bluuebunny/crossref_metadata_2025 huggingface dataset:
Action Video Game Experience Related to Altered Large-Scale White Matter Networks
Authors: Gong Diankun , Ma Weiyi , Gong Jinnan , He Hui , Dong Li , Zhang Dan , Li Jianfu , Luo Cheng , Yao Dezhong
Published: June 2017

With action video games (AVGs) becoming increasingly popular worldwide, the cognitive benefits of AVG experience have attracted continuous research attention over the past two decades. Research has repeatedly shown that AVG experience can causally enhance cognitive ability and is related to neural plasticity in gray matter and functional networks in the brain. However, the relation between AVG experience and the plasticity of white matter (WM) network still remains unclear. WM network modulates the distribution of action potentials, coordinating the communication between brain regions and acting as the framework of neural networks. And various types of cognitive deficits are usually accompanied by impairments of WM networks. Thus, understanding this relation is essential in assessing the influence of AVG experience on neural plasticity and using AVG experience as an interventional tool for impairments of WM networks. Using graph theory, this study analyzed WM networks in AVG experts and amateurs. Results showed that AVG experience is related to altered WM networks in prefrontal networks, limbic system, and sensorimotor networks, which are related to cognitive control and sensorimotor functions. These results shed new light on the influence of AVG experience on the plasticity of WM networks and suggested the clinical applicability of AVG experience.
Factors Associated with the Incidence and Severity of New-Onset Atrial Fibrillation in Adult Critically Ill Patients
Authors: Duarte Péricles A. D. , Leichtweis Gustavo Elias , Andriolo Luiza , Delevatti Yasmim A. , Jorge Amaury C. , Fumagalli Andreia C. , Santos Luiz Claudio , Miura Cecilia K. , Saito Sergio K.
Published: June 2017

Background. Acute Atrial Fibrillation (AF) is common in critically ill patients, with significant morbidity and mortality; however, its incidence and severity in Intensive Care Units (ICUs) from low-income countries are poorly studied. Additionally, impact of vasoactive drugs on its incidence and severity is still not understood. This study aimed to assess epidemiology and risk factors for acute new-onset AF in critically ill adult patients and the role of vasoactive drugs. Method. Cohort performed in seven general ICUs (including cardiac surgery) in three cities in Paraná State (southern Brazil) for 45 days. Patients were followed until hospital discharge. Results. Among 430 patients evaluated, the incidence of acute new-onset AF was 11.2%. Patients with AF had higher ICU and hospital mortality. Vasoactive drugs use (norepinephrine and dobutamine) was correlated with higher incidence of AF and higher mortality in patients with AF; vasopressin (though used in few patients) had no effect on development of AF. Conclusions. In general ICU patients, incidence of new-onset AF was 11.2% with a high impact on morbidity and mortality, particularly associated with the presence of Acute Renal Failure. The use of vasoactive drugs (norepinephrine and dobutamine) could lead to a higher incidence of new-onset AF-associated morbidity and mortality.
An Ensemble Multilabel Classification for Disease Risk Prediction
Authors: Li Runzhi , Liu Wei , Lin Yusong , Zhao Hongling , Zhang Chaoyang
Published: June 2017

It is important to identify and prevent disease risk as early as possible through regular physical examinations. We formulate the disease risk prediction into a multilabel classification problem. A novel Ensemble Label Power-set Pruned datasets Joint Decomposition (ELPPJD) method is proposed in this work. First, we transform the multilabel classification into a multiclass classification. Then, we propose the pruned datasets and joint decomposition methods to deal with the imbalance learning problem. Two strategies size balanced (SB) and label similarity (LS) are designed to decompose the training dataset. In the experiments, the dataset is from the real physical examination records. We contrast the performance of the ELPPJD method with two different decomposition strategies. Moreover, the comparison between ELPPJD and the classic multilabel classification methods RAkEL and HOMER is carried out. The experimental results show that the ELPPJD method with label similarity strategy has outstanding performance.
Assessment of Haemodynamic Response to Nonselective Beta-Blockers in Portal Hypertension by Phase-Contrast Magnetic Resonance Angiography
Authors: McDonald Natasha , Lilburn David M. L. , Lachlan Neil J. , Macnaught Gillian , Patel Dilip , Jayaswal Arjun N. A. , Hayes Peter C. , Semple Scott I. , Fallowfield Jonathan A.
Published: June 2017

