bluuebunny/crossref_metadata_2025_split huggingface dataset:
The effects of parental education on exercise behavior in childhood and youth: a study in Dutch and Finnish twins
Authors: Huppertz C. , Bartels M. , de Geus E. J. C. , van Beijsterveldt C. E. M. , Rose R. J. , Kaprio J. , Silventoinen K. 
Published: July 2016

Twin studies have estimated the relative contribution of genes and the environment to variance in exercise behavior and it is known that parental education positively affects exercise levels. This study investigates the role of parental education as a potential modifier of variance in exercise behavior from age 7 to 18 years. The study is based on large datasets from the Netherlands Twin Register (NTR: N = 24 874 twins; surveys around the ages of 7, 10, 12, 14, 16 and 18 years) and two Finnish twin cohorts (FinnTwin12: N = 4399; 12, 14 and 17 years; FinnTwin16: N = 4648; 16, 17 and 18 years). Regular participation in moderate‐to‐vigorous exercise activities during leisure time was assessed by survey. Parental education was dichotomized (“both parents with a low education” vs “at least one parent with a high education”). The mean in exercise behavior tended to be higher and the variance tended to be lower in children of high educated parents. Evidence for gene‐by‐environment interaction was weak. To develop successful interventions that specifically target children of low educated parents, the mechanisms causing the mean and variance differences between the two groups should be better understood.
Successful treatment of a disseminated infection with extensively drug‐resistant Klebsiella pneumoniae in a liver transplant recipient with a fosfomycin‐based multidrug regimen
Authors: Mills J.P. , Wilck M.B. , Weikert B.C. , Porrett P.M. , Timko D. , Alby K. , Bonomo R.A. , Blumberg E.A. 
Published: July 2016

AbstractDonor‐derived infections with multidrug‐resistant gram‐negative bacteria are associated with poor outcomes, in part because of limited treatment options. Here, we describe a case of donor‐derived, disseminated infection with colistin‐resistant, carbapenemase‐producing Klebsiella pneumoniae in a liver transplant recipient that was cured with addition of intravenous fosfomycin to a multidrug regimen, in conjunction with aggressive surgical source control. Intravenous fosfomycin represents a promising adjunctive agent for use in treatment of extensively drug‐resistant infections in immunocompromised hosts.
Physical Education Teachers’ Perspectives and Experiences When Teaching FMS to Early Adolescent Girls
Authors: Lander Natalie J. , Hanna Lisa , Brown Helen , Telford Amanda , Morgan Philip J. , Salmon Jo , Barnett Lisa M. 
Published: July 2016

Purpose:Competence in fundamental movement skills (FMSs) is positively associated with physical activity, fitness, and healthy weight status. However, adolescent girls exhibit very low levels of fundamental movement skill (FMS) proficiency.Method:In the current study, interviews were carried out with physical education teachers to investigate their perspectives of: (i) the importance and relevance of teaching FMSs to Year 7 girls, and (ii) the factors influencing effective FMS instruction.Results:There were two major findings in the data: Year 7 was perceived to be a critical period to instruct girls in FMSs; and current teaching practices were perceived to be suboptimal for effective FMS instruction.Conclusion:Apparent deficits in current FMS teaching practice may be improved with more comprehensive teacher training (both during physical education teacher education (PETE) and in in-service professional development) in pedagogical strategies, curriculum interpretation, and meaningful assessment.
Use of Comparative Genomics To Characterize the Diversity of Acinetobacter baumannii Surveillance Isolates in a Health Care Institution
Authors: Wallace Lalena , Daugherty Sean C. , Nagaraj Sushma , Johnson J. Kristie , Harris Anthony D. , Rasko David A. 
Published: July 2016

ABSTRACT

Despite the increasing prevalence of the nosocomial pathogen
Acinetobacter baumannii
, little is known about which genomic components contribute to clinical presentation of this important pathogen. Most whole-genome comparisons of
A. baumannii
have focused on specific genomic regions associated with phenotypes in a limited number of genomes. In this work, we describe the results of a whole-genome comparative analysis of 254 surveillance isolates of
Acinetobacter
species, 203 of which were
A. baumannii
, isolated from perianal swabs and sputum samples collected as part of an infection control active surveillance program at the University of Maryland Medical Center. The collection of surveillance isolates includes both carbapenem-susceptible and -resistant isolates. Based on the whole-genome phylogeny, the
A. baumannii
isolates collected belong to two major phylogenomic lineages. Results from multilocus sequence typing indicated that one of the major phylogenetic groups of
A. baumannii
was comprised solely of strains from the international clonal lineage 2. The genomic content of the
A. baumannii
isolates was examined using large-scale BLAST score ratio analysis to identify genes that are associated with carbapenem-susceptible and -resistant isolates, as well as genes potentially associated with the source of isolation. This analysis revealed a number of genes that were exclusive or at greater frequency in each of these classifications. This study is the most comprehensive genomic comparison of
Acinetobacter
isolates from a surveillance study to date and provides important information that will contribute to our understanding of the success of
A. baumannii
as a human pathogen.
A High-Throughput Approach To Identify Compounds That Impair Envelope Integrity in Escherichia coli
Authors: Baker Kristin R. , Jana Bimal , Franzyk Henrik , Guardabassi Luca 
Published: July 2016

