bluuebunny/crossref_metadata_2025_split huggingface dataset:
Redox-Active Sensing by Bacterial DksA Transcription Factors Is Determined by Cysteine and Zinc Content
Authors: Crawford Matthew A. , Tapscott Timothy , Fitzsimmons Liam F. , Liu Lin , Reyes Aníbal M. , Libby Stephen J. , Trujillo Madia , Fang Ferric C. , Radi Rafael , Vázquez-Torres Andrés 
Published: April 2016

ABSTRACT

The four-cysteine zinc finger motif of the bacterial RNA polymerase regulator DksA is essential for protein structure, canonical control of the stringent response to nutritional limitation, and thiol-based sensing of oxidative and nitrosative stress. This interdependent relationship has limited our understanding of DksA-mediated functions in bacterial pathogenesis. Here, we have addressed this challenge by complementing Δ
dksA Salmonella
with
Pseudomonas aeruginosa
dksA
paralogues that encode proteins differing in cysteine and zinc content. We find that four-cysteine, zinc-bound (C4) and two-cysteine, zinc-free (C2) DksA proteins are able to mediate appropriate stringent control in
Salmonella
and that thiol-based sensing of reactive species is conserved among C2 and C4 orthologues. However, variations in cysteine and zinc content determine the threshold at which individual DksA proteins sense and respond to reactive species. In particular, zinc acts as an antioxidant, dampening cysteine reactivity and raising the threshold of posttranslational thiol modification with reactive species. Consequently, C2 DksA triggers transcriptional responses in
Salmonella
at levels of oxidative or nitrosative stress normally tolerated by
Salmonella
expressing C4 orthologues. Inappropriate transcriptional regulation by C2 DksA increases the susceptibility of
Salmonella
to the antimicrobial effects of hydrogen peroxide and nitric oxide, and attenuates virulence in macrophages and mice. Our findings suggest that the redox-active sensory function of DksA proteins is finely tuned to optimize bacterial fitness according to the levels of oxidative and nitrosative stress encountered by bacterial species in their natural and host environments.

IMPORTANCE
In order to cause disease, pathogenic bacteria must rapidly sense and respond to antimicrobial pressures encountered within the host. Prominent among these stresses, and of particular relevance to intracellular pathogens such as
Salmonella
, are nutritional restriction and the enzymatic generation of reactive oxygen and nitrogen species. The conserved transcriptional regulator DksA controls adaptive responses to nutritional limitation, as well as to oxidative and nitrosative stress. Here, we demonstrate that each of these functions contributes to bacterial pathogenesis. Our observations highlight the importance of metabolic adaptation in bacterial pathogenesis and show the mechanism by which DksA orthologues are optimized to sense the levels of oxidative and nitrosative stress encountered in their natural habitats. An improved understanding of the conserved processes used by bacteria to sense, respond to, and limit host defense will inform the development of novel strategies to treat infections caused by pathogenic, potentially multidrug-resistant bacteria.
Traditional medicine used in childbirth and for childhood diarrhoea in Nigeria's Cross River State: interviews with traditional practitioners and a statewide cross-sectional study
Authors: Sarmiento Iván , Zuluaga Germán , Andersson Neil 
Published: April 2016

ObjectivesExamine factors associated with use of traditional medicine during childbirth and in management of childhood diarrhoea.DesignCross-sectional cluster survey, household interviews in a stratified last stage random sample of 90 census enumeration areas; unstructured interviews with traditional doctors.SettingOil-rich Cross River State in south-eastern Nigeria has 3.5 million residents, most of whom depend on a subsistence agriculture economy.Participants8089 women aged 15–49 years in 7685 households reported on the health of 11 305 children aged 0–36 months in July–August 2011.Primary and secondary outcome measuresTraditional medicine used at childbirth and for management of childhood diarrhoea; covariates included access to Western medicine and education, economic conditions, engagement with the modern state and family relations. Cluster-adjusted analysis relied on the Mantel-Haenszel procedure and Mantel extension.Results24.1% (1371/5686) of women reported using traditional medicine at childbirth; these women had less education, accessed antenatal care less, experienced more family violence and were less likely to have birth certificates for their children. 11.3% (615/5425) of young children with diarrhoea were taken to traditional medical practitioners; these children were less likely to receive BCG, to have birth certificates, to live in households with a more educated head, or to use fuel other than charcoal for cooking. Education showed a gradient with decreasing use of traditional medicine for childbirth (χ2135.2) and for childhood diarrhoea (χ277.2).ConclusionsUse of traditional medicine is associated with several factors related to cultural transition and to health status, with formal education playing a prominent role. Any assessment of the effectiveness of traditional medicine should anticipate confounding by these factors, which are widely recognised to affect health in their own right.
p27 Is a Candidate Prognostic Biomarker and Metastatic Promoter in Osteosarcoma
Authors: Li Yiting , Nakka Manjula , Kelly Aaron J. , Lau Ching C. , Krailo Mark , Barkauskas Donald A. , Hicks John M. , Man Tsz-Kwong 
Published: April 2016