A significant unmet need exists for accurate, reproducible, noninvasive diagnostic tools to assess and monitor portal hypertension (PHT). We report the first use of quantitative MRI markers for the haemodynamic assessment of nonselective beta-blockers (NSBB) in PHT. In a randomized parallel feasibility study in 22 adult patients with PHT and a clinical indication for NSBB, we acquired haemodynamic data at baseline and after 4 weeks of NSBB (propranolol or carvedilol) using phase-contrast MR angiography (PC-MRA) in selected intra-abdominal vessels. T1 mapping of liver and spleen was undertaken to assess changes in tissue composition. Target NSBB dose was achieved in 82%. There was a substantial reduction from baseline in mean average flow in the superior abdominal aorta after 4 weeks of NSBB therapy (4.49±0.98versus3.82±0.86 L/min,P=0.03) but there were no statistically significant differences in flow in any other vessels, even in patients with >25% decrease in heart rate (47% of patients). Mean percentage change in liver and spleen T1 following NSBB was small and highly variable. In conclusion, PC-MRA was able to detect reduction in cardiac output by NSBB but did not detect significant changes in visceral blood flow or T1. This trial was registered with the ISRCTN registry (ISRCTN98001632).
A Decade of GWAS Results in Lung Cancer
Authors: Bossé Yohan , Amos Christopher I.
Published: June 2017

Genome-wide association studies (GWAS) were successful to identify genetic factors robustly associated with lung cancer. This review aims to synthesize the literature in this field and accelerate the translation of GWAS discoveries into results that are closer to clinical applications. A chronologic presentation of published GWAS on lung cancer susceptibility, survival, and response to treatment is presented. The most important results are tabulated to provide a concise overview in one read. GWAS have reported 45 lung cancer susceptibility loci with varying strength of evidence and highlighted suspected causal genes at each locus. Some genetic risk loci have been refined to more homogeneous subgroups of lung cancer patients in terms of histologic subtypes, smoking status, gender, and ethnicity. Overall, these discoveries are an important step for future development of new therapeutic targets and biomarkers to personalize and improve the quality of care for patients. GWAS results are on the edge of offering new tools for targeted screening in high-risk individuals, but more research is needed if GWAS are to pay off the investment. Complementary genomic datasets and functional studies are needed to refine the underlying molecular mechanisms of lung cancer preliminarily revealed by GWAS and reach results that are medically actionable. Cancer Epidemiol Biomarkers Prev; 27(4); 363–79. ©2018 AACR.

See all articles in this CEBP Focus section, “Genome-Wide Association Studies in Cancer.”
Molecular Pathways: Targeting the Microenvironment of Liver Metastases
Authors: Milette Simon , Sicklick Jason K. , Lowy Andrew M. , Brodt Pnina
Published: June 2017

Curative treatment for metastatic solid cancers remains elusive. The liver, which is nourished by a rich blood supply from both the arterial and portal venous systems, is the most common site of visceral metastases, particularly from cancers arising in the gastrointestinal tract, with colorectal cancer being the predominant primary site in Western countries. A mounting body of evidence suggests that the liver microenvironment (LME) provides autocrine and paracrine signals originating from both parenchymal and nonparenchymal cells that collectively create both pre- and prometastatic niches for the development of hepatic metastases. These resident cells and their molecular mediators represent potential therapeutic targets for the prevention and/or treatment of liver metastases (LM). This review summarizes: (i) the current therapeutic options for treating LM, with a particular focus on colorectal cancer LM; (ii) the role of the LME in LM at each of its phases; (iii) potential targets in the LME identified through preclinical and clinical investigations; and (iv) potential therapeutic approaches for targeting elements of the LME before and/or after the onset of LM as the basis for future clinical trials. Clin Cancer Res; 23(21); 6390–9. ©2017 AACR.
PD-L2 Expression in Human Tumors: Relevance to Anti-PD-1 Therapy in Cancer
Authors: Yearley Jennifer H. , Gibson Christopher , Yu Ni , Moon Christina , Murphy Erin , Juco Jonathan , Lunceford Jared , Cheng Jonathan , Chow Laura Q.M. , Seiwert Tanguy Y. , Handa Masahisa , Tomassini Joanne E. , McClanahan Terrill
Published: June 2017