ABSTRACT

The envelope of Gram-negative bacteria constitutes an impenetrable barrier to numerous classes of antimicrobials. This intrinsic resistance, coupled with acquired multidrug resistance, has drastically limited the treatment options against Gram-negative pathogens. The aim of the present study was to develop and validate an assay for identifying compounds that increase envelope permeability, thereby conferring antimicrobial susceptibility by weakening of the cell envelope barrier in Gram-negative bacteria. A high-throughput whole-cell screening platform was developed to measure
Escherichia coli
envelope permeability to a β-galactosidase chromogenic substrate. The signal produced by cytoplasmic β-galactosidase-dependent cleavage of the chromogenic substrate was used to determine the degree of envelope permeabilization. The assay was optimized by using known envelope-permeabilizing compounds and
E. coli
gene deletion mutants with impaired envelope integrity. As a proof of concept, a compound library comprising 36 peptides and 45 peptidomimetics was screened, leading to identification of two peptides that substantially increased envelope permeability. Compound 79 reduced significantly (from 8- to 125-fold) the MICs of erythromycin, fusidic acid, novobiocin and rifampin and displayed synergy (fractional inhibitory concentration index, <0.2) with these antibiotics by checkerboard assays in two genetically distinct
E. coli
strains, including the high-risk multidrug-resistant, CTX-M-15-producing sequence type 131 clone. Notably, in the presence of 0.25 μM of this peptide, both strains were susceptible to rifampin according to the resistance breakpoints (
R
> 0.5 μg/ml) for Gram-positive bacterial pathogens. The high-throughput screening platform developed in this study can be applied to accelerate the discovery of antimicrobial helper drug candidates and targets that enhance the delivery of existing antibiotics by impairing envelope integrity in Gram-negative bacteria.
Failure of the Amikacin, Cefoxitin, and Clarithromycin Combination Regimen for Treating Pulmonary Mycobacterium abscessus Infection
Authors: Ferro Beatriz E. , Srivastava Shashikant , Deshpande Devyani , Pasipanodya Jotam G. , van Soolingen Dick , Mouton Johan W. , van Ingen Jakko , Gumbo Tawanda 
Published: July 2016

ABSTRACT

In a hollow-fiber model, we mimicked the drug exposures achieved in the lungs of humans treated with standard amikacin, clarithromycin, and cefoxitin combination therapy for
Mycobacterium abscessus
infection. At optimal dosing, a kill rate of −0.09 (95% confidence interval, −0.04 to 0.03) log
10
CFU per ml/day was achieved over the first 14 days, after which there was regrowth due to acquired drug resistance. Thus, the standard regimen quickly failed. A new regimen is needed.
Fusidic Acid Inhibits Hepatic Transporters and Metabolic Enzymes: Potential Cause of Clinical Drug-Drug Interaction Observed with Statin Coadministration
Authors: Gupta Anshul , Harris Jennifer J. , Lin Jianrong , Bulgarelli James P. , Birmingham Bruce K. , Grimm Scott W. 
Published: July 2016

