bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antibiotics alter the window of competence for natural transformation in streptococci
Authors: Sturød K. , Salvadori G. , Junges R. , Petersen F.C. 
Published: July 2018

SummaryStreptococcus pneumoniae transformation occurs within a short competence window, during which the alternative sigma factor X (SigX) is activated to orchestrate the expression of genes allowing extracellular DNA uptake and recombination. Importantly, antibiotic stress promotes transcriptional changes that may affect more than 20% of the S. pneumoniae genome, including competence genes. These can be activated or repressed, depending on the antibiotic agent. For most antibiotics, however, it remains unknown whether transcriptional effects on competence translate into altered transformability. Here we investigate the effect of antibiotic subinhibitory concentrations on sigX expression using a luciferase reporter, and correlate for the first time with transformation kinetics. Induction of sigX expression by ciprofloxacin and novobiocin correlated with increased and prolonged transformability in S. pneumoniae. The prolonged effect of ciprofloxacin on competence and transformation was also observed in the streptococcal relatives Streptococcus mitis and Streptococcus mutans. In contrast, tetracycline and erythromycin, which induced S. pneumoniae sigX expression, had either an inhibitory or a nonsignificant effect on transformation, whereas streptomycin and the β‐lactam ampicillin, inhibited both sigX expression and transformation. Thus, the results show that antibiotics may vary in their effects on competence, ranging from inhibitory to stimulatory effects, and that responses affecting transcription of sigX do not always correlate with the transformation outcomes. Antibiotics that increase or decrease transformation are of particular clinical relevance, as they may alter the ability of S. pneumoniae to escape vaccines and antibiotics.
Inflammation Due to Voriconazole‐induced Photosensitivity Enhanced Skin Phototumorigenesis in Xpa‐knockout Mice
Authors: Kunisada Makoto , Yamano Nozomi , Hosaka Chieko , Takemori Chihiro , Nishigori Chikako 
Published: July 2018

AbstractVoriconazole is an antifungal agent and used as a prophylactic measure, especially in immunocompromised patients. However, there have been several reports of its adverse reactions, namely photosensitivity with intense inflammatory rashes and subsequent skin cancer development. To assess the effects of photosensitizing drugs voriconazole and hydrochlorothiazide (HCTZ) on the enhancement of UV‐induced inflammatory responses and UV‐induced tumorigenesis, we utilized Xpa‐knockout mice, which is DNA repair‐deficient and more susceptible to UV‐induced inflammation and tumor development than wild‐type mice. Administration of voriconazole prior to broadband UVB exposure significantly upregulated multiple inflammatory cytokines compared with the vehicle‐ or HCTZ‐administered groups. Voriconazole administration along with chronic UVB exposure produced significantly higher number of skin tumors than HCTZ or vehicle in Xpa‐knockout mice. Furthermore, the investigation of UVB‐induced DNA damage using embryonic fibroblasts of Xpa‐knockout mice revealed a significantly higher 8‐oxo‐7,8‐dihydroguanine level in cells treated with voriconazole N‐oxide, a voriconazole‐metabolite during UV exposure. The data suggest that voriconazole plus UVB‐induced inflammatory response may be related to voriconazole‐induced skin phototumorigenesis.
Effects of Interval Aerobic Training Program with Recovery bouts on cardiorespiratory and endurance fitness in seniors
Authors: Bouaziz Walid , Schmitt Elise , Vogel Thomas , Lefebvre François , Remetter Romain , Lonsdorfer Evelyne , Leprêtre Pierre‐Marie , Kaltenbach Georges , Geny Bernard , Lang Pierre‐Olivier 
Published: July 2018

Interval aerobic training programs (IATP) improve cardiorespiratory and endurance parameters. They are, however, unsuitable to seniors as frequently associated with occurrence of exhaustion and muscle pain. The purpose of this study was to measure the benefits of an IATP designed with recovery bouts (IATP‐R) in terms of cardiorespiratory and endurance parameters and its acceptability among seniors (≥70 years). Sedentary healthy volunteers were randomly assigned either to IATP‐R or sedentary lifestyle. All participants performed an incremental cycle exercise and 6‐minute walk test (6‐MWT) at baseline and 9.5 weeks later. The first ventilatory threshold (VT1); maximal tolerated power (MTP); peak of oxygen uptake (VO2peak); maximal heart rate (HRmax); and distance walked at 6‐MWT were thus measured. IATP‐R consisted of 19 sessions of 30‐minute (6 × 4‐min at VT1 + 1‐minute at 40% of VT1) cycling exercise over 9.5 weeks. With an adherence rate of 94.7% without any significant adverse events, 9.5 weeks of IATP‐R, compared to controls, enhanced endurance (VT1: +18.3 vs −4.6%; HR at baseline VT1: −5.9 vs +0.2%) and cardiorespiratory parameters (VO2peak: +14.1 vs −2.7%; HRmax: +1.6 vs −1.7%; MTP: +19.2 vs −2.3%). The walk distance at the 6‐MWT was also significantly lengthened (+11.6 vs. −3.1%). While these findings resulted from an interim analysis planned when 30 volunteers were enrolled in both groups, IATP‐R appeared as effective, safe, and applicable among sedentary healthy seniors. These characteristics are decisive for exercise training prescription and adherence.
Left ventricular function during exercise in trained pre‐adolescent soccer players
Authors: Unnithan Viswanath B. , Rowland Thomas W. , George Keith , Lord Rachel , Oxborough David 
Published: July 2018

