bluuebunny/crossref_metadata_2025 huggingface dataset:
Aberrant miRNA promoter methylation and EMT‐involving miRNAs in breast cancer metastasis: Diagnosis and therapeutic implications
Authors: Zare Maryam , Bastami Milad , Solali Saeed , Alivand Mohammad Reza
Published: August 2017

Breast cancer (BC) is the most prevalent cancer in women worldwide. Although extensive studies are ongoing concerning its intricate molecular mechanisms, development of novel therapies and more accurate diagnostic and prognostic approaches is still a challenge. Epithelial–mesenchymal transition (EMT) enables the invasion of metastatic cancer cells and has recently been highlighted in a Cancer Stem Cell (CSC) model of BC. Epigenetic events as well as miRNA expression are the master regulators of tumorigenesis and add a further layer to the complexity of BC pathogenesis. The miRNAs are related to epigenetic event and additionally affect epigenetic pathways. Recent evidence demonstrates that epigenetic mechanisms such as DNA methylation may control miRNA expression. Because each miRNA may regulate several target genes, dysregulation of miRNA caused by aberrant DNA methylation patterns of the locus may influence important downstream pathways. Furthermore, some miRNAs is believed to regulate important DNA methylator factors. Any disruption or modification of this intricate network can contribute to the disease process; thus, it is essential to understand these changes. Advancements in new sequencing technologies to detect DNA methylation patterns has provided the opportunity to determine differentially methylated regions (DMRs) of the miRNA locus and their effect on expression profiles to improve BC diagnosis and treatment. The current review examines the interplay of DNA methylation mechanisms and miRNA function in invasive tumorigenesis, specifically EMT and CSC of BC, to highlight its potential for advancements on BC etiology, diagnosis, and therapy.
Annexin A2 positively regulates milk synthesis and proliferation of bovine mammary epithelial cells through the mTOR signaling pathway
Authors: Zhang Minghui , Chen Dongying , Zhen Zhen , Ao Jinxia , Yuan Xiaohan , Gao Xuejun
Published: August 2017

Annexin A2 (AnxA2) has been shown to play multiple roles in growth, development, and metabolism, but the functions of AnxA2 and the signaling pathways associated with AnxA2 are still not fully understood. In this study, we aim to reveal whether and how AnxA2 could be involved in milk synthesis and proliferation of bovine mammary epithelial cells (BMECs). Using gene function study approaches, we found that AnxA2 positively regulates PIP3 level, phosphorylation of mTOR, and protein levels of SREBP‐1c and Cyclin D1 leading to milk synthesis and cell proliferation. We further observed that both AnxA2‐36 kD phosphorylated form and AnxA2‐33 kD protein could be induced from AnxA2‐36 kD protein in BMECs under methionine, leucine, estrogen or prolactin stimulation. These above results strongly demonstrate that AnxA2 functions as a critical regulator for amino acid or hormone‐induced milk synthesis and cell proliferation via the PI3K‐mTOR‐SREBP‐1c/Cyclin D1 signaling pathway.
TLR4 and NFκB signaling is critical for taxol resistance in ovarian carcinoma cells
Authors: Sun Nian‐Kang , Huang Shang‐Lang , Chang Ting‐Chang , Chao Chuck C.‐K.
Published: August 2017

We report here that toll‐like receptor 4 (TLR4) and ABCB1 are upregulated in SKOV3 ovarian carcinoma cells that acquired resistance to the anticancer drug taxol. Silencing of TLR4 using short‐hairpin RNA sensitized taxol‐resistant SKOV3 cells to taxol (4.6 fold), whereas ectopic expression of TLR4 in parental, taxol‐sensitive SKOV3 cells or TLR4‐null HEK293 cells induced taxol resistance (∼2 fold). A sub‐lethal dose of taxol induced ABCB1 protein expression in taxol‐resistant SKOV3 cells. Inactivation of TLR4 using chemical inhibitors (CLI‐095 and AO‐I) downregulated ABCB1 protein expression and enhanced the cytotoxic activity of taxol in taxol‐resistant SKOV3 cells. While the sensitization effect of TLR4 inactivation was also detected in TOV21G ovarian cancer cells, which express moderate level of TLR4, ectopic expression of ABCB1 prevented the sensitization effect in these cells. Notably, the NFκB pathway was significantly activated by taxol, and inhibition of this pathway suppressed TLR4‐regulated ABCB1 expression. Furthermore, taxol‐induced NFκB signaling was reduced following TLR4 silencing in taxol‐resistant SKOV3 cells. Consistent with these results, ectopic expression of TLR4 in taxol‐sensitive SKOV3 cells enhanced ABCB1 expression and conferred resistance to taxol. The protective effect of exogenous TLR4 expression against taxol was reduced by treatment with NFκB inhibitor in these cells. These results demonstrate that taxol activates the TLR4‐NFκB pathway which in turn induces ABCB1 gene expression. This cellular pathway thus represents a novel target to limit resistance to taxol in ovarian cancer cells.
Redefining the psychological autopsy: A proposal for collaboration between forensic pathology and investigative psychology
Authors: Solomon Nadia
Published: August 2017

