bluuebunny/crossref_metadata_2025_split huggingface dataset:
Oxysterol-Binding Protein Family I Is the Target of Minor Enviroxime-Like Compounds
Authors: Arita Minetaro , Kojima Hirotatsu , Nagano Tetsuo , Okabe Takayoshi , Wakita Takaji , Shimizu Hiroyuki 
Published: January 2013

ABSTRACT
Enviroxime is an antipicornavirus compound that targets host phosphatidylinositol 4-kinase III beta (PI4KB) activity for its antipicornavirus activity. To date, several antipoliovirus (PV) compounds similar to enviroxime that are associated with a common resistance mutation in viral protein 3A (a G5318A [3A-Ala70Thr] mutation in PV) have been identified. Most of these compounds have a direct inhibitory effect on PI4KB activity, as well as enviroxime (designated major enviroxime-like compounds). However, one of the compounds, AN-12-H5, showed no inhibitory effect on PI4KB and was considered to belong to another group of enviroxime-like compounds (designated minor enviroxime-like compounds). In the present study, we performed a small interfering RNA (siRNA) sensitization assay targeting PI4KB-related genes and identified oxysterol-binding protein (OSBP) as a target of minor enviroxime-like compounds. Knockdown of OSBP and OSBP2 increased the anti-PV activities of AN-12-H5 and a newly identified minor enviroxime-like compound, T-00127-HEV2, and also to T-00127-HEV1 to a minor extent, in the cells. A ligand of OSBP, 25-hydroxycholesterol (25-HC), acted as a minor enviroxime-like compound. Minor enviroxime-like compounds induced relocalization of OSBP to the Golgi apparatus in cells. Treatment of the cells with major or minor enviroxime-like compounds suppressed the expression of genes (HMGCS1 and SQLE) in the SREBP/SCAP regulatory pathway and diminished endogenous phosphatidylinositol 4-phosphate (PI4P) at the Golgi apparatus. Our results suggested that minor enviroxime-like compounds are phenotypically identical to 25-HC and that major and minor enviroxime-like compounds suppress the production and/or accumulation of PI4P in PV-infected cells by targeting PI4KB and OSBP family I activities, respectively.
The development of healthy tennis clubs in the Netherlands
Authors: Pluim Babette M , Earland Jane , Pluim Nicole E 
Published: January 2013

ObjectivesTo explore the factors that facilitate or hinder the development of healthy tennis clubs in the Netherlands and to identify suitable interventions that would help clubs to reach ‘healthy club’ status.MethodsA maximum variation, purposive sampling strategy was used to identify and recruit board members (n=16) from 10 Dutch tennis clubs. Data were collected using in-depth interviews based on an interview guide. The interviews explored what steps the clubs had taken to create a healthy tennis club, and what the respondents perceived to be the barriers to reaching healthy club status. The data were analysed using thematic content analysis. An ecological model was used to frame the interpretation of the themes and guide the development of the interventions.ResultsFour emerging themes were identified: provision of healthy foods, injury prevention and health services, social health and safety around the club. The main facilitators were found to be support from club management, having appropriate policies in place and having appointed officers. The main barriers were identified as a lack of policy templates, inadequate knowledge of coaches on injury prevention and injury management and fragmented access to relevant information.ConclusionsGuided by an ecological model, this study demonstrates the many factors that influence tennis clubs and the individual members of a healthy tennis club. Using this model, a multilevel intervention framework has been created that could be used by the Royal Netherlands Lawn Tennis Association to increase the number of healthy tennis clubs in the Netherlands.
Vancomycin Ophthalmic Ointment 1% for methicillin-resistantStaphylococcus aureusor methicillin-resistantStaphylococcus epidermidisinfections: a case series
Authors: Sotozono Chie , Fukuda Masahiko , Ohishi Masao , Yano Keiko , Origasa Hideki , Saiki Yoshinori , Shimomura Yoshikazu , Kinoshita Shigeru 
Published: January 2013