Abstract
Metastatic progression is the major cause of death in osteosarcoma, the most common bone malignancy in children and young adults. However, prognostic biomarkers and efficacious targeted treatments for metastatic disease remain lacking. Using an immunoproteomic approach, we discovered that autoantibodies against the cell-cycle kinase inhibitor p27 (KIP1, CDKN1B) were elevated in plasma of high-risk osteosarcoma patients. Using a large cohort of serum samples from osteosarcoma patients (n = 233), we validated that a higher level of the p27 autoantibody significantly correlated with poor overall and event-free survival (P &lt; 0.05). Immunohistochemical analysis also showed that p27 was mislocalized to the cytoplasm in the majority of osteosarcoma cases and in highly metastatic osteosarcoma cell lines. We demonstrated that ectopic expression of cytoplasmic p27 promoted migration and invasion of osteosarcoma cells, whereas shRNA-mediated gene silencing suppressed these effects. In addition, mutations at the p27 phosphorylation sites S10 or T198, but not T157, abolished the migratory and invasive phenotypes. Furthermore, the development of pulmonary metastases increased in mice injected with cells expressing cytoplasmic p27 compared with an empty vector control. Collectively, our findings support further investigation of p27 as a potential prognostic biomarker and therapeutic target in osteosarcoma cases exhibiting aberrant p27 subcellular localization. Cancer Res; 76(13); 4002–11. ©2016 AACR.
Dual Carfilzomib and Doxorubicin–Loaded Liposomal Nanoparticles for Synergistic Efficacy in Multiple Myeloma
Authors: Ashley Jonathan D. , Quinlan Charissa J. , Schroeder Valerie A. , Suckow Mark A. , Pizzuti Vincenzo J. , Kiziltepe Tanyel , Bilgicer Basar 
Published: April 2016

Abstract
Here, we report the synthesis and evaluation of dual drug–loaded nanoparticles as an effective means to deliver carfilzomib and doxorubicin to multiple myeloma tumor cells at their optimal synergistic ratio. First, various molar ratios of carfilzomib to doxorubicin were screened against multiple myeloma cell lines to determine the molar ratio that elicited the greatest synergy using the Chou–Talalay method. The therapeutic agents were then incorporated into liposomes at the optimal synergistic ratio of 1:1 to yield dual drug–loaded nanoparticles with a narrow size range of 115 nm and high reproducibility. Our results demonstrated that the dual drug–loaded liposomes exhibited synergy in vitro and were more efficacious in inhibiting tumor growth in vivo than a combination of free drugs, while at the same time reducing systemic toxicity. Taken together, this study presents the synthesis and preclinical evaluation of dual drug–loaded liposomes containing carfilzomib and doxorubicin for enhanced therapeutic efficacy to improve patient outcome in multiple myeloma. Mol Cancer Ther; 15(7); 1452–9. ©2016 AACR.
In Vitro and In Vivo Activity of AMG 337, a Potent and Selective MET Kinase Inhibitor, in MET-Dependent Cancer Models
Authors: Hughes Paul E. , Rex Karen , Caenepeel Sean , Yang Yajing , Zhang Yihong , Broome Martin A. , Kha Hue T. , Burgess Teresa L. , Amore Benny , Kaplan-Lefko Paula J. , Moriguchi Jodi , Werner Jonathan , Damore Michael A. , Baker Daniel , Choquette Deborah M. , Harmange Jean-Christophe , Radinsky Robert , Kendall Richard , Dussault Isabelle , Coxon Angela 
Published: April 2016