Excepting psychiatry, psychology and medicine remain largely separate disciplines. In forensic inquiries, the psychologist assesses the mind, whereas the pathologist examines the body. Both fields, however, actively participate in the same investigations, albeit from different standpoints, contributing to explorations of crime scene dynamics, identification of offenders, and legal proceedings. In recent years, peer review has become a staple of research, because subjecting work to scrutiny by other experts promotes accuracy. Forensic pathologists would benefit from insights provided by investigative psychology, particularly if asked to apply psychology to their testimony, and integration with forensic pathology may increase the acceptance of empirical profiling evidence in the courtroom. Additionally, incorporation of medical findings—such as wound patterns, evidence of range of fire, and cause of death determinations—could add another level of detail to techniques like smallest space analysis. The following functions as a proposal for the incorporation of forensic pathological findings into investigative psychology research and the application of investigative psychology to forensic pathology practice. Cooperation has the potential to extend the scope of knowledge in both disciplines, to increase their applicability to and acceptance in legal contexts and to maximize the probative value of evidence provided in the court of law.
Impact of Coxsackievirus A6 emergence on hand, foot, and mouth disease epidemic in Osaka City, Japan
Authors: Kanbayashi Daiki , Kaida Atsushi , Yamamoto Seiji P. , Hirai Yuki , Kubo Hideyuki , Fujimori Ryoko , Hakui Noritaka , Hirokawa Hidetetsu , Iritani Nobuhiro
Published: August 2017

Hand, foot, and mouth disease (HFMD) is an acute febrile illness characterized by fever; sore throat; and vesicular eruptions on the hands, feet, and oral mucosa. Until 2010, HFMD was predominantly associated with enterovirus (EV) A71 and coxsackievirus (CV) A16 in Japan. In 2011, CV‐A6 emerged as a primary causative agent, causing the largest HFMD epidemic in Japan since 1981. Since then, CV‐A6 has caused large HFMD epidemics every 2 years. The phylogenetic analysis of complete Viral Protein 1 (VP1) sequences revealed that most CV‐A6 strains detected from 2011 to 2015 in Osaka City were classified into a different clade compared with CV‐A6 strains detected from 1999 until 2009. The majority of CV‐A6 strains detected in 2011 and most CV‐A6 strains detected from 2013 to 2015 were mainly divided into two distinct genetic groups. Each epidemic strain carried unique amino acid substitutions in the presumed DE, EF, and GH loops of the VP1 protein that is exposed on the surface of the virion. There is a possibility that the appearance of substitutions on the surface of the virion and an accumulation of a susceptible population are significant factors in recent HFMD epidemics.
High‐risk papillomavirus infection among women living with human Immunodeficiency virus: Brazilian multicentric study
Authors: Miranda Angelica E. , Silveira Mariangela F. , Travassos Ana G. , Tenório Teresinha , Val Isabel C.C. , Lannoy Leonor , Mattos Junior Hortensio S. , Carvalho Newton S.
Published: August 2017

Cervical cancer is an important health issue in Latin America. Although HPV infections can have spontaneous clearance, persistence of high‐risk (HR) HPV is a risk factor for cervical cancer among women and it is even higher in HIV‐infected women. To determine the prevalence of HR‐HPV and risk factors among HIV‐infected women attending reference services for HIV/AIDS in different regions of Brazil. Cross‐sectional study conducted among HIV‐infected women attended at referral care centers for HIV/AIDS in nine states of Brazil. Women from 18 to 49 years that accept to participate and were not pregnant at the time of the approach were recruited for the study. The HPV screening was realized using qPCR in closed system, in vitro Diagnostic, COBAS®‐HPV Roche. The cytology results were available by the Bethesda System. A total of 802(89.1%) from the selected women agreed to participate in the study. Median age was 39(Inter quartile range [IQR34‐46]) years and median education was 9(IQR6‐11) years. General prevalence of HR‐HPV was 28.4%(228/802). HPV‐16 prevalence rate was 8.1%(65/802), HPV‐18 was 3.7%(30/802) and other types of HR‐HPV were 23.6% (189/802). Risk factors for HR‐HPV infection in the multivariate logistic regression analysis were: age ranging from 18 to 34 years (OR = 1.43[95%CI:1.18‐1.75]), illicit drugs use (OR = 1.61[95%CI:1.10‐2.42]) and abnormal cervical cytology (OR = 1.56[95%CI:1.34‐1.81]). Results showed a prevalence rate of 28.4% of HR‐HPV infection in women living with HIV in Brazil. These infections were significantly associated with having less than 35 years old, illicit drug use and abnormal cervical cytology.
Motoneuron activity is required for enhancements in functional recovery after peripheral nerve injury in exercised female mice
Authors: Jaiswal Poonam B. , Tung Jack K. , Gross Robert E. , English Arthur W.
Published: August 2017

Inhibitory luminopsins (iLMO2) integrate opto‐ and chemo‐genetic approaches and allow for cell‐type specific inhibition of neuronal activity. When exposed to a Renilla luciferase substrate, Coelenterazine (CTZ), iLMO2 generates bioluminescence‐mediated activation of its amino‐terminal halorhodopsin, resulting in neuronal inhibition. Moderate daily exercise in the form of interval treadmill‐training (IT) applied following a peripheral nerve injury results in enhanced motor axon regeneration and muscle fiber reinnervation in female mice. We hypothesized that iLMO2 mediated inhibition of motoneuron activity during IT would block this enhancement. Unilateral intramuscular injections of Cre‐dependent AAV2/9‐EF1a‐DIO‐iLMO2 (∼8.5 x 1013 vg/ml) were made into the gastrocnemius and tibialis anterior muscles of young female ChAT‐IRES‐Cre mice, thereby limiting iLMO2 expression specifically to their motoneurons. Four to six weeks were allowed for retrograde viral transduction after which a unilateral sciatic nerve transection (Tx) and repair was performed. Animals were randomized into four groups: IT only, IT + CTZ, CTZ only, and untreated (UT). Three weeks post Tx‐repair, the maximal amplitude direct muscle responses (M‐max) in both muscles in the IT only group were significantly greater than in UT mice, consistent with the enhancing effects of this exercise regimen. Inhibiting motoneuron activity during exercise by a single injection of CTZ, administered 30 minutes prior to exercise, completely blocked the enhancing effect of exercise. Similar treatments with CTZ in mice without iLMO2 had no effect on regeneration. Neuronal activity is required for successful enhancement of motor axon regeneration by exercise.
Impact of ET0 method on the simulation of historical and future crop yields: a case study of millet growth in Senegal
Authors: Ramarohetra Johanna , Sultan Benjamin
Published: August 2017