ObjectivesTo investigate the efficacy and safety of Vancomycin Ophthalmic Ointment 1% (Toa Pharmaceutical Co., Ltd, Toyama, Japan) in patients with external ocular infections caused by methicillin-resistantStaphylococcus aureus(MRSA) or methicillin-resistantStaphylococcus epidermidis(MRSE).DesignA case series.SettingThis study was a multicentre, open-label, uncontrolled study in Japan approved as orphan drug status.ParticipantsPatients with MRSA or MRSE external ocular infections unresponsive to the treatment of fluoroquinolone eye drops.InterventionsVancomycin Ophthalmic Ointment 1% was administered four times daily.Primary and secondary outcome measuresThe subjective and objective clinical scores and bacterial cultures were collected at days 0 (baseline), 3, 7 and 14. The primary outcome was clinical response evaluation (efficacy rate) determined ascomplete response,partial response,no responseandworsening. Secondary outcome was the eradication of the bacteria. Safety was assessed by adverse events including cases in which neither MRSA nor MRSE was detected.ResultsTwenty-five cases with MRSA (20) or MRSE (5) infections were enrolled. Of these 25 cases, 4 discontinued the treatment due to the negative results for bacterial culture during screening or at baseline. Of the 21 cases with conjunctivitis (14), blepharitis (3), meibomitis (1), dacryocystitis (2) or keratitis (1), 14 (66.7%) cases were evaluated as being excellently (complete response, 2 cases) or well (partial response, 12 cases) treated. The eradication rates were 68.4% in MRSA (13 of 19 cases) and 100% in MRSE (2 of 2 cases). Ten adverse events occurred in 7 (28.0%) of 25 cases at the local administration site.ConclusionsVancomycin Ophthalmic Ointment 1% was considered to be useful for the treatment of intractable ocular MRSA/MRSE infections.
Analysis of DNA Repair–Related Genes in Breast Cancer Reveals CUL4A Ubiquitin Ligase as a Novel Biomarker of Trabectedin Response
Authors: García María J. , Saucedo-Cuevas Laura Paula , Muñoz-Repeto Iván , Fernández Victoria , Robles María J. , Domingo Samuel , Palacios José , Aracil Miguel , Nieto Antonio , Tercero Juan Carlos , Benítez Javier 
Published: January 2013

Abstract
Trabectedin is more active in nucleotide excision repair (NER)-efficient and homologous recombination repair (HRR)-deficient cells. As up to 25% of sporadic breast tumors present somatic inactivation of the HRR pathway (BRCAness phenotype), we sought to characterize trabectedin effect in BRCA1-proficient and BRCA1-null breast cancer cell lines. We evaluated whether HRR and NER gene expression correlates with trabectedin sensitivity and explored the response predictive value of the CUL4A ubiquitin ligase, which ubiquitinates NER pathway members. We characterized trabectedin cytotoxicity, cell-cycle effects, and BRCA1, BRCA2, XRCC3, XPG, ERCC1, and CUL4A expression in 10 breast cancer cell lines. Gene expression and trabectedin sensitivity association were determined in cell lines. Survival assays after trabectedin treatment were conducted in CUL4A-silenced BRCA1-proficient and -deficient cells. Because of limited phase II clinical trials evaluating trabectedin efficacy in patients with breast cancer, we assessed CUL4A immunohistochemical staining in a retrospective series of 118 sarcomas from trabectedin-treated patients to validate in vivo our in vitro observations. In cell lines, greater trabectedin sensitivity was associated with higher CUL4A expression and lower BRCA1/ERCC5, BRCA1/CUL4A, and XRCC3/CUL4A expression ratios. In agreement, BRCA1-deficient CUL4A-knockdown cells presented higher cell survival after trabectedin exposure than did scramble control cells. Lack of effect in BRCA1-proficient cells suggests that HRR impairment is key in CUL4A-mediated trabectedin sensitivity. High CUL4A expression in nontranslocation-related patients with sarcoma predicted improved progression-free survival [PFS; HR, 0.37; 95% confidence interval (CI), 0.20–0.68, P = 0.001] and overall survival (OS; HR, 0.44; 95% CI, 0.21–0.93, P = 0.026). Our observations support the notion of greater trabectedin activity in tumors exhibiting BRCAness and reveal CUL4A as a potential biomarker for definition of trabectedin target patients. Mol Cancer Ther; 12(4); 530–41. ©2013 AACR.
Poly(β-amino ester) Nanoparticle Delivery of TP53 Has Activity against Small Cell Lung Cancer In Vitro and In Vivo
Authors: Kamat Chandrashekhar D. , Shmueli Ron B. , Connis Nick , Rudin Charles M. , Green Jordan J. , Hann Christine L. 
Published: January 2013