Abstract
The MET receptor tyrosine kinase is involved in cell growth, survival, and invasion. Clinical studies with small molecule MET inhibitors have shown the role of biomarkers in identifying patients most likely to benefit from MET-targeted therapy. AMG 337 is an oral, small molecule, ATP-competitive, highly selective inhibitor of the MET receptor. Herein, we describe AMG 337 preclinical activity and mechanism of action in MET-dependent tumor models. These studies suggest MET is the only therapeutic target for AMG 337. In an unbiased tumor cell line proliferation screen (260 cell lines), a closely related analogue of AMG 337, Compound 5, exhibited activity in 2 of 260 cell lines; both were MET-amplified. Additional studies examining the effects of AMG 337 on the proliferation of a limited panel of cell lines with varying MET copy numbers revealed that high-level focal MET amplification (&gt;12 copies) was required to confer MET oncogene addiction and AMG 337 sensitivity. One MET-amplified cell line, H1573 (&gt;12 copies), was AMG 337 insensitive, possibly because of a downstream G12A KRAS mutation. Mechanism-of-action studies in sensitive MET-amplified cell lines demonstrated that AMG 337 inhibited MET and adaptor protein Gab-1 phosphorylation, subsequently blocking the downstream PI3K and MAPK pathways. AMG 337 exhibited potency in pharmacodynamic assays evaluating MET signaling in tumor xenograft models; &gt;90% inhibition of Gab-1 phosphorylation was observed at 0.75 mg/kg. These findings describe the preclinical activity and mechanism of action of AMG 337 in MET-dependent tumor models and indicate its potential as a novel therapeutic for the treatment of MET-dependent tumors. Mol Cancer Ther; 15(7); 1568–79. ©2016 AACR.
Angiographic Correlates of Cerebral Hemodynamic Changes With Diamox Challenge Assessed by Quantitative Magnetic Resonance Angiography
Authors: Bahr-Hosseini Mersedeh , Shakur Sophia F. , Amin-Hanjani Sepideh , Charbel Fady T. , Alaraj Ali 
Published: April 2016

Background and Purpose—
Impaired cerebrovascular reserve in chronic steno-occlusive disease has been shown to be associated with poor leptomeningeal collaterals (LMCs) on digital subtraction angiography and increased stroke risk. We examined the relationship between the degree of LMCs and the flow change with Diamox challenge measured using quantitative magnetic resonance angiography (QMRA).

Methods—

Patients with steno-occlusion in the internal carotid artery or middle cerebral artery (MCA) at our institution between 2007 and 2013 were retrospectively studied. Intracranial flows were obtained using QMRA, and flow change with Diamox (QMRA
Δd
) was calculated as follows: ([flow after Diamox−flow before Diamox]/[flow before Diamox])×100%. Poor LMC was defined as grade 1 or 2, and robust LMC was defined as grade 3 or 4 based on the ASITN/SIR (American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology) grading system on digital subtraction angiography.

Results—

Thirty-eight patients had angiographic and flow data. Ipsilateral MCA QMRA
Δd
was significantly lower versus the contralateral side (flow, 85.5 versus 135.9 mL/min;
P
<0.001 and QMRA
Δd
, 24.0% versus 45.6%;
P
=0.01). If LMCs were robust (n=12), MCA QMRA
Δd
was significantly higher (21.4% versus −26.8%;
P
=0.04) compared with patients with poor LMC (n=4).

Conclusions—

We show that patients with more robust LMC have better MCA QMRA
Δd
. Therefore, QMRA
Δd
may be used for the functional assessment of LMC as a surrogate for cerebrovascular reserve in chronic internal carotid artery or MCA steno-occlusive disease.
The Development of a Tracheostomy-Specific Quality of Life Questionnaire
Authors: Smith Kristine A. , Bosch John Douglas , Pelletier Guy , MacKenzie Marianne , Hoy Monica Y. 
Published: April 2016

