bluuebunny/crossref_metadata_2025 huggingface dataset:
Multicenter Population Pharmacokinetic Study of Colistimethate Sodium and Colistin Dosed as in Normal Renal Function in Patients on Continuous Renal Replacement Therapy
Authors: Leuppi-Taegtmeyer Anne B. , Decosterd Laurent , Osthoff Michael , Mueller Nicolas J. , Buclin Thierry , Corti Natascia
Published: November 2018

Intravenous colistimethate sodium (CMS) is used to treat infections with multiresistant Gram-negative bacteria. Optimal dosing in patients undergoing continuous renal replacement therapy (CRRT) is unclear.
Evaluation of the ePlex Blood Culture Identification Panels for Detection of Pathogens in Bloodstream Infections
Authors: Huang Te-Din , Melnik Ekaterina , Bogaerts Pierre , Evrard Stephanie , Glupczynski Youri
Published: November 2018

Rapid identification and susceptibility testing results are of importance for the early appropriate therapy of bloodstream infections. The ePlex (GenMark Diagnostics) blood culture identification (BCID) panels are fully automated PCR-based assays designed to identify Gram-positive and Gram-negative bacteria, fungi, and bacterial resistance genes within 1.5 h from positive blood culture.
Cell Cycle Arrest in G
2
/M Phase Enhances Replication of Interferon-Sensitive Cytoplasmic RNA Viruses via Inhibition of Antiviral Gene Expression
Authors: Bressy Christian , Droby Gaith N. , Maldonado Bryant D. , Steuerwald Nury , Grdzelishvili Valery Z.
Published: November 2018

Vesicular stomatitis virus (VSV) (a rhabdovirus) and its variant VSV-ΔM51 are widely used model systems to study mechanisms of virus-host interactions. Here, we investigated how the cell cycle affects replication of VSV and VSV-ΔM51. We show that G
2
/M cell cycle arrest strongly enhances the replication of VSV-ΔM51 (but not of wild-type VSV) and Sendai virus (a paramyxovirus) via inhibition of antiviral gene expression, likely due to mitotic inhibition of transcription, a global repression of cellular transcription during G
2
/M phase. Our data suggest that the G
2
/M phase could represent an “Achilles’ heel” of the infected cell, a phase when the cell is inadequately protected. This model could explain at least one of the reasons why many viruses have been shown to induce G
2
/M arrest, and it has important implications for oncolytic virotherapy, suggesting that frequent cell cycle progression in cancer cells could make them more permissive to viruses.
Predicting Intraserotypic Recombination in Enterovirus 71
Authors: Woodman Andrew , Lee Kuo-Ming , Janissen Richard , Gong Yu-Nong , Dekker Nynke H. , Shih Shin-Ru , Cameron Craig E.
Published: November 2018

Recombination is a mechanism that contributes to genetic diversity. We describe the first assay to study EV-A71 recombination. Results from this assay mimic what is observed in nature and can be used by others to predict future recombination events within the enterovirus species A group. In addition, our results highlight the central role played by the viral RNA-dependent RNA polymerase (RdRp) in the recombination process. Further, our results show that changes to a conserved residue in the RdRp from different species groups have a similar impact on viable recombinant virus yields, which is indicative of conservation in mechanism.
Using a cross-contextual reciprocal learning approach in a multisite implementation research project to improve self-management for type 2 diabetes
Authors: van Olmen Josefien , Delobelle Peter , Guwatudde David , Absetz Pilvikki , Sanders David , Mölsted Alvesson Helle , Puoane Thandi , Ostenson Claes-Goran , Tomson Göran , Mayega Roy William , Sundberg Carl Johan , Peterson Stefan , Daivadanam Meena
Published: November 2018

This paper reports on the use of reciprocal learning for identifying, adopting and adapting a type 2 diabetes self-management support intervention in a multisite implementation trial conducted in a rural setting in a low-income country (Uganda), a periurban township in a middle-income country (South Africa) and socioeconomically disadvantaged suburbs in a high-income country (Sweden). The learning process was guided by a framework for knowledge translation and structured into three learning cycles, allowing for a balance between evidence, stakeholder interaction and contextual adaptation. Key factors included commitment, common goals, leadership and partnerships. Synergistic outcomes were the cocreation of knowledge, interventions and implementation methods, including reverse innovations such as adaption of community-linked models of care. Contextualisation was achieved by cross-site exchanges and local stakeholder interaction to balance intervention fidelity with local adaptation. Interdisciplinary and cross-site collaboration resulted in the establishment of learning networks. Limitations of reciprocal learning relate to the complexity of the process with unpredictable outcomes and the limited generalisability of results.
Diagnosis of diaphragm injuries using modern 256-slice CT scanners: too early to abandon operative exploration
Authors: Uhlich Rindi , Kerby Jeffrey David , Bosarge Patrick , Hu Parker
Published: November 2018

Background

Missed injury of the diaphragm may result in hernia formation, enteric strangulation, and death. Compounding the problem, diaphragmatic injuries are rare and difficult to diagnose with standard imaging. As such, for patients with high suspicion of injury, operative exploration remains the gold standard for diagnosis. As no current data currently exist, we sought to perform a pragmatic evaluation of the diagnostic ability of 256-slice multidetector CT scanners for diagnosing diaphragmatic injuries after trauma.

Methods

A retrospective review of trauma patients from 2011 to 2018 was performed at an American College of Surgeons-verified level 1 trauma center to identify the diagnostic accuracy of CT scan for acute diaphragm injury. All patients undergoing abdominal operation were eligible for inclusion. Two separate levels of CT scan technology, 64-slice and 256-slice, were used during this time period. The prospective imaging reports were reviewed for the diagnosis of diaphragm injury and the results confirmed with the operative record. Injuries were graded using operative description per the American Association for the Surgery of Trauma guidelines.