Abstract
Small cell lung cancer (SCLC) is an aggressive disease with one of the highest case-fatality rates among cancer. The recommended therapy for SCLCs has not changed significantly over the past 30 years; new therapeutic approaches are a critical need. TP53 is mutated in the majority of SCLC cases and its loss is required in transgenic mouse models of the disease. We synthesized an array of biodegradable poly(β-amino ester) (PBAE) polymers that self-assemble with DNA and assayed for transfection efficiency in the p53-mutant H446 SCLC cell line using high-throughput methodologies. Two of the top candidates were selected for further characterization and TP53 delivery in vitro and in vivo. Nanoparticle delivery of TP53 resulted in expression of exogenous p53, induction of p21, induction of apoptosis, and accumulation of cells in sub-G1 consistent with functional p53 activity. Intratumoral injection of subcutaneous H446 xenografts with polymers carrying TP53 caused marked tumor growth inhibition. This is the first demonstration of TP53 gene therapy in SCLC using nonviral polymeric nanoparticles. This technology may have general applicability as a novel anticancer strategy based on restoration of tumor suppressor gene function. Mol Cancer Ther; 12(4); 405–15. ©2013 AACR.
SNF5 Reexpression in Malignant Rhabdoid Tumors Regulates Transcription of Target Genes by Recruitment of SWI/SNF Complexes and RNAPII to the Transcription Start Site of Their Promoters
Authors: Kuwahara Yasumichi , Wei Darmood , Durand Joel , Weissman Bernard E. 
Published: January 2013

Abstract
Malignant rhabdoid tumor (MRT), a highly aggressive cancer of young children, displays inactivation or loss of the hSNF5/INI1/SMARCB1 gene, a core subunit of the SWI/SNF chromatin-remodeling complex, in primary tumors and cell lines. We have previously reported that reexpression of hSNF5 in some MRT cell lines causes a G1 arrest via p21CIP1/WAF1 (p21) mRNA induction in a p53-independent manner. However, the mechanism(s) by which hSNF5 reexpression activates gene transcription remains unclear. We initially searched for other hSNF5 target genes by asking whether hSNF5 loss altered regulation of other consensus p53 target genes. Our studies show that hSNF5 regulates only a subset of p53 target genes, including p21 and NOXA, in MRT cell lines. We also show that hSNF5 reexpression modulates SWI/SNF complex levels at the transcription start site (TSS) at both loci and leads to activation of transcription initiation through recruitment of RNA polymerase II (RNAPII) accompanied by H3K4 and H3K36 modifications. Furthermore, our results show lower NOXA expression in MRT cell lines compared with other human tumor cell lines, suggesting that hSNF5 loss may alter the expression of this important apoptotic gene. Thus, one mechanism for MRT development after hSNF5 loss may rely on reduced chromatin-remodeling activity of the SWI/SNF complex at the TSS of critical gene promoters. Furthermore, because we observe growth inhibition after NOXA expression in MRT cells, the NOXA pathway may provide a novel target with clinical relevancy for treatment of this aggressive disease.
Visual Overview: http://mcr.aacrjournals.org/content/11/3/251/F1.large.jpg.
Mol Cancer Res; 11(3); 251–60. ©2013 AACR.
Inhibition of TWIST1 Leads to Activation of Oncogene-Induced Senescence in Oncogene-Driven Non–Small Cell Lung Cancer
Authors: Burns Timothy F. , Dobromilskaya Irina , Murphy Sara C. , Gajula Rajendra P. , Thiyagarajan Saravanan , Chatley Sarah N.H. , Aziz Khaled , Cho Yoon-Jae , Tran Phuoc T. , Rudin Charles M. 
Published: January 2013

