bluuebunny/crossref_metadata_2025_split huggingface dataset:
Expression and Significance of Hypoxia‐Inducible Factor–1α and Survivin in Laryngeal Carcinoma Tissue and Cells
Authors: Li Da‐wei , Zhou Liang , Jin Bin , Xie Jin , Dong Pin 
Published: October 2012

ObjectiveThe aim was to evaluate hypoxia‐inducible factor–1α (HIF‐1α) and survivin expression in laryngeal squamous cell carcinoma (LSCC) tissues and cell lines and to investigate whether HIF‐1α has an effect on the regulation of survivin gene expression in LSCC cells under hypoxia.Study DesignProspective, observational.SettingShanghai Jiaotong University Affiliated First People’s Hospital.Subjects and MethodsThe expression of HIF‐1α and survivin protein in human LSCC tissues was analyzed by immunohistochemistry. HIF‐1α and survivin gene expression levels in Hep‐2 cells were detected by real‐time quantitative reverse transcription polymerase chain reaction (RT‐PCR) and Western blot under normoxic or hypoxic conditions. In hypoxic cells, HIF‐1α expression was inhibited by RNA interference.ResultsHIF‐1α and survivin were both highly expressed in LSCC tissues and significantly related to the clinical stage and lymph node metastasis (P <. 05). Meanwhile, a positive correlation existed between HIF‐1α and survivin expression (r = 0.456, P <. 01). In LSCC cells, HIF‐1α and survivin expression were obviously upregulated in response to hypoxia (P <. 05). The downregulation of HIF‐1α expression dramatically decreased survivin gene expression in hypoxic cells (P <. 05).ConclusionHIF‐1α could be considered as an important regulator for the upregulation of survivin gene expression induced by hypoxia in LSCC cells, and both proteins could be regarded as 2 key predictors of malignant progression and metastasis of LSCC.
The clinical significance of NOTCH1 and SF3B1 mutations in the UK LRF CLL4 trial
Authors: Oscier David G. , Rose-Zerilli Matthew J. J. , Winkelmann Nils , Gonzalez de Castro David , Gomez Belen , Forster Jade , Parker Helen , Parker Anton , Gardiner Anne , Collins Andrew , Else Monica , Cross Nicholas C. P. , Catovsky Daniel , Strefford Jonathan C. 
Published: October 2012

Abstract
NOTCH1 and SF3B1 mutations have been previously reported to have prognostic significance in chronic lymphocytic leukemia but to date they have not been validated in a prospective, controlled clinical trial. We have assessed the impact of these mutations in a cohort of 494 patients treated within the randomized phase 3 United Kingdom Leukaemia Research Fund Chronic Lymphocytic Leukemia 4 (UK LRF CCL4) trial that compared chlorambucil and fludarabine with and without cyclophosphamide in previously untreated patients. We investigated the relationship of mutations in NOTCH1 (exon 34) and SF3B1 (exon 14-16) to treatment response, survival and a panel of established biologic variables. NOTCH1 and SF3B1 mutations were found in 10% and17% of patients, respectively. NOTCH1 mutations correlated with unmutated IGHV genes, trisomy 12, high CD38/ ZAP-70 expression and were associated with reduced overall (median 54.8 vs 74.6 months, P = .02) and progression-free (median 22.0 vs 26.4 months, P = .02) survival. SF3B1 mutations were significantly associated with high CD38 expression and with shorter overall survival (median 54.3 vs 79.0 months, P < .001). Furthermore, multivariate analysis, including baseline clinical variables, treatment, and adverse prognostic factors demonstrated that although TP53 alterations remained the most informative marker of dismal survival in this cohort, NOTCH1 (HR 1.58, P = .03) and SF3B1 (HR 1.52, P = .01) mutations have added independent prognostic value.
A Hypomethylated population of Brassica rapa for forward and reverse Epi-genetics
Authors: Amoah Stephen , Kurup Smita , Rodriguez Lopez Carlos Marcelino , Welham Sue J , Powers Stephen J , Hopkins Clare J , Wilkinson Michael J , King Graham J 
Published: October 2012

