bluuebunny/crossref_metadata_2025_split huggingface dataset:
Scutellarin alleviates interstitial fibrosis and cardiac dysfunction of infarct rats by inhibiting TGFβ1 expression and activation of p38‐MAPK and ERK1/2
Authors: Pan Zhenwei , Zhao Weiming , Zhang Xiangying , Wang Bing , Wang Jinghao , Sun Xuelin , Liu Xuantong , Feng Shuya , Yang Baofeng , Lu Yanjie 
Published: October 2010

BACKGROUND AND PURPOSEInterstitial fibrosis plays a causal role in the development of heart failure after chronic myocardial infarction (MI), and anti‐fibrotic therapy represents a promising strategy to mitigate this pathological process. The purpose of this study was to investigate the effect of long‐term administration of scutellarin (Scu) on cardiac interstitial fibrosis of myocardial infarct rats and the underlying mechanisms.EXPERIMENTAL APPROACHScu was administered to rats that were subjected to coronary artery ligation. Eight weeks later, its effects on cardiac fibrosis were assessed by examining cardiac function and histology. The number and collagen content of cultured cardiac fibroblasts exposed to angiotensin II (Ang II) were determined after the administration of Scu in vitro. Protein expression was detected by Western blot technique, and mRNA levels by quantitative reverse transcription‐PCR.KEY RESULTSThe echocardiographic and haemodynamic measurements showed that Scu improved the impaired cardiac function of infarct rats and decreased interstitial fibrosis. Scu inhibited the expression of FN1 and TGFβ1, but produced no effects on inflammatory cytokines (TNFα, IL‐1β and IL‐6) in the 8 week infarct hearts. Scu inhibited the proliferation and collagen production of cardiac fibroblasts (CFs) and the up‐regulation of FN1 and TGFβ1 induced by Ang II. The enhanced phosphorylation of p38‐MAPK and ERK1/2 in both infarct cardiac tissue and cultured CFs challenged by Ang II were suppressed by Scu.CONCLUSIONS AND IMPLICATIONSLong‐term administration of Scu improved the cardiac function of MI rats by inhibiting interstitial fibrosis, and the mechanisms may involve the suppression of pro‐fibrotic cytokine TGFβ1 expression and inhibition of p38 MAPK and ERK1/2 phosphorylation.
Disulphide trapping of the GABAA receptor reveals the importance of the coupling interface in the action of benzodiazepines
Authors: Hanson Susan M. , Czajkowski Cynthia 
Published: October 2010

BACKGROUND AND SIGNIFICANCEAlthough the functional effects of benzodiazepines (BZDs) on GABAA receptors have been well characterized, the structural mechanism by which these modulators alter activation of the receptor by GABA is still undefined.EXPERIMENTAL APPROACHWe used disulphide trapping between engineered cysteines to probe BZD‐induced conformational changes within the γ2 subunit and at the α1/γ2 coupling interface (Loops 2, 7 and 9) of α1β2γ2 GABAA receptors.KEY RESULTSCrosslinking γ2Loop 9 to γ2β‐strand 9 (via γ2S195C/F203C and γ2S187C/L206C) significantly decreased maximum potentiation by flurazepam, suggesting that modulation of GABA‐induced current (IGABA) by flurazepam involves movements of γ2Loop 9 relative to γ2β‐strand 9. In contrast, tethering γ2β‐strand 9 to the γ2 pre‐M1 region (via γ2S202C/S230C) significantly enhanced potentiation by both flurazepam and zolpidem, indicating γ2S202C/S230C trapped the receptor in a more favourable conformation for positive modulation by BZDs. Intersubunit disulphide bonds formed at the α/γ coupling interface between α1Loop 2 and γ2Loop 9 (α1D56C/γ2L198C) prevented flurazepam and zolpidem from efficiently modulating IGABA. Disulphide trapping α1Loop 2 (α1D56C) to γ2β‐strand 1 (γ2P64C) decreased maximal IGABA as well as flurazepam potentiation. None of the disulphide bonds affected the ability of the negative modulator, 3‐carbomethoxy‐4‐ethyl‐6,7‐dimethoxy‐β‐carboline (DMCM), to inhibit IGABA.CONCLUSIONS AND IMPLICATIONSPositive modulation of GABAA receptors by BZDs requires reorganization of the loops in the α1/γ2 coupling interface. BZD‐induced movements at the α/γ coupling interface likely synergize with rearrangements induced by GABA binding at the β/α subunit interfaces to enhance channel activation by GABA.
Individualizing treatment duration in hepatitis C virus genotype 2/3‐infected patients
Authors: Mangia Alessandra 
Published: October 2010

