bluuebunny/crossref_metadata_2025 huggingface dataset:
Phosphorylcholine surface modified flow diverter associated with reduced intimal hyperplasia
Authors: Caroff Jildaz , Tamura Takamitsu , King Robert M , Lylyk Pedro N , Langan Erin T , Brooks Olivia W , Clarençon Frédéric , Wainwright John Michael , Spelle Laurent , Marosfoi Miklos , Gounis Matthew J , Puri Ajit S
Published: March 2018

Background

Optical coherence tomography (OCT) is a high-resolution, intra-vascular diagnostic technique widely used for the characterization of vascular pathologies and optimization of stent implantation during percutaneous coronary intervention. OCT was used to investigate the in vivo vascular response to a new phosphorylcholine surface modified flow diverter (sPED).

Methods

In an in vivo rabbit aneurysmal model, we used two different types of flow diverters (classic Pipeline – cPED; and sPED) with or without dual antiplatelet therapy (four groups, n=10 per group). OCT cross-sectional area measurements were compared with histology in all animals. Neointimal hyperplasia (NIH) ratio was compared between OCT and histology at five different levels for each stent. The severity of NIH was also compared between the different stents, antiplatelet protocols, and vessel locations.

Results

OCT was used to calculate in-stent hyperplasia in 227 different locations corresponding to histology sections. OCT measurement strongly correlated with gold standard histology (r2=0.83; slope=0.988; P<0.0001). sPED had significantly less in-stent NIH than non-treated flow diverters (mean percent of lumen reduction 5.7% for sPED versus 8.9% for cPED; P<0.0001). The NIH ratio was slightly higher with dual antiplatelet therapy (DAPT) (NIH ratio=7.9% with DAPT versus 6.8% without DAPT; P<0.05). Complete and near complete occlusion rates of the aneurysms were not different with the cPED or sPED.

Conclusion

OCT is a promising technique for immediate and long-term evaluation of flow diverter stent treatments. In an animal model, phosphorylcholine surface modified flow diverters induces less NIH after stent implant without reducing aneurysm occlusion rates.
In situ evaluation of performance of reclamation measures implemented on abandoned reactive tailings disposal site
Authors: Ethier Marie-Pier , Bussière Bruno , Aubertin Michel , Maqsoud Abdelkabir , Demers Isabelle , Broda Stefan
Published: March 2018

The abandoned Manitou mine site produced acid mine drainage for decades. One of the site’s tailings storage facilities (TSF 2) was reclaimed in 2009 using an elevated water table combined with a monolayer cover made of low-sulphur tailings. A field investigation was undertaken from 2012 to 2015 to verify the performance of the reclamation technique in stemming the production of contaminants. This verification is based on two main criteria, i.e., the minimum water table level and maximum oxygen flux reaching the Manitou tailings. Thirteen monitoring stations were installed in TSF 2. The hydrogeological behavior and oxygen migration were investigated at each station by measuring volumetric water content, suction, water table level, gaseous pore oxygen concentration, and oxygen consumption. Analyses of field data showed that the minimum water table level criterion was reached with the exception of a portion of TSF 2 during the summer months. Oxygen fluxes reaching the Manitou tailings were determined using numerical simulations and analytical solutions; their yearly mean was many times lower than maximum targets generally used on reclaimed tailings disposal areas. The current system met the targeted performance criteria over the studied period.
Carbon balance in production forestry in relation to rotation length
Authors: Lundmark Tomas , Poudel Bishnu Chandra , Stål Gustav , Nordin Annika , Sonesson Johan
Published: March 2018

The choice of a rotation length is an integral part of even-aged forest management regimes. In this study, we simulated stand development and carbon pools in four even-aged stands representing the two most common tree species in Fennoscandia, Norway spruce (Picea abies (L.) Karst.) and Scots pine (Pinus sylvestris L.), growing on high- and low-productivity sites. We hypothesized that increased rotation lengths (+10, +20, and +30 years) in comparison with today’s practice would increase forests’ average carbon stock during a rotation cycle but decrease the average yield. The results showed that for spruce, a moderate increase in rotation length (+10 years) increased both average standing carbon stock and average yield. For the longer alternatives (+20 and +30 years) for spruce and for all pine alternatives, prolonging rotation lengths resulted in increased average standing carbon stocks but decreased average yield, resulting in decreased carbon storage in forest products and decreased substitution effects. Decreasing the rotation lengths (–10 years) always resulted in both decreased average standing carbon stocks and decreased yields. We conclude that a moderate increase of rotation lengths may slightly increase forests’ climate benefits for spruce sites, but for all other alternatives, there was a trade-off between the temporary gain of increasing carbon stocks and the permanent loss in productivity and, consequently, substitution potential.
On-Line Analysis of Stuck-at Faults in On-Chip Network Interconnects
Authors: Bhowmik Biswajit , Deka Jatindra Kumar , Biswas Santosh
Published: March 2018

Reliability has become a major concern when link-wires in on-chip networks (NoCs) suffer from stuck-at faults (SAFs). This paper presents an extended and scalable test scheme that addresses these faults in NoC links to improve yield and reliability. The scheme detects the stuck-at faults on and identifies faulty link-wires. Experiments demonstrate the effectiveness of the proposed scheme and reveal deep insights of the faults on several performance metrics.
Study of Gamow–Teller strength and associated weak-rates on odd-A nuclei in stellar matter
Authors: Majid Muhammad , Nabi Jameel-Un , Riaz Muhammad
Published: March 2018