AbstractBackgroundEpigenetic marks superimposed on the DNA sequence of eukaryote chromosomes provide agility and plasticity in terms of modulating gene expression, ontology, and response to the environment. Modulating the methylation status of cytosine can generate epialleles, which have been detected and characterised at specific loci in several plant systems, and have the potential to generate novel and relatively stable phenotypes. There have been no systematic attempts to explore and utilise epiallelic variation, and so extend the range of phenotypes available for selection in crop improvement. We developed an approach for generating novel epialleles by perturbation of the DNA methylation status. 5- Azacytidine (5-AzaC) provides selective targeting of5mCG, which in plants is associated with exonic DNA. Targeted chemical intervention using 5-AzaC has advantages over transgenic or mutant modulation of methyltransferases, allowing stochastic generation of epialleles across the genome.ResultsWe demonstrate the potential of stochastic chemically-induced hypomethylation to generate novel and valuable variation for crop improvement. Systematic analysis of dose–response to 5-AzaC inB. rapaguided generation of a selfed stochastically hypomethylated population, used for forward screening of several agronomic traits. Dose–response was sigmoidal for several traits, similar to that observed for chemical mutagens such as EMS. We demonstrated transgenerational inheritance of some phenotypes. BraRoAZ is a unique hypomethylated population of 1000 E2 sib lines. When compared to untreated controls, 5-Aza C-treated lines exhibited reduced immuno-staining of5mC on pachytene chromosomes, and Methylation Sensitive Amplified Polymorphism (MSAP) profiles that were both divergent and more variable. There was coincident phenotypic variation among these lines for a range of seed yield and composition traits, including increased seed protein content and decreased oil content, as well as decreased erucic acid and corresponding increases in linoleic and/or palmitic acid. Each 5-AzaC-treated line represents a unique combination of hypomethylated epialleles.ConclusionsThe approach and populations developed are available for forward and reverse screening of epiallelic variation and subsequent functional and inheritance studies. The generation of stochastically hypomethylated populations has utility in epiallele discovery for a wide range of crop plants, and has considerable potential as an intervention strategy for crop improvement.
Versican expression in canine carcinomas in benign mixed tumours: is there an association with clinical pathological factors, invasion and overall survival?
Authors: Damasceno Karine A , Bertagnolli Angélica C , Estrela-Lima Alessandra , Ribeiro Lorena GR , Rabelo Bruna S , Campos Cecília B , Barros André LB , Cassali Geovanni D 
Published: October 2012

Abstract

Background
Components of the extracellular matrix have been studied in an attempt to elucidate the mechanisms involved in the biological behaviour of tumours. The presence of the proteoglycan versican has been strongly associated with cancer development and progression. However, relationship between versican expression and clinical pathological factors and overall survival has not been previously studied in veterinary medicine. Carcinomas in benign mixed tumours (CBMTs) are one of the most common malignant tumours in female canines and can serve as models for studies of tumour progression. The aim of this study was to evaluate the expression of versican in in situ and invasive carcinomatous areas of canine CBMTs and to evaluate possible associations of versican expression with other classic prognostic factors and overall survival.

Results
Clinical staging; histological grade determination; immunohistochemical staining for versican, E-cadherin and Ki-67; and confirmation of invasion areas by staining for p63 and smooth muscle α-actin (α-SMA) were performed on 49 canine cases of CBMT. Tumour invasion was considered when suspicious Haematoxylin-Eosin (HE)-stained areas showed a total loss of α-SMA and p63 immunoreactivity. Versican immunoreactivity was less intense in the areas adjacent to the in situ carcinomatous regions, compared to invasive regions, which showed extensive and strong staining.

Conclusions
Our data reveal that in canine CBMTs, versican expression differs significantly between invasive and in situ areas, suggesting a role for this molecule in tumour progression. Although a direct relationship exists between versican and invasiveness, our results indicate that the isolated evaluation of this proteoglycan does not represent an independent prognostic factor in canine CBMTs.
Thyroid Hormone Receptor Agonists Reduce Serum Cholesterol Independent of the LDL Receptor
Authors: Lin Jean Z. , Martagón Alexandro J. , Hsueh Willa A. , Baxter John D. , Gustafsson Jan-Åke , Webb Paul , Phillips Kevin J. 
Published: October 2012

AbstractThe majority of cholesterol reduction therapies, such as the statin drugs, work primarily by inducing the expression of hepatic low-density lipoprotein receptors (LDLRs), rendering these therapeutics only partially effective in animals lacking LDLRs. Although thyroid hormones and their synthetic derivatives, often referred to as thyromimetics, have been clearly shown to reduce serum cholesterol levels, this action has generally been attributed to their ability to increase expression of hepatic LDLRs. Here we show for the first time that the thyroid hormone T3 and the thyroid hormone receptor-β selective agonists GC-1 and KB2115 are capable of markedly reducing serum cholesterol in mice devoid of functional LDLRs by inducing Cyp7a1 expression and stimulating the conversion and excretion of cholesterol as bile acids. Based on this LDLR-independent mechanism, thyromimetics such as GC-1 and KB2115 may represent promising cholesterol-lowering therapeutics for the treatment of diseases such as homozygous familial hypercholesterolemia, a rare genetic disorder caused by a complete lack of functional LDLRs, for which there are limited treatment options because most therapeutics are only minimally effective.
Angiotensin Receptor Blockade Recovers Hepatic UCP2 Expression and Aconitase and SDH Activities and Ameliorates Hepatic Oxidative Damage in Insulin Resistant Rats
Authors: Montez Priscilla , Vázquez-Medina José Pablo , Rodríguez Rubén , Thorwald Max A. , Viscarra José A. , Lam Lisa , Peti-Peterdi Janos , Nakano Daisuke , Nishiyama Akira , Ortiz Rudy M. 
Published: October 2012