The reference evapotranspiration (ET0) is an integrated climatic variable from which many crop models derive simulated crop yields. In most of these models, different equations are parameterized leaving the choice of the equation to the user. However, the impact of the choice of the ET0 equations on crop yield prediction has been little studied.

The present study proposes a sensitivity analysis of the impact of the choice of the ET0 equation on simulated millet yields using SARRA‐H crop model over 12 Senegalese stations representative of the Sudano‐Sahelian climate conditions of West Africa.

Priestley‐Taylor, a modified Priestley‐Taylor and Hargreaves equations lead to simulated yields up to 19% than those calculated using the Penman‐Monteith equation. Despite high biases in wind speed, among the tested methods, the Penman‐Monteith method remains the most robust to derive ET0 and yield over the major part of Senegal, Hargreaves equation being more appropriated under dry climates. The choice of ET0 formulation introduces uncertainties representing 8% of baseline yield regardless of precipitation changes; for wet conditions these uncertainties approach 30% of the overall climate change impact. The choice of ET0 equation is increasingly important, with local temperature changes out to 4 °C, while extreme changes above 6 °C depend less on the ET0 equation.
Stratigraphy, age and correlation of Lepué Tephra: a widespread c. 11 000 cal a BP marker horizon sourced from the Chaitén Sector of southern Chile
Authors: Alloway Brent V. , Moreno Patricio I. , Pearce Nick J. G. , De Pol‐Holz Ricardo , Henríquez William I. , Pesce Oscar H. , Sagredo Esteban , Villarosa Gustavo , Outes Valeria
Published: August 2017

We describe the stratigraphy, age and correlation of a prominent tephra marker, named Lepué Tephra, extensively distributed in north‐western Patagonia. Lepué Tephra is well dated at c. 11 000 cal a BP from numerous lake and soil cover‐bed sequences and its recognition is useful for assessing the rate and timing of deglaciation as well as associated environmental changes in this region during the last glacial termination and early Holocene. Lepué Tephra has attributes typical of a complex and compositionally zoned phreatomagmatic eruptive. While the initial rhyolitic phase can be readily distinguished from multiple eruptive products sourced from the adjacent Volcán Chaitén, the main erupted end member is of basaltic–andesitic bulk composition − similar to younger tephras sourced from Holocene monogenetic cones adjacent to the Volcán Michimahuida massif (tMim). Lepué Tephra can be correlated to an equivalent‐aged pyroclastic flow deposit (Amarillo Ignimbrite) prominently distributed in the south‐eastern sector of tMim. The source vent for these co‐eruptive events is obscured by an extensive ice field and is currently unknown. The widespread radially symmetrical distribution of Lepué Tephra centred on tMim cannot be attributed solely to volcanological considerations. Reduced Southern Hemisphere westerly wind influence interpreted from climate proxies at the time of eruption are also implicated. Copyright © 2017 John Wiley & Sons, Ltd.
Characterization of primary rat nasal epithelial cultures in CFTR knockout rats as a model for CF sinus disease
Authors: Tipirneni Kiranya E. , Cho Do‐Yeon , Skinner Daniel F. , Zhang Shaoyan , Mackey Calvin , Lim Dong‐Jin , Woodworth Bradford A.
Published: August 2017

Objective

The objectives of the current experiments were to develop and characterize primary rat nasal epithelial cultures and evaluate their usefulness as a model of cystic fibrosis (CF) sinonasal transepithelial transport and CF transmembrane conductance regulator (CFTR) function.

Study Design

Laboratory in vitro and animal studies.

Methods

CFTR+/+ and CFTR−/− rat nasal septal epithelia (RNSE) were cultured on semipermeable supports at an air–liquid interface to confluence and full differentiation. Monolayers were mounted in Ussing chambers for pharmacologic manipulation of ion transport and compared to similar filters containing murine (MNSE) and human (HSNE) epithelia. Histology and scanning electron microscopy (SEM) were completed. Real‐time polymerase chain reaction of CFTR+/+ RNSE, MNSE, and HSNE was performed to evaluate relative CFTR gene expression.

Results

Forskolin‐stimulated anion transport (ΔIsc in μA/cm2) was significantly greater in epithelia derived from CFTR+/+ when compared to CFTR−/− animals (100.9 ± 3.7 vs. 10.5 ± 0.9; P < 0.0001). Amiloride‐sensitive ISC was equivalent (−42.3 ± 2.8 vs. −46.1 ± 2.3; P = 0.524). No inhibition of CFTR‐mediated chloride (Cl−) secretion was exhibited in CFTR−/− epithelia with the addition of the specific CFTR inhibitor, CFTRInh‐172. However, calcium‐activated Cl− secretion (UTP) was significantly increased in CFTR−/− RNSE (CFTR−/− −106.8 ± 1.6 vs. CFTR+/+ −32.2 ± 3.1; P < 0.0001). All responses were larger in RNSE when compared to CFTR+/+ and CFTR−/− (or F508del/F508del) murine and human cells (P < 0.0001). Scanning electron microscopy demonstrated 80% to 90% ciliation in all RNSE cultures. There was no evidence of infection in CFTR−/− rats at 4 months. CFTR expression was similar among species.