ABSTRACT

Fusidic acid (FA), which was approved in the 1960s in many European and Asian countries, has gained renewed interest due to its continued effectiveness against methicillin-resistant
Staphylococcus aureus
. As rhabdomyolysis has been reported upon coadministration of FA with statins, we aimed to elucidate the underlying molecular mechanisms that contribute to FA-statin drug-drug interactions. Because of the association between rhabdomyolysis and increased exposure to statins, we investigated if cytochrome P450 (CYP) enzymes and transporters involved in the disposition of various statins are inhibited by FA. FA was found to inhibit BCRP and OATP1B1 but not P-gp. In overexpressing cell systems, FA inhibited BCRP-mediated efflux (50% inhibitory concentration [IC
50
], ∼50 to 110 μM) and OATP1B1-mediated uptake (IC
50
, ∼4 to 35 μM) of statins at clinically relevant concentrations achievable in the intestine and liver (based on a 550-mg oral dose of FA, the expected maximum theoretical gastrointestinal concentration is ∼4 mM, and the maximum total or unbound concentration in the inlet to the liver was reported to be up to 223 μM or 11 μM, respectively, upon multiple dosing). Similarly, FA inhibited metabolism of statins in human liver microsomes (IC
50
, ∼17 to 195 μM). These data suggest that FA inhibits at least 3 major dispositional pathways (BCRP, OATP1B1, and CYP3A) and thus affects the clearance of several statins. We confirmed that FA is eliminated via phase 1 metabolism (primarily via CYP3A); however, there is also some phase 2 metabolism (mediated primarily by UGT1A1). Taken together, these data provide evidence for molecular mechanisms that may explain the occurrence of rhabdomyolysis when FA is administered with statins.
Proinflammatory M1 Macrophages Inhibit RANKL-Induced Osteoclastogenesis
Authors: Yamaguchi Tsuguno , Movila Alexandru , Kataoka Shinsuke , Wisitrasameewong Wichaya , Ruiz Torruella Montserrat , Murakoshi Michiaki , Murakami Shinya , Kawai Toshihisa 
Published: July 2016

ABSTRACT

In response to a defined panel of stimuli, immature macrophages can be classified into two major phenotypes: proinflammatory (M1) and anti-inflammatory (M2). Although both phenotypes have been implicated in several chronic inflammatory diseases, their direct role in bone resorption remains unclear. The present study investigated the possible effects of M1 and M2 macrophages on RANKL-induced osteoclastogenesis. In osteoclastogenesis assays using RAW264.7 cells or bone marrow cells as osteoclast precursors, addition of M1 macrophages significantly suppressed RANKL-induced osteoclastogenesis compared to nonstimulated conditions (M0), addition of M2 macrophages, or no macrophage addition (
P
< 0.05), suggesting that M1 macrophages can downregulate osteoclastogenesis. This effect was maintained when direct contact between M1 and osteoclast precursors was interrupted by cell culture insertion, indicating engagement of soluble factors released from M1. M1 macrophages developed from interferon gamma (IFN-γ) knockout (IFN-γ–KO) mice lost the ability to downregulate osteoclastogenesis. Antibody-based neutralization of interleukin-12 (IL-12), but not IL-10, produced by M1 macrophages also abrogated M1-mediated downregulation of osteoclastogenesis. Real-time PCR analyses showed that IFN-γ suppressed gene expression of NFATc1, a master regulator of osteoclastogenesis, whereas IL-12 increased the apoptosis of osteoclasts, suggesting molecular mechanisms underlying the possible roles of IFN-γ or IL-12 in M1-mediated inhibition of osteoclastogenesis. These findings were confirmed in an
in vivo
ligature-induced mouse periodontitis model in which adoptive transfer of M1 macrophages showed a significantly lower level of bone loss and less tartrate-resistant acid phosphatase (TRAP)-positive cell induction than M0 or M2 macrophage transfer. In conclusion, by its secretion of IFN-γ and IL-12, M1, but not M0 or M2, was demonstrated to inhibit osteoclastogenesis.
An investigation of routes to cancer diagnosis in 10 international jurisdictions, as part of the International Cancer Benchmarking Partnership: survey development and implementation
Authors: Weller David , Vedsted Peter , Anandan Chantelle , Zalounina Alina , Fourkala Evangelia Ourania , Desai Rakshit , Liston William , Jensen Henry , Barisic Andriana , Gavin Anna , Grunfeld Eva , Lambe Mats , Law Rebecca-Jane , Malmberg Martin , Neal Richard D , Kalsi Jatinderpal , Turner Donna , White Victoria , Bomb Martine , Menon Usha 
Published: July 2016