Abstract
Metabolic syndrome (MetS) is commonly associated with elevated renin-angiotensin system, oxidative stress, and steatohepatitis with down-regulation of uncoupling proteins (UCPs). However, the mechanisms linking renin-angiotensin system, steatosis, and UCP2 to hepatic oxidative damage during insulin resistance are not described. To test the hypothesis that angiotensin receptor activation contributes to decreased hepatic UCP2 expression and aconitase activity and to increased oxidative damage after increased glucose intake in a model of MetS, lean and obese Long Evans rats (n = 10/group) were randomly assigned to the following groups: 1) untreated Long Evans Tokushima Otsuka (lean, strain control), 2) untreated Otsuka Long Evans Tokushima Fatty (OLETF) (MetS model), 3) OLETF + angiotensin receptor blocker (ARB) (10 mg olmesartan/kg·d × 6 wk), 4) OLETF + high glucose (HG) (5% in drinking water × 6 wk), and 5) OLETF + ARB + HG (ARB/HG × 6 wk). HG increased body mass (37%), plasma triglycerides (TGs) (35%), plasma glycerol (87%), plasma free fatty acids (28%), and hepatic nitrotyrosine (74%). ARB treatment in HG decreased body mass (12%), plasma TG (15%), plasma glycerol (23%), plasma free fatty acids (14%), and hepatic TG content (42%), suggesting that angiotensin receptor type 1 (AT1) activation and increased adiposity contribute to the development of obesity-related dyslipidemia. ARB in HG also decreased hepatic nitrotyrosine and increased hepatic UCP2 expression (59%) and aconitase activity (40%), as well as antioxidant enzyme activities (50-120%), suggesting that AT1 activation also contributes to protein oxidation, impaired lipid metabolism, and antioxidant metabolism in the liver. Thus, in addition to promoting obesity-related hypertension, AT1 activation may also impair lipid metabolism and antioxidant capacity, resulting in steatosis via decreased UCP2 and tricarboxylic acid cycle activity.
Wnt Inhibitory Factor 1 (Wif1) Is Regulated by Androgens and Enhances Androgen-Dependent Prostate Development
Authors: Keil Kimberly P. , Mehta Vatsal , Branam Amanda M. , Abler Lisa L. , Buresh-Stiemke Rita A. , Joshi Pinak S. , Schmitz Christopher T. , Marker Paul C. , Vezina Chad M. 
Published: October 2012

AbstractFetal prostate development from urogenital sinus (UGS) epithelium requires androgen receptor (AR) activation in UGS mesenchyme (UGM). Despite growing awareness of sexually dimorphic gene expression in the UGS, we are still limited in our knowledge of androgen-responsive genes in UGM that initiate prostate ductal development. We found that WNT inhibitory factor 1 (Wif1) mRNA is more abundant in male vs. female mouse UGM in which its expression temporally and spatially overlaps androgen-responsive steroid 5α-reductase 2 (Srd5a2). Wif1 mRNA is also present in prostatic buds during their elongation and branching morphogenesis. Androgens are necessary and sufficient for Wif1 expression in mouse UGS explant mesenchyme, and testicular androgens remain necessary for normal Wif1 expression in adult mouse prostate stroma. WIF1 contributes functionally to prostatic bud formation. In the presence of androgens, exogenous WIF1 protein increases prostatic bud number and UGS basal epithelial cell proliferation without noticeably altering the pattern of WNT/β-catenin-responsive Axin2 or lymphoid enhancer binding factor 1 (Lef1) mRNA. Wif1 mutant male UGSs exhibit increased (Sfrp)2 and (Sfrp)3 expression and form the same number of prostatic buds as the wild-type control males. Collectively our results reveal Wif1 as one of the few known androgen-responsive genes in the fetal mouse UGM and support the hypothesis that androgen-dependent Wif1 expression is linked to the mechanism of androgen-induced prostatic bud formation.
Long-term outcome in patients with acromegaly: analysis of 1344 patients from the German Acromegaly Register
Authors: Schöfl Christof , Franz Holger , Grussendorf Martin , Honegger Jürgen , Jaursch-Hancke Cornelia , Mayr Bernhard , Schopohl Jochen , _ _ 
Published: October 2012