Results

One thousand and sixty-eight patients underwent operation after preoperative CT scan. Acute diaphragm injury was identified intraoperatively in 14.7%. Most with diaphragmatic injury underwent 64-slice CT (134 of 157, 85.4%). Comparing patients receiving 64-slice or 256-slice CT scan, there was no difference in the side of injury (left side 57.5% vs. 69.6%, p=0.43) or median injury grade (3 (3, 3) vs. 3 (2, 3), p=0.65). Overall sensitivity, specificity, and diagnostic accuracy of the 256-slice CT were similar to the 64-slice CT (56.5% vs. 45.5%, 93.7% vs. 98.1%, and 89.0% vs. 90.2%).

Discussion

The new 256-slice multidetector CT scanner fails to sufficiently improve diagnostic accuracy over the previous technology. Patients with suspicion of diaphragm injury should undergo operative intervention.

Level of evidence

I, diagnostic test or criteria.
Vitamin E supplementation and caloric restriction promotes regulation of insulin secretion and glycemic homeostasis by different mechanisms in rats
Authors: Venturini Paula R. , Thomazini Bruna Fontana , Oliveira Camila Andréa , Alves Armindo A. , Camargo Thaís Furtado , Domingues Caio E.C. , Barbosa-Sampaio Helena C.L. , do Amaral Maria Esméria C.
Published: November 2018

Vitamin E and caloric restriction have antioxidant effects in mammals. The aim of this study was to evaluate effects of vitamin E supplementation and caloric restriction upon insulin secretion and glucose homeostasis in rats. Male Wistar rats were distributed among the following groups: C, control group fed ad libitum; R, food quantity reduction of 40%; CV, control group supplemented with vitamin E [30 mg·kg–1·day–1]; and RV, food-restricted group supplemented with vitamin E. The experiments ran for 21 days. Glucose tolerance and insulin sensitivity was higher in the CV, R, and RV groups. Insulin secretion stimulated with different glucose concentrations was lower in the R and RV groups, compared with C and CV. In the presence of glucose and secretagogues, insulin secretion was higher in the CV group and was lower in the R and RV groups. An increase in insulin receptor occurred in the fat pad and muscle tissue of groups CV, R, and RV. Levels of hepatic insulin receptor and phospho-Akt protein were higher in groups R and RV, compared with C and CV, while muscle phospho-Akt was increased in the CV group. There was a reduction in hepatic RNA levels of the hepatocyte growth factor gene and insulin degrading enzyme in the R group, and increased levels of insulin degrading enzyme in the CV and RV groups. Thus, vitamin E supplementation and caloric restriction modulate insulin secretion by different mechanisms to maintain glucose homeostasis.
MicroRNA-3666 inhibits lung cancer cell proliferation, migration, and invasiveness by targeting BPTF
Authors: Pan Linqing , Tang Zhipeng , Pan Lina , Tang Ranran
Published: November 2018

A previous study by our group indicted that overexpression of bromodomain PHD-finger transcription factor (BPTF) occurs in lung adenocarcinoma, and is closely associated with advanced clinical stage, higher numbers of metastatic lymph nodes, the occurrence of distant metastasis, low histological grade, and poor prognosis. Down-regulation of BPTF inhibited lung adenocarcinoma cell proliferation and promoted lung adenocarcinoma cell apoptosis. The purpose of this study is to identify valuable microRNAs (miRNAs) that target BPTF to modulate lung adenocarcinoma cell proliferation. In our results, we found that miR-3666 was notably reduced in lung adenocarcinoma tissues and cell lines. Using an miR-3666 mimic, we discovered that cell proliferation, migration, and invasiveness were suppressed by miR-3666 overexpression, but these were all enhanced when the expression of miR-3666 was reduced. Moreover, bioinformatics analysis using the TargetScan database and miRanda software suggested a putative target site in BPTF 3′-UTR. Furthermore, using a luciferase reporter assay, we verified that miR-3666 directly targets the 3′-UTR of BPTF. Using Western blot we discovered that overexpression of miR-3666 negatively regulates the protein expression of BPTF. Finally, we identified that the PI3K–AKT and epilthelial–mesenchymal transition (EMT) signaling pathways were inhibited by miR-3666 overexpression in lung cancer cells. In conclusion, our data indicate that miR-3666 could play an essential role in cell proliferation, migration, and invasiveness by targeting BPTF and partly inhibiting the PI3K–AKT and EMT signaling pathways in human lung cancers.
EDITORIAL
Authors: D’ORAZIO PAOLA , FABRETTI ANNALISA
Published: November 2018

In the last decade, the economic community has been characterized by a growing debate on the methods used in research. In particular, the financial crisis exposed the mainstream general equilibrium models used by economists to their flaws and drawbacks (Fagiolo and Roventini, 2017) and also policymakers claimed to feel ''abandoned'' by the conventional tools (Trichet, 2010). The weaknesses of conducting economic analyses relying on highly sophisticated mathematical models focused on the analysis of the system in equilibrium, are being addressed by many researchers both in the mainstream (Romer, 2016; Reis, 2017) and in the agentbased community. In particular, agent-based models (ABMs) are emerging as a potential new paradigm (D’Orazio, 2017) because of their ability to deal with complexity, heterogeneity, and decentralized interaction mechanisms. In this framework, this topical issue is particularly relevant in that it gathers contributions that aim at developing a multi-disciplinary approach and suggests some advances in the methodology.
piRNA-Guided Genome Defense: From Biogenesis to Silencing
Authors: Czech Benjamin , Munafò Marzia , Ciabrelli Filippo , Eastwood Evelyn L. , Fabry Martin H. , Kneuss Emma , Hannon Gregory J.
Published: November 2018

