediate the transfer of DNA among bacteria and deliver DNA and proteins to eukaryotic cells during bacterial infections. Horizontal transmission has dominated the evolution of the TFSS, as demonstrated here by a lack of congruence between the tree topology inferred from components of the TFSS and the presumed bacterial species divergence pattern. A parsimony analysis suggests that conjugation represents the ancestral state and that the divergence from conjugation to secretion of effector molecules has occurred independently at multiple sites in the tree. The result shows that the nodes at which functional shifts have occurred coincide with those of horizontal gene transfers among distantly related bacteria. We suggest that it is the transfer between species that paved the way for the divergence of the TFSSs and discuss the general role of horizontal gene transfers for the evolution of novel gene functions.
Decline of daily activity in COPD patients with frequent and infrequent exacerbations
Authors: Ayedh AlAhmari, Anant Patel, Beverly Kowlessar, Alex Mackay, Richa Singh, James Allinson, Jadwiga Wedzicha, Gavin Donaldson
Journal: European Respiratory Journal (2013)

Increased breathlessness during COPD exacerbations may lead to reduced physical activity and skeletal muscle dysfunction. We evaluated the longitudinal trend of daily activity in frequent and infrequent COPD exacerbators.

73 outpatients from the London COPD cohort wore a pedometer (Yamax SW-200) and recorded their daily step count on diary cards. We excluded patients using walking sticks or ambulatory oxygen; and data 2 weeks before, during and 2 weeks after each symptom-defined exacerbation. Each patient’s exacerbation frequency was determined over one year prior to when they started with the pedometer. The patients were then divided into two groups, infrequent (<2 exacerbations/year) and frequent (≥2/year) exacerbators. The data was analysed by random-effects GLS regression models.

The 73 COPD patients (64 male, 30 current smokers) had a mean (±SD) age 71 (±8) years and FEV1 53 (±16) %predicted. Daily step count was recorded in the stable state on 14653 days (median 169 days/patient; IQR 113-285; max 488). Step count fell in the infrequent exacerbators (n=33) by 337 steps /year and among frequent exacerbators (n=40) by 707 steps/year (both p<0.001). The decline was faster in frequent exacerbators (p=0.002; see fig1).

Frequent COPD exacerbators have an accelerated decline in physical activity compared to infrequent exacerbators. Further study is required to determine the mechanisms and appropriate management strategies.

![Figure][1]  [1]: pending:yes
Occupational allergic contact dermatitis due to leatherleaf fern Arachniodes adiantiformis (Forst) Tindale
Authors: B.M. HAUSEN, K.H. SCHULZ
Journal: British Journal of Dermatology (1978)

Leatherleaf fern has been imported from the United States, Honduras and Puerto Rico to the Federal Republic of Germany since 1966 and cultivated in Germany since 1970/71. It is slowly displacing the floral arrangements with asparagus used until now as filler and background material. This change is due primarily to its better keeping quality. Continuous contact with the leatherleaf fern induced an allergic contact dermatitis of the palms and fingers in a female florist. Patch tests wiih the leaf revealed the allergic origin of the dermatitis. Five fractions of a chromatographically separated extract of the fern were tested on sensitized guinea‐pigs and on the patient. Only the first fraction gave a positive patch test response. By further separation colourless crystals of the contact allergen could be obtained. Elucidation of the structure is in progress. The sensitizer could only be detected during sporogenesis of the fern, that means when sporecapsules are present on the surface of the leaves.
The Prognostic Significance and Therapeutic Potential of Hedgehog Signaling in Intrahepatic Cholangiocellular Carcinoma
Authors: Liang Tang, Ye-Xiong Tan, Bei-Ge Jiang, Yu-Fei Pan, Shuang-Xi Li, Guang-Zhen Yang, Min Wang, Qing Wang, Jian Zhang, Wei-Ping Zhou, Li-Wei Dong, Hong-Yang Wang
Journal: Clinical Cancer Research (2013)