AbstractThe drugs currently licensed for the treatment of hepatitis C are Peg‐Interferon (PEG‐IFN) and ribavirin. In recent years, the recommendation to treat hepatitis C virus genotype 2‐ and 3‐infected patients with a fixed 800 mg/day dose of ribavirin in combination with PEG‐IFN and for just 24 weeks has been challenged by the concept of tailoring the length of therapy according to on‐treatment viral response. Therefore, the objective of the present review was to highlight the different designs of the studies on short treatment duration and the role of wk4‐R as a predictor of sustained virological response after an abbreviated course of treatment. The secondary aim was to verify whether we had enough evidence to support the implementation of a short treatment course in subsets of patients with genotype 2 and 3 infection. We will also focus on how drug dosing may have influenced the outcome of treatment. To clarify reasons for discrepant results in the studies so far published, the recently discovered genetic variant near the interleukin 28B gene will be presented and its predictive role will be discussed. Finally, we will face the debated issue of whether the subset of patients with genotype 2 or 3 requires an extended treatment duration.
An Integrative Review of Factors Associated With Falls During Post‐Stroke Rehabilitation
Authors: Campbell Grace B. , Matthews Judith Tabolt 
Published: October 2010

Abstract Purpose: Our aims were to evaluate evidence of risk factors for falls among patients in stroke rehabilitation and to offer recommendations for clinical practice and future research. Method: We conducted an integrative review of the literature published from 1990 to 2009 that describes empirical investigations of risk factors for post‐stroke falls during inpatient rehabilitation. We searched Medline, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycInfo, and Embase databases, using the search terms “accidental falls,”“fall risk,”“risk factors,”“risk assessment,”“stroke,” and “cerebrovascular disorders.” We extracted information regarding study design, sample, potential risk factors, analytic methods, findings, and limitations from the 14 articles that met our inclusion criteria, and we rated the level of evidence for each study. Findings: Available empirical evidence points to impaired balance, visuospatial hemineglect, and impaired performance of activities of daily living as risk factors for falls during inpatient rehabilitation for stroke. Associations between falls and cognitive function, incontinence, visual field deficits, and stroke type were less clear, while relationships between falls and age, gender, stroke location, and impaired vision and hearing were not supported. Conclusions: The relatively sparse literature pertaining to risk factors for falls among stroke rehabilitation inpatients indicates that deficits affecting balance, perception, and self‐care significantly increase the likelihood of falls. Particularly intriguing is the less well established role of post‐stroke cognition in falls in this population. A conceptual model is needed to guide scientific inquiry and clinical practice in this area. Clinical Relevance: When clinicians in the inpatient stroke rehabilitation setting evaluate which patients are at greatest risk to fall, stroke‐specific risk factors such as impaired balance, visuospatial hemineglect, and self‐care deficits may be better predictors than more general risk factors such as age, incontinence, and sensory impairments. Patients with these stroke‐specific deficits may benefit from the use of aggressive fall prevention interventions.
Differential expression of MSX2 in nodular hyperplasia, high‐grade prostatic intraepithelial neoplasia and prostate adenocarcinoma
Authors: CHUA CHEE‐WAI , CHIU YUNG‐TUEN , YUEN HIU‐FUNG , CHAN KWOK‐WAH , WANG XIANGHONG , LING MING‐TAT , WONG YONG‐CHUAN 
Published: October 2010

Chua C‐W, Chiu Y‐T, Yuen H‐F, Chan K‐W, Wang X, Ling M‐T, Wong Y‐C. Differential expression of MSX2 in nodular hyperplasia, high‐grade prostatic intraepithelial neoplasia and prostate adenocarcinoma. APMIS 2010; 118: 918–26.One of the common features in advanced prostate cancer is bone metastasis. In this study, we investigated the clinical relevance of a bone factor, MSX2, in predicting the metastatic ability of prostate adenocarcinoma. Evaluation of MSX2 expression was performed using prostate cell lines as well as patient specimens. A sharp decrease in MSX2 was found in primary prostate cancer cells, 22Rv1, when compared with the non‐malignant counterparts, followed by a gradual increase in more aggressive prostate cancer cell lines. Interestingly, the MSX2 protein was upregulated and predominantly expressed in the nucleus in aggressive prostate cancer cell line, C4‐2b, compared with the less aggressive 22Rv1. Consistent with the in vitro results, MSX2 nuclear expression was significantly higher in nodular hyperplasia when compared with high‐grade prostatic intraepithelial neoplasia (PIN), while MSX2 nuclear expression in prostate adenocarcinoma was higher than that in high‐grade PIN. Importantly, MSX2 expression was increased significantly in tumors with metastasis compared with those without metastasis. Finally, MSX2 nuclear scores were significantly increased in patients with preoperative serum PSA >20 ng/mL. No correlation between MSX2 nuclear score and Gleason score was found. Taken together, MSX2 may serve as a potential biomarker in predicting primary prostate tumors with higher metastatic capability.
Genetic Diversity of Human Zoonotic Leishmaniasis in Iberian Peninsula
Authors: Cortes S. , Chicharro C. , Cruz I. , Cristovão J. M. , Cañavate C. , Campino L. 
Published: October 2010