PIWI-interacting RNAs (piRNAs) and their associated PIWI clade Argonaute proteins constitute the core of the piRNA pathway. In gonadal cells, this conserved pathway is crucial for genome defense, and its main function is to silence transposable elements. This is achieved through posttranscriptional and transcriptional gene silencing. Precursors that give rise to piRNAs require specialized transcription and transport machineries because piRNA biogenesis is a cytoplasmic process. The ping-pong cycle, a posttranscriptional silencing mechanism, combines the cleavage-dependent silencing of transposon RNAs with piRNA production. PIWI proteins also function in the nucleus, where they scan for nascent target transcripts with sequence complementarity, instructing transcriptional silencing and deposition of repressive chromatin marks at transposon loci. Although studies have revealed numerous factors that participate in each branch of the piRNA pathway, the precise molecular roles of these factors often remain unclear. In this review, we summarize our current understanding of the mechanisms involved in piRNA biogenesis and function.
Non–Vitamin K Antagonist Oral Anticoagulants in the Treatment of Atrial Fibrillation
Authors: Fanaroff Alexander C. , Ohman E. Magnus
Published: November 2018

Atrial fibrillation (AF) increases a patient's stroke risk four- to five-fold. Anticoagulation with the vitamin K antagonist (VKA) warfarin reduces the risk of stroke by 67%, but warfarin carries a significant risk of major bleeding and has unpredictable pharmacodynamics with a narrow therapeutic window, necessitating frequent monitoring of its anticoagulant effect. The non–vitamin K antagonist oral anticoagulants (NOACs) dabigatran, rivaroxaban, apixaban, and edoxaban provide more predictable anticoagulant activity than warfarin with a lower risk of major bleeding, and each is noninferior to warfarin for the prevention of stroke. All have earned regulatory approval in the past eight years. At least one of the NOACs is approved for use in all patients with AF, except those with mechanical valves and rheumatic mitral valve disease, for whom warfarin remains the only option. Recent clinical trials have shown that antithrombotic regimens including NOACs are safe and effective in patients with AF who need potent antiplatelet therapy.
Novel HAX1 Gene Mutation in a Vietnamese Boy with Severe Congenital Neutropenia
Authors: Tran Tham Thi , Vu Quang Van , Wada Taizo , Yachie Akihiro , Le Thi Minh Huong , Nguyen Sang Ngoc
Published: November 2018

Severe congenital neutropenia (SCN) is a rare disease that involves a heterogeneous group of hereditary diseases. Mutations in the HAX1 gene can cause an autosomal recessive form of SCN-characterized low blood neutrophil count from birth, increased susceptibility to recurrent and life-threatening infections, and preleukemia predisposition. A 7-year-old boy was admitted due to life-threatening infections, mental retardation, and severe neutropenia. He had early-onset bacterial infections, and his serial complete blood count showed persistent severe neutropenia. One older sister and one older brother of the patient died at the age of 6 months and 5 months, respectively, because of severe infection. Bone marrow analysis revealed a maturation arrest at the promyelocyte/myelocyte stage with few mature neutrophils. In direct DNA sequencing analysis, we found a novel homozygous frameshift mutation (c.423_424insG, p.Gly143fs) in the HAX1 gene, confirming the diagnosis of SCN. The patient was successfully treated with granulocyte colony-stimulating factor (G-CSF) and antibiotics. A child with early-onset recurrent infections and neutropenia should be considered to be affected with SCN. Genetic analysis is useful to confirm diagnosis. Timely diagnosis and suitable treatment with G-CSF and antibiotics are important to prevent further complication.
A Succession of MRI Scans Supports the Diagnosis of Lumbar Ligamentum Flavum Hematoma: A Case Report and Review of the Literature
Authors: Ishimoto Yuyu , Kawakami Mamoru , Curtis Elizabeth , Cooper Cyrus , Moriguchi Nami , Nakagawa Yukihiro
Published: November 2018

Ligamentum flavum hematoma (LFH) is a rare cause of spinal nerve compression. This condition remains challenging to diagnose using MRI due to the changing intensity of the hematoma on imaging. The aim of this study was to describe the patient with LFH who had a succession of MRI scans carried out. We report on a 71-year-old woman with a mass at L4/5 and decompression surgery was performed for her left leg symptom. She had MRI carried out in a previous hospital and also had MRI again in our hospital. In a 2nd MRI of the same area, after a 2-week interval, a newly isointense mass was present within the anterior part of the previously identified lesion on T1-weighted image and the hyperintense area in the lesion was a little extended on T2-weighted imaging. Her symptoms were resolved immediately after decompression surgery. Following a review of previous cases, we suggest that consecutive MRI scanning may support the diagnostic process for LFH.
Future Roadmaps for Precision Medicine Applied to Diabetes: Rising to the Challenge of Heterogeneity
Authors: Bowman P. , Flanagan S. E. , Hattersley A. T.
Published: November 2018