ObjectivesThis paper describes the methods used in the International Cancer Benchmarking Partnership Module 4 Survey (ICBPM4) which examines time intervals and routes to cancer diagnosis in 10 jurisdictions. We present the study design with defining and measuring time intervals, identifying patients with cancer, questionnaire development, data management and analyses.Design and settingRecruitment of participants to the ICBPM4 survey is based on cancer registries in each jurisdiction. Questionnaires draw on previous instruments and have been through a process of cognitive testing and piloting in three jurisdictions followed by standardised translation and adaptation. Data analysis focuses on comparing differences in time intervals and routes to diagnosis in the jurisdictions.ParticipantsOur target is 200 patients with symptomatic breast, lung, colorectal and ovarian cancer in each jurisdiction. Patients are approached directly or via their primary care physician (PCP). Patients’ PCPs and cancer treatment specialists (CTSs) are surveyed, and ‘data rules’ are applied to combine and reconcile conflicting information. Where CTS information is unavailable, audit information is sought from treatment records and databases.Main outcomesReliability testing of the patient questionnaire showed that agreement was complete (κ=1) in four items and substantial (κ=0.8, 95% CI 0.333 to 1) in one item. The identification of eligible patients is sufficient to meet the targets for breast, lung and colorectal cancer. Initial patient and PCP survey response rates from the UK and Sweden are comparable with similar published surveys. Data collection was completed in early 2016 for all cancer types.ConclusionAn international questionnaire-based survey of patients with cancer, PCPs and CTSs has been developed and launched in 10 jurisdictions. ICBPM4 will help to further understand international differences in cancer survival by comparing time intervals and routes to cancer diagnosis.
Antitumor Effect of Programmed Death-1 (PD-1) Blockade in Humanized the NOG-MHC Double Knockout Mouse
Authors: Ashizawa Tadashi , Iizuka Akira , Nonomura Chizu , Kondou Ryota , Maeda Chie , Miyata Haruo , Sugino Takashi , Mitsuya Koichi , Hayashi Nakamasa , Nakasu Yoko , Maruyama Kouji , Yamaguchi Ken , Katano Ikumi , Ito Mamoru , Akiyama Yasuto 
Published: July 2016

Abstract
Purpose: Humanized mouse models using NOD/Shi-scid-IL2rγnull (NOG) and NOD/LtSz-scid IL2rγnull (NSG) mouse are associated with several limitations, such as long incubation time for stem cell engraftment and the development of xenograft versus host disease in mice injected with peripheral blood mononuclear cells (PBMCs). To solve problems, we used humanized major histocompatibility class I- and class II-deficient NOG mice (referred to as NOG-dKO) to evaluate the antitumor effect of anti-programmed death-1 (PD-1) antibody.
Experimental Design: Humanized NOG-dKO mice, in which human PBMCs and human lymphoma cell line SCC-3, or glioblastoma cell line U87 were transplanted, were used as an immunotherapy model to investigate the effect of anti-PD-1 antibody. A biosimilar anti-PD-1 mAb generated in our laboratory was administered to humanized NOG-dKO mice transplanted with tumors.
Results: Within 4 weeks after transplantation, human CD45+ cells in antibody-treated mice constituted approximately 70% of spleen cells. The injection of anti-PD-1 antibody reduced by more 50% the size of SCC-3 and U87 tumors. In addition, induction of CTLs against SCC-3 cells and upregulation of natural killer cell activity was observed in the antibody-treated group. Tumor-infiltrating lymphocyte profiling showed that more exhausted marker (PD1+TIM3+LAG3+) positive T cells maintained in anti-PD-1 antibody–treated tumor. A greater number of CD8+ and granzyme-producing T cells infiltrated the tumor in mice treated with the anti-PD-1 antibody.
Conclusions: These results suggest that NOG-dKO mice might serve as a good humanized immunotherapy model to evaluate the efficacy of anti-PD-1 antibody prior to the clinical treatment. Clin Cancer Res; 23(1); 149–58. ©2016 AACR.
Hypoxia-Driven Mechanism of Vemurafenib Resistance in Melanoma
Authors: Qin Yong , Roszik Jason , Chattopadhyay Chandrani , Hashimoto Yuuri , Liu Chengwen , Cooper Zachary A. , Wargo Jennifer A. , Hwu Patrick , Ekmekcioglu Suhendan , Grimm Elizabeth A. 
Published: July 2016

Abstract
Melanoma is molecularly and structurally heterogeneous, with some tumor cells existing under hypoxic conditions. Our cell growth assays showed that under controlled hypoxic conditions, BRAF(V600E) melanoma cells rapidly became resistant to vemurafenib. By employing both a three-dimensional (3D) spheroid model and a two-dimensional (2D) hypoxic culture system to model hypoxia in vivo, we identified upregulation of HGF/MET signaling as a major mechanism associated with vemurafenib resistance as compared with 2D standard tissue culture in ambient air. We further confirmed that the upregulation of HGF/MET signaling was evident in drug-resistant melanoma patient tissues and mouse xenografts. Pharmacologic inhibition of the c-Met/Akt pathway restored the sensitivity of melanoma spheroids or 2D hypoxic cultures to vemurafenib. Mol Cancer Ther; 15(10); 2442–54. ©2016 AACR.
Vitamin D Enhances the Efficacy of Irinotecan through miR-627–Mediated Inhibition of Intratumoral Drug Metabolism
Authors: Sun Meiyan , Zhang Qunshu , Yang Xiaoyu , Qian Steven Y. , Guo Bin 
Published: July 2016