BackgroundAcromegaly is a rare disease with significant morbidity and increased mortality. Epidemiological data about therapeutic outcome under ‘real life’ conditions are scarce.ObjectiveTo describe biochemical long-term outcome of acromegaly patients in Germany.Design and methodsRetrospective data analysis from 1344 patients followed in 42 centers of the German Acromegaly Register. Patients' data were collected 8.6 (range 0–52.6) years after diagnosis. Controlled disease was defined by an IGF1 within the center-specific reference range.ResultsNine hundred and seventeen patients showed a normalized IGF1 (157 (range 25–443) ng/ml). In patients with a diagnosis dated back >2 years (n=1013), IGF1 was normalized in 76.9%. Of the patients, 19.5% had an elevated IGF1 and a random GH ≥1 ng/ml, 89% of the patients had at least one surgical intervention, 22% underwent radiotherapy, and 43% received medical treatment. After surgery 38.8% of the patients were controlled without any further therapy. The control rates were higher in surgical centers with a higher caseload (P=0.034). Of the patients with adjunctive radiotherapy 34.8% had a normal IGF1 8.86 (0–44.9) years post irradiation, 65.2% of the medically treated patients were controlled, and 47.2% of the patients with an elevated IGF1 received no medical therapy.ConclusionThe majority of acromegaly patients were controlled according to their IGF1 status. Long-term outcome could be improved by exploiting medical treatment options especially in patients who are not controlled by surgery and/or radiotherapy.
More Than the Sum of Its Parts: A Complex Epistatic Network Underlies Natural Variation in Thermal Preference Behavior inCaenorhabditis elegans
Authors: Gaertner Bryn E , Parmenter Michelle D , Rockman Matthew V , Kruglyak Leonid , Phillips Patrick C 
Published: October 2012

AbstractBehavior is a complex trait that results from interactions among multiple genes and the environment. Both additive and nonadditive effects are expected to contribute to broad-sense heritability of complex phenotypes, although the relative contribution of each of these mechanisms is unknown. Here, we mapped genetic variation in the correlated phenotypes of thermal preference and isothermal dispersion in the nematode Caenorhabditis elegans. Genetic variation underlying these traits is characterized by a set of linked quantitative trait loci (QTL) that interact in a complex epistatic network. In particular, two loci located on the X chromosome interact with one another to generate extreme thermophilic behavior and are responsible for ∼50% of the total variation observed in a cross between two parental lines, even though these loci individually explain very little of the among-line variation. Our results demonstrate that simultaneously considering the influence of a quantitative trait locus (QTL) on multiple scales of behavior can inform the physiological mechanism of the QTL and show that epistasis can explain significant proportions of otherwise unattributed variance within populations.
Surprising Differences in the Variability of Y Chromosomes in African and Cosmopolitan Populations ofDrosophila melanogaster
Authors: Larracuente Amanda M , Clark Andrew G 
Published: October 2012

AbstractThe nonrecombining Drosophila melanogaster Y chromosome is heterochromatic and has few genes. Despite these limitations, there remains ample opportunity for natural selection to act on the genes that are vital for male fertility and on Y factors that modulate gene expression elsewhere in the genome. Y chromosomes of many organisms have low levels of nucleotide variability, but a formal survey of D. melanogaster Y chromosome variation had yet to be performed. Here we surveyed Y-linked variation in six populations of D. melanogaster spread across the globe. We find surprisingly low levels of variability in African relative to Cosmopolitan (i.e., non-African) populations. While the low levels of Cosmopolitan Y chromosome polymorphism can be explained by the demographic histories of these populations, the staggeringly low polymorphism of African Y chromosomes cannot be explained by demographic history. An explanation that is entirely consistent with the data is that the Y chromosomes of Zimbabwe and Uganda populations have experienced recent selective sweeps. Interestingly, the Zimbabwe and Uganda Y chromosomes differ: in Zimbabwe, a European Y chromosome appears to have swept through the population.
Mellkasi trauma: ki, hogyan és mit?
Authors: Molnár F. Tamás 
Published: October 2012