Precision medicine, the concept that specific treatments can be targeted to groups of individuals with specific genetic, cellular, or molecular features, is a key aspect of modern healthcare, and its use is rapidly expanding. In diabetes, the application of precision medicine has been demonstrated in monogenic disease, where sulphonylureas are used to treat patients with neonatal diabetes due to mutations in ATP-dependent potassium (KATP) channel genes. However, diabetes is highly heterogeneous, both between and within polygenic and monogenic subtypes. Making the correct diagnosis and using the correct treatment from diagnosis can be challenging for clinicians, but it is crucial to prevent long-term morbidity and mortality. To facilitate precision medicine in diabetes, research is needed to develop a better understanding of disease heterogeneity and its impact on potential treatments for specific subtypes. Animal models have been used in diabetes research, but they are not translatable to humans in the majority of cases. Advances in molecular genetics and functional laboratory techniques and availability and sharing of large population data provide exciting opportunities for human studies. This review will map the key elements of future diabetes research in humans and its potential for clinical translation to promote precision medicine in all diabetes subtypes.
Stroke in the21stCentury: A Snapshot of the Burden, Epidemiology, and Quality of Life
Authors: Donkor Eric S.
Published: November 2018

Stroke is ranked as the second leading cause of death worldwide with an annual mortality rate of about 5.5 million. Not only does the burden of stroke lie in the high mortality but the high morbidity also results in up to 50% of survivors being chronically disabled. Thus stroke is a disease of immense public health importance with serious economic and social consequences. The public health burden of stroke is set to rise over future decades because of demographic transitions of populations, particularly in developing countries. This paper provides an overview of stroke in the21stcentury from a public health perspective.
Rub‐Impact Detection in Rotor Systems with Pedestal Looseness Using a Nonlinearity Evaluation
Authors: Jiang Mian , Kuang Yingwei , Wu Jigang , Li Xuejun
Published: November 2018

In this paper, a nonlinearity evaluation is proposed in order to identify the rub‐impact in rotor systems with pedestal looseness. Nonlinear mathematical models have been established for bearing‐rotor systems with single pedestal looseness and pedestal looseness coupled with rub‐impact. Piecewise linear stiffness and damping are considered regarding the position of pedestal looseness, while radial impact forces are defined using the Colulomb type of frictional relationship during rub‐impact. The nonlinearity evaluation is employed to quantify the nonlinearity of the dynamics of bearing‐rotor systems, which are calculated at different looseness clearances. The experiments for rotor systems with pure pedestal looseness and pedestal looseness coupled with rub‐impact are conducted respectively to collect the vibration signals on different looseness clearances. Two different curves are obtained using the nonlinear fitting method for the values of nonlinearity evaluation. The rub‐impact within rotor systems with pedestal looseness can then be identified by comparing the curves that denote the trend of nonlinearity evaluation for the measured vibration responses.
Idiopathic Hypoparathyroidism and Severe Hypocalcemia in Pregnancy
Authors: Richa Carine Ghassan , Issa Ali Ihsan , Echtay Akram Salim , El Rawas Mohamad Souheil
Published: November 2018

The objective of this study is to report a case of severe hypocalcemia secondary to hypoparathyroidism in a pregnant woman. We report a case of a 45-year-old woman who presented for tonico-clonic seizure in the third trimester of gestation. She was diagnosed with idiopathic hypoparathyroidism for the first time during pregnancy. She was successfully treated with calcium and calcitriol in the rest of her pregnancy with resolution of symptoms but her infant was born with hypercalcemia and secondary hyperparathyroidism due to the late maternal presentation. To the best of our knowledge, hypoparathyroidism is a disorder rarely observed during pregnancy, resulting in most cases from surgical thyroidectomy.
Treatment Adherence and Its Associated Factors in Patients with Type 2 Diabetes: Results from the Rio de Janeiro Type 2 Diabetes Cohort Study
Authors: Marinho Fernanda S. , Moram Camila B. M. , Rodrigues Priscila C. , Leite Nathalie C. , Salles Gil F. , Cardoso Claudia R. L.
Published: November 2018

Objectives. To investigate treatment adherence in patients with type 2 diabetes and to evaluate its associated factors. Methods. The Summary of Diabetes Self-Care Activities (SDSCA) questionnaire was used to assess treatment adherence. Good adherence was defined as ≥5 days a week in each SDSCA item. Pain, emotional, and physical domains of the SF-36 quality of life questionnaire and the Canadian Occupational Performance Measure (COPM) were also evaluated. Multivariable logistic regressions explored the independent correlates of good general adherence and of specific items of the SDSCA (diet, exercise, and medications). Results. Good adherence was 93.5% for medication use, 59.3% for foot care, 56.1% for blood glucose monitoring, 29.2% for diet, and 22.5% for exercise. Patients with general good adherence had lower BMI, better serum lipid profile, higher values of functional capacity, emotional and pain domains of SF-36, better occupational performance, and lower prevalence of pain or limitation in the upper and lower limbs than patients with worse adherence. The variables associated with good adherence were younger age, lower BMI, presence of macrovascular complications, better occupational performance and emotional domain of SF-36, and higher HDL cholesterol levels. The presence of pain/limitation in the upper limbs was associated with worse adherence. Good medication adherence was associated with longer diabetes duration, lower BMI, and lower HbA1c levels. Higher values of pain and emotional domains of the SF-36 and lower BMI were related to better exercise and diet adherence, while the presence of peripheral neuropathy and joint pain/limitation were associated with worse exercise adherence. Conclusions. Emotional and physical performances are important determinants of good diabetic treatment adherence. Good adherence has beneficial impact on BMI, lipid, and glycemic control.
Food-Grade Saponin Extract as an Emulsifier and Immunostimulant in Emulsion-Based Subunit Vaccine for Pigs
Authors: Burakova Yulia , Madera Rachel , Wang Lihua , Buist Sterling , Lleellish Karen , Schlup John R. , Shi Jishu
Published: November 2018