The correlation of the hedgehog signaling pathway with the progression, prognosis, and therapeutics of intrahepatic cholangiocellular carcinoma (ICC) has not been well documented. The study aimed to investigate the expression, prognostic significance, and therapeutic value of hedgehog components in ICC.Two independent cohorts of 200 patients with ICC were enrolled. By real-time PCR and immunohistochemistry assay, hedgehog components expression was evaluated. The prognostic values of hedgehog proteins were identified and verified. Cyclopamine or siRNA-targeting Gli was used to block the hedgehog signaling. Cell proliferation and apoptosis were observed by CCK8, cell cycle, and annexin V staining assays. In vivo murine tumor model was used to evaluate the role of hedgehog in ICC.In ICC tissues, the Gli1 nuclear immune-intensity was associated with intrahepatic metastasis and the expression of Gli2 was associated with intrahepatic metastasis, venous invasion, and Unio Internationale Contra Cancrum (UICC) pT characteristics. In survival analysis, high Gli1 or Gli2 expressers had an unfavorable overall survival (OS) prognosis and a shorter disease-free survival (DFS) than those with low expression. In multivariate analysis, Gli1 expression was found to be an independent prognostic factor of OS, which was validated by another independent cohort. Furthermore, blocking the hedgehog signaling by cyclopamine or siRNA-targeting Gli1 resulted in apoptosis and growth inhibition in ICC cells.This study shows, for the first time, activation of hedgehog pathway associated with the progression and metastasis in ICC, which may provide prognostic and therapeutic values for this tumor.
ExaBayes: Massively Parallel Bayesian Tree Inference for the Whole-Genome Era
Authors: Andre J. Aberer, Kassian Kobert, Alexandros Stamatakis
Journal: Molecular Biology and Evolution (2014)

Modern sequencing technology now allows biologists to collect the entirety of molecular evidence for reconstructing evolutionary trees. We introduce a novel, user-friendly software package engineered for conducting state-of-the-art Bayesian tree inferences on data sets of arbitrary size. Our software introduces a nonblocking parallelization of Metropolis-coupled chains, modifications for efficient analyses of data sets comprising thousands of partitions and memory saving techniques. We report on first experiences with Bayesian inferences at the whole-genome level using the SuperMUC supercomputer and simulated data.
Interleukin 4 potently enhances murine macrophage mannose receptor activity: a marker of alternative immunologic macrophage activation.
Authors: M Stein, S Keshav, N Harris, S Gordon
Journal: The Journal of Experimental Medicine (1992)

Expression of the macrophage mannose receptor is inhibited by interferon gamma (IFN-gamma), a T helper type 1 (Th-1)-derived lymphokine. Interleukin 4 (IL-4), a Th-2 lymphocyte product, upregulates major histocompatibility class II antigen expression but inhibits inflammatory cytokine production by macrophages. We have studied the effect of IL-4 on expression of the macrophage mannose receptor (MMR) by elicited peritoneal macrophages. We found that recombinant murine IL-4 enhances MMR surface expression (10-fold) and activity (15-fold), as measured by the respective binding and degradation of 125I-mannose-bovine serum albumin. Polymerase chain reaction analysis of cDNAs from purified primary macrophage populations revealed that MMR, but not lysozyme or tumor necrosis factor alpha, mRNA levels were markedly increased by IL-4. The above effects were associated with morphologic changes. These data establish IL-4 as a potent and selective enhancer of murine MMR activity in vitro. IL-4 induces inflammatory macrophages to adopt an alternative activation phenotype, distinct from that induced by IFN-gamma, characterized by a high capacity for endocytic clearance of mannosylated ligands, enhanced (albeit restricted) MHC class II antigen expression, and reduced proinflammatory cytokine secretion.
Targeting Factors Involved in Bone Remodeling as Treatment Strategies in Prostate Cancer Bone Metastasis
Authors: Robert L. Vessella, Eva Corey
Journal: Clinical Cancer Research (2006)

Abstract Prostate cancer is the most commonly diagnosed cancer in men within the western world and the third leading cause of cancer-related deaths. Even if the cancer is considered localized to the prostate, there is a 15% to 20% incidence of subsequent metastatic disease. Prostate cancer has a very high proclivity for metastasizing to bone, with ∼90% of men with advanced disease having skeletal lesions. The prostate cancer metastases are characteristically osteoblastic, with extensive new bone deposition, unlike other tumors that metastasize to bone and cause an osteolytic response reflective of bone degradation. There are a considerable number of studies relating to inhibition of the osteoblastic response, including interference with endothelin-1, bone morphogenetic proteins, and Wnt signaling pathways. Within the past few years, several studies showed that increased osteolytic activity also occurs in the background of the prostate cancer skeletal metastases. Because growth factors are being released from the bone matrix during degradation, it suggests that inhibition of osteolysis might be effective in slowing tumor growth. Several strategies are being developed and applied to affect directly the osteolytic events, including use of bisphosphonates and targeting the critical biological regulators of osteoclastogenesis, receptor activator of nuclear factor-κB and receptor activator of nuclear factor-κB ligand. This review focuses on several of the clinical and preclinical strategies to inhibit the growth of prostate cancer cells in bone and to alleviate the multitude of associated skeletal-related events.
A TRANSPLANTABLE CARCINOMA OF THE GUINEA PIG
Authors: F. S. Jones
Journal: The Journal of Experimental Medicine (1916)