SummaryLeishmaniasis caused by Leishmania (Leishmania) infantum is a zoonotic disease endemic in South Europe, from Portugal to the Middle East. The aim of the present study was to investigate the genetic diversity of L. infantum parasites in Iberian Peninsula. Twenty‐four L. infantum strains isolated from immunocompetent patients with leishmaniasis from several localities of Portugal and Spain were studied. The use of kinetoplast DNA–PCR–restriction fragment length polymorphism as a molecular marker revealed intra‐specific variation. No association was found between genotype and clinical form of the disease or patients age group. Two main clusters were identified with this marker: (i) zymodeme MON‐1 strains and (ii) non‐MON‐1 strains. However, no association was found between strains variability and geographical distribution suggesting that parasite populations of different regions in the Iberian Peninsula are homogenous.
Antimicrobial Resistance in Swiss Laying Hens, Prevalence and Risk Factors
Authors: Harisberger M. , Gobeli S. , Hoop R. , Dewulf J. , Perreten V. , Regula G. 
Published: October 2010

SummaryAntimicrobial resistance is an emerging concern to public health, and food‐producing animals are known to be a potential source for transmission of resistant bacteria to humans. As legislation of the European Union requires to ban conventional cages for the housing of laying hens on the one hand, and a high food safety standard for eggs on the other hand, further investigations about the occurrence of antimicrobial resistance in alternative housing types are required. In this study, we determined antimicrobial resistance in indicator bacteria from 396 cloacal swabs from 99 Swiss laying hen farms among four alternative housing types during a cross‐sectional study. On each farm, four hens were sampled and exposure to potential risk factors was identified with a questionnaire. The minimal inhibitory concentration was determined using broth microdilution in Escherichia coli (n = 371) for 18 antimicrobials and in Enterococcus faecalis (n = 138) and Enterococcus faecium (n = 153) for 16 antimicrobials. All antimicrobial classes recommended by the European Food Safety Authority for E. coli and enterococci were included in the resistance profile. Sixty per cent of the E. coli isolates were susceptible to all of the considered antimicrobials and 30% were resistant to at least two antimicrobials. In E. faecalis, 33% of the strains were susceptible to all tested antimicrobials and 40% were resistant to two or more antimicrobials, whereas in E. faecium these figures were 14% and 39% respectively. Risk factor analyses were carried out for bacteria species and antimicrobials with a prevalence of resistance between 15% and 85%. In these analyses, none of the considered housing and management factors showed a consistent association with the prevalence of resistance for more than two combinations of bacteria and antimicrobial. Therefore we conclude that the impact of the considered housing and management practices on the egg producing farms on resistance in laying hens is low.
Estimating the National Impact of the Financial Crisis in Indonesia by Combining a Rapid Qualitative Study with Nationally Representative Surveys
Authors: McCulloch Neil , Grover Amit 
Published: October 2010

SummaryThis paper draws on a rapid qualitative assessment of the impact of the financial crisis in Indonesia, to generate hypotheses about the potential national impacts. We test these hypotheses using nationally representative labour force surveys from before and after the onset of the financial crisis. We find that Indonesia weathered the storm rather well: there is no evidence for increased school dropout; labour force participation fell, particularly for young workers, whilst unemployment rose for the young, but fell for workers over 25. The changes for female workers were the same as those for male workers and there do not appear to have been any major sectoral shifts in labour. Surprisingly, we find that real wages for employees rose significantly during the crisis period, although those in the informal sector did not benefit to the same extent. Our results are similar to those from the earlier qualitative study, except that, because it focused on areas harder hit by the crisis, the qualitative study did not observe the significant gains made by employees over the crisis period.
Cdc42-Interacting Protein 4 Promotes Breast Cancer Cell Invasion and Formation of Invadopodia through Activation of N-WASp
Authors: Pichot Christina S. , Arvanitis Constadina , Hartig Sean M. , Jensen Samuel A. , Bechill John , Marzouk Saad , Yu Jindan , Frost Jeffrey A. , Corey Seth J. 
Published: October 2010