In a recent study by Cole et al. [A. L. Cole et al., Phys. Rev. C 86 (2012) 015809], it was concluded that quasi-particle random phase approximation (QRPA) calculations show larger deviations and overestimate the total experimental Gamow–Teller (GT) strength. It was also concluded that QRPA calculated electron capture rates exhibit larger deviation than those derived from the measured GT strength distributions. The main purpose of this study is to probe the findings of the Cole et al. paper. This study gives useful information on the performance of QRPA-based nuclear models. As per simulation results, the capturing of electrons that occur on medium heavy isotopes have a significant role in decreasing the ratio of electron-to-baryon content of the stellar interior during the late stages of core evolution. We report the calculation of allowed charge-changing transitions strength for odd-[Formula: see text] [Formula: see text]-shell nuclei ([Formula: see text]Sc and [Formula: see text]Mn) by employing the deformed pn-QRPA approach. The computed GT transition strength is compared with previous theoretical calculations and measured data. For stellar applications, the corresponding electron capture rates are computed and compared with rates using previously calculated and measured GT values. Our finding shows that our calculated results are in decent accordance with measured data. At higher stellar temperature, our calculated electron capture rates are larger than those calculated by independent particle model (IPM) and shell model. It was further concluded that at low temperature and high density regions, the positron emission weak-rates from [Formula: see text]Sc and [Formula: see text]Mn may be neglected in simulation codes.
SMOOTH UPPER BOUNDS FOR THE PRICE FUNCTION OF AMERICAN STYLE OPTIONS
Authors: BHIM LOUIS , KAWAI REIICHIRO
Published: March 2018

We introduce a new approach for systematically obtaining smooth deterministic upper bounds for the price function of American style options. These bounding functions are characterized by sufficient conditions, under which the bounds may be infimized. In a single implementation, the proposed approach obtains explicit bounds in the form of piecewise polynomial functions, which bound the price function from above over the whole problem domain both in time and state. As a consequence, these global bounds store a continuum of information in the form of a finite number of polynomial coefficients. The proposed approach achieves these bounds, free from statistical error, without recourse to sample path simulation, without truncating the naturally unbounded domain that arises in this problem, and without discretizing the time and state variables. Throughout the paper, we demonstrate the effectiveness of the proposed method in obtaining tight upper bounds for American style option prices in a variety of market models and with various payoff structures, such as the multivariate Black Scholes and Heston stochastic volatility models and the American put and butterfly payoff structures. We also discuss extensions of the proposed methodology to perpetual American style options and frameworks in which the underlying asset contains jumps.
Personalized Cancer Genomics
Authors: Simon Richard M.
Published: March 2018

Developments in biotechnology have enabled the design of whole genome assays for nucleic acid sequencing, gene expression monitoring, gene copy number evaluation, and epigenetic silencing that have had major effects on biology, cancer drug development, and clinical trial design. Because cancer is a disease of DNA alteration, these developments have had a particularly important effect on the development of personalized oncology. Facilitating this transition has been development of statistical methods for transforming this high dimensional data into useful biological information, p > n classification methods, and new designs for clinical trials. In this article we review some of the key statistical developments in this area.
Histopathological Breast Cancer Image Classification by Deep Neural Network Techniques Guided by Local Clustering
Authors: Nahid Abdullah-Al , Mehrabi Mohamad Ali , Kong Yinan
Published: March 2018

Breast Cancer is a serious threat and one of the largest causes of death of women throughout the world. The identification of cancer largely depends on digital biomedical photography analysis such as histopathological images by doctors and physicians. Analyzing histopathological images is a nontrivial task, and decisions from investigation of these kinds of images always require specialised knowledge. However, Computer Aided Diagnosis (CAD) techniques can help the doctor make more reliable decisions. The state-of-the-art Deep Neural Network (DNN) has been recently introduced for biomedical image analysis. Normally each image contains structural and statistical information. This paper classifies a set of biomedical breast cancer images (BreakHis dataset) using novel DNN techniques guided by structural and statistical information derived from the images. Specifically a Convolutional Neural Network (CNN), a Long-Short-Term-Memory (LSTM), and a combination of CNN and LSTM are proposed for breast cancer image classification. Softmax and Support Vector Machine (SVM) layers have been used for the decision-making stage after extracting features utilising the proposed novel DNN models. In this experiment the best Accuracy value of 91.00% is achieved on the 200x dataset, the best Precision value 96.00% is achieved on the 40x dataset, and the best F-Measure value is achieved on both the 40x and 100x datasets.
HOTAIR Is a Potential Novel Biomarker in Patients with Congenital Heart Diseases
Authors: Jiang Yu , Mo Hongdan , Luo Jing , Zhao Suhong , Liang Shuang , Zhang Maomao , Yuan Jie
Published: March 2018

Objective. To investigate the expression of HOX transcript antisense RNA (HOTAIR) in cardiac tissues and plasma of patients with congenital heart diseases (CHDs). Methods. qRT-PCR was used to detect the expression of HOTAIR in right atrial appendage tissues of 16 patients with CHDs and 14 patients with rheumatic valvular heart diseases (RVHDs), as well as in plasma of 36 normal people and 90 patients with CHDs including 36 cases of ASD, 23 cases of VSD, and 31 cases of PDA. Besides, the proteins interacting with HOTAIR were obtained from databases. Results. The HOTAIR expression in cardiac tissues of CHDs group was significantly higher than that of the RVHDs group (P<0.01). Compared with the control group, the expression of plasma HOTAIR in the ASD group, the VSD group, and the PDA group was all remarkably upregulated (P<0.01), whereas there was no relationship between HOTAIR and pulmonary arterial hypertension and defects size. Databases show that HOTAIR is associated with polycomb repressive complex 2 (PRC2) which contributes to heart development. Conclusion. The levels of HOTAIR were increased in cardiac tissues and plasma of patients with CHDs. HOTAIR is a potential novel diagnostic biomarker in patients with CHDs.
NMDA Receptor Subunits Change after Synaptic Plasticity Induction and Learning and Memory Acquisition
Authors: Baez María Verónica , Cercato Magalí Cecilia , Jerusalinsky Diana Alicia
Published: March 2018