Conclusion

The successful development of the CFTR−/− rat enables improved evaluation of CF sinus disease based on characteristic abnormalities of ion transport.

Level of Evidence

NA. Laryngoscope, 127:E384–E391, 2017
Macrolide‐associated sensorineural hearing loss: A systematic review
Authors: Ikeda Allison K. , Prince Anthony A. , Chen Jenny X. , Lieu Judith E. C. , Shin Jennifer J.
Published: August 2017

Objectives

To investigate the potential association of macrolide antibiotics with sensorineural hearing loss (SNHL) and which agents and dosage may be related. To evaluate whether an optimal treatment exists for reversing SNHL that occurs after macrolide therapy.

Study Design

Systematic review of the literature.

Methods

Computerized (PubMed, EMBASE, Cochrane Library) and manual searches were performed to identify human studies of all ages (patients) who received macrolides (intervention, with or without control) and documented SNHL (outcome). All study designs were assessed. Extracted data included macrolide regimen details, as well as the timing, severity, and reversibility of SNHL with drug cessation alone or with additional medical intervention. Study designs and the associated risk of bias were assessed.

Results

The 44 publications (3 prospective, 41 retrospective) that met these criteria described 78 cases of audiometrically confirmed SNHL. SNHL was associated with oral and intravenous macrolide administration at standard and elevated doses. SNHL was irreversible in six cases, despite macrolide cessation (n = 5) and oral steroid treatment (n = 1). Irreversible SNHL was observed following 2 to 3 days of exposure. SNHL was reversible with macrolide cessation alone in 70 cases. In two cases, macrolide cessation coupled with oral steroid administration restored hearing. Reversible cases improved within hours to days. Nine studies also described 42 cases of subjective patient‐reported hearing loss. Limitations in the data arose from study design, related comorbidities, and concomitant drug administration.

Conclusion

SNHL may follow macrolide exposure, even at standard oral doses. Further research is needed to understand the incidence, prevalence, and biological mechanism of its ototoxicity. Laryngoscope, 128:228–236, 2018
Main Issues for Preserving Mediterranean Soil Resources From Water Erosion Under Global Change
Authors: Raclot Damien , Le Bissonnais Yves , Annabi Mohamed , Sabir Mohamed , Smetanova Anna
Published: August 2017

Soil resources are important for the socioeconomic development of the Mediterranean area. Their durability may be threatened because of intense erosion processes that result in severe degradation in the field (on‐site effects) and downstream degradation (off‐site effects). Based on the literature and results obtained during several research projects, this paper presents the main lessons and challenges dealing with Mediterranean soil resources under global change. After a review of the main drivers of Mediterranean soil erosion and the main impacts of water erosion processes, the paper highlights that the nature and intensity of active erosion processes are as diverse as the mosaic of the Mediterranean landscape. It then discusses the expected evolution of Mediterranean soil resources under global change and illustrates the prevalent influences of land use (partly depending on climatic constraints) on the evolution of erosion risk and soil vulnerability. Finally, it details some main challenges for the future of Mediterranean soil resources dealing with a better knowledge of factors and processes involved in soil erosion, a better evaluation of soil vulnerability through a combined quantitative and qualitative soil erosion approach, and the need for a site‐specific conservation strategy for Mediterranean soil resources. Copyright © 2017 John Wiley & Sons, Ltd.
Registration of pencil beam proton radiography data with X‐ray CT
Authors: Deffet Sylvain , Macq Benoît , Righetto Roberto , Vander Stappen François , Farace Paolo
Published: August 2017

Purpose

Proton radiography seems to be a promising tool for assessing the quality of the stopping power computation in proton therapy. However, range error maps obtained on the basis of proton radiographs are very sensitive to small misalignment between the planning CT and the proton radiography acquisitions. In order to be able to mitigate misalignment in postprocessing, the authors implemented a fast method for registration between pencil proton radiography data obtained with a multilayer ionization chamber (MLIC) and an X‐ray CT acquired on a head phantom.

Methods

The registration was performed by optimizing a cost function which performs a comparison between the acquired data and simulated integral depth‐dose curves. Two methodologies were considered, one based on dual orthogonal projections and the other one on a single projection. For each methodology, the robustness of the registration algorithm with respect to three confounding factors (measurement noise, CT calibration errors, and spot spacing) was investigated by testing the accuracy of the method through simulations based on a CT scan of a head phantom.

Results

The present registration method showed robust convergence towards the optimal solution. For the level of measurement noise and the uncertainty in the stopping power computation expected in proton radiography using a MLIC, the accuracy appeared to be better than 0.3° for angles and 0.3 mm for translations by use of the appropriate cost function. The spot spacing analysis showed that a spacing larger than the 5 mm used by other authors for the investigation of a MLIC for proton radiography led to results with absolute accuracy better than 0.3° for angles and 1 mm for translations when orthogonal proton radiographs were fed into the algorithm. In the case of a single projection, 6 mm was the largest spot spacing presenting an acceptable registration accuracy.