Objective: A long-term tracheostomy can be a life-altering event and can have significant effects on patients’ quality of life (QOL). There is currently no instrument available to evaluate tracheostomy-specific QOL. To address this deficiency, the objective of this study was to create and preliminarily validate a pilot tracheostomy-specific QOL questionnaire to assess its feasibility. Methods: A multidisciplinary team developed the pilot tracheostomy-specific QOL questionnaire (TQOL) in 3 phases: item generation, item review, and scale construction. The survey was administered at 0 and 2 weeks to a pilot group of tracheostomy patients with concurrent administration of a validated general QOL questionnaire at week 0. Convergence validity, test-retest reliability, and internal consistency were the primary outcome measures. Results: A total of 37 patients completed the study (mean tracheostomy duration = 90 weeks). The convergence validity of the TQOL was moderately strong ( r = 0.72), and the test-retest reliability was strong ( r = 0.75). The TQOL also demonstrated good internal consistency (Cronbach’s alpha = 0.82). Conclusion: The TQOL has moderately strong internal consistency, convergence validity, and test-retest reliability. While additional refinement and validation may improve the questionnaire, these initial results are promising and support further development of this tool.
Mindfulness-based cognitive therapy for recurrent major depression: A ‘best buy’ for health care?
Authors: Shawyer Frances , Enticott Joanne C , Özmen Mehmet , Inder Brett , Meadows Graham N 
Published: April 2016

Objective: While mindfulness-based cognitive therapy is effective in reducing depressive relapse/recurrence, relatively little is known about its health economic properties. We describe the health economic properties of mindfulness-based cognitive therapy in relation to its impact on depressive relapse/recurrence over 2 years of follow-up. Method: Non-depressed adults with a history of three or more major depressive episodes were randomised to mindfulness-based cognitive therapy + depressive relapse active monitoring ( n = 101) or control (depressive relapse active monitoring alone) ( n = 102) and followed up for 2 years. Structured self-report instruments for service use and absenteeism provided cost data items for health economic analyses. Treatment utility, expressed as disability-adjusted life years, was calculated by adjusting the number of days an individual was depressed by the relevant International Classification of Diseases 12-month severity of depression disability weight from the Global Burden of Disease 2010. Intention-to-treat analysis assessed the incremental cost–utility ratios of the interventions across mental health care, all of health-care and whole-of-society perspectives. Per protocol and site of usual care subgroup analyses were also conducted. Probabilistic uncertainty analysis was completed using cost–utility acceptability curves. Results: Mindfulness-based cognitive therapy participants had significantly less major depressive episode days compared to controls, as supported by the differential distributions of major depressive episode days (modelled as Poisson, p < 0.001). Average major depressive episode days were consistently less in the mindfulness-based cognitive therapy group compared to controls, e.g., 31 and 55 days, respectively. From a whole-of-society perspective, analyses of patients receiving usual care from all sectors of the health-care system demonstrated dominance (reduced costs, demonstrable health gains). From a mental health-care perspective, the incremental gain per disability-adjusted life year for mindfulness-based cognitive therapy was AUD83,744 net benefit, with an overall annual cost saving of AUD143,511 for people in specialist care. Conclusion: Mindfulness-based cognitive therapy demonstrated very good health economic properties lending weight to the consideration of mindfulness-based cognitive therapy provision as a good buy within health-care delivery.
Beliefs about the causes and cures of depression
Authors: Furnham Adrian , Ritchie William , Lay Alixe 
Published: April 2016

Background: This study used attitude statement and vignette methodology to examine a mixed British sample’s belies about the causes and consequences of depression. Aims: To test whether the group would recognise both vignettes with having depression and that the favoured cure would be Psychotherapy/Talking Cure. Method: In all, 320 adults completed a two-part questionnaire. In the first part, they were given two vignettes describing a 30-year-old female and a 45-year-old male both with depression. They were asked what they thought (if anything) was wrong with the person and how they could best be helped. In the second part, they completed two questionnaires, one which lists 47 possible causes and the other 48 possible treatments for depression. Results: Most participants ‘diagnosed’ depression for the two vignettes although they chose very different terms and offered a variety of ‘cures’, including medication and counselling. The questionnaires about cause and cure factored into seven interpretable factors which were logically correlated. A series of regressions showed that sex, age, media interest, political beliefs, experience with depression and other mental illnesses as well as having known of others diagnosed with depression predicted different beliefs about the causes and cures of depression. Conclusion: People have a detailed and multidimensional view of the causes and cures for depression which is systematically related to each other.
Candidate Biomarkers for HPV‐Negative Head and Neck Cancer Identified via Gene Expression Barcode Analysis
Authors: Yang Shiayin F. , Bier‐Laning Carol M. , Adams William , Zilliox Michael J. 
Published: April 2016