Subunit vaccines consisting of highly purified antigens require the presence of adjuvants to create effective and long-lasting protective immunity. Advances on adjuvant research include designing combination adjuvants which incorporate two or more adjuvants to enhance vaccine efficacy. Previously, an oil-in-water emulsion adjuvant (OW-14) composed of mineral oil and an inexpensive gum Arabic emulsifier has been reported demonstrating enhanced and robust immune responses when used as an adjuvant in swine subunit vaccines. This study presents a modified version of OW-14 prepared with food-gradeQuillajasaponin extract (OWq). In new OWq emulsion, saponin extract served as an emulsifier for stabilization of emulsion droplets and as an immunoactive compound. The use of saponins allowed to reduce the required amount of emulsifier in the original OW-14. However, emulsion stabilized with saponins demonstrated extended physical stability even at elevated temperature (37°C). The two-dose vaccination with a classical swine fever virus (CSFV) glycoprotein E2-based vaccine formulated with OWq produced higher levels of E2-specific IgG and virus neutralizing antibodies in pigs in contrast with animals that received the vaccine adjuvanted with oil only. In addition, new OWq adjuvant was safe to use in the vaccination of pigs.
Clinical Significance of Serum Galectin-9 and Soluble CD155 Levels in Patients with Systemic Sclerosis
Authors: Chihara Mami , Kurita Miki , Yoshihara Yuki , Asahina Akihiko , Yanaba Koichi
Published: November 2018

Signaling through coinhibitory receptors downregulates the immune response to prevent excessive immune activation and maintain optimal immunity and tolerance. The aim of this study was to examine the levels of the soluble forms of coinhibitory receptors and their ligands, namely, galectin-9 (the ligand of T-cell immunoglobulin and mucin domain 3) and CD155 (the ligand of T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain), and their association with clinical features in patients with systemic sclerosis (SSc). The serum levels of galectin-9 and soluble sCD155 were examined by enzyme-linked immunosorbent assays in patients with SSc, and the results were evaluated with respect to clinical features. Patients with SSc exhibited raised serum levels of galectin-9, but not sCD155. Serum galectin-9 levels were raised not only in patients with diffuse cutaneous SSc but also in patients with limited cutaneous SSc. Furthermore, serum galectin-9 levels correlated positively with the erythrocyte sedimentation rate. In addition, increased serum galectin-9 levels tended to be associated with higher mortality and serious organ involvement. These results suggest that galectin-9, but not CD155, may be involved in the pathogenesis of SSc. In addition, the measurement of serum galectin-9 levels could be used to predict serious organ involvement and high mortality in patients with SSc.
STING Promotes Homeostasis via Regulation of Cell Proliferation and Chromosomal Stability
Authors: Ranoa Diana Rose E. , Widau Ryan C. , Mallon Stephen , Parekh Akash D. , Nicolae Claudia M. , Huang Xiaona , Bolt Michael J. , Arina Ainhoa , Parry Renate , Kron Stephen J. , Moldovan George-Lucian , Khodarev Nikolai N. , Weichselbaum Ralph R.
Published: November 2018

Given the integral role of stimulator of interferon genes (STING, TMEM173) in the innate immune response, its loss or impairment in cancer is thought to primarily affect antitumor immunity. Here we demonstrate a role for STING in the maintenance of cellular homeostasis through regulation of the cell cycle. Depletion of STING in human and murine cancer cells and tumors resulted in increased proliferation compared with wild-type controls. Microarray analysis revealed genes involved in cell-cycle regulation are differentially expressed in STINGko compared with WT MEFs. STING-mediated regulation of the cell cycle converged on NFκB- and p53-driven activation of p21. The absence of STING led to premature activation of cyclin-dependent kinase 1 (CDK1), early onset to S-phase and mitosis, and increased chromosome instability, which was enhanced by ionizing radiation. These results suggest a pivotal role for STING in maintaining cellular homeostasis and response to genotoxic stress.

Significance:

These findings provide clear mechanistic understanding of the role of STING in cell-cycle regulation, which may be exploited in cancer therapy because most normal cells express STING, while many tumor cells do not.

See related commentary by Gius and Zhu, p. 1295
Aspirin, NSAIDs, and Glioma Risk: Original Data from the Glioma International Case–Control Study and a Meta-analysis
Authors: Amirian E. Susan , Ostrom Quinn T. , Armstrong Georgina N. , Lai Rose K. , Gu Xiangjun , Jacobs Daniel I. , Jalali Ali , Claus Elizabeth B. , Barnholtz-Sloan Jill S. , Il'yasova Dora , Schildkraut Joellen M. , Ali-Osman Francis , Sadetzki Siegal , Jenkins Robert B. , Lachance Daniel H. , Olson Sara H. , Bernstein Jonine L. , Merrell Ryan T. , Wrensch Margaret R. , Johansen Christoffer , Houlston Richard S. , Scheurer Michael E. , Shete Sanjay , Amos Christopher I. , Melin Beatrice , Bondy Melissa L.
Published: November 2018

Background:

There have been few studies of sufficient size to address the relationship between glioma risk and the use of aspirin or NSAIDs, and results have been conflicting. The purpose of this study was to examine the associations between glioma and aspirin/NSAID use, and to aggregate these findings with prior published studies using meta-analysis.

Methods:

The Glioma International Case-Control Study (GICC) consists of 4,533 glioma cases and 4,171 controls recruited from 2010 to 2013. Interviews were conducted using a standardized questionnaire to obtain information on aspirin/NSAID use. We examined history of regular use for ≥6 months and duration-response. Restricted maximum likelihood meta-regression models were used to aggregate site-specific estimates, and to combine GICC estimates with previously published studies.