It is unclear, what the underlying cardiovascular mechanisms are that give rise to the high level of aerobic fitness seen in youth soccer players. The aim of the study was to evaluate global and regional markers of systolic and diastolic function in a group of pre‐adolescent soccer players during an incremental exercise test. Twenty‐two, male soccer players (SP) from two professional soccer clubs (age: 12.0 ± 0.3 years) volunteered for the study. Fifteen recreationally active boys (CON), of similar age (age: 11.7 ± 0.2 years) were also recruited. All boys underwent a cycle ergometer test to exhaustion. Cardiac dimensions were determined using M‐mode echocardiography. During submaximal and maximal exercise, continuous‐wave Doppler ultrasound techniques were used to derive stroke volume (SVIndex). Tissue‐Doppler imaging was used to quantify systolic (S′adj) and diastolic function (E; E′adj and E/E′) at rest and both submaximal and maximal exercise intensities. Speckle tracking echocardiography was used to determine peak longitudinal ε at submaximal exercise intensities. SP demonstrated significantly (P ≤ 0.05) greater peak VO2 values than CON (SP: 48.0 ± 5.0 vs CON: 40.1 ± 7.5 mL/kg/min). Allometrically scaled to body surface area left ventricular end‐diastolic volume (LVEDV) was larger (P ≤ 0.05) in the SP (51.3 ± 9.0) compared to CON (44.6 ± 5.8 mL·BSA1.5). At the same relative, submaximal exercise intensities, the SP demonstrated greater SVIndex, cardiac output (QIndex), and E. No differences were noted for peak longitudinal ε during submaximal exercise. Factors that augment pre‐load and LV volume appear to determine the superior aerobic fitness seen in the soccer players.
Kinome Expansion in the Fusarium oxysporum Species Complex Driven by Accessory Chromosomes
Authors: DeIulio Gregory A. , Guo Li , Zhang Yong , Goldberg Jonathan M. , Kistler H. Corby , Ma Li-Jun 
Published: July 2018

Isolates of
Fusarium oxysporum
are adapted to survive a wide range of host and nonhost conditions. In addition,
F. oxysporum
was recently recognized as the top emerging opportunistic fungal pathogen infecting immunocompromised humans. The sensory and response networks of these fungi undoubtedly play a fundamental role in establishing the adaptability of this group. We have examined the kinomes of 12
F. oxysporum
isolates and highlighted kinase families that distinguish
F. oxysporum
from other fungi, as well as different isolates from one another. The amplification of kinases involved in environmental signal relay and regulating downstream cellular responses clearly sets
Fusarium
apart from other
Ascomycetes
. Although the functions of many of these kinases are still unclear, their specific proliferation highlights them as a result of the evolutionary forces that have shaped this species complex and clearly marks them as targets for exploitation in order to combat disease.
Functional outcome in contemporary children and young adults with tetralogy of Fallot after repair
Authors: Hock Julia , Häcker Anna-Luisa , Reiner Barbara , Oberhoffer Renate , Hager Alfred , Ewert Peter , Müller Jan 
Published: July 2018