Conclusions

For registration of proton radiography data with X‐ray CT, the use of a direct ray‐tracing algorithm to compute sums of squared differences and corrections of range errors showed very good accuracy and robustness with respect to three confounding factors: measurement noise, calibration error, and spot spacing. It is therefore a suitable algorithm to use in the in vivo range verification framework, allowing to separate in postprocessing the proton range uncertainty due to setup errors from the other sources of uncertainty.
Motion‐corrected k‐space reconstruction for interleaved EPI diffusion imaging
Authors: Dong Zijing , Wang Fuyixue , Ma Xiaodong , Dai Erpeng , Zhang Zhe , Guo Hua
Published: August 2017

Purpose

To develop a new approach to correct for physiological and macroscopic motion in multishot, interleaved echo‐planar diffusion imaging.

Theory

This work built on the previous SPIRiT (iterative self‐consistent parallel imaging reconstruction) based reconstruction for physiological motion correction in multishot diffusion‐weighted imaging to account for macroscopic motion. In‐plane rotation, translation correction, data rejection, and weighted combination are integrated in SPIRiT‐based reconstruction to correct for ghosting artifacts, blurring, altered b‐matrix, and residual artifacts caused by motion.

Methods

Numerical simulations (one data set was obtained from the Human Connectome Project) and in vivo experiments with deliberate bulk motion were performed to demonstrate the effectiveness of the proposed method. Diffusion images and quantitative tensor parameters were calculated to evaluate the correction performance.

Results

The proposed method provided images with reduced artifacts and diffusion tensors with improved accuracy in both simulations and in vivo experiments. For in vivo experiments with deliberate motion, the percentage error of fractional anisotropy in the genu of the corpus callosum was significantly reduced from 17.01 ± 12.64 to 5.73 ± 3.77 through motion correction.

Conclusions

The proposed method can effectively correct for physiological and macroscopic motion artifacts in multishot interleaved echo‐planar imaging, generate high resolution diffusion images, and improve the accuracy of tensor calculation. Magn Reson Med 79:1992–2002, 2018. © 2017 International Society for Magnetic Resonance in Medicine.
The Quality of Governance in China and Beyond: Introduction to Special Issue
Authors: Gong Ting , Collins Paul , Chan Hon S.
Published: August 2017

As a result of the movement from government to governance, various institutional reforms have taken place across countries to shift powers and responsibilities of government to public and private partnerships or quasi‐government and nongovernment actors. Much has been said about the dynamics and processes of this shift, but its outcomes remain practically obscured and theoretically underexplored. Changing modes of governance does not necessarily lead to improved outcomes. Government service should be assessed not only by quantity but also by quality. For any society, healthy social development is no less important than economic growth and material affluence. As China's case indicates, the ways, processes and results of effective governance in fulfilling social, ethical and environmental responsibilities still remain challenging despite or because of rapid GDP growth, significant expansion of public services and considerable improvement in living standards. China's experience in dealing with a range of governance issues provides both positive and negative lessons for other societies that are facing similar problems. Copyright © 2017 John Wiley & Sons, Ltd.
Endostatin sensitizes p53‐deficient non‐small‐cell lung cancer to genotoxic chemotherapy by targeting DNA‐dependent protein kinase catalytic subunit
Authors: Jia Lin , Lu Xin‐an , Liu Guanghua , Wang Shan , Xu Min , Tian Yang , Zhang Shaosen , Fu Yan , Luo Yongzhang
Published: August 2017

Endostatin was discovered as an endogenous angiogenesis inhibitor with broad‐spectrum antitumour activities. Although clinical efficacy was observed when endostatin was combined with standard chemotherapy for non‐small cell lung cancer (NSCLC), as well as other cancer types, the specific mechanisms underlying the benefit of endostatin are not completely understood. Extensive investigations suggest that endostatin is a multifunctional protein possessing more than anti‐angiogenic activity. Here, we found that endostatin exerts a direct chemosensitizing effect on p53‐deficient tumour cells. Concomitant treatment with endostatin and genotoxic drugs resulted in therapeutic synergy in both cellular and animal models of p53‐deficient NSCLC. Mechanistically, endostatin specifically interacts with DNA‐dependent protein kinase catalytic subunit (DNA‐PKcs) in tumour cells and suppresses its DNA repair activity. Using isogenic NSCLC cells with different p53 statuses, we discovered that p53‐deficient tumour cells show chemoresistance to genotoxic drugs, creating a synthetic dependence on DNA‐PKcs‐mediated DNA repair. In this setting, endostatin exerted inhibitory effects on DNA‐PKcs activity, leading to accumulation of DNA lesions and promotion of the therapeutic effect of genotoxic chemotherapy. In contrast, p53‐proficient tumour cells were more sensitive to genotoxic drugs so that DNA‐PKcs could be cleaved by drug‐activated caspase‐3, making DNA‐PKcs inhibition less effective during this ongoing apoptotic process. Therefore, our data demonstrate a novel mechanism for endostatin as a DNA‐PKcs suppressor, and indicate that combination therapy of endostatin with genotoxic drugs could be a promising treatment strategy for cancer patients with p53‐deficient tumours. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Comprehensive T‐cell immunophenotyping and next‐generation sequencing of human papillomavirus (HPV)‐positive and HPV‐negative head and neck squamous cell carcinomas
Authors: Poropatich Kate , Fontanarosa Joel , Swaminathan Suchitra , Dittmann Dave , Chen Siqi , Samant Sandeep , Zhang Bin
Published: August 2017