Abstract
A large fraction of non–small cell lung cancers (NSCLC) are dependent on defined oncogenic driver mutations. Although targeted agents exist for EGFR- and EML4-ALK–driven NSCLCs, no therapies target the most frequently found driver mutation, KRAS. Furthermore, acquired resistance to the currently targetable driver mutations is nearly universally observed. Clearly a novel therapeutic approach is needed to target oncogene-driven NSCLCs. We recently showed that the basic helix-loop-helix transcription factor Twist1 cooperates with mutant Kras to induce lung adenocarcinoma in transgenic mouse models and that inhibition of Twist1 in these models led to Kras-induced senescence. In the current study, we examine the role of TWIST1 in oncogene-driven human NSCLCs. Silencing of TWIST1 in KRAS-mutant human NSCLC cell lines resulted in dramatic growth inhibition and either activation of a latent oncogene-induced senescence program or, in some cases, apoptosis. Similar effects were observed in EGFR mutation–driven and c-Met–amplified NSCLC cell lines. Growth inhibition by silencing of TWIST1 was independent of p53 or p16 mutational status and did not require previously defined mediators of senescence, p21 and p27, nor could this phenotype be rescued by overexpression of SKP2. In xenograft models, silencing of TWIST1 resulted in significant growth inhibition of KRAS-mutant, EGFR-mutant, and c-Met–amplified NSCLCs. Remarkably, inducible silencing of TWIST1 resulted in significant growth inhibition of established KRAS-mutant tumors. Together these findings suggest that silencing of TWIST1 in oncogene driver–dependent NSCLCs represents a novel and promising therapeutic strategy. Mol Cancer Res; 11(4); 329–38. ©2013 AACR.
Diminished Origin-Licensing Capacity Specifically Sensitizes Tumor Cells to Replication Stress
Authors: Zimmerman Kristin M. , Jones Rebecca M. , Petermann Eva , Jeggo Penelope A. 
Published: January 2013

Abstract
Previous studies have shown that dormant licensed replication origins can be exploited to enhance recovery from replication stress. Since tumor cells express high levels of origin-licensing proteins, we examined whether depletion of such factors might specifically sensitize tumor versus nontumor cells. Consistent with previous findings, we observed that three tumor-derived cell lines overexpress ORC1, a licensing component, compared with four nontumor cell lines and that a greater level of ORC1 was required to maintain viability in the tumor cells. We determined siRNA-mediated knockdown conditions for each line that maximally reduced ORC1 but did not impact upon viability, which we considered would optimally deplete dormant origins. ORC1 depletion hypersensitized the tumor-derived cells to hydroxyurea and H202 but did not affect the sensitivity of the nontumor lines. Similar results were observed following depletion of ORC6 or CDC6. Furthermore, codepletion of p53 and ORC1 modestly impaired viability of 1BR3hTERT nontumor fibroblasts and more dramatically caused hypersensitivity to hydroxyurea. Finally, overexpression of the c-Myc oncogene combined with ORC1 depletion in nontumor BJhTERT cells diminished viability. Collectively, these findings suggest that tumor cells may have a reliance on origin-licensing capacity, suggesting that licensing factors could represent a target for drug-based cancer therapy. Mol Cancer Res; 11(4); 370–80. ©2013 AACR.
Implications of Early Aortic Stiffening in Patients With Transposition of the Great Arteries After Arterial Switch Operation
Authors: Voges Inga , Jerosch-Herold Michael , Hedderich Jürgen , Hart Christopher , Petko Colin , Scheewe Jens , Andrade Ana Cristina , Pham Minh , Gabbert Dominik , Kramer Hans-Heiner , Rickers Carsten 
Published: January 2013

Background—
The elastic function of the aorta in patients with transposition of the great arteries after arterial switch operation (ASO) is suspected to be important for long-term prognosis.