NMDA ionotropic glutamate receptors (NMDARs) are crucial in activity-dependent synaptic changes and in learning and memory. NMDARs are composed of two GluN1 essential subunits and two regulatory subunits which define their pharmacological and physiological profile. In CNS structures involved in cognitive functions as the hippocampus and prefrontal cortex, GluN2A and GluN2B are major regulatory subunits; their expression is dynamic and tightly regulated, but little is known about specific changes after plasticity induction or memory acquisition. Data strongly suggest that following appropriate stimulation, there is a rapid increase in surface GluN2A-NMDAR at the postsynapses, attributed to lateral receptor mobilization from adjacent locations. Whenever synaptic plasticity is induced or memory is consolidated, more GluN2A-NMDARs are assembled likely using GluN2A from a local translation and GluN1 from local ER. Later on, NMDARs are mobilized from other pools, and there are de novo syntheses at the neuron soma. Changes in GluN1 or NMDAR levels induced by synaptic plasticity and by spatial memory formation seem to occur in different waves of NMDAR transport/expression/degradation, with a net increase at the postsynaptic side and a rise in expression at both the spine and neuronal soma. This review aims to put together that information and the proposed hypotheses.
Investigating Multiphase Flow Phenomena in Fine-Grained Reservoir Rocks: Insights from Using Ethane Permeability Measurements over a Range of Pore Pressures
Authors: Letham Eric Aidan , Bustin Robert Marc
Published: March 2018

The ability to quantify effective permeability at the various fluid saturations and stress states experienced during production from shale oil and shale gas reservoirs is required for efficient exploitation of the resources, but to date experimental challenges prevent measurement of the effective permeability of these materials over a range of fluid saturations. To work towards overcoming these challenges, we measured effective permeability of a suite of gas shales to gaseous ethane over a range of pore pressures up to the saturated vapour pressure. Liquid/semiliquid ethane saturation increases due to adsorption and capillary condensation with increasing pore pressure resulting in decreasing effective permeability to ethane gas. By how much effective permeability to ethane gas decreases with adsorption and capillary condensation depends on the pore size distribution of each sample and the stress state that effective permeability is measured at. Effective permeability decreases more at higher stress states because the pores are smaller at higher stress states. The largest effective permeability drops occur in samples with dominant pore sizes in the mesopore range. These pores are completely blocked due to capillary condensation at pore pressures near the saturated vapour pressure of ethane. Blockage of these pores cuts off the main fluid flow pathways in the rock, thereby drastically decreasing effective permeability to ethane gas.
An Inhomogeneous Cell‐Based Smoothed Finite Element Method for Free Vibration Calculation of Functionally Graded Magnetoelectroelastic Structures
Authors: Cai Yan , Meng Guangwei , Zhou Liming
Published: March 2018

To overcome the overstiffness and imprecise magnetoelectroelastic coupling effects of finite element method (FEM), we present an inhomogeneous cell‐based smoothed FEM (ICS‐FEM) of functionally graded magnetoelectroelastic (FGMEE) structures. Then the ICS‐FEM formulations for free vibration calculation of FGMEE structures were deduced. In FGMEE structures, the true parameters at the Gaussian integration point were adopted directly to replace the homogenization in an element. The ICS‐FEM provides a continuous system with a close‐to‐exact stiffness, which could be automatically and more easily generated for complicated domains, thus significantly decreasing the numerical error. To verify the accuracy and trustworthiness of ICS‐FEM, we investigated several numerical examples and found that ICS‐FEM simulated more accurately than the standard FEM. Also the effects of various equivalent stiffness matrices and the gradient function on the inherent frequency of FGMEE beams were studied.
Recent Advances in the Molecular Mechanisms Underlying Pyroptosis in Sepsis
Authors: Gao Yu-Lei , Zhai Jian-Hua , Chai Yan-Fen
Published: March 2018

Sepsis is recognized as a life-threatening organ dysfunctional disease that is caused by dysregulated host responses to infection. Up to now, sepsis still remains a dominant cause of multiple organ dysfunction syndrome (MODS) and death among severe condition patients. Pyroptosis, originally named after the Greek words “pyro” and “ptosis” in 2001, has been defined as a specific programmed cell death characterized by release of inflammatory cytokines. During sepsis, pyroptosis is required for defense against bacterial infection because appropriate pyroptosis can minimize tissue damage. Even so, pyroptosis when overactivated can result in septic shock, MODS, or increased risk of secondary infection. Proteolytic cleavage of gasdermin D (GSDMD) by caspase-1, caspase-4, caspase-5, and caspase-11 is an essential step for the execution of pyroptosis in activated innate immune cells and endothelial cells stimulated by cytosolic lipopolysaccharide (LPS). Cleaved GSDMD also triggers NACHT, LRR, and PYD domain-containing protein (NLRP) 3-mediated activation of caspase-1 via an intrinsic pathway, while the precise mechanism underlying GSDMD-induced NLRP 3 activation remains unclear. Hence, this study provides an overview of the recent advances in the molecular mechanisms underlying pyroptosis in sepsis.
Fatigue Performance of SFPSC under Hot‐Wet Environments and Cyclic Bending Loads
Authors: Luo Shanshan , Huang Peiyan , Guo Xinyan , Zheng Xiaohong
Published: March 2018

