bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Drug Repositioning Approach Reveals that Streptococcus mutans Is Susceptible to a Diverse Range of Established Antimicrobials and Nonantibiotics
Authors: Saputo S. , Faustoferri R. C. , Quivey R. G. 
Published: October 2017

ABSTRACT

Streptococcus mutans
is the primary causative agent of dental caries and contributes to the multispecies biofilm known as dental plaque. An adenylate kinase-based assay was optimized for
S. mutans
to detect cell lysis when exposed to the Selleck library (Selleck Chemical, Houston, TX) of 853 FDA-approved drugs in, to our knowledge, the first high-throughput drug screen in
S. mutans
. We found 126 drugs with activity against
S. mutans
planktonic cultures, and they were classified into six categories: antibacterials (61), antineoplastics (23), ion channel effectors (9), other antimicrobials (7), antifungals (6), and other (20). These drugs were also tested for activity against
S. mutans
biofilm cultures, and 24 compounds were found to inhibit biofilm formation, 6 killed preexisting biofilms, 84 exhibited biofilm inhibition and killing activity, and 12 had no activity against biofilms. The activities of 9 selected compounds that exhibited antimicrobial activity were further characterized for their activity against
S. mutans
planktonic and biofilm cultures. Together, our results suggest that
S. mutans
exhibits a susceptibility profile to a diverse array of established and novel antibacterials.
Assessing Noninferiority in Treatment Trials for Severe Infectious Diseases: an Extension to the Entire Follow-Up Period Using a Cure-Death Multistate Model
Authors: Sommer Harriet , Bluhmki Tobias , Beyersmann Jan , Schumacher Martin 
Published: October 2017

ABSTRACT
In current and former clinical trials for the development of antibacterial drugs, various primary endpoints have been used, and treatment effects are evaluated mostly in noninferiority analyses at the end of follow-up, which varies between studies. A more convincing and highly patient-relevant statement would be a noninferiority assessment over the entire follow-up period with cure and death as coprimary endpoints, while preserving the desired alpha level for statistical testing. To account for the time-dynamic pattern of cure and death, we apply a cure-death multistate model. The endpoint of interest is “get cured and stay alive over time.” Noninferiority between treatments over the entire follow-up period is studied by means of one-sided confidence bands provided by a flexible resampling technique. We illustrate the technique by applying it to a recently published study and establish noninferiority in being cured and alive over a time frame of interest for the entire population, patients with hospital-acquired pneumonia, but not for the subset of patients with ventilator-associated pneumonia. Our analysis improves the original results in the sense that our endpoint is more patient benefiting, a stronger noninferiority statement is demonstrated, and the time dependency of cure and death, competing events, and different follow-up times is captured. Multistate methodology combined with confidence bands adds a valuable statistical tool for clinical trials in the context of infection control. The framework is not restricted to the cure-death model but can be adapted to more complex multistate endpoints and equivalence or superiority analyses.
Intrapulmonary Pharmacokinetics of Laninamivir, a Neuraminidase Inhibitor, after a Single Nebulized Administration of Laninamivir Octanoate in Healthy Japanese Subjects
Authors: Toyama Kaoru , Furuie Hidetoshi , Ishizuka Hitoshi 
Published: October 2017

ABSTRACT

A single dose of laninamivir octanoate (LO) inhaled using a dry powder inhaler (DPI) is effective for the treatment and prophylaxis of influenza. Nebulizers are an option for pediatric and elderly patients who may have difficulty in using a DPI. A single-center, open-label study was conducted to evaluate the plasma and intrapulmonary pharmacokinetics (PK) of laninamivir after a single nebulized administration of LO in healthy male Japanese subjects for identifying a safe and effective dosage regimen for a nebulizer. A single dose of LO (40 to 320 mg) was administered using a nebulizer, and plasma concentrations of LO and laninamivir were analyzed up to 168 h after inhalation by validated liquid chromatography-tandem mass spectrometry methods. Subgroups of 6 subjects each underwent bronchoalveolar lavage at specified time intervals over 4 to 168 h following a single nebulized administration of LO (160 mg), and the concentrations in epithelial lining fluid (ELF) were calculated by the urea diffusion method. PK parameters were determined by noncompartment analysis. Inhaled nebulized LO was found to be safe and well tolerated up to the highest dose evaluated (320 mg). Plasma laninamivir concentrations increased almost dose proportionally. Laninamivir concentrations in ELF exceeded the 50% inhibitory concentrations for viral neuraminidase up to 168 h after the nebulized inhalation of 160 mg LO. Thus, similarly to the DPI, ELF concentration profiles of laninamivir after a single nebulized administration support its long-lasting effect against influenza virus infection. This study has been registered at JAPIC Clinical Trials Information (
http://www.clinicaltrials.jp/
) under registration no. JAPIC CTI-152996.
Cell Invasion and Pyruvate Oxidase-Derived H
2
O
2
Are Critical for Streptococcus pneumoniae-Mediated Cardiomyocyte Killing
Authors: Brissac Terry , Shenoy Anukul T. , Patterson LaDonna A. , Orihuela Carlos J. 
Published: October 2017