Abstract
Cytochrome P450 enzyme CYP3A4 is an important drug-metabolizing enzyme, and high levels of tumoral expression of CYP3A4 are linked to drug resistance. We investigated the function of vitamin D–regulated miR-627 in intratumoral CYP3A4 suppression and its role in enhancing the efficacy of chemotherapy. We found that miR-627 targets CYP3A4 and suppresses CYP3A4 expression in colon cancer cell lines. Furthermore, calcitriol (the active form of vitamin D) suppressed CYP3A4 expression by activating miR-627. As a result, calcitriol inhibited CYP3A4-mediated metabolism of irinotecan (a topoisomerase I inhibitor) in cancer cells. We show that calcitriol enhanced the efficacy of irinotecan in growth inhibition and apoptosis induction. When miR-627 is inhibited, calcitriol fails to enhance the activity of irinotecan. In addition, overexpression of miR-627 or siRNA knockdown of CYP3A4 enhanced the efficacy of irinotecan in growth inhibition and apoptosis induction. In contrast, overexpression of CYP3A4 abolished the effects of calcitriol on the activity of irinotecan. Using a nude mouse xenograft model, we demonstrated that calcitriol inhibited CYP3A4 and enhanced the in vivo antitumor activity of irinotecan without causing side effects. Our study identified a novel target for improving cancer therapy, i.e., modulating the intratumoral CYP3A4-mediated drug metabolism with vitamin D. This strategy could enhance the therapeutic efficacy without eliciting the side effects. Mol Cancer Ther; 15(9); 2086–95. ©2016 AACR.
Abstract 1098: MiR-203 suppresses cutaneous squamous cell carcinoma growth and targets the myc oncogene
Authors: Lohcharoenkal Warangkana , Harada Masako , Lovén Jakob , Meisgen Florian , Landén Ning Xu , Zhang Lingyun , Nissinen Liisa , Kähäri Veli-Matti , Ståhle Mona , Sonkoly Enikö , Grander Dan , Arsenian-Henriksson Marie , Pivarcsi Andor 
Published: July 2016

Abstract
Cutaneous squamous cell carcinoma (cSCC) is the second most common cancer in man and accounts for approximately 20% of non-melanoma skin cancers. Although most cSCC are benign, poorly differentiated cSCC poses a significant risk of metastasis and death. To date, little is known about the difference in molecular background between low-risk and high risk cSCC. MicroRNAs are short regulatory RNAs that can regulate gene expression and cellular functions. Here we demonstrate for the first time that the expression of miR-203 in cSCC correlates with tumor differentiation grade, being down-regulated in poorly but not in moderately or well differentiated cSCC. In vitro, miR-203 causes a delay in G1 to S phase transition and suppresses cell proliferation in human cSCC cells. Furthermore, miR-203 suppresses scratch-wound closure, cell migration, cell invasion, colony forming ability and angiogenesis-inducing capacity of cSCC cells. Transcriptomic analysis of cSCC cells with ectopic overexpression of miR-203 reveals dramatic changes in gene networks related to carcinogenesis, with significant suppression of genes with known oncogenic functions (e.g. PCNA, EGFR, HGF). Using luciferase reporter assays and site-specific mutagenesis, we identify c-MYC as a novel target of miR-203. Highlighting the importance of c-MYC within miR-203-regulated gene network, in rescue experiments overexpression of c-MYC reverses miR-203-induced growth arrest in cSCC. In vivo, overexpression of miR-203 in cSCC cell lines result in reduced xenograft tumor volume and decreased vessel density. Together our data show that miR-203 acts a tumor suppressor in cSCC, affecting several oncogenic and angiogenic mechanisms. Importantly, its restoration may provide therapeutic benefit in particular in poorly differentiated cSCC.
Citation Format: Warangkana Lohcharoenkal, Masako Harada, Jakob Lovén, Florian Meisgen, Ning Xu Landén, Lingyun Zhang, Liisa Nissinen, Veli-Matti Kähäri, Mona Ståhle, Enikö Sonkoly, Dan Grander, Marie Arsenian-Henriksson, Andor Pivarcsi. MiR-203 suppresses cutaneous squamous cell carcinoma growth and targets the myc oncogene. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1098.