AbsztraktA szerző ismerteti a három éve működő pécsi modell elveit a nemzetközi szakirodalom tükrében, a sebészet és ezen belül a mellkassebészet szerepét az áthatoló testüregi (has, mellkas) sérülések ellátásában. A mellűri drainage kiemelt szerepű úgy a terápiában, mint a sebészi döntéshozatalban, a diagnosztikában. A thoracotomia melletti döntés és elvégzése sebészi kompetencia, akárcsak a damage control. A definitív ellátás és a szövődmények kezelése általános mellkassebészt igényel. Hangsúlyozza a multidiszciplinaritást.
Inhibition of Transforming Growth Factor β1/Smad3 Signaling Decreases Hypoxia‐Inducible Factor‐1α Protein Stability by Inducing Prolyl Hydroxylase 2 Expression in Human Periodontal Ligament Cells
Authors: Watanabe Teppei , Yasue Akihiro , Tanaka Eiji 
Published: October 2012

Background: Hypoxia‐inducible factor‐1α (HIF‐1α), the α subunit of the heterodimeric transcription factor HIF‐1, maintains oxygen homeostasis by regulating gene expression. Under normoxic conditions, HIF‐1α expression is maintained at low steady‐state levels by the critical oxygen sensor prolyl hydroxylase 2 (PHD2). Transforming growth factor β1 (TGF‐β1) activates Smad3 signaling and contributes to HIF‐1α stabilization under normoxic conditions. In chronic periodontitis, HIF‐1α is expressed highly in gingival fibroblasts and upregulates inflammatory factor transcription, which promotes periodontal inflammation. Here, the authors investigated the effect of TGF‐β1/Smad3 signaling and its blockade by the specific inhibitor of Smad3 (SIS3) on HIF‐1α expression and stability in human periodontal ligament cells.Methods: The authors investigated the effect of TGF‐β1 on HIF‐1α protein stability using cycloheximide. Furthermore, they analyzed HIF‐1α expression, PHD2 expression, and Smad3 phosphorylation following TGF‐β1 stimulation in the presence or absence of SIS3.Results: The half‐life of HIF‐1α was prolonged in TGF‐β1–treated cells. TGF‐β1 treatment induced HIF‐1α gene expression and enhanced HIF‐1α protein stability while decreasing PHD2 expression and activating Smad3 phosphorylation. Notably, HIF‐1α protein expression was not detectable prior to TGF‐β1 stimulation. Furthermore, SIS3 treatment abrogated Smad3 phosphorylation, impaired TGF‐β1–induced HIF‐1α gene expression and protein stability, and stimulated TGF‐β1–mediated PHD2 inhibition.Conclusion: These results demonstrate that HIF‐1α transcription and protein synthesis are controlled by TGF‐β1/Smad3 signaling, whereas HIF‐1α protein stability is controlled by PHD2, which is regulated by TGF‐β1/Smad3 signaling.
Timing and Outcome of Renal Replacement Therapy in Patients with Congenital Malformations of the Kidney and Urinary Tract
Authors: Wühl Elke , van Stralen Karlijn J. , Verrina Enrico , Bjerre Anna , Wanner Christoph , Heaf James Goya , Zurriaga Oscar , Hoitsma Andries , Niaudet Patrick , Palsson Runolfur , Ravani Pietro , Jager Kitty J. , Schaefer Franz 
Published: October 2012

Summary

Background and objectives
Congenital anomalies of the kidney and urinary tract (CAKUT) are the leading cause of ESRD in children, but the proportion of patients with individual CAKUT entities progressing to ESRD during adulthood and their long-term clinical outcomes are unknown. This study assessed the age at onset of renal replacement therapy (RRT) and patient and renal graft survival in patients with CAKUT across the entire age range.

Design, setting, participants, & measurements
Patients with CAKUT were compared with age-matched patients who were undergoing RRT for other renal disorders on the basis of data from the European Renal Association-European Dialysis and Transplant Association Registry. Competing risk and Cox regression analyses were conducted.

Results
Of 212,930 patients commencing RRT from 1990 to 2009, 4765 (2.2%) had renal diagnoses consistent with CAKUT. The proportion of incident RRT patients with CAKUT decreased from infancy to childhood and then increased until age 15–19 years, followed by a gradual decline throughout adulthood. Median age at RRT start was 31 years in the CAKUT cohort and 61 years in the non-CAKUT cohort (P<0.001). RRT was started earlier (median, 16 years) in patients with isolated renal dysplasia than in those with renal hypoplasia and associated urinary tract disorders (median, 29.5–39.5 years). Patients with CAKUT survived longer than age- and sex-matched non-CAKUT controls because of lower cardiovascular mortality (10-year survival rate, 76.4% versus 70.7%; P<0.001).

Conclusions
CAKUT leads to ESRD more often at adult than pediatric age. Treatment outcomes differ from those of acquired kidney diseases and vary within CAKUT subcategories.