ABSTRACT

Streptococcus pneumoniae
(the pneumococcus) is the leading cause of community-acquired pneumonia and is now recognized to be a direct contributor to adverse acute cardiac events. During invasive pneumococcal disease,
S. pneumoniae
can gain access to the myocardium, kill cardiomyocytes, and form bacterium-filled “microlesions” causing considerable acute and long-lasting cardiac damage. While the molecular mechanisms responsible for bacterial translocation into the heart have been elucidated, the initial interactions of heart-invaded
S. pneumoniae
with cardiomyocytes remain unclear. In this study, we used a model of low multiplicity of
S. pneumoniae
infection with HL-1 mouse cardiomyocytes to investigate these early events. Using adhesion/invasion assays and immunofluorescent and transmission electron microscopy, we showed that
S. pneumoniae
rapidly adhered to and invaded cardiomyocytes. What is more, pneumococci existed as intravacuolar bacteria or escaped into the cytoplasm. Pulse-chase assays with BrdU confirmed intracellular replication of pneumococci within HL-1 cells. Using endocytosis inhibitors, bacterial isogenic mutants, and neutralizing antibodies against host proteins recognized by
S. pneumoniae
adhesins, we showed that
S. pneumoniae
uptake by cardiomyocytes is not through the well-studied canonical interactions identified for vascular endothelial cells. Indeed,
S. pneumoniae
invasion of HL-1 cells occurred through clathrin-mediated endocytosis (CME) and independently of choline binding protein A (CbpA)/laminin receptor, CbpA/polymeric immunoglobulin receptor, or cell wall phosphorylcholine/platelet-activating factor receptor. Subsequently, we determined that pneumolysin and streptococcal pyruvate oxidase-derived H
2
O
2
production were required for cardiomyocyte killing. Finally, we showed that this cytotoxicity could be abrogated using CME inhibitors or antioxidants, attesting to intracellular replication of
S. pneumoniae
as a key first step in pneumococcal pathogenesis within the heart.
Polyphenol- and Caffeine-Rich Postfermented Pu-erh Tea Improves Diet-Induced Metabolic Syndrome by Remodeling Intestinal Homeostasis in Mice
Authors: Gao Xiaoyu , Xie Qiuhong , Kong Ping , Liu Ling , Sun Sheng , Xiong Boyu , Huang Baojia , Yan Liang , Sheng Jun , Xiang Hongyu 
Published: October 2017

ABSTRACT

Postfermented Pu-erh tea (PE) protects against metabolic syndrome (MS), but little is known regarding its underlying mechanisms. Animal experiments were performed to determine whether the gut microbiota mediated the improvement in diet-induced MS by PE and its main active components (PEAC). We confirmed that PE altered the body composition and energy efficiency, attenuated metabolic endotoxemia and systemic and multiple-tissue inflammation, and improved the glucose and lipid metabolism disorder in high-fat diet (HFD)-fed mice via multiple pathways. Notably, PE promoted the lipid oxidation and browning of white adipose tissue (WAT) in HFD-fed mice. Polyphenols and caffeine (CAF) played critical roles in improving these parameters. Meanwhile, PE remodeled the disrupted intestinal homeostasis that was induced by the HFD. Many metabolic changes observed in the mice were significantly correlated with alterations in specific gut bacteria.
Akkermansia muciniphila
and
Faecalibacterium prausnitzii
were speculated to be the key gut bacterial links between the PEAC treatment and MS at the genus and species levels. Interestingly,
A. muciniphila
administration altered body composition and energy efficiency, promoted the browning of WAT, and improved the lipid and glucose metabolism disorder in the HFD-fed mice, whereas
F. prausnitzii
administration reduced the HFD-induced liver and intestinal inflammatory responses. In summary, polyphenol- and CAF-rich PE improved diet-induced MS, and this effect was associated with a remodeling of the gut microbiota.
DksA and ppGpp Regulate the σ
S
Stress Response by Activating Promoters for the Small RNA DsrA and the Anti-Adapter Protein IraP
Authors: Girard Mary E. , Gopalkrishnan Saumya , Grace Elicia D. , Halliday Jennifer A. , Gourse Richard L. , Herman Christophe 
Published: October 2017