A new structural material named “steel fiber polymer structural concrete (SFPSC)” with features of both high strength and high toughness was developed by this research group and applied to the bridge superstructures in the hot‐wet environments. In order to investigate the fatigue performance and durability of SFPSC under hot‐wet environments, the environment and fatigue load uncoupling method and the coupling action of environment and fatigue load were used or developed. Three‐point bending fatigue experiments with uncoupling action of environments and cyclic loads were carried out for SFPSC specimens which were pretreated under hot‐wet environments, and the experiments with the coupling action of environments and cyclic loads for SFPSC specimens were carried out under hot‐wet environments. Then, the effects of hot‐wet environments and the experimental methods on the fatigue mechanism of SFPSC material were discussed, and the environmental fatigue equations of SFPSC material under coupling and uncoupling action of hot‐wet environments and cyclic bending loads were established. The research results show that the fatigue limits of SFPSC under the coupling action of the environments and cyclic loads were lower about 15%. The proposed fatigue equations could be used to estimate the fatigue lives and fatigue limits of SFPSC material.
Association of Three Polymorphisms rs11614913, rs2910146, and rs3746444 in miRNA-196a2, miRNA-146a, and miRNA-499 with Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis
Authors: Liu Ying , Xiong Lingxin , Zhou Yan , Zheng Bingzhen , Liu Tongjun , Xie Wei
Published: March 2018

Background. It has been found that single-nucleotide polymorphisms (SNPs) of microRNA might be involved in the development of inflammatory bowel diseases (IBDs). However, the related retrospective research has not been reported. In this work, we performed a meta-analysis to derive a more precise estimation of the associated relationship. Methods. We searched the studies on the association of SNPs of microRNA with the hereditary susceptibility of IBD in PubMed and Embase; eligible research was selected by screening the abstract and full text. The meta-analysis was performed based on the statistical software Stata 14.0, and besides, the odds ratio and 95% confidence interval were calculated to evaluate the strength of the association. Results. 159 papers were acquired from the PubMed and Embase databases, and five eligible articles containing nine case-control studies were selected. In the study, we first found that the association between miRNA-196a2 rs11614913 and IBD was insignificant. Then, the susceptibility of miRNA-146a rs2910146 to IBD increased significantly in allelic comparison, homozygote model, heterozygote model, and dominant model. Moreover, a positive relationship between miRNA-499 rs3746444 and IBD was identified in the homozygote model. Conclusion. Our findings demonstrated that miRNA-146a rs2910146 (G>C) polymorphism was associated with the susceptibility to IBD and miRNA-196a2 rs11614913 (T>C) and miRNA-499 rs3746444 (A>G) did not reveal an obvious relationship with the IBD susceptibility.
Does the Use of Nitroglycerin Patch Improve Local Anaesthetic Effects in Bier’s Block? A Double-Blind Placebo Controlled Study
Authors: Elgebaly Ahmed Said
Published: March 2018

Aim. The aim of the study was to assess the nitroglycerin patch as a new additive to Bier’s block and its impact on the effects and dose of lidocaine. Methods. Forty patients of each sex belonging to ASA I or II underwent elective tendon repair surgeries of the forearm and hand. The patients were divided into two equal groups as follows: Group C received only lidocaine (1.5 mg/kg, 0.25%) and Group N received lidocaine (1.5 mg/kg, 0.25%) + 5 mg transcutaneous nitroglycerin patch. Onset and recovery times for sensory and motor block, visual analogue scale (VAS) scores for bandage pain, postoperative VAS score, analgesic requirements, patients’ satisfaction, and surgeons’ opinion were recorded. Results. Sensory block onset time was shorter in Group N (3.80 ± 1.0) than that in Group C (5.72 ± 1.46), and motor block onset time was shorter in Group N (10.72 ± 1.93) than that in Group C (13.56 ± 1.26). Sensory block recovery time was prolonged in Group N (10.56 ± 1.12) than Group C (6.88 ± 1.45), recovery time of motor block was prolonged in Group N (13.04 ± 1.57) than Group C (11.96 ± 1.72). Bandage pain had lower VAS scores in Group N. Postoperative VAS scores showed significant differences between both groups at the following points of measurement: 30 minutes, 1 hour, and 4 hours after bandage deflation. Postoperative analgesic effect was the longest in Group N (187.20 ± 60.79 min) than Group C (51.60 ± 25.28 min). Patients’ satisfaction and surgeons’ opinion were better in Group N than Group C. Conclusion. Supplementation of Bier’s block with transcutaneous nitroglycerin patch reduces the lidocaine dose, the sensory and motor block onset times, VAS scores, and analgesic consumption intra- and postoperatively. Length of the block recovery times for the sensory and motor effects, duration of postoperative analgesic effect, and the first time to analgesic requirement improved the quality of Bier’s block with better patients’ satisfaction and surgeons’ opinion and had no adverse effects.
Liquid Biopsy in Rare Cancers: Lessons from Hemangiopericytoma
Authors: Nicolazzo Chiara , Colangelo Luciano , Corsi Alessandro , Carpino Guido , Gradilone Angela , Sonato Chiara , Raimondi Cristina , Gaudio Eugenio , Gazzaniga Paola , Gianni Walter
Published: March 2018

Hemangiopericytoma (HPT) is a rare mesenchymal tumor of fibroblastic type and for its rarity is poorly studied. The most common sites of metastatic disease in patients with intracranial HPT are the bone, liver, and lung, suggestive for an hematogenous dissemination; for this reason, we investigated, for the first time, the presence of circulating tumor cells (CTCs) in hemangiopericytoma patient by CellSearch® and SceenCell® devices. Peripheral blood samples were drawn and processed by CellSearch, an EpCAM-dependent device, and ScreenCell®, a device size based. We found nontypical CTCs by CellSearch system and the immunofluorescence analysis performed on CTCs isolate by ScreenCell demonstrated the presence of single CTCs and CTC clusters. The molecular characterization of single CTCs and CTC clusters, using antibodies directed against EpCAM, CD34, cytokeratins (8, 18, and 19), and CD45, showed a great heterogeneity in CTC clusters. We believe that the present study may open a new scenario in the rare tumors: the introduction of the liquid biopsy and the molecular characterization of circulating tumor cells could lead to personalized targeted treatments and also for rare tumors.
PD-1 Blockade and CD27 Stimulation Activate Distinct Transcriptional Programs That Synergize for CD8+ T-Cell–Driven Antitumor Immunity
Authors: Buchan Sarah L. , Fallatah Mohannad , Thirdborough Stephen M. , Taraban Vadim Y. , Rogel Anne , Thomas Lawrence J. , Penfold Christine A. , He Li-Zhen , Curran Michael A. , Keler Tibor , Al-Shamkhani Aymen
Published: March 2018

Purpose: PD-1 checkpoint blockade has revolutionized the field of cancer immunotherapy, yet the frequency of responding patients is limited by inadequate T-cell priming secondary to a paucity of activatory dendritic cells (DC). DC signals can be bypassed by CD27 agonists, and we therefore investigated if the effectiveness of anti–PD-1/L1 could be improved by combining with agonist anti-CD27 monoclonal antibodies (mAb).