An adenocarcinoma of the mammary gland of an old guinea pig has been successfully transplanted through eight successive series of animals. It now appears much earlier and grows more rapidly. The number of takes also has increased. In two instances metastasis to the regional lymph glands (inguinal) has been observed. Once microscopic metastases were found in the kidney. The so called precancerous changes observed in the breasts of women and mice suffering from mammary carcinoma were found in the mammary gland of the spontaneous tumor animal. It is hoped that the tumor may soon be utilized for experimental purposes.
Estrogen Actions in the Brain and the Basis for Differential Action in Men and Women: A Case for Sex-Specific Medicines
Authors: Glenda E. Gillies, Simon McArthur
Journal: Pharmacological Reviews (2010)

The classic view of estrogen actions in the brain was confined to regulation of ovulation and reproductive behavior in the female of all mamamalian species studied, including humans. Burgeoning evidence now documents profound effects of estrogens on learning, memory, and mood as well as neurodevelopmental and neurodegenerative processes. Most data derive from studies in females, but there is mounting recognition that estrogens play important roles in the male brain, where they can be generated from circulating testosterone by local aromatase enzymes or synthesized de novo by neurons and glia. Estrogen-based therapy therefore holds considerable promise for brain disorders that affect both men and women. However, as investigations are beginning to consider the role of estrogens in the male brain more carefully, it emerges that they have different, even opposite, effects as well as similar effects in male and female brains. This review focuses on these differences, including sex dimorphisms in the ability of estradiol to influence synaptic plasticity, neurotransmission, neurodegeneration, and cognition, which, we argue, are due in a large part to sex differences in the organization of the underlying circuitry. There are notable sex differences in the incidence and manifestations of virtually all central nervous system disorders, including neurodegenerative disease (Parkinson9s and Alzheimer9s), drug abuse, anxiety, and depression. Understanding the cellular and molecular basis of sex differences in brain physiology and responses to estrogen and estrogen mimics is, therefore, vitally important for understanding the nature and origins of sex-specific pathological conditions and for designing novel hormone-based therapeutic agents that will have optimal effectiveness in men or women.
A novel role for mitochondrial dysfunction in the inflammatory response of rheumatoid arthritis
Authors: M N Valcarcel-Ares, C Vaamonde-Garcia, R R Riveiro-Naveira, B Lema, F J Blanco, M J Lopez-Armada
Journal: Annals of the Rheumatic Diseases (2010)

PurposeThe infl ammation hypothesis of ageing suggests that molecular infl ammation could be an underpinning of ageing and age-related diseases such as rheumatoid arthritis (RA).Besides, mitochondrial alterations may contribute to the progression of RA.In this study we investigated the relationship between mitochondrial dysfunction and the in vitro expression of cyclooxigenase-2 (COX-2), prostaglandin E2 (PGE2) and interleukin-8 (IL8) in normal human synoviocytes.Method Commonly used inhibitors to induce mitochondrial dysfunction were employed (antimycin A (AA) and oligomycin (OLI), inhibitors of complexes III and V of mitochondrial respiratory chain (MRC), respectively) in synoviocytes.IL1β and tumour necrosis factor α (TNFα) were used as infl ammatory mediators.To identify possible pathways we used N-acetylcysteine as ROS scavenger; the natural antioxidant resveratrol; and BAY as an inhibitor of NF-κ activation.COX-2 protein and mRNA expression and both PGE2 and IL8 levels were analysed by fl ow cytometry, RT-PCR and ELISA, respectively.Results We found that exposure of synoviocytes to AA and OLI signifi cantly increased COX-2 protein expression in a time-and dose-dependent manner.The maximal response was observed at 6 h with 20 µg/ml AA and 25 µg/ ml OLI (3.0±0.3,p<0.001 and 6.5±1.9, p<0.001, respectively vs basal 1) while the positive control, 1 ng/ml IL1, expression was 12.6±3.4.Quantifi cation of COX-2 mRNA expression at 4 h showed similar results.PGE2 levels were also increased when cells were stimulated for 9 h with OLI.We then determined if mitochondrial dysfunction could modulate the response induced by suboptimal doses of IL1 (0.1 ng/ml) on COX-2 protein expression and PGE2 production.We found that pretreatment of synoviocytes with 10 µg/ml OLI for 30 min signifi cantly increased the IL1-induced COX-2 protein expression (32.5±2.5 OLI+IL1 vs 6.5±2.4IL1 and 4.5±1.7 OLI, p<0.001) and COX-2 mRNA expression.Similar results were obtained when PGE2 production was assessed (277.0±67.6OLI+IL1 vs 15.4±2.6 IL1 and 97.5±45.6OLI, expressed as pg/50000 cells, n=duplicate, p<0.005).Equivalent results were observed when TNFα or AA was employed.We also explored whether OLI together with IL1 signifi cantly potentiates the expression of the proinfl ammatory chemokine IL8.Finally, we observed that this infl ammatory response was counteracted by the addition of N-acetylcysteine, resveratrol or BAY, demonstrating the involvement of ROS and NF-κB in this process.Conclusion Besides inducing a slight infl ammatory response, dysfunction of mitochondrial respiratory activity signifi cantly potentiates the cytokine-induced infl ammatory response in synoviocytes in relation to PGE2 and IL8 release via ROS production and NF-κB activation, contributing to chronic infl ammation of synovial tissue in RA and ageing joints.on June 15,
Randomised placebo controlled trial of daytime function after continuous positive airway pressure (CPAP) therapy for the sleep apnoea/hypopnoea syndrome
Authors: H. M Engleman, S. E Martin, R. N Kingshott, T. W Mackay, I. J Deary, N. J Douglas
Journal: Thorax (1998)