Objectives(1) Reanalyze publicly available genomic data for HPV‐negative oral cavity squamous cell carcinoma to look for candidate biomarkers. (2) Evaluate the association of the identified biomarkers with survival.Study DesignRetrospective cohort study.SettingTertiary care.Subjects and MethodsGene expression barcode analysis was applied to an existing publicly available data set of 54 HPV‐negative oral cavity squamous cell carcinoma tumor samples to identify candidate genes associated with poor prognosis. Genes identified were evaluated for their association with survival on the basis of univariable and multivariable Cox proportional hazards models.ResultsThree genes were found to be associated with poor prognosis. The most significant association was seen with spectrin expression. Subjects whose tumors expressed spectrin were 4.60 times more likely (hazard ratio; 95% confidence interval: 1.88‐11.25) to die at any given time when compared with those without spectrin (P =. 001). On univariable analysis, subjects with late‐stage cancer were 6.34 times more likely (hazard ratio; 95% confidence interval: 1.41‐28.53; P =. 02) to die at any given time, but interestingly, after controlling for spectrin, this effect was attenuated (P =. 07). Despite controlling for several possible confounding effects, the effect of spectrin remained hazardous throughout all multivariable models. This was true even after controlling for cancer stage and extracapsular extension (P =. 004).ConclusionOur analysis of public genomic data shows promise in identifying biomarkers that may allow clinicians to make more accurate survival predictions. Spectrin is a strong candidate for further biomarker testing.
A Systematic Review of Psychiatric, Psychological, and Behavioural Outcomes following Mild Traumatic Brain Injury in Children and Adolescents
Authors: Emery Carolyn A. , Barlow Karen M. , Brooks Brian L. , Max Jeffrey E. , Villavicencio-Requis Angela , Gnanakumar Vithya , Robertson Helen Lee , Schneider Kathryn , Yeates Keith Owen 
Published: April 2016

Background: Evidence regarding longer-term psychiatric, psychological, and behavioural outcomes (for example, anxiety, mood disorders, depression, and attention disorders) following mild traumatic brain injury (mTBI) in children and adolescents has not been previously synthesized. Objective: To conduct a systematic review of the available evidence examining psychiatric, psychological, and behavioural outcomes following mTBI in children and adolescents. Materials and Methods: Nine electronic databases were systematically searched from 1980 to August 2014. Studies selected met the following criteria: original data; study design was a randomized controlled trial, quasi-experimental design, cohort or historical cohort study, case-control study, or cross-sectional study; exposure included mTBI (including concussion); population included children and adolescents (<19 years) at the time of mTBI, as well as a comparison group (for example, healthy children, children with orthopaedic injuries); and included psychiatric, psychological, or behavioural outcomes (for example, anxiety, mood disorders, depression, attention disorders). Two authors independently assessed the quality and level of evidence with the Downs and Black (DB) criteria and Oxford Centre of Evidence-Based Medicine (OCEBM) model, respectively, for each manuscript. Results: Of 9472 studies identified in the initial search, 30 were included and scored. Heterogeneity in methodology and injury definition precluded meta-analyses. The median methodological quality for all 30 studies, based on the DB criteria, was 15/33 (range 6 to 19). The highest level of evidence demonstrated by all reviewed studies was level 2b based on OCEBM criteria, with the majority (28/30 studies) classified at this level. Based on the literature included in this systematic review, psychological and psychiatric problems in children with a history of mTBI were found to be more prevalent when mTBI is associated with hospitalization, when assessment occurs earlier in the recovery period (that is, resolves over time), when there are multiple previous mTBIs, in individuals with preexisting psychiatric illness, when outcomes are based on retrospective recall, and when the comparison group is noninjured healthy children (as opposed to children with injuries not involving the head). Conclusions: Overall, few rigorous prospective studies have examined psychological, behavioural, and psychiatric outcomes following mTBI. In the absence of true reports of preinjury problems and when ideally comparing mild TBI to non-TBI injured controls, there is little evidence to suggest that psychological, behavioural, and/or psychiatric problems persist beyond the acute and subacute period following an mTBI in children and adolescents.