ObjectiveFunctional outcome measures are of growing importance in the aftercare of patients with congenital heart disease. This study addresses the functional status with regard to exercise capacity, health-related physical fitness (HRPF) and arterial stiffness in a recent cohort of children, adolescents and young adults with tetralogy of Fallot (ToF) after repair.DesignSingle-centre, uncontrolled and prospective cohort study.SettingOutpatient department of the German Heart Centre Munich; July 2014–January 2018.PatientsOne hundred and six patients with ToF after repair (13.5±3.7 years, 40 females) were included. Data were compared with a recent cohort of healthy controls (HCs) (n=1700, 12.8±2.6 years, 833 females).Main outcome measuresPatients underwent a symptom-limited cardiopulmonary exercise test, performed an HRPF test (FitnessGram) and had an assessment of their arterial stiffness (Mobil-O-Graph).ResultsCompared with HC, patients with ToF showed lower predicted V.O2 peak (ToF: 80.4% ± 16.8% vs HC: 102.6% ± 18.1%, p<0.001), impaired ventilatory efficiency (ToF: 29.6 ± 3.6 vs HC: 27.4 ± 2.9, p<0.001), chronotropic incompetence (ToF: 167 ± 17 bpm vs HC: 190 ± 17 bpm, p<0.001) and reduced HRPF (ToF z-score: −0.65 ± 0.87 vs HC z-score: 0.03 ± 0.65, p<0.001). Surrogates of arterial stiffness, central and peripheral systolic blood pressure, did not differ between the two groups.ConclusionsContemporary children, adolescents and young adults with ToF still have functional limitations. How impaired HRPF and limited exercise capacity interact and how they can be modified needs to be evaluated in further intervention studies.
Comprehensive overview of the pharmacogenetic diversity in Ashkenazi Jews
Authors: Zhou Yitian , Lauschke Volker M 
Published: July 2018

BackgroundAdverse drug reactions are a major concern in drug development and clinical therapy. Genetic polymorphisms in genes involved in drug metabolism and transport are major determinants of treatment efficacy and adverse reactions, and constitute important biomarkers for drug dosing, efficacy and safety. Importantly, human populations and subgroups differ substantially in their pharmacogenetic variability profiles, with important consequences for personalised medicine strategies and precision public health approaches. Despite their long migration history, Ashkenazi Jews constitute a rather isolated population with a unique genetic signature that is distinctly different from other populations.ObjectiveTo provide a comprehensive overview of the pharmacogenetic profile in Ashkenazim.MethodsWe analysed next-generation sequencing data from 5076 Ashkenazim individuals and used sequence data from 117 425 non-Jewish individuals as reference.ResultsWe derived frequencies of 164 alleles in 17 clinically relevant pharmacogenes and derived profiles of putative functional consequences, providing the most comprehensive data set of Jewish pharmacogenetic diversity published to date. Furthermore, we detected 127 variants with an aggregated frequency of 20.7% that were specifically found in Ashkenazim, of which 55 variants were putatively deleterious (aggregated frequency of 9.4%).ConclusionThe revealed pattern of pharmacogenetic variability in Ashkenazi Jews is distinctly different from other populations and is expected to translate into unique functional consequences, especially for the metabolism of CYP2A6, CYP2C9, NAT2 and VKORC1 substrates. We anticipate that the presented data will serve as a powerful resource for the guidance of pharmacogenetic treatment decisions and the optimisation of population-specific genotyping strategies in the Ashkenazi diaspora.
Effects of solvents on the crystal structure of cross-linked lysozyme crystals
Authors: Yamada Yohei , Toyama Shota , Yabutani Tomoki 
Published: July 2018

The effects of solvents on the structural stability of cross-linked lysozyme crystals were investigated by an immersion test using alkaline (0.1 M ammonia [NH3] and 0.1 M sodium hydroxide [NaOH]), acidic (0.1 M acetic acid [CH3COOH] and 0.1 M hydrochloric acid [HCl]) and organic (50% [v/v] and undiluted ethanol, acetone, 2-propanol and dimethyl sulfoxide [DMSO]) solvents. The morphology and lattice constants were monitored by optical microscopy and X-ray crystallography. The cross-linked crystals exhibited good stability against NH3, CH3COOH, HCl, ethanol, acetone and 2-propanol. However, samples preserved in DMSO and NaOH were severely degraded.
Effectiveness of surgical versus conservative treatment for carpal tunnel syndrome: A systematic review, meta-analysis and qualitative analysis
Authors: Klokkari Diony , Mamais Ioannis 
Published: July 2018