Abstract
In the earliest stages of metastasis, breast cancer cells must reorganize the cytoskeleton to affect cell shape change and promote cell invasion and motility. These events require the cytoskeletal regulators Cdc42 and Rho, their effectors such as N-WASp/WAVE, and direct inducers of actin polymerization such as Arp2/3. Little consideration has been given to molecules that shape the cell membrane. The F-BAR proteins CIP4, TOCA-1, and FBP17 generate membrane curvature and act as scaffolding proteins for activated Cdc42 and N-WASp. We found that expression of CIP4, but not TOCA-1 or FBP17, was increased in invasive breast cancer cell lines in comparison with weakly or noninvasive breast cancer cell lines. Endogenous CIP4 localized to the leading edge of migrating cells and to invadopodia in cells invading gelatin. Because CIP4 serves as a scaffolding protein for Cdc42, Src, and N-WASp, we tested whether loss of CIP4 could result in decreased N-WASp function. Interaction between CIP4 and N-WASp was epidermal growth factor responsive, and CIP4 silencing by small interfering RNA caused decreased tyrosine phosphorylation of N-WASp at a Src-dependent activation site (Y256). CIP4 silencing also impaired the migration and invasion of MDA-MB-231 cells and was associated with decreased formation of invadopodia and gelatin degradation. This study presents a new role for CIP4 in the promotion of migration and invasion of MDA-MB-231 breast cancer cells and establishes the contribution of F-BAR proteins to cancer cell motility and invasion. Cancer Res; 70(21); 8347–56. ©2010 AACR.
Protein Kinase D1 Suppresses Epithelial-to-Mesenchymal Transition through Phosphorylation of Snail
Authors: Du Cheng , Zhang Chuanyou , Hassan Sazzad , Biswas Md. Helal Uddin , Balaji K.C. 
Published: October 2010

Abstract
Cancer cells undergo epithelial-mesenchymal transition (EMT) as a program of increased invasion and metastasis during cancer progression. Here, we report that a novel regulator of EMT in cancer cells is protein kinase D1 (PKD1), which is downregulated in advanced prostate, breast, and gastric cancers. Ectopic reexpression of PKD1 in metastatic prostate cancer cells reversibly suppressed expression of mesenchyme-specific genes and increased epithelial markers such as E-cadherin, whereas small interfering RNA–mediated knockdown of PKD1 increased expression of mesenchyme markers. Further, PKD1 inhibited tumor growth and metastasis in a tumor xenograft model. PKD1 phosphorylates Ser11 (S11) on transcription factor Snail, a master EMT regulator and repressor of E-cadherin expression, triggering nuclear export of Snail via 14-3-3σ binding. Snail S11 mutation causes acquisition of mesenchymal traits and expression of stem cell markers. Together, our results suggest that PKD1 functions as a tumor and metastasis suppressor, at least partly by regulating Snail-mediated EMT, and that loss of PKD1 may contribute to acquisition of an aggressive malignant phenotype. Cancer Res; 70(20); 7810–9. ©2010 AACR.
Ionizing Radiation Activates the Nrf2 Antioxidant Response
Authors: McDonald J. Tyson , Kim Kwanghee , Norris Andrew J. , Vlashi Erina , Phillips Tiffany M. , Lagadec Chann , Della Donna Lorenza , Ratikan Josephine , Szelag Heather , Hlatky Lynn , McBride William H. 
Published: October 2010