Results:

A history of daily aspirin use for ≥6 months was associated with a 38% lower glioma risk, compared with not having a history of daily use [adjusted meta-OR = 0.62; 95% confidence interval (CI), 0.54–0.70]. There was a significant duration-response trend (P = 1.67 × 10−17), with lower ORs for increasing duration of aspirin use. Duration-response trends were not observed for NSAID use. In the meta-analysis aggregating GICC data with five previous studies, there was a marginally significant association between use of aspirin and glioma (mOR = 0.84; 95% CI, 0.70–1.02), but no association for NSAID use.

Conclusions:

Our study suggests that aspirin may be associated with a reduced risk of glioma.

Impact:

These results imply that aspirin use may be associated with decreased glioma risk. Further research examining the association between aspirin use and glioma risk is warranted.
Leveraging TCR Affinity in Adoptive Immunotherapy against Shared Tumor/Self-Antigens
Authors: Miller Aaron M. , Bahmanof Milad , Zehn Dietmar , Cohen Ezra E.W. , Schoenberger Stephen P.
Published: November 2018

Adoptive cellular therapy (ACT) using T-cell receptor (TCR)–engineered lymphocytes holds promise for eradication of disseminated tumors but also an inherent risk of pathologic autoimmunity if targeted antigens or antigenic mimics are expressed by normal tissues. We evaluated whether modulating TCR affinity could allow CD8+ T cells to control tumor outgrowth without inducing concomitant autoimmunity in a preclinical murine model of ACT. RIP-mOVA mice express a membrane-bound form of chicken ovalbumin (mOVA) as a self-antigen in kidney and pancreas. Such mice were implanted with OVA-expressing ID8 ovarian carcinoma cells and subsequently treated with CD8+ T lymphocytes (CTL) expressing either a high-affinity (OT-I) or low-affinity (OT-3) OVA-specific TCR. The effects on tumor growth versus organ-specific autoimmunity were subsequently monitored. High-affinity OT-I CTLs underwent activation and proliferation in both tumor-draining and pancreatic lymph nodes, leading to both rapid eradication of ID8-OVA tumors and autoimmune diabetes in all treated mice. Remarkably, the low-affinity OT-3 T cells were activated only by tumor-derived antigen and mediated transient regression of ID8-OVA tumors without concomitant autoimmunity. The OT-3 cells eventually upregulated inhibitory receptors PD-1, TIM-3, and LAG-3 and became functionally unresponsive, however, allowing the tumors in treated mice to reestablish progressive growth. Antibody-mediated blockade of the inhibitory receptors prevented exhaustion and allowed tumor clearance, but these mice also developed autoimmune diabetes. The findings reveal that low-affinity TCRs can mediate tumor regression and that functional avidity can discriminate between tumor-derived and endogenous antigen, while highlighting the risks involved in immune-checkpoint blockade on endogenous self-reactive T cells.
Quantitative Electroencephalography Analyzed by Statistical Pattern Recognition as a Diagnostic and Prognostic Tool in Mild Cognitive Impairment: Results from a Nordic Multicenter Cohort Study
Authors: Schjønning Nielsen Malene , Simonsen Anja Hviid , Siersma Volkert , Engedal Knut , Jelic Vesna , Andersen Birgitte Bo , Naik Mala , Hasselbalch Steen Gregers , Høgh Peter
Published: November 2018

Aim: To examine diagnostic and prognostic potential of quantitative electroencephalography (qEEG) analyzed by the statistical pattern recognition (SPR) method in patients with cognitive impairment. We compared the differential diagnostic ability of SPR to visual EEG analysis. Correlation between SPR findings and cerebrospinal fluid (CSF) Alzheimer disease (AD) biomarkers were evaluated. Methods: It is a multicenter cohort study involving 129 patients, (mild cognitive impairment [MCI], AD, and healthy controls). Standardized EEG was performed at baseline. Patients were continuously clinically evaluated. Results: Receiver Operating Characteristic curves showed a low discriminative ability of SPR and no ability to predict clinical progression in patients with MCI. Moderate correlation between SPR analysis and CSF AD biomarkers was found. Conclusion: The diagnostic and prognostic abilities of qEEG were low. The SPR method was superior to the visual EEG analysis. The qEEG method correlates well to CSF AD biomarkers, suggesting association with pathology in AD.
Long-Term Outcomes of Bilateral Pallidal Deep Brain Stimulation for X-Linked Dystonia and Parkinsonism
Authors: Kilbane Camilla , Witt Jennifer , Galifianakis Nicholas B. , Glass Graham A. , Volz Monica , Heath Susan  , Starr Philip A. , Ostrem Jill Louise
Published: November 2018

Background: X-linked dystonia parkinsonism (XDP) causes adult-onset progressive dystonia and parkinsonism, which may not respond to pharmacotherapy. Objective: Previous case reports have reported beneficial effects from bilateral pallidal (GPi) deep brain stimulation (DBS). Here, we report the long-term clinical outcomes of 3 patients treated at our center. Methods: All patients presented with medication refractory dystonia and parkinsonism. They were followed prospectively. Clinical evaluations included the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) and the Unified Parkinson’s Disease Rating Scale (UPDRS). Adverse events were recorded. Results: The average length of follow-up was 45.7 months. No serious adverse events occurred. All patients experienced an immediate and sustained improvement in dystonia. Mean percentage improvement in motor subscores of BFMDRS was 63.5% at the last follow-up visit. Parkinsonism was less responsive to neuromodulation, with a mean improvement in UPDRS-III of 39.5%. Standard pallidal stimulation parameters were used. Freezing of gait developed after DBS therapy in 2 patients, stimulation-induced in one and due to disease progression in the other. Conclusion: Bilateral pallidal DBS resulted in significant and sustained improvement in dystonia and moderate improvement in parkinsonism. Pallidal DBS represents an important treatment option for XPD for the management of motor symptoms.
Ophthalmic Insert versus Eye Drops for Mydriasis in Neonates: A Randomized Clinical Trial
Authors: Bremond-Gignac Dominique , Jacqz-Aigrain Evelyne  , Abdoul Hendy  , Daruich Alejandra , Beresniak Ariel , Baud Olivier , Alberti Corinne ,   on behalf of the CLAIR FO Study Group
Published: November 2018