Purpose: Tumor-associated PD-L1 expression is predictive of clinical response to PD-1–directed immunotherapy. However, PD-L1–negative patients may also respond to PD-1 checkpoint blockade, suggesting that other PD-1 ligands may be relevant to the clinical activity of these therapies. The prevalence of PD-L2, the other known ligand of PD-1, and its relationship to response to anti-PD-1 therapy were evaluated.

Experimental Design: PD-L2 expression was assessed in archival tumor tissue from seven indications using a novel immunohistochemical assay. In addition, relationships between clinical response and PD-L2 status were evaluated in tumor tissues from patients with head and neck squamous cell carcinoma (HNSCC) with recurrent or metastatic disease, treated with pembrolizumab.

Results: PD-L2 expression was observed in all tumor types and present in stromal, tumor, and endothelial cells. The prevalence and distribution of PD-L2 correlated significantly with PD-L1 (P = 0.0012–<0.0001); however, PD-L2 was detected in the absence of PD-L1 in some tumor types. Both PD-L1 and PD-L2 positivity significantly predicted clinical response to pembrolizumab on combined tumor, stromal and immune cells, with PD-L2 predictive independent of PD-L1. Response was greater in patients positive for both PD-L1 and PD-L2 (27.5%) than those positive only for PD-L1 (11.4%). PD-L2 status was also a significant predictor of progression-free survival (PFS) with pembrolizumab independent of PD-L1 status. Longer median times for PFS and overall survival were observed for PD-L2–positive than PD-L2–negative patients.

Conclusions: Clinical response to pembrolizumab in patients with HNSCC may be related partly to blockade of PD-1/PD-L2 interactions. Therapy targeting both PD-1 ligands may provide clinical benefit in these patients. Clin Cancer Res; 23(12); 3158–67. ©2017 AACR.
The Novel Association of Circulating Tumor Cells and Circulating Megakaryocytes with Prostate Cancer Prognosis
Authors: Xu Lei , Mao Xueying , Guo Tianyu , Chan Pui Ying , Shaw Greg , Hines John , Stankiewicz Elzbieta , Wang Yuqin , Oliver R. Tim D. , Ahmad Amar Sabri , Berney Daniel , Shamash Jonathan , Lu Yong-Jie
Published: June 2017

Purpose: To develop an approach for the investigation of different subtypes of circulating tumor cells (CTC) and other cells to evaluate their potential prognostic value of prostate cancer.

Experimental Design: Malignancy of CTCs undergoing epithelial-to-mesenchymal transition (EMT) was confirmed by repeated FISH. Subgroups of CTCs in 81 patients with prostate cancer (43 castration resistant and 38 untreated localized) were correlated to disease aggressiveness parameters. AUC analysis was applied to compare the performance for metastasis prediction between serum PSA level alone and a combined risk score using both PSA and EMTing CTC count. Circulating megakaryocytes and cancer patient survival association was performed using Cox model.