Experimental Design: The efficacy of PD-1/L1 blockade or agonist anti-CD27 mAb was compared with a dual-therapy approach in multiple tumor models. Global transcriptional profiling and flow cytometry analysis were used to delineate mechanisms underpinning the observed synergy.

Results: PD-1/PD-L1 blockade and agonist anti-CD27 mAb synergize for increased CD8+ T-cell expansion and effector function, exemplified by enhanced IFNγ, TNFα, granzyme B, and T-bet. Transcriptome analysis of CD8+ T cells revealed that combination therapy triggered a convergent program largely driven by IL2 and Myc. However, division of labor was also apparent such that anti–PD-1/L1 activates a cytotoxicity–gene expression program whereas anti-CD27 preferentially augments proliferation. In tumor models, either dependent on endogenous CD8+ T cells or adoptive transfer of transgenic T cells, anti-CD27 mAb synergized with PD-1/L1 blockade for antitumor immunity. Finally, we show that a clinically relevant anti-human CD27 mAb, varlilumab, similarly synergizes with PD-L1 blockade for protection against lymphoma in human–CD27 transgenic mice.

Conclusions: Our findings suggest that suboptimal T-cell invigoration in cancer patients undergoing treatment with PD-1 checkpoint blockers will be improved by dual PD-1 blockade and CD27 agonism and provide mechanistic insight into how these approaches cooperate for CD8+ T-cell activation. Clin Cancer Res; 24(10); 2383–94. ©2018 AACR.
Cross-Cohort Analysis Identifies a TEAD4–MYCN Positive Feedback Loop as the Core Regulatory Element of High-Risk Neuroblastoma
Authors: Rajbhandari Presha , Lopez Gonzalo , Capdevila Claudia , Salvatori Beatrice , Yu Jiyang , Rodriguez-Barrueco Ruth , Martinez Daniel , Yarmarkovich Mark , Weichert-Leahey Nina , Abraham Brian J. , Alvarez Mariano J. , Iyer Archana , Harenza Jo Lynne , Oldridge Derek , De Preter Katleen , Koster Jan , Asgharzadeh Shahab , Seeger Robert C. , Wei Jun S. , Khan Javed , Vandesompele Jo , Mestdagh Pieter , Versteeg Rogier , Look A. Thomas , Young Richard A. , Iavarone Antonio , Lasorella Anna , Silva Jose M. , Maris John M. , Califano Andrea
Published: March 2018

High-risk neuroblastomas show a paucity of recurrent somatic mutations at diagnosis. As a result, the molecular basis for this aggressive phenotype remains elusive. Recent progress in regulatory network analysis helped us elucidate disease-driving mechanisms downstream of genomic alterations, including recurrent chromosomal alterations. Our analysis identified three molecular subtypes of high-risk neuroblastomas, consistent with chromosomal alterations, and identified subtype-specific master regulator proteins that were conserved across independent cohorts. A 10-protein transcriptional module—centered around a TEAD4–MYCN positive feedback loop—emerged as the regulatory driver of the high-risk subtype associated with MYCN amplification. Silencing of either gene collapsed MYCN-amplified (MYCNAmp) neuroblastoma transcriptional hallmarks and abrogated viability in vitro and in vivo. Consistently, TEAD4 emerged as a robust prognostic marker of poor survival, with activity independent of the canonical Hippo pathway transcriptional coactivators YAP and TAZ. These results suggest novel therapeutic strategies for the large subset of MYCN-deregulated neuroblastomas.

Significance: Despite progress in understanding of neuroblastoma genetics, little progress has been made toward personalized treatment. Here, we present a framework to determine the downstream effectors of the genetic alterations sustaining neuroblastoma subtypes, which can be easily extended to other tumor types. We show the critical effect of disrupting a 10-protein module centered around a YAP/TAZ-independent TEAD4–MYCN positive feedback loop in MYCNAmp neuroblastomas, nominating TEAD4 as a novel candidate for therapeutic intervention. Cancer Discov; 8(5); 582–99. ©2018 AACR.

This article is highlighted in the In This Issue feature, p. 517
AMD3100 Augments the Efficacy of Mesothelin-Targeted, Immune-Activating VIC-008 in Mesothelioma by Modulating Intratumoral Immunosuppression
Authors: Li Binghao , Zeng Yang , Reeves Patrick M. , Ran Chongzhao , Liu Qiuyan , Qu Xiying , Liang Yingying , Liu Zhao , Yuan Jianping , Leblanc Pierre R. , Ye Zhaoming , Sluder Ann E. , Gelfand Jeffrey A. , Brauns Timothy A. , Chen Huabiao , Poznansky Mark C.
Published: March 2018