Background: Carpal tunnel syndrome (CTS) is the most common entrapment neuropathy of the upper limb. Treatment options include physiotherapy, splinting, steroid injections or surgery. Objective: To compare the effectiveness of surgical versus conservative treatment for CTS for symptom and functional improvement and improvement of neurophysiological parameters. Methods: Systematic searches of PubMed and EBSCO host were conducted to identify the studies published between 1990 and 2016, comparing any surgical treatment to any conservative treatment. Participants were adults with a diagnosis of CTS, with symptom duration ranging from 8 months to 3 years. A meta-analysis and a qualitative analysis were conducted to summarize the results of the included studies and establish any agreement between the two. Results: A total of 15 studies were included in the study and 10 were included in the meta-analysis, involving 1787 wrists. The qualitative and quantitative analyses were consistent with the results of both indicating that surgical treatment leads to a greater improvement of symptoms at six months (mean difference: 0.52, 95%CI 0.27 to 0.78) and a greater improvement of neurophysiological parameters [distal motor latency (mean difference: 0.31, 95%CI 0.06 to 0.56), sensory nerve conduction velocity (mean difference: 3.71 m/s, 95%CI 1.94 to 5.49)]. At 3 months and 12 months, the results were not significant in favor of surgery or conservative treatment. Conclusion: Conservative treatment for CTS should be preferred for mild and short-term CTS. Surgery is more effective than conservative in CTS, and should be considered in persisting symptoms, taking into account the complications, which are more severe after surgery. Further research should focus on the field of manual therapy and compare it to surgical treatment for CTS.
Paclitaxel Sensitivity of Ovarian Cancer Can be Enhanced by Knocking Down Pairs of Kinases that Regulate MAP4 Phosphorylation and Microtubule Stability
Authors: Yang Hailing , Mao Weiqun , Rodriguez-Aguayo Cristian , Mangala Lingegowda S. , Bartholomeusz Geoffrey , Iles Lakesla R. , Jennings Nicholas B. , Ahmed Ahmed Ashour , Sood Anil K. , Lopez-Berestein Gabriel , Lu Zhen , Bast Robert C. 
Published: July 2018

Abstract
Purpose: Most patients with ovarian cancer receive paclitaxel chemotherapy, but less than half respond. Pre-treatment microtubule stability correlates with paclitaxel response in ovarian cancer cell lines. Microtubule stability can be increased by depletion of individual kinases. As microtubule stability can be regulated by phosphorylation of microtubule-associated proteins (MAPs), we reasoned that depletion of pairs of kinases that regulate phosphorylation of MAPs could induce microtubule stabilization and paclitaxel sensitization.
Experimental Design: Fourteen kinases known to regulate paclitaxel sensitivity were depleted individually in 12 well-characterized ovarian cancer cell lines before measuring proliferation in the presence or absence of paclitaxel. Similar studies were performed by depleting all possible pairs of kinases in six ovarian cancer cell lines. Pairs that enhanced paclitaxel sensitivity across multiple cell lines were studied in depth in cell culture and in two xenograft models.
Results: Transfection of siRNA against 10 of the 14 kinases enhanced paclitaxel sensitivity in at least six of 12 cell lines. Dual knockdown of IKBKB/STK39 or EDN2/TBK1 enhanced paclitaxel sensitivity more than silencing single kinases. Sequential knockdown was superior to concurrent knockdown. Dual silencing of IKBKB/STK39 or EDN2/TBK1 stabilized microtubules by inhibiting phosphorylation of p38 and MAP4, inducing apoptosis and blocking cell cycle more effectively than silencing individual kinases. Knockdown of IKBKB/STK39 or EDN2/TBK1 enhanced paclitaxel sensitivity in two ovarian xenograft models.
Conclusions: Sequential knockdown of dual kinases increased microtubule stability by decreasing p38-mediated phosphorylation of MAP4 and enhanced response to paclitaxel in ovarian cancer cell lines and xenografts, suggesting a strategy to improve primary therapy. Clin Cancer Res; 24(20); 5072–84. ©2018 AACR.
Consensus on Molecular Subtypes of High-Grade Serous Ovarian Carcinoma
Authors: Chen Gregory M. , Kannan Lavanya , Geistlinger Ludwig , Kofia Victor , Safikhani Zhaleh , Gendoo Deena M.A. , Parmigiani Giovanni , Birrer Michael , Haibe-Kains Benjamin , Waldron Levi 
Published: July 2018