The success of programmed cell death 1 (PD‐1) inhibition in achieving a clinical response in a subset of head and neck squamous cell carcinoma (HNSCC) patients emphasizes the need to better understand the immunobiology of HNSCC. Immunophenotyping was performed for 30 HCSCC patients [16 human papillomavirus (HPV)‐positive; 14 HPV‐negative] on matched tissue from the primary tumour site, locally metastatic cervical lymph nodes (LNs), uninvolved local cervical LNs, and peripheral blood. CD4+ and CD8+ T‐cell lymphocytes obtained from tissue were analysed for expression levels of the inhibitory receptors PD‐1, TIM‐3 and CTLA‐4. Next‐generation sequencing of the T‐cell receptor (TCR) β chain was performed on patients (n = 9) to determine receptor repertoire diversity and for clonality analysis. HPV‐negative HNSCC patients, particularly those with stage IV disease, had significantly higher proportions of CD8+ T cells expressing CTLA‐4 in tumour tissue (P = 0.0013) and in peripheral blood (P = 0.0344) than HPV‐positive patients, as well as higher expression levels of TIM‐3+PD‐1+ CD8+ T cells (P = 0.0072) than controls. For all patients, PD‐1 expression on CD8+ T cells – particularly in HPV‐negative HNSCC cases – strongly correlated (r = 0.63, P = 0.013) with tumour size at the primary site. The top CD8+ TCR clones from tumour tissue significantly overlapped with circulating peripheral blood TCR clones (r = 0.946), and HPV‐positive patients had frequently expanded TCR clones that were more hydrophobic – and potentially more immunogenic – than those from HPV‐negative patients. Collectively, our findings demonstrate, for the first time, that high‐stage HPV‐negative HNSCC patients with primary tumours at different sites in the head and neck have elevated peripheral CTLA‐4+CD8+ T‐cell levels, that tumour‐familiar CD8+ T cells are detectable in peripheral blood from HNSCC patients, and that TCRs from HPV‐positive HNSCC patients potentially recognize distinctly immunogenic cognate antigens. However, our findings are preliminary, and need to be further confirmed in a larger patient cohort; also, how these factors affect patient response to immunotherapy needs to be determined. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Impact of clinical evidence communications and drug regulation changes concerning rosiglitazone on prescribing patterns of antidiabetic therapies
Authors: Noh Yoojin , Kang Dae Ryong , Kim Dae Jung , Lee Kwang Jae , Lee Sukhyang , Shin Sooyoung
Published: August 2017

Purpose

Cardiovascular safety alerts about rosiglitazone resulted in regulatory actions in several countries in 2010, but the Food and Drug Administration eliminated access restrictions in 2013, reflecting new evidence concerning the drug safety. We investigated the effects of safety signals and regulation shifts concerning rosiglitazone on prescribing of antidiabetic drugs (ADs).

Methods

Patient data were extracted from the Korean health insurance claims database for 2007 to 2015. Linear regression and interrupted time series analyses were performed to examine drug utilization trends and the impact of 5 milestone events regarding rosiglitazone safety on AD utilization.

Results

A steady growth was observed in the AD consumption, with metformin preserving its dominant market share throughout the period. Pioglitazone use has increased since 2008 in response to safety issues surrounding rosiglitazone. A significant decline in rosiglitazone use was observed after Nissen's meta‐analysis and safety warnings (2007) and after restriction/suspension of access to rosiglitazone (2010), associated with a drop in prevalence by 29.5%/year and 99.5%/year, respectively. The most common AD newly started among users who discontinued rosiglitazone in 2010 was pioglitazone, followed by dipeptidyl peptidase‐4 (DPP‐4) inhibitors. Our concomitancy analysis showed that DPP‐4 inhibitors have overtaken sulfonylureas since 2014 as the most common add‐on to metformin.

Conclusions

The most frequently added AD in diabetes patients who had switched off rosiglitazone in 2010 was pioglitazone, followed by DPP‐4 inhibitors. Despite new evidence from a long‐term clinical trial and the Food and Drug Administration's subsequent decision to eliminate access restrictions on rosiglitazone in 2013, domestic regulations were left intact; hence, its use remained negligible in Korea.
Metamizole use during first trimester—A prospective observational cohort study on pregnancy outcome
Authors: Dathe Katarina , Padberg Stephanie , Hultzsch Stefanie , Meixner Katja , Tissen‐Diabaté Tatjana , Meister Reinhard , Beck Evelin , Schaefer Christof
Published: August 2017

Introduction

The analgesic metamizole (dipyrone) is not recommended during pregnancy due to limited experience. In several countries, metamizole has no market authorization because of agranulocytosis as a rare but severe adverse effect. However, in others, metamizole is available and widely used as a pain reliever, and its use occurs also during pregnancy, often followed by fears of potential teratogenic risk.

Methods

This prospective observational cohort study compared pregnancy outcomes of 446 women exposed with metamizole in the first trimester with a randomly selected control cohort comprising 887 women not exposed to metamizole. Relevant data were obtained via structured questionnaires applied during the first trimester and 2 months after the expected date of birth between January 2000 and December 2015.

Results

The rate of major birth defects (7/373, 1.9%) was not increased in the metamizole cohort (OR adjusted 1.15, 95% CI 0.4‐3.5). The cumulative incidences for spontaneous abortions did not reveal a significant difference between the exposed (12.2%, 32/446) and comparison cohort (19.4%, 77/887) (HR adjusted 0.72, 95% CI 0.5‐1.1). Elective terminations of pregnancy (ETOP), mostly for “social” reasons, were more frequent in the metamizole (12.5%, 45/446) than in the comparison cohort (9.4%, 50/887; HR adjusted 1.48, 95% CI 0.98‐2.2).