Methods and Results—

Fifty-one patients and 34 controls were studied at 3.0 Tesla with MRI. Forty-three patients (12.8±6.9 years) underwent 1-stage ASO, 8 patients (23.8±6.9 years) had prior pulmonary artery banding (2-stage ASO). Aortic dimensions, distensibility, pulse wave velocity, aortic arch angle, left ventricular (LV) mass, LV systolic function and left atrial (LA) volumes, and LA passive emptying function as marker of LV diastolic function were assessed. Compared with controls, patients had increased aortic root areas (602.6±240.5 versus 356.8±113.4 mm
2
/m;
P
<0.01) and reduced distensibility of the thoracic aorta most pronounced at the aortic root (3.2±2.0 versus 9.1±4.7×10
−3
mm Hg
−1
;
P
<0.01). Aortic distensibility correlated negatively with the aortic areas (
P
<0.01). Pulse wave velocity was higher in adults after ASO (5.0±1.0 versus 3.8±1.3 m/s;
P
<0.01). In contrast to controls pulse wave velocity and distensibility correlated with age in patients (
P
=0.04 to <0.01), LV mass was higher in patients (
P
=0.02). LA volumes correlated negatively with aortic root and ascending aortic distensibility and positively with pulse wave velocity (
P
<0.05). In patients, LA passive emptying function was lower (27.3±8.9 versus 41.1±6.0;
P
<0.01) and correlated with aortic root distensibility (
P
=0.004).

Conclusions—
Reduced aortic bioelasticity and aortic root dilatation are present in transposition of the great artery patients post ASO and are likely to contribute to LV diastolic dysfunction. Impaired aortic bioelasticity was strongly associated with age, suggesting the usefulness of follow-up studies for early onset of degenerative cardiovascular disease.
Role of the Seasonal Cycle in the Subduction Rates of Upper–Southern Ocean Waters
Authors: Kwon Eun Young , Downes Stephanie M. , Sarmiento Jorge L. , Farneti Riccardo , Deutsch Curtis 
Published: February 2013

Abstract
A kinematic approach is used to diagnose the subduction rates of upper–Southern Ocean waters across seasonally migrating density outcrops at the base of the mixed layer. From an Eulerian viewpoint, the term representing the temporal change in the mixed layer depth (which is labeled as the temporal induction in this study; i.e., Stemp = ∂h/∂t where h is the mixed layer thickness, and t is time) vanishes over several annual cycles. Following seasonally migrating density outcrops, however, the temporal induction is attributed partly to the temporal change in the mixed layer thickness averaged over a density outcrop following its seasonally varying position and partly to the lateral movement of the outcrop position intersecting the sloping mixed layer base. Neither the temporal induction following an outcrop nor its integral over the outcrop area vanishes over several annual cycles. Instead, the seasonal eddy subduction, which arises primarily because of the subannual correlations between the seasonal cycles of the mixed layer depth and the outcrop area, explains the key mechanism by which mode waters are transferred from the mixed layer to the underlying pycnocline. The time-mean exchange rate of waters across the base of the mixed layer is substantially different from the exchange rate of waters across the fixed winter mixed layer base in mode water density classes. Nearly 40% of the newly formed Southern Ocean mode waters appear to be diapycnally transformed within the seasonal pycnocline before either being subducted into the main pycnocline or entrained back to the mixed layer through lighter density classes.
Opiate agonists and antagonists modulate taste perception in opiate-maintained and recently detoxified subjects
Authors: Green Amy , Kaul Arun , O’Shea Jacinta , Sharma Ekta , Bennett Lisa , Mullings Emma L , Munafò Marcus R , Nutt David J , Melichar Jan K , Donaldson Lucy F 
Published: January 2013

Heroin addicts consume large quantities of refined sugars. This study investigated the effect of opiate use and antagonism on sweet taste in opiate-maintained drug users and detoxified former chronic opiate users, using a within-subject design. Seven opiate users received methadone and seven buprenorphine maintenance. Six detoxified subjects received naltrexone. Sucrose recognition thresholds and measurements of pleasantness and intensity were determined before and four hours after 1) a single dose of methadone or buprenorphine or 2) naltrexone. Control data were taken from a cohort of healthy volunteers including smokers. All measures of sweet and salt taste perception were significantly greater in opiate users and recently detoxified subjects compared to control subjects, with the exception of sweet pleasantness, which returned to control level after detoxification. Acute methadone administration reduced salt thresholds and unpleasantness to control levels. Increased sweet thresholds and salt unpleasantness in detoxified subjects were reversed by acute opioid antagonism, returning to control levels. These results suggest that opiate use and antagonism alters taste perception. Some of the alterations reverse on detoxification (sweet pleasantness), and others can be reversed by opioid antagonism (sweet threshold, salt unpleasantness). Changes in taste perception may underlie altered consumption of refined sugars in opiate users.