Background: Eye drop treatment routinely used to obtain mydriasis prior to fundoscopy in neonates requires repeated instillations of mydriatic agents that can lead to systemic side effects. Objectives: The aim of this study was to compare the mydriatic efficacy and tolerance of administration of phenylephrine and tropicamide via the ophthalmic insert Mydriasert® versus standard eye drop treatment in neonates. Methods: In this prospective, single-blinded, noninferiority study, 80 hospitalized neonates (age < 18 months) requiring bilateral fundus examination were randomized to receive eye drops (repeated instillations of 2.5% phenylephrine and 0.5% tropicamide) or the insert. The primary outcome was mydriasis suitable for fundoscopy 75 min after mydriatic agent introduction (T75). Results: Mydriasis was successfully achieved in both eyes at T75 in 97.5% (n = 39/40) of the insert group patients versus 90% (n = 36/40) receiving eye drops (between-group difference 7.5%, demonstrating noninferiority). Mydriasis remained stable in 60.0% of patients (n = 24/40) in the insert group versus 15% (n = 6/40) in the eye drop group (p < 0.0001). The insert group required fewer nursing interventions than the eye drop group (p = 0.0001). Mean blood pressure were significantly higher in the insert versus the eye drop group (p < 0.0001 and p = 0.0003, respectively); mean heart rate was not significantly different between the groups (p = 0.37). In the insert group, 2 patients reported an adverse event (bradycardia, n = 1, and gastroesophageal reflux, n = 1; both appeared to be related to neonate pathology). Conclusions: The degree of mydriasis achieved with Mydriasert® was noninferior to that obtained with eye drops. The insert appears to be safe to use in neonates without a history of increased vagal tone or gastrointestinal reflux.
Advanced Renal Cell Cancer and Low-Dose Palliative Radiation Treatment: A Case of a Substantial and Sustained Treatment Response
Authors: van Gysen Kirsten , Kneebone Andrew , Eade Thomas , Guminski Alexander , Hruby George
Published: November 2018

Clear cell carcinoma is the most common form of renal cell carcinoma (RCC). Metastatic RCC is poorly responsive to treatment and has a bleak prognosis. Newer systemic agents have improved outcomes. Furthermore, their interaction with radiation treatment (RT) may provide further therapeutic options. RCC is considered to be radioresistant, however we report the case of a patient with progression on targeted therapy and immunotherapy who achieved a substantial and sustained local, and possibly abscopal, response to low dose palliative radiation therapy.
A Randomized Controlled Trial of Immediate versus Delayed Umbilical Cord Clamping in Multiple-Birth Infants Born Preterm
Authors: Ruangkit Chayatat , Bumrungphuet Sommart , Panburana Panyu , Khositseth Anant , Nuntnarumit Pracha
Published: November 2018

Background: Delayed cord clamping (DCC) improves placental transfusion and increases blood volume in preterm infants when compared with immediate cord clamping (ICC). However, evidence to support DCC in multiple-birth preterm infants is still lacking. Objective: To compare the outcomes of ICC versus DCC in preterm infants of multiple births. Study Design: Women with a multiple pregnancy, including twins and triplets with a gestational age of 28–36 weeks, were randomized to receive ICC (23 women and 50 infants) or DCC for 30–60 s (24 and 51 infants). The infants’ hematocrit on admission, superior vena cava (SVC) flow measured within 24 h, and hematocrit at 8 weeks of age were compared. The use of uterotonic agents during delivery was not controlled in this study. Result: All infants were delivered by cesarean section (CS) except for 2 sets of twins, 1 in each group. Maternal and infant baseline characteristics in both groups were comparable. There were no significant differences between the groups in admission hematocrit, SVC flow measured within 24 h, hematocrit at 8 weeks of age, or any other neonatal outcomes. The incidence of maternal postpartum hemorrhage (PPH) was higher in the DCC group (4.3% in ICC vs. 25% in DCC, p = 0.04). Conclusion: DCC for 30–60 s did not improve placental transfusion or increase systemic blood flow in multiple-birth infants born preterm, mostly by CS, when compared with ICC. The finding of a higher PPH rate in the DCC group raises concerns about the maternal safety of this procedure in this patient population.
Paraoxonase 1 Gene Polymorphisms (Q192R and L55M) Are Associated with Coronary Artery Disease Susceptibility in Asian Indians
Authors: Kaur Sumanpreet , Bhatti Gurjit Kaur , Vijayvergiya Rajesh , Singh Puneetpal , Mastana Sarabjit Singh , Tewari Rupinder , Bhatti Jasvinder Singh
Published: November 2018