Conclusions

Metamizole exposure in the first trimester does not seem to bear a substantial teratogenic risk. Our study results support reassurance in those instances where metamizole has been used during an unrecognized pregnancy or where its use appears indispensable.
Helium permeation as a fast quality indicator for barrier properties of solar cell encapsulates
Authors: Schulze Stefan‐H. , Ehrich Christian , Meitzner Rico , Pander Matthias
Published: August 2017

The advent of flexible electronic devices and flexible thin‐film photovoltaic modules increases the need for transparent and flexible high‐barrier films. Conventional methods for measuring the barrier properties of such films are costly and time consuming. In our work, we present a method where we correlate water vapor and helium transmission rate measurements on strained barrier films with thin‐film solar module performance. We show that the detected properties correlate well with the performance of a CIGS mini module exposed to damp‐heat environment. The critical strain limit for a substantial decrease in barrier properties was identified for an ETFE‐based barrier film incorporating an inorganic barrier layer. It was found that the detection of the helium transmission rate provides a fast and reliable way to identify damage to barrier films and is therefore suitable as means for quality control or incoming goods inspection.
Divergent Proteome Patterns of Egg Albumen from Domestic Chicken, Duck, Goose, Turkey, Quail and Pigeon
Authors: Sun Congjiao , Liu Junnian , Li Wenbo , Xu Guiyun , Yang Ning
Published: August 2017

To uncover a diversity of genetic and biological unknowns, a comprehensive and comparative proteomic analysis is performed on egg albumen of domestic chicken, duck, goose, turkey, quail, and pigeon with tandem mass tags quantification technology. In this study, a total of 148, 138, 150, 162, 183, and 179 proteins are identified in egg albumen of the above six species, respectively. Venn plots, PCA, and cluster analysis all reveal the highest similarity of protein composition between duck and goose (≈75%). Additionally, the six species have 52 proteins detected in common in the egg albumen. As revealed by GO and pathway analyses, the plausible functions of these highly conserved proteins are to provide a secure environment and prevent the early death of embryonic cells. Species‐specific proteins such as haptoglobin in pigeon, serpin‐like protein HMSD in duck, and ovodefensin in chicken are also screened and are likely associated with species‐dependent biological processes. Furthermore, Enzyme Code analysis indicated egg albumen have abundant enzyme activity, with hydrolases accounting for more than half of the total enzymes. This study is the first to provide the proteome profiles of egg albumen for the major poultry species, which will be instructive for the understanding of species‐specific biological problems with egg albumen.
Cyclopropyllithium aggaregation and199Hg NMR as a tool for exchange studies with organo‐mercury compounds
Authors: Fox Thomas , Günther Harald
Published: August 2017

Low‐temperature NMR studies revealed aggregate formation in cyclopropyllithium compounds. For C3H5Li (1), a static tetramer [1J(6Li,13C) = 6.5 Hz] was found in diethylether (DEE), while in tetrahydrofuran (THF) a dimer and a fluxional tetramer [1J(6Li,13C) = 9.3 and 4.7 Hz, respectively] were detected.Trans‐2,3‐dimethyl‐1 (2) yielded in DEE/THF (1:1) diastereomeric dimers [1J(6Li,13C) = 9.3 Hz] and 2,2,3,3‐tetramethyl‐1 (3) formed dimers in DEE and DEE/THF [1J(6Li,13C) = 10.0 and 9.6 Hz, respectively]. For bis‐(trans‐2,3‐dimethylcyclopropyl)‐mercury (7), ligand exchange could be detected by the isotopic fingerprint method with199Hg NMR at room temperature.199Hg NMR in connection with specific deuteration may thus be used for ligand exchange studies in the field of organomercury compounds.
Interrupter technique in infancy: Higher airway resistance and lower short‐term variability in preterm versus term infants
Authors: Usemann Jakob , Demann Désirée , Anagnostopoulou Pinelopi , Korten Insa , Gorlanova Olga , Schulzke Sven , Frey Urs , Latzin Philipp
Published: August 2017

Background

In preschool children, measurement of airway resistance using interrupter technique (Rint) is feasible to assess the degree of bronchial obstruction. Although some studies measured Rint in infancy, values of Rint and its variability in preterm infants are unknown. In this study, Rint and its variability was measured at infancy and compared between healthy term and preterm infants.

Methods

High quality Rint measurements in term (n = 50) and preterm (n = 48) infants were obtained at postmenstrual age of 42‐50 weeks in two study centers in Switzerland. Intra‐measurement variability of Rint in one measurement and inter‐measurement variability between two subsequent measurements was assessed by coefficient of variation (CV).

Results

Mean Rint in term infants was 4.2 ± (SD; 1.9) kPa · s · L−1and in preterm infants was 5.6 ± (2.8) kPa · s · L−1. Mean CV in term infants was 29.6 ± (14.9)% and in preterm infants was 20.2 ± (8.4)%. Rint was significantly lower (95%CI −2.31 to −0.38;P = 0.007) and CV significantly higher (95%CI 4.53‐14.3;P < 0.001) in term compared to preterm infants. There were no differences in mean Rint and mean CV between the first and the second measurement obtained in a subgroup of term (n = 24, 48%) and preterm (n = 22, 45%) infants.