Results: The majority of vimentin (VIM)+/CD45− cells were malignant, with genomic alterations in several genomic regions. The number of cytokeratin (CK)−/VIM+/CD45− CTCs correlated with disease burden, tumor aggressiveness, and poorer survival. Meanwhile, CK+/VIM+/CD45− CTCs were associated with metastases better than other subtypes of CTCs in these limited samples. Combination of PSA level and the number of CK+/VIM+/CD45− CTCs enhanced the prediction of cancer metastases [AUC, 0.921; 95% confidence interval (CI), 0.858–0.985]. The number of circulating megakaryocytes was potentially associated with good patient survival in advanced prostate cancer (HR, 0.849; 95% CI, 0.628–1.146, per cell increase), and the difference between the number of mesenchymal CTCs and megakaryocytes strongly correlated to poor survival (HR, 10.17; 95% CI, 2.164–47.789, if score ≥2.0).

Conclusions: This CTC analysis approach and the potential association of megakaryocytes with cancer prognosis may greatly enhance our ability to investigate the cancer metastasis process and to predict/monitor cancer progression. Clin Cancer Res; 23(17); 5112–22. ©2017 AACR.
Cancer Surveillance in Gorlin Syndrome and Rhabdoid Tumor Predisposition Syndrome
Authors: Foulkes William D. , Kamihara Junne , Evans D. Gareth R. , Brugières Laurence , Bourdeaut Franck , Molenaar Jan J. , Walsh Michael F. , Brodeur Garrett M. , Diller Lisa
Published: June 2017

Gorlin syndrome and rhabdoid tumor predisposition syndrome (RTPS) are autosomal dominant syndromes associated with an increased risk of childhood-onset brain tumors. Individuals with Gorlin syndrome can manifest a wide range of phenotypic abnormalities, with about 5% of family members developing medulloblastoma, usually occurring in the first 3 years of life. Gorlin syndrome is associated with germline mutations in components of the Sonic Hedgehog pathway, including Patched1 (PTCH1) and Suppressor of fused (SUFU). SUFU mutation carriers appear to have an especially high risk of early-onset medulloblastoma. Surveillance MRI in the first years of life in SUFU mutation carriers is, therefore, recommended. Given the risk of basal cell carcinomas, regular dermatologic examinations and sun protection are also recommended. Rhabdoid tumors (RT) are tumors initially defined by the descriptive “rhabdoid” term, implying a phenotypic similarity with rhabdomyoblasts at the microscopic level. RTs usually present before the age of 3 and can arise within the cranium as atypical teratoid/rhabdoid tumors or extracranially, especially in the kidney, as malignant rhabdoid tumors. However, RTs of both types share germline and somatic mutations in SMARCB1 or, more rarely, SMARCA4, each of which encodes a chromatin remodeling family member. SMARCA4 mutations are particularly associated with small cell carcinoma of the ovary, hypercalcemic type (SCCOHT). The outcome following a diagnosis of any of these tumors is often poor, and the value of surveillance is unknown. International efforts to determine surveillance protocols are underway, and preliminary recommendations are made for carriers of SMARCB1 and SMARCA4 mutations. Clin Cancer Res; 23(12); e62–e67. ©2017 AACR.

See all articles in the online-only CCR Pediatric Oncology Series.
A Phase Ib Open-Label Multicenter Study of AZD4547 in Patients with Advanced Squamous Cell Lung Cancers
Authors: Paik Paul K. , Shen Ronglai , Berger Michael F. , Ferry David , Soria Jean-Charles , Mathewson Alastair , Rooney Claire , Smith Neil R. , Cullberg Marie , Kilgour Elaine , Landers Donal , Frewer Paul , Brooks Nigel , André Fabrice
Published: June 2017

Purpose: Squamous cell lung cancers (SQCLC) account for 25% of all NSCLCs, yet the prognosis of these patients is poor and treatment options are limited. Amplified FGFR1 is one of the most common oncogenic events in SQCLCs, occurring in approximately 20% of cases. AZD4547 is a potent and selective FGFR1-3 inhibitor with antitumor activity in FGFR1-amplified SQCLC cell lines and patient-derived xenografts.

Experimental Design: On the basis of these data, we performed a phase I study of AZD4547 in patients with previously treated stage IV FGFR1-amplified SQCLCs (NCT00979134). FGFR1 amplification (FGFR1:CEP8 ≥ 2) was determined by FISH. The primary endpoint was safety/tolerability. Secondary endpoints included antitumor activity, pharmacokinetics, pharmacodynamics, and molecular analyses.