Background: Coronary artery disease (CAD) is a complex metabolic disorder in which lifestyle and genetic factors are known to play key roles in pathogenesis. The paraoxonase 1 (PON1) enzyme has a defensive effect against CAD progression, as it safeguards low-density lipoproteins (LDLs) from oxidative modifications. The most extensively studied genetic variants in the PON1 gene are Q192R and L55M, which have been related with LDL antioxidative activity and risk of CAD. Objective: The present case-control study intended to examine the Q192R and L55M polymorphisms and their association with the risk of CAD patients in north Indians. Methods: A total of 872 subjects (412 CAD patients and 460 controls) were recruited from north India. The PON1 gene was amplified and genotypes were studies using PCR-RFLP. χ2 analysis was performed to compare genotype/allele frequencies in patients and controls. Results: The present study indicated abdominal obesity, elevated body mass index, and dyslipidemia with increased levels of total cholesterol and triglycerides as well as reduced high-density lipoprotein cholesterol in CAD subjects compared to healthy controls (p < 0.05). Logistic regression analysis of the data revealed an association of the RR genotype of the Q192R polymorphism with an about 2-fold elevated risk of CAD (OR = 2.23, 95% CI = 1.47–3.37, p = 0.0001). Contrariwise, the L55M polymorphism did not show significant association with CAD (OR = 1.81, 95% CI = 0.66–4.95, p = 0.326). Conclusions: The Q192R polymorphism in the PON1 gene may be a susceptibility gene associated with increased risk of CAD in an Asian Indian population.
A Case Report of Cronkhite-Canada Syndrome Complicated by Membranous Nephropathy
Authors: Firth Christine , Harris Lucinda A. , Smith Maxwell L. , Thomas Leslie F.
Published: November 2018

Cronkhite-Canada syndrome (CCS) is a very rare disorder with less than 500 reported cases. It is characterized by extensive gastrointestinal polyposis and ectodermal anomalies including alopecia, cutaneous hyperpigmentation, and onychodystrophy. Only 3 cases of associated kidney disease (membranous nephropathy [MN]) have been reported. A 71-year-old male with CCS was referred for further evaluation of proteinuria. The patient initially presented with abdominal discomfort, weight loss, dysgeusia, skin hyperpigmentation, alopecia, and dystrophic nails. Endoscopic evaluation showed widespread gastrointestinal nodular inflammation and polyps. Histopathology was consistent with CCS. Initial treatment was with prednisone, azathioprine, and ranitidine. He had moderate clinical improvement but developed nephrotic-range proteinuria. Renal biopsy showed MN, and cyclosporine was started. The patient had significant improvement in his CCS manifestations; however, his proteinuria and renal function worsened. Rituximab was added to his regimen of cyclosporine and azathioprine, which resulted in remission of his MN, marked improvement in his polyposis, and near resolution of his cutaneous symptoms. This case represents a unique presentation of CCS associated with MN treated with rituximab. The excellent clinical response observed for both CCS and MN advocates consideration of this treatment, especially for refractory disease.
EFHB is a Novel Cytosolic Ca2+ Sensor That Modulates STIM1-SARAF Interaction
Authors: Albarran Letizia , Lopez Jose J. , Jardin Isaac , Sanchez-Collado Jose , Berna-Erro Alejandro , Smani Tarik , Camello Pedro J. , Salido Gines M. , Rosado Juan A.
Published: November 2018

Background/Aims: STIM1 and Orai1 are the key components of store-operated Ca2+ entry (SOCE). Among the proteins involved in the regulation of SOCE, SARAF prevents spontaneous activation of SOCE and modulates STIM1 function. Methods: Cytosolic Ca2+ mobilization was estimated in fura-2-loaded cells using an epifluorescence inverted microscope. STIM1 interaction with Orai1, EFHB (EF-hand domain family member B, also known as CFAP21) and SARAF was detected by immunoprecipitation followed by Western blotting using specific antibodies. The involvement of EFHB in the translocation of NFAT to the nucleus was detected by confocal microscopy. Results: Here, we report the identification of EFHB as a new SOCE regulator. EFHB interacts with STIM1 upon store depletion and dissociates through a Ca2+-dependent mechanism. RNAi-mediated silencing as well as overexpression studies revealed that EFHB plays a relevant role in the interaction of STIM1 and Orai1 upon store depletion, the activation of SOCE and NFAT translocation from the cytosol to the nucleus. Silencing EFHB expression abolished the dissociation of SARAF from STIM1, which indicates that EFHB might play an important role in the dynamic interaction between both proteins, which is relevant for the activation of Orai1 channels upon Ca2+ store depletion and their subsequent modulation via slow Ca2+-dependent inactivation. Conclusion: Our results indicate that EFHB is a new SOCE regulator that modulates STIM1-SARAF interaction.
iTRAQ-Based Differential Proteomic Analysis Reveals the Pathways Associated with Tigecycline Resistance in Acinetobacter baumannii
Authors: Yang Ni , Liu Yuan  , He Ping , Ke Rui , Zhao Yujie , Feng Yanjing , Jing Rong , Ma Shuzhen , Liu Congrui , Geng Yan , Wu Xiaokang , Wei Yang
Published: November 2018

Background/Aims: Acinetobacter baumannii is an aerobic and Gram-negative bacterial pathogen with high morbidity and mortality. It remains a serious public health problem arising from its multidrug-resistant and extensive antibiotic resistance spectrum. Methods: In the present study, iTRAQ coupled with 2D LC-MS/MS was used to evaluate the proteome in standard Acinetobacter baumannii standard strains and tigecycline-resistant strains. Results: A total of 3639 proteins were identified and 961 proteins were identified to be differentially expressed in tigecycline-resistant Acinetobacter baumannii strains compared to the standard strains. 506 (52.6%) proteins were up-regulated and 455 (47.4%) proteins were down-regulated. Based on the GO enrichment analysis and KEGG pathway analysis, we concluded that most differentially expressed proteins were associated with stress responses, cellular component organization, proteins synthesis, degradation and function. Moreover, β-lactam resistance, the longevity regulating pathway and other related pathways were also involved in the regulation of tigecycline-resistant Acinetobacter baumannii. The differential expression of key proteins were evaluated by transcript analysis using quantitative RT-PCR. Conclusion: These results may provide new insights into the mechanisms of drug resistance in Acinetobacter baumannii.