Conclusions

Our results suggest that differences in airway mechanics between term and preterm infants can be assessed with the interrupter technique during early infancy. Before clinical application of Rint measurements in this age group, reasons underlying the variability of measurements should be further investigated.
A new insight into CFTR allele frequency in Brazil through next generation sequencing
Authors: Nunes Luisa M. , Ribeiro Roberto , Niewiadonski Vivian D.T. , Sabino Ester , Yamamoto Guilherme L. , Bertola Débora R. , Gaburo Nelson , da Silva Filho Luiz Vicente R.F.
Published: August 2017

Background

As of 2013, fewer than 20% of patients in the Brazilian CF Registry had two CFTR mutations identified. The aim of this study was to sequence the coding region of the CFTR in Brazilian CF patients and determine the frequency of mutations in this cohort.

Methods

Patients with CF and those with suspected atypical CF or CFTR‐related disorders were invited to enroll. Total DNA was extracted from blood samples, quantified, and purified. Library preparation was performed using Ion Xpress™ Plus gDNA and Amplicon Library preparation kits (Life Technologies), as well as sequencing using the Ion Torrent platform (Life Technologies).

Results

A total of 141 patients were enrolled, and 45 mutations were identified. Among 126 CF patients, we identified mutations in 97.2% of alleles. The three most common mutations were F508del, G542X, and 3120 + 1G‐>A. Five novel pathogenic mutations were also identified.

Conclusions

Next generation sequencing (NGS) allowed the identification of mutations in most CF alleles and confirmed allelic heterogeneity in our population.
The Financial and Public Health Emergencies in Flint, Michigan: Crisis Management and the American Federalism
Authors: Nukpezah Julius A.
Published: August 2017

The case study uses secondary information to examine the financial crisis that morphed into public health emergency in Flint, Michigan. While previous crisis management studies have examined financial crises and public health emergencies, the present study embodies both of them and offers an opportunity to understand how multi‐level governments cooperate in responding to multiple emergencies. The overarching question of interest is how do local governments cooperate with multi‐level governments to respond to multiple local emergencies? The specific research questions are as follows: (i) What are the causes, consequences, cautions, and coping strategies of the Flint crises; (ii) What are the roles of multi‐level governments in responding to the Flint crises? and (iii) What are the indicators of success and failure in the response by multi‐level governments to the Flint crises? The paper draws on the American federalism and crisis management scholarship for context and finds that crisis management leadership, effective communication, subsidiarity principles as in multi‐level response, and accountability are necessary for effective response efforts that build resilient organizations. The findings corroborate previous studies making the present study generalizable to other emergencies. Local governments can learn from the Flint experience in mitigating the impact of crises.
Meta‐Governance and Collaborative Crisis Management—Competing Rationalities in the Management of the Swedish Security Communications System
Authors: Larsson Oscar L.
Published: August 2017

It is well recognized that contemporary crisis call for collaborative efforts across both organizational and jurisdictional boundaries. One of the key challenges for governments and public authorities responsible for organizing crisis management is to find adequate ways in which they can support decentralized and collaborative responses. This effort can be analyzed through the meta‐governance approach that suggests that different instruments can be used to support decentralized collaborative efforts. This article analyzes the management of crisis communication in Sweden and the implementation of a new national Security Communications System (SCS) as a specific case of meta‐governance. The main finding suggests that meta‐governance may be impaired by combining different types of governance (sovereignty, markets, or network management) due to competing rationality invested in each governance style. The deadlock was, however, resolved by direct involvement and increased deliberation between the meta‐governors and the end users as it generated a shared understanding of crisis management and the utility of a single SCS. Besides identifying the importance of direct involvement in terms of network management the article also suggests that meta‐governors need to develop a deeper and more sensitive understanding of the self‐organizing nature of networks in order to be able to support collaborative crisis management.
Investigation of minimum shear strength of reinforced concrete elements without transverse reinforcement
Authors: Fernández‐Montes David , González Valle Enrique , Díaz Heredia Elena
Published: August 2017

The paucity of experimental research and several incongruences in boundary conditions of actual sectional design procedures of empirical nature may raise doubts about the validity of the minimum value for the shear strength of reinforced concrete members in Eurocode 2 (EC‐2). Although a minimum reinforcement due to bending is supposed before shear strength checking, EC‐2 Commentary gives an explanation about a conservative value for a minimum on the basis of the tensile strength of the concrete. This manuscript highlights the gaps in the state of present knowledge and incorporates a new proposal.
The politics of water: a review of hydropolitical frameworks and their application in China
Authors: Rogers Sarah , Crow‐Miller Britt
Published: August 2017

Academic literature on the politics of water encompasses hydrosocial relations at different scales, the role of technology in hydropolitics, and the various rationalities and discourses behind the governance of water. In this advanced review, we outline the key hydropolitical frameworks, tracing the development of scholarship that examines the relations between power, water, society, and technology. We then synthesize the literature on hydropolitics in China, which boasts both the world's largest dam (by installed capacity) and the world's largest interbasin transfer project. We consider the extent to which different frameworks have been productively applied in a Chinese context, not just to understand big infrastructure, but to question of water pollution, agricultural water use, and water scarcity. In doing so, we find that critical scholarship on hydropolitics in China has a number of significant gaps. These gaps constrain our understanding of the inherent political nature of the many acute water challenges China currently faces and challenges that have impacts well beyond its borders.WIREs Water2017, 4:e1239. doi: 10.1002/wat2.1239

This article is categorized under:

Engineering Water > Planning Water

Human Water > Rights to Water

Human Water > Water Governance