AbstractThe transcription factor NF-E2-related factor 2 (Nrf2) binds the antioxidant DNA response element (ARE) to activate important cellular cytoprotective defense systems. Recently several types of cancers have been shown to overexpress Nrf2, but its role in the cellular response to radiation therapy has yet to be fully determined. In this study, we report that single doses of ionizing radiation from 2 to 8 Gy activate ARE-dependent transcription in breast cancer cells in a dose-dependent manner, but only after a delay of five days. Clinically relevant daily dose fractions of radiation also increased ARE-dependent transcription, but again only after five days. Downstream activation of Nrf2-ARE-dependent gene and protein markers, such as heme oxygenase-1, occurred, whereas Nrf2-deficient fibroblasts were incapable of these responses. Compared with wild-type fibroblasts, Nrf2-deficient fibroblasts had relatively high basal levels of reactive oxygen species that increased greatly five days after radiation exposure. Further, in vitro clonogenic survival assays and in vivo sublethal whole body irradiation tests showed that Nrf2 deletion increased radiation sensitivity, whereas Nrf2-inducing drugs did not increase radioresistance. Our results indicate that the Nrf2-ARE pathway is important to maintain resistance to irradiation, but that it operates as a second-tier antioxidant adaptive response system activated by radiation only under specific circumstances, including those that may be highly relevant to tumor response during standard clinical dose-fractionated radiation therapy. Cancer Res; 70(21); 8886–95. ©2010 AACR.
Tumor Cell Kill by c-MYC Depletion: Role of MYC-Regulated Genes that Control DNA Double-Strand Break Repair
Authors: Luoto Kaisa R. , Meng Alice X. , Wasylishen Amanda R. , Zhao Helen , Coackley Carla L. , Penn Linda Z. , Bristow Robert G. 
Published: October 2010

Abstract
MYC regulates a myriad of genes controlling cell proliferation, metabolism, differentiation, and apoptosis. MYC also controls the expression of DNA double-strand break (DSB) repair genes and therefore may be a potential target for anticancer therapy to sensitize cancer cells to DNA damage or prevent genetic instability. In this report, we studied whether MYC binds to DSB repair gene promoters and modulates cell survival in response to DNA-damaging agents. Chromatin immunoprecipitation studies showed that MYC associates with several DSB repair gene promoters including Rad51, Rad51B, Rad51C, XRCC2, Rad50, BRCA1, BRCA2, DNA-PKcs, XRCC4, Ku70, and DNA ligase IV. Endogenous MYC protein expression was associated with increased RAD51 and KU70 protein expression of a panel of cancer cell lines of varying histopathology. Induction of MYC in G0-G1 and S-G2-M cells resulted in upregulation of Rad51 gene expression. MYC knockdown using small interfering RNA (siRNA) led to decreased RAD51 expression but minimal effects on homologous recombination based on a flow cytometry direct repeat green fluorescent protein assay. siRNA to MYC resulted in tumor cell kill in DU145 and H1299 cell lines in a manner independent of apoptosis. However, MYC-dependent changes in DSB repair protein expression were not sufficient to sensitize cells to mitomycin C or ionizing radiation, two agents selectively toxic to DSB repair–deficient cells. Our results suggest that anti-MYC agents may target cells to prevent genetic instability but would not lead to differential radiosensitization or chemosensitization. Cancer Res; 70(21); 8748–59. ©2010 AACR.
Phosphorylation of RalB Is Important for Bladder Cancer Cell Growth and Metastasis
Authors: Wang Hong , Owens Charles , Chandra Nidhi , Conaway Mark R. , Brautigan David L. , Theodorescu Dan 
Published: October 2010

AbstractRalA and RalB are monomeric G proteins that are 83% identical in amino acid sequence but have paralogue-specific effects on cell proliferation, metastasis, and apoptosis. Using in vitro kinase assays and phosphosite-specific antibodies, here we show phosphorylation of RalB by protein kinase C (PKC) and RalA by protein kinase A. We used mass spectrometry and site-directed mutagenesis to identify S198 as the primary PKC phosphorylation site in RalB. Phorbol ester [phorbol 12-myristate 13-acetate (PMA)] treatment of human bladder carcinoma cells induced S198 phosphorylation of stably expressed FLAG-RalB as well as endogenous RalB. PMA treatment caused RalB translocation from the plasma membrane to perinuclear regions in a S198 phosphorylation–dependent manner. Using RNA interference depletion of RalB followed by rescue with wild-type RalB or RalB(S198A) as well as overexpression of wild-type RalB or RalB(S198A) with and without PMA stimulation, we show that phosphorylation of RalB at S198 is necessary for actin cytoskeletal organization, anchorage-independent growth, cell migration, and experimental lung metastasis of T24 or UMUC3 human bladder cancer cells. In addition, UMUC3 cells transfected with a constitutively active RalB(G23V) exhibited enhanced subcutaneous tumor growth, whereas those transfected with phospho-deficient RalB(G23V-S198A) were indistinguishable from control cells. Our data show that RalA and RalB are phosphorylated by different kinases, and RalB phosphorylation is necessary for in vitro cellular functions and in vivo tumor growth and metastasis. Cancer Res; 70(21); 8760–9. ©2010 AACR.