Abstract
Purpose: The majority of ovarian carcinomas are of high-grade serous histology, which is associated with poor prognosis. Surgery and chemotherapy are the mainstay of treatment, and molecular characterization is necessary to lead the way to targeted therapeutic options. To this end, various computational methods for gene expression–based subtyping of high-grade serous ovarian carcinoma (HGSOC) have been proposed, but their overlap and robustness remain unknown.
Experimental Design: We assess three major subtype classifiers by meta-analysis of publicly available expression data, and assess statistical criteria of subtype robustness and classifier concordance. We develop a consensus classifier that represents the subtype classifications of tumors based on the consensus of multiple methods, and outputs a confidence score. Using our compendium of expression data, we examine the possibility that a subset of tumors is unclassifiable based on currently proposed subtypes.
Results: HGSOC subtyping classifiers exhibit moderate pairwise concordance across our data compendium (58.9%–70.9%; P &lt; 10−5) and are associated with overall survival in a meta-analysis across datasets (P &lt; 10−5). Current subtypes do not meet statistical criteria for robustness to reclustering across multiple datasets (prediction strength &lt; 0.6). A new subtype classifier is trained on concordantly classified samples to yield a consensus classification of patient tumors that correlates with patient age, survival, tumor purity, and lymphocyte infiltration.
Conclusions: A new consensus ovarian subtype classifier represents the consensus of methods and demonstrates the importance of classification approaches for cancer that do not require all tumors to be assigned to a distinct subtype. Clin Cancer Res; 24(20); 5037–47. ©2018 AACR.
Role of EphB3 Receptor in Mediating Head and Neck Tumor Growth, Cell Migration, and Response to PI3K Inhibitor
Authors: Bhatia Shilpa , Griego Anastacia , Lennon Shelby , Oweida Ayman , Sharma Jaspreet , Rohmer Christina , Uyanga Nomin , Bukkapatnam Sanjana , Van Court Benjamin , Raben David , Young Christian , Heasley Lynn , Karam Sana D. 
Published: July 2018

Abstract
Eph proteins have emerged as critical drivers affecting tumor growth and progression in human malignancies. Our The Cancer Genome Atlas (TCGA) data analysis showed that EphB3, a receptor tyrosine kinase, is frequently coamplified with PIK3CA in head and neck squamous cell carcinoma (HNSCC). We therefore hypothesized that EphB3 amplification plays a protumorigenic role in HNSCC and that EphB3 and PIK3CA are cooperating oncogenes that contribute toward its pathogenesis. This hypothesis was not experimentally supported, because EphB3 knockdown failed to alter HNSCC tumor cell growth in vitro or in vivo with an orthotopic model. However, responsiveness of EphB3 knockdown tumors to the PI3K inhibitor, BKM120, was significantly decreased in terms of both tumor growth delay and survival. This is correlated with an increase in prosurvival proteins, S6 and BcL-XL, in the EphB3 shRNA tumors treated with BKM120 compared with controls. We further observed that EphB3 knockdown resulted in increased migration in vitro and increased EMT gene signature in vivo. To explain these results, we examined EphB3 phosphorylation levels in HNSCC at baseline. Although total EphB3 levels were high, we found low phospho-EphB3 levels in HNSCCs. Forced EphB3 phosphorylation with an ephrin-B2–Fc fusion protein resulted in decreased HNSCC migration and cell growth, and enhanced response to BKM120 in vitro. These data collectively indicate that progression of HNSCC selects for low/inhibited EphB3 activity to enhance their survival and migratory abilities and decrease response to PI3K signaling. Therefore, strategies focused on activating EphB3 might be helpful to inhibit tumor growth and enhance sensitivity to PI3K inhibitors in HNSCC. Mol Cancer Ther; 17(9); 2049–59. ©2018 AACR.
In Vitro Study of Endotoxin Adsorption by a Polymyxin B-Immobilized Fiber Column
Authors: Yamashita Chizuru , Moriyama Kazuhiro , Hasegawa Daisuke , Kato Yu , Sakai Toshikazu , Kawaji Takahiro , Shimomura Yasuyo , Kurimoto Yasuyoshi , Nagata Mariko , Nishida Osamu 
Published: July 2018

<b><i>Background:</i></b> Polymyxin B-immobilized fiber (PMX-F) columns are used as therapeutic interventions for septic shock. The clinical efficacy has been reported for 2-h applications, but their ability to adsorb endotoxin over longer treatments has not been fully elucidated. We hypothesized that PMX-F columns are capable of endotoxin removal for more than 2 h. <b><i>Method:</i></b> We designed closed circuits incorporating either a PMX-F column with an 8.5-mL priming volume (PMX-01R) or a sham-control column, and used inactivated fetal bovine serum as the circulating perfusate. Endotoxin was continuously injected at a fixed rate for 24 h, and perfusate endotoxin concentrations were measured at fixed time points. PMX-01R endotoxin adsorption was calculated from the difference in the endotoxin concentrations. <b><i>Results:</i></b> PMX-01R endotoxin adsorption increased continuously in a virtually linear manner. <b><i>Conclusions:</i></b> The PMX-01R column showed sustained endotoxin adsorption for at least 24 h. This indicated that PMX-F columns would be capable of clinical endotoxin removal for 24 h.