<h3>BACKGROUND</h3> Patients with the sleep apnoea/hypopnoea syndrome (SAHS) report improved sleepiness, cognitive function, and psychological well being after continuous positive airway pressure (CPAP) therapy, and it is for these daytime features that CPAP is usually given. However, few randomised or controlled studies exist on the effects of CPAP on daytime function. <h3>METHODS</h3> A prospective, randomised, single blind, placebo controlled, crossover trial of daytime function after CPAP was conducted in 23 patients with SAHS, all with ⩾15 apnoeas+hypopnoeas/hour and ⩾2 symptoms of SAHS. All patients spent four weeks on CPAP therapy and four weeks on oral placebo treatment, following randomisation to treatment order. With ethics committee approval, patients were told the placebo tablet might improve upper airway function. Average effective CPAP use was monitored using hidden time clocks. Assessments of objective and subjective sleepiness, symptoms, cognitive performance, and psychological well being were performed on the last day of each treatment and compared. <h3>RESULTS</h3> Objective sleepiness measured by sleep onset latency on the multiple sleep latency test improved with CPAP (mean difference from placebo +2.4 min, 95% CI 0.8 to 4.0; p&lt;0.001) as did subjective sleepiness on the Epworth scale (mean difference –6, 95% CI –3 to –9; p = 0.001). Symptom total score also fell with CPAP (mean difference –1.6, 95% CI –2.2 to –1.0; p&lt;0.001). No determinants of these changes with active treatment were identified, and no significant enhancements to cognitive function or psychosocial well being were found in this small sample. <h3>CONCLUSIONS</h3> These findings provide further evidence for clinically significant benefits to daytime function from CPAP.
[-215G&gt;A; IVS3+2T&gt;C] mutation in the SPINK1 gene causes exon 3 skipping and loss of the trypsin binding site
Authors: K Kume
Journal: Gut (2005)

Previous studies have shown an association between chronic pancreatitis (CP) and mutations, especially the N34S mutation, in the serine protease inhibitor Kazal type 1 ( SPINK1 ) gene.1,2 The human SPINK1 gene is approximately 7.5 kb long and consists of four exons.3 The gene product consists of 79 amino acids, including a 23 amino acid signal peptide. In exon 3, SPINK1 possesses a reactive site that serves as a specific target substrate for trypsin.4 It has been suggested that SPINK1 mutations might result in altered interaction between SPINK1 and trypsin, thus affecting the protease/antiprotease balance within the pancreas.1,2 But the underlying molecular mechanisms remain unclear. Splicing defects are estimated to account for approximately 10–15% of disease causing mutations in humans.5 Changes in the splicing patterns and in levels of normal transcripts lead to phenotypic differences. The prevalence of splicing mutations …
Monocanalicular nasolacrimal duct intubation11Bruno Fayet, MD, is the original patent owner of the Monoka and currently holds financial interests in this device. Jean-Antoine Bernard, MD, is a paid consultant for FCI, manufacturer of the Monoka. Michael Assouline, MD, PhD, has no financial interest in any of the devices cited in this letter.
Authors: Bruno Fayet, Michael Assouline, Jean-Antoine Bernard
Journal: Ophthalmology (1998)