ABSTRACT

σ
S
is an alternative sigma factor, encoded by the
rpoS
gene, that redirects cellular transcription to a large family of genes in response to stressful environmental signals. This so-called σ
S
general stress response is necessary for survival in many bacterial species and is controlled by a complex, multifactorial pathway that regulates σ
S
levels transcriptionally, translationally, and posttranslationally in
Escherichia coli
. It was shown previously that the transcription factor DksA and its cofactor, ppGpp, are among the many factors governing σ
S
synthesis, thus playing an important role in activation of the σ
S
stress response. However, the mechanisms responsible for the effects of DksA and ppGpp have not been elucidated fully. We describe here how DksA and ppGpp directly activate the promoters for the anti-adaptor protein IraP and the small regulatory RNA DsrA, thereby indirectly influencing σ
S
levels. In addition, based on effects of DksA
N88I
, a previously identified DksA variant with increased affinity for RNA polymerase (RNAP), we show that DksA can increase σ
S
activity by another indirect mechanism. We propose that by reducing rRNA transcription, DksA and ppGpp increase the availability of core RNAP for binding to σ
S
and also increase transcription from other promoters, including P
dsrA
and P
iraP
. By improving the translation and stabilization of σ
S
, as well as the ability of other promoters to compete for RNAP, DksA and ppGpp contribute to the switch in the transcription program needed for stress adaptation.

IMPORTANCE
Bacteria spend relatively little time in log phase outside the optimized environment found in a laboratory. They have evolved to make the most of alternating feast and famine conditions by seamlessly transitioning between rapid growth and stationary phase, a lower metabolic mode that is crucial for long-term survival. One of the key regulators of the switch in gene expression that characterizes stationary phase is the alternative sigma factor σ
S
. Understanding the factors governing σ
S
activity is central to unraveling the complexities of growth, adaptation to stress, and pathogenesis. Here, we describe three mechanisms by which the RNA polymerase binding factor DksA and the second messenger ppGpp regulate σ
S
levels.
Identification of health risk behaviours among adolescent refugees resettling in Western Australia
Authors: Hirani Kajal , Cherian Sarah , Mutch Raewyn , Payne Donald N 
Published: October 2017

ObjectiveAdolescent refugees encounter traumatic stressors and are at risk of developing psychosocial health problems; limited research data exist internationally. This study aims to identify health risk behaviours among adolescent refugees resettling in Western Australia and assess the feasibility of using a standardised adolescent health questionnaire for this purpose.DesignRefugees aged 12 years and above attending a tertiary Refugee Health Service (RHS) were recruited over 12 months. Sociodemographic data were collected. Psychosocial assessments based on the ‘Home, Education/Eating, Activities, Drugs, Sexuality, Suicide/mental health’ (HEADSS) framework were undertaken utilising interpreters where required. Health concerns identified were managed through the RHS.ResultsA total of 122 adolescents (20 ethnicities) participated; 65% required interpreters. Median age (range) was 14 (12–17) years. Most (80%) had nuclear family separation. Almost half (49%) had a deceased/missing family member. A third (37%) had lived in refugee camps and 20% had experienced closed detention. The median time (range) since arrival in Australia was 11 (2–86) months. Every adolescent had at least one health concern identified during the psychosocial assessment. Frequency of health concerns identified in each domain were 87% for home, 66% for education, 23% for eating, 93% for activities, 5% for drugs, 88% for sexuality and 61% for suicide/mental health. Most adolescents (75%) required intervention, consisting of counselling for health risk behaviours and/or referral to health or community services.ConclusionIt is feasible to use a standardised adolescent health questionnaire to identify health risk behaviours among a cohort of ethnically diverse adolescent refugees. Use of the questionnaire identified a large burden of psychosocial health issues requiring multidisciplinary intervention.
Supporting Continuous Changes to Business Intents
Authors: Silvander Johan , Wilson Magnus , Wnuk Krzysztof , Svahnberg Mikael 
Published: October 2017