AMD3100 (plerixafor), a CXCR4 antagonist, has been demonstrated to suppress tumor growth and modulate intratumoral T-cell trafficking. However, the effect of AMD3100 on immunomodulation remains elusive. Here, we explored immunomodulation and antitumor efficacy of AMD3100 in combination with a previously developed mesothelin-targeted, immune-activating fusion protein, VIC-008, in two syngeneic, orthotopic models of malignant mesothelioma in immunocompetent mice. We showed that combination therapy significantly suppressed tumor growth and prolonged animal survival in two mouse models. Tumor control and survival benefit were associated with enhanced antitumor immunity. VIC-008 augmented mesothelin-specific CD8+ T-cell responses in the spleen and lymph nodes and facilitated intratumoral lymphocytic infiltration. However, VIC-008 treatment was associated with increased programmed cell death protein-1 (PD-1) expression on intratumoral CD8+ T cells, likely due to high CXCL12 in the tumor microenvironment. AMD3100 alone and in combination with VIC-008 modulated immunosuppression in tumors and the immune system through suppression of PD-1 expression on CD8+ T cells and conversion of regulatory T cells (Tregs) into CD4+CD25–Foxp3+IL2+CD40L+ helper-like cells. In mechanistic studies, we demonstrated that AMD3100-driven Treg reprogramming required T cell receptor (TCR) activation and was associated with loss of PTEN due to oxidative inactivation. The combination of VIC-008 augmentation of tumor-specific CD8+ T-cell responses with AMD3100 abrogation of immunosuppression conferred significant benefits for tumor control and animal survival. These data provide new mechanistic insight into AMD3100-mediated immunomodulation and highlight the enhanced antitumor effect of AMD3100 in combination with a tumor antigen–targeted therapy in mouse malignant mesothelioma, which could be clinically relevant to patients with this difficult-to-treat disease. Cancer Immunol Res; 6(5); 539–51. ©2018 AACR.
Cutaneous Angiosarcoma
Authors: Rampinelli Heloisa , Ramos-e-Silva Marcia , Quintella Danielle Carvalho , Fernandes Nurimar Conceição
Published: March 2018

Cutaneous angiosarcoma is a rare malignant tumor showing blood or lymphatic vessel differentiation, corresponding to < 2% of all sarcomas. It preferably affects elderly, with predilection for the head and neck. Diagnosis is frequently late due to the early interpretation by the patient as a benign lesion similar to ecchymosis, which explains its aggressiveness with high metastasis and recurrence rates. We report the case of an elderly man whose histopathologic diagnosis confirmed the clinical suspicion of cutaneous angiosarcoma.
A Case Report of Triple-Positive Micropapillary Carcinoma of the Male Breast
Authors: Shuja Jamila , Ahmad Iftikhar , Arshad Sidra , Manzoor Hina , Kakar Shahwali , Ahmad Khushnaseeb
Published: March 2018

Background: Micropapillary carcinoma (MPC), a morphologically distinct subtype of invasive ductal carcinoma, of the male breast is an exceedingly uncommon disease. Case Report: Herein, we report a case of triple-positive MPC of the male breast with axillary lymph node involvement and no recurrence for over 2 years. Specifically, a 60-year-old male patient presented with a hard, elastic, and well-defined painless mass in the right breast. The patient underwent unilateral (right) modified radical mastectomy with axillary clearance. Histopathology revealed MPC grade 3 and metastasis in 16/16 lymph nodes. Hormone receptor analysis demonstrated strong positivity (total score 08) for estrogen/progesterone receptors and overexpression (score 3+) of human epidermal growth factor receptor 2. The patient received adjuvant chemotherapy (6 courses of CAF: cyclophosphamide, doxorubicin, and 5-fluorouracil), radiation, and tamoxifen. The patient has remained disease-free for over 2 years. Conclusion: This study demonstrates that triple-positive MPC of the male breast as a rare malignancy appears to respond promisingly to multimodality treatment.
Bladder Dysfunction in Children with Neurofibromatosis Type I: Report of Four Cases and Review of the Literature
Authors: Bouty Aurore , Dobremez Eric , Harper Luke , Harambat Jérôme , Bouteiller Cécile , Zaghet Brigitte , Wolkenstein Pierre , Ducassou Stéphane , Lefevre Yan
Published: March 2018

Aim: Neurofibromatosis type 1 (NF1) is a rare autosomal dominant disorder. Malignant transformation into malignant peripheral nerve sheath tumors (MPNST) can occur. However, urinary tract involvement is rare. We report 4 cases of NF1 with bladder dysfunction. Methods: A retrospective single center analysis of 4 patients was conducted over a 17-year period, focusing on urinary tract involvement. Results: NF1 was diagnosed at a median of 16.5 months (4–36) and urinary involvement occurred at a median of 5.25 years (4–9) after diagnosis. Bladder dysfunction was due to spinal cord compression in 2 cases, bladder invasion in 1 case, and cerebral lesions in 1 case. Malignant transformation of neurofibromas into MPNST occurred in 2 patients. Mechanisms of urinary involvement in NF1 are diverse and no pre-established protocol of management and follow-up exists. Conclusion: Although rare, dysfunction of the bladder can arise in NF1 and innovative strategies then need to be considered. This is best achieved with the help of a multidisciplinary team and a national reference center when available.
Investigation of Exposure Factors for Various Breast Composition and Thicknesses in Digital Screening Mammography Related to Breast Dose
Authors: Alkhalifah Khaled , Brindhaban Ajit
Published: March 2018

Objective: To investigate the effect of exposure factors used in digital screening mammography on image quality of different breast compositions. Material and Methods: A digital mammography unit, with tungsten (W) as target, rhodium (Rh) and silver (Ag) as filters, and amorphous selenium detectors, was used to image Computerized Imaging Reference Systems (CIRS) Model 12A phantoms of thickness 4, 5, and 6 cm. Images of each phantom were obtained using target-filter combinations of W/Rh and W/Ag, at 28, 30, and 32 kVp. Images were evaluated by 5 senior technologists with experience in mammography. Image scores were assigned, for each type of feature present in the phantom. Statistical analysis was performed using nonparametric tests to compare sets of image scores at p = 0.05. Results: A small but statistically significant improvement was detected in the visibility of microcalcifications (8.8 ± 0.2; p = 0.031) for the W/Rh combination but this did not show any differences in the visibility of masses or fibers. The entrance skin dose (ESD) and mean glandular dose (MGD) were lower for the W/Ag (ESD = 1.30–3.70; MGD = 0.44–0.93 mGy) combination compared to W/Rh (ESD = 1.66–5.40; MGD = 0.52–1.12 mGy). The Mann-Whitney test revealed that 30-kV exposure with the W/Rh combination showed a significantly better visibility of specks in the 30/70 phantom compared to other exposures. Conclusion: The use of an Rh filter showed a better image quality for all phantoms. 28 and 30 kVp with the W/Rh combination provided a slightly better image quality, and the MGD is less than 1.2 mGy.
МОЖЛИВОСТІ ПРОТИФІБРОЗНОЇ ТЕРАПІЇ ПІСЛЯ ЕЛІМІНАЦІЇ ВІРУСУ ГЕПАТИТУ С
Authors: Hospodarskyi I. Ya. , Havryliuk N. M. , Prokopchuk O. V.
Published: March 2018

Мета: дослідження можливостей протифіброзної терапії у хворих на хронічний гепатит (ХГ) С після завершення противірусного лікування шляхом призначення гепатопротекторного препарату біциклол протягом 3 місяців.Матеріали і методи. Обстежено в динаміці 27 па­цієнтів з ХГС без ознак цирозу та супутньої патології печінки й жовчовивідних шляхів, віком від 20 до 68 років, які завершили курс противірусної терапії і мали початковий рівень фіброзу F2-F3. Аналіз проводили шляхом визначення показників фіброгенезу (гідроксипролін, колаген IV) і ступеня фіброзу (фібротест, еластографія).Висновки. Встановлено, що після успішного завершення противірусного лікування у хворих на ХГС з вираженим фіброзом, як правило, не відбувається спонтанного регресу фібротичних явищ у печінці. Більше того, у частини пацієнтів фіброз продовжує прогресувати. В усіх пацієнтів з рівнем фіброзу F2-F3 відзначаються суттєво підвищені показники колагену IV і гідроксипроліну у сироватці крові, що свідчить про продовження процесу фіброзування навіть після елімінації вірусу.
ХАРАКТЕРИСТИКА ВІЛ-АСОЦІЙОВАНИХ ЗАХВОРЮВАНЬ ЦЕНТРАЛЬНОЇ НЕРВОВОЇ СИСТЕМИ В ОСІБ СТАРШОГО ВІКУ
Authors: Shostakovych-Koretska L. R. , Lytvyn K. Yu. , Hubar I. O. , Chykarenko Z. O. , Volikova O. O. , Chukhalova I. V. , Lisnycha O. O.
Published: March 2018

Мета роботи – вивчити основні характеристики ВІЛ-асоційованих захворювань центральної нервової системи в осіб старше 50 років і визначити частоту і відношення шансів розвитку неврологічних захворювань залежно від вікових аспектів.Пацієнти і методи. Проведений ретроспективний аналіз 428 медичних карт пацієнтів з ВІЛ-асоці­йованими захворюваннями ЦНС, які перебували на лікуванні у відділеннях Дніпропетровського обласного та міського центрів СНІД в період з 2010 по 2016 роки. Висновки. Отримані дані свідчать про особливості ВІЛ-асоційованих захворювань ЦНС у пацієнтів старше 50 років. У даній віковій категорії число осіб, інфікованих статевим шляхом, було значно більше, ніж серед молодших осіб, ВІЛ-інфекцію було діаг­ностовано пізніше і, відповідно, менша кількість пацієнтів отримувала АРТ. На момент розвитку неврологічних захворювань у пацієнтів старше 50 років спостерігався більший рівень RNA HIV viralload при відсутності статистично значущих імунологічних відмінностей. В даній групі визначені високі шанси розвитку ПМЛ, EBV-енцефалітів, когнітивних розладів і тенденцію до більшої частоти інсультів, що може призводити до тяжких наслідків, і підкреслює важливість більш детального обліку вікового аспекту.
СТАН НАДАННЯ ПОСЛУГ АРТ ВІЛ-ІНФІКОВАНИМ ОСОБАМ І ХВОРИМ НА СНІД У ТЕРНОПІЛЬСЬКІЙ ОБЛАСТІ
Authors: Halanov V. S. , Pankiv N. B. , Burtniak T. V. , Masiuk L. A.
Published: March 2018

Питання протидії ВІЛ-інфекції/СНІДу є одним із пріоритетних напрямів державної політики у сфері охорони здоров’я. Мета роботи − оцінити результативність впровадження послуг антиретровірусної терапії (АРТ) у Тернопільській області для формування рекомендацій з розробки національної та регіональної програм протидії ВІЛ-інфекції/СНІД на 2019-2023 роки. Матеріали і методи. Для визначення тенденцій епідеміологічних показників проведений аналіз та синтез даних рутинного епідеміологічного нагляду, прогнозування епідемії ВІЛ-інфекції/СНІДу у програмі SPECTRUM за 2009-2016 роки.Результати досліджень і висновки. Рівень охоплення людей, що живуть з ВІЛ (ЛЖВ), АРТ недостатній для здійснення позитивного впливу на епідемічну ситуацію з ВІЛ-інфекції. Показник смертності населення від хвороб, зумовлених ВІЛ, має тенденцію до зростання. Існує прогрес в охопленні послугами АРТ населення області, проте зростає і частка осіб, які потребують, але не отримують АРТ. Лікування призначається відповідно до встановленої квоти набору пацієнтів. Мережа сайтів АРТ в області потребує розширення. Лише одна неурядова організація (НУО) надає ці послуги і ними охоплені винятково жителі обласного центру. Послугами з догляду та підтримки не охоплені працівники комерційного сексу та чоловіки, які практикують секс з чоловіками.
ПОШИРЕНІСТЬ ПОЛІМОРФІЗМУ ГЕНА TLR 9 ТИПУ У ХВОРИХ З ХРОНІЧНИМИ ФОРМАМИ ВЕБ-ІНФЕКЦІЇ
Authors: Liadova T. I.
Published: March 2018