Results: Fifteen FGFR1-amplified patients were treated. The most common related adverse events (AE) were gastrointestinal and dermatologic. Grade ≥3–related AEs occurred in 3 patients (23%). Thirteen patients were evaluable for radiographic response assessment. The overall response rate was 8% (1 PR). Two of 15 patients (13.3%) were progression-free at 12 weeks, and the median overall survival was 4.9 months. Molecular tests, including next-generation sequencing, gene expression analysis, and FGFR1 immunohistochemistry, showed poor correlation between gene amplification and expression, potential genomic modifiers of efficacy, and heterogeneity in 8p11 amplicon.

Conclusions: AZD4547 was tolerable at a dosage of 80 mg oral twice a day, with modest antitumor activity. Detailed molecular studies show that these tumors are heterogeneous, with a range of mutational covariates and stark differences in gene expression of the 8p11 amplicon that likely explain the modest efficacy of FGFR inhibition in this disease. Clin Cancer Res; 23(18); 5366–73. ©2017 AACR.
Ormeloxifene Suppresses Prostate Tumor Growth and Metastatic Phenotypes via Inhibition of Oncogenic β-catenin Signaling and EMT Progression
Authors: Hafeez Bilal Bin , Ganju Aditya , Sikander Mohammed , Kashyap Vivek K. , Hafeez Zubair Bin , Chauhan Neeraj , Malik Shabnam , Massey Andrew E. , Tripathi Manish K. , Halaweish Fathi T. , Zafar Nadeem , Singh Man M. , Yallapu Murali M. , Chauhan Subhash C. , Jaggi Meena
Published: June 2017

Ormeloxifene is a clinically approved selective estrogen receptor modulator, which has also shown excellent anticancer activity, thus it can be an ideal repurposing pharmacophore. Herein, we report therapeutic effects of ormeloxifene on prostate cancer and elucidate a novel molecular mechanism of its anticancer activity. Ormeloxifene treatment inhibited epithelial-to-mesenchymal transition (EMT) process as evident by repression of N-cadherin, Slug, Snail, vimentin, MMPs (MMP2 and MMP3), β-catenin/TCF-4 transcriptional activity, and induced the expression of pGSK3β. In molecular docking analysis, ormeloxifene showed proficient docking with β-catenin and GSK3β. In addition, ormeloxifene induced apoptosis, inhibited growth and metastatic potential of prostate cancer cells and arrested cell cycle in G0–G1 phase via modulation of cell-cycle regulatory proteins (inhibition of Mcl-1, cyclin D1, and CDK4 and induction of p21 and p27). In functional assays, ormeloxifene remarkably reduced tumorigenic, migratory, and invasive potential of prostate cancer cells. In addition, ormeloxifene treatment significantly (P < 0.01) regressed the prostate tumor growth in the xenograft mouse model while administered through intraperitoneal route (250 μg/mouse, three times a week). These molecular effects of ormeloxifene were also observed in excised tumor tissues as shown by immunohistochemistry analysis. Our results, for the first time, demonstrate repurposing potential of ormeloxifene as an anticancer drug for the treatment of advanced stage metastatic prostate cancer through a novel molecular mechanism involving β-catenin and EMT pathway. Mol Cancer Ther; 16(10); 2267–80. ©2017 AACR.
Heterogeneity in Gastric Cancer: From Pure Morphology to Molecular Classifications
Authors: Gullo Irene , Carneiro Fátima , Oliveira Carla , Almeida Gabriela M.
Published: June 2017

Gastric cancer (GC) represents a global health concern. Despite advances in prevention, diagnosis, and therapy, GC is still the third leading cause of cancer mortality worldwide, with more than 720,000 estimated deaths in 2012. Overall survival for advanced disease is about 1 year, a dismal prognosis that is partly due to the high