Software supporting an enterprise’s business, also known as a business support system, needs to support the correlation of activities between actors as well as influence the activities based on knowledge about the value networks in which the enterprise acts. This requires the use of policies and rules to guide or enforce the execution of strategies or tactics within an enterprise as well as in collaborations between enterprises. With the help of policies and rules, an enterprise is able to capture an actor’s intent in its business support system, and act according to this intent on behalf of the actor. Since the value networks an enterprise is part of will change over time the business intents’ life cycle states might change. Achieving the changes in an effective and efficient way requires knowledge about the affected intents and the correlation between intents. The aim of the study is to identify how a business support system can support continuous changes to business intents. The first step is to find a theoretical model which serves as a foundation for intent-driven systems. We conducted a case study using a focus group approach with employees from Ericsson. This case study was influenced by the spiral case study process. The study resulted in a model supporting continuous definition and execution of an enterprise. The model is divided into three layers; Define, Execute, and a common governance view layer. This makes it possible to support continuous definition and execution of business intents and to identify the actors needed to support the business intents’ life cycles. This model is supported by a meta-model for capturing information into viewpoints. The research question is addressed by suggesting a solution supporting continuous definition and execution of an enterprise as a model of value architecture components and business functions. The results will affect how Ericsson will build the business studio for their next generation business support systems.
Meiosis-like Functions in Oncogenesis: A New View of Cancer
Authors: McFarlane Ramsay J. , Wakeman Jane A. 
Published: October 2017

Abstract
Cancer cells have many abnormal characteristics enabling tumors to grow, spread, and avoid immunologic and therapeutic destruction. Central to this is the innate ability of populations of cancer cells to rapidly evolve. One feature of many cancers is that they activate genes that are normally associated with distinct developmental states, including germ cell–specific genes. This has historically led to the proposal that tumors take on embryonal characteristics, the so called embryonal theory of cancer. However, one group of germline genes, not directly associated with embryonic somatic tissue genesis, is the one that encodes the specific factors to drive the unique reductional chromosome segregation of meiosis I, which also results in chromosomal exchanges. Here, we propose that meiosis I–specific modulators of reductional segregation can contribute to oncogenic chromosome dynamics and that the embryonal theory for cancer cell growth/proliferation is overly simplistic, as meiotic factors are not a feature of most embryonic tissue development. We postulate that some meiotic chromosome-regulatory functions contribute to a soma-to-germline model for cancer, in which activation of germline (including meiosis) functions drive oncogenesis, and we extend this to propose that meiotic factors could be powerful sources of targets for therapeutics and biomonitoring in oncology. Cancer Res; 77(21); 5712–6. ©2017 AACR.
KRAS Mutation and Consensus Molecular Subtypes 2 and 3 Are Independently Associated with Reduced Immune Infiltration and Reactivity in Colorectal Cancer
Authors: Lal Neeraj , White Brian S. , Goussous Ghaleb , Pickles Oliver , Mason Mike J. , Beggs Andrew D. , Taniere Philippe , Willcox Benjamin E. , Guinney Justin , Middleton Gary W. 
Published: October 2017