Мета дослідження – встановлення частоти поліморфізму -1486 T/C гена TLR-9 у пацієнтів з ХВЕБІ.Матеріали та методи. Дослідження для визначення поліморфізму -1486 T/C гена TLR-9 було проведено у 44 пацієнтів з хронічними формами ВЕБ-інфекції. Контрольна група для вивчення поширеності поліморфізму -1486 T/C гена TLR-9 становила 40 здорових донорів. Для виявлення ДНК ВЕБ методом ПЛР зі зворотною транскрипцією з гібридизаційно-флуоресцентною детекцією продуктів ампліфікації використовували набори реагентів «Амплісенс» (Росія). Виділення ДНК із зразків проводили за допомогою набору фірми «Минипреп» (Силекс М, Росія), використовуючи методику сорбції ДНК на сорбенті.Поліморфний регіон -1486 T/C, rs187084 гена TLR9 вивчався шляхом ампліфікації ПЛР в реальному часі шляхом визначення довжини фрагментів рестрикції ПЛР, за допомогою рестрикційного ензиму Ncol та олігонуклеотидних праймерів.Результати. Аналіз отриманих результатів поліморфізму -1486 Т/С гена TLR-9 дозволив виділити три основних генотипи – ТТ, ТС, СС. Дослідження частоти окремих генотипів виявило домінування генотипу ТС, порівняно з гомозиготними генотипами ТТ та СС. Вивчення розподілу частот поліморфізму -1486 Т/С гена TLR-9 для різних генотипів продемонструвало специфічність змін для генотипу ТС у хворих з ХВЕБІ та відсутність таких для генотипів ТТ та СС.
ЕТІОЛОГІЧНА ДІАГНОСТИКА ГОСТРИХ ВІРУСНИХ ІНФЕКЦІЙ: РОЛЬ У СУЧАСНІЙ СИСТЕМІ ОХОРОНИ ЗДОРОВ’Я ТА ЕКОНОМІЧНА ЕФЕКТИВНІСТЬ
Authors: Dziublyk I. V. , Soloviov S. O. , Kovaliuk O.` V.
Published: March 2018

Мета роботи – визначити роль етіологічної діагностики гострих вірусних інфекцій в сучасній системі охорони здоров’я та методи оцінки її економічної ефективності.Результати. Інновації останніх років в етіологічній діагностиці вірусних захворювань, серед яких молекулярно-біологічні технології, технології на основі імунохроматографічного аналізу, використання біочипів та інші, показали позитивні діагностичні та клінічні результати та мають важливе значення для вдосконалення системи охорони здоров’я. Основними операційними характеристиками лабораторних тестів є чутливість, специфічність, відтворюваність, точність, контроль якості та час виконання.Висновки. Якісне надання медичної допомоги пацієнтам з вірусними захворюваннями може бути досягнуто, орієнтуючись на цілі системи охорони здоров’я для підвищення якості та корисності медичної допомоги, в тому числі етіологічної діагностики вірусних інфекцій.
ЕПІДЕМІОЛОГІЧНІ ТА КЛІНІЧНІ ОСОБЛИВОСТІ NIPAH-ВІРУСНОЇ ІНФЕКЦІЇ
Authors: Andreychyn M. A. , Nychyk N. A. , Zavidnyuk N. H. , Iosyk Ia. I.
Published: March 2018

Мета роботи – узагальнити дані про етіологію, епідеміологічні особливості, клінічні прояви та підходи до лабораторної діагностики Ніпаг-вірусної інфекції, подати основні рекомендації ВООЗ і CDC стосовно її профілактики та лікування.Висновок. Наведені найновіші дані про хворобу, спричинену вірусом Ніпаг (NiV), особливості її розповсюдження, характерні клінічні симптоми та ускладнення свідчать про особливу небезпеку цього захворювання для людства. NiV, згідно із СDC, належить до патогенів з найвищим (4) рівнем біологічної безпеки для збудників інфекційних хвороб, що поширюються повітряно-краплинним механізмом. На даний час методами боротьби з цією інфекцією, згідно з основними рекомендаціями ВООЗ і CDC, є лише профілактичні заходи. Ефективні методи лікування ще не розроблено.
ПЕРИПЕТІЇ ДІАГНОСТИКИ НЕЙРОБОРЕЛІОЗУ
Authors: Kopcha V. S. , Korodiuk V. I. , Radetska L. V. , Kadubets O. Ya.
Published: March 2018

Мета роботи – описати випадок маніфестації безеритемного Лайм-бореліозу (ЛБ) у вигляді швидкопрогресуючої нейроінфекції на тлі імуносупресивної терапії, яка була призначена у зв’язку з встановленням у хворого дерматоміозиту. Становлять інтерес широта диференційно-діагностичного пошуку, ускладненого деяким атипізмом дебюту і перебігу дерматоміозиту, і початок спостереження за хворим вже на тлі лікування глюкокортикоїдами. Зроблено огляд літератури щодо патогенезу, клініки і діагностики нейробореліозу. Автоімунні механізми з переважним порушенням гуморальної відповіді (інтратекальний синтез антибореліозних моноклональних антитіл, частина з яких схожа з мієліном) зумовлюють розпад мієліну і вторинне аксональне ураження нервової системи на кшталт механізму «молекулярної мімікрії».Висновки. У зв’язку з тим, що борелії, ймовірно, беруть участь в ініціації автоімунного процесу в результаті активації мієліноспецифічних Т-клітин і виявлення автореактивних антитіл до мієліну і компонент мієліну, при здійсненні диференційної діагностики варто враховувати можливість поєднання ЛБ з іншими автоімунними захворюваннями.