Abstract
Purpose: KRAS mutation is a common canonical mutation in colorectal cancer, found at differing frequencies in all consensus molecular subtypes (CMS). The independent immunobiological impacts of RAS mutation and CMS are unknown. Thus, we explored the immunobiological effects of KRAS mutation across the CMS spectrum.
Experimental Design: Expression analysis of immune genes/signatures was performed using The Cancer Genome Atlas (TCGA) RNA-seq and the KFSYSCC microarray datasets. Multivariate analysis included KRAS status, CMS, tumor location, MSI status, and neoantigen load. Protein expression of STAT1, HLA-class II, and CXCL10 was analyzed by digital IHC.
Results: The Th1-centric co-ordinate immune response cluster (CIRC) was significantly, albeit modestly, reduced in KRAS-mutant colorectal cancer in both datasets. Cytotoxic T cells, neutrophils, and the IFNγ pathway were suppressed in KRAS-mutant samples. The expressions of STAT1 and CXCL10 were reduced at the mRNA and protein levels. In multivariate analysis, KRAS mutation, CMS2, and CMS3 were independently predictive of reduced CIRC expression. Immune response was heterogeneous across KRAS-mutant colorectal cancer: KRAS-mutant CMS2 samples have the lowest CIRC expression, reduced expression of the IFNγ pathway, STAT1 and CXCL10, and reduced infiltration of cytotoxic cells and neutrophils relative to CMS1 and CMS4 and to KRAS wild-type CMS2 samples in the TCGA. These trends held in the KFSYSCC dataset.
Conclusions: KRAS mutation is associated with suppressed Th1/cytotoxic immunity in colorectal cancer, the extent of the effect being modulated by CMS subtype. These results add a novel immunobiological dimension to the biological heterogeneity of colorectal cancer. Clin Cancer Res; 24(1); 224–33. ©2017 AACR.
Comprehensive Pharmacogenomic Profiling of Malignant Pleural Mesothelioma Identifies a Subgroup Sensitive to FGFR Inhibition
Authors: Quispel-Janssen Josine M. , Badhai Jitendra , Schunselaar Laurel , Price Stacey , Brammeld Jonathan , Iorio Francesco , Kolluri Krishna , Garnett Matthew , Berns Anton , Baas Paul , McDermott Ultan , Neefjes Jacques , Alifrangis Constantine 
Published: October 2017

Abstract
Purpose: Despite intense research, treatment options for patients with mesothelioma are limited and offer only modest survival advantage. We screened a large panel of compounds in multiple mesothelioma models and correlated sensitivity with a range of molecular features to detect biomarkers of drug response.
Experimental design: We utilized a high-throughput chemical inhibitor screen in a panel of 889 cancer cell lines, including both immortalized and primary early-passage mesothelioma lines, alongside comprehensive molecular characterization using Illumina whole-exome sequencing, copy-number analysis and Affymetrix array whole transcriptome profiling. Subsequent validation was done using functional assays such as siRNA silencing and mesothelioma mouse xenograft models.
Results: A subgroup of immortalized and primary MPM lines appeared highly sensitive to FGFR inhibition. None of these lines harbored genomic alterations of FGFR family members, but rather BAP1 protein loss was associated with enhanced sensitivity to FGFR inhibition. This was confirmed in an MPM mouse xenograft model and by BAP1 knockdown and overexpression in cell line models. Gene expression analyses revealed an association between BAP1 loss and increased expression of the receptors FGFR1/3 and ligands FGF9/18. BAP1 loss was associated with activation of MAPK signaling. These associations were confirmed in a cohort of MPM patient samples.
Conclusions: A subgroup of mesotheliomas cell lines harbor sensitivity to FGFR inhibition. BAP1 protein loss enriches for this subgroup and could serve as a potential biomarker to select patients for FGFR inhibitor treatment. These data identify a clinically relevant MPM subgroup for consideration of FGFR therapeutics in future clinical studies. Clin Cancer Res; 24(1); 84–94. ©2017 AACR.
SEED GERMINATION OF Avicennia marina (Forsk.) Vierh. BY PERICARP REMOVAL TREATMENT
Authors: Purnobasuki Hery , Utami Edy Setiti Wida 
Published: October 2017

Avicennia marina is one species used for building coastal ecosystem stabilization in Surabaya shores because of its tolerance to high salinity level and resistance to wave energy. Their existence is threatened byÂ various factors i.e. land conversion, pollution and interisland bridge existence. Â Growth of A. marina is currently limited by seed dormancy. In an effort to increase propagation efficiency, seed viability and vigor were compared based on collection dates and pericarp removal methods. The results showed no relationship between salinity levels of soaking water or seed buoyancy and seed viability or seed vigor. Collection dates may influence seed viability and vigor. Seeds collected in October and November germinated more quickly than those collected in December, although there were no differences in total germination. Hand-peeled seeds germinated more slowly than soaked seeds for all collections, but with no differences in total germination. Seeds collected in October and November grew more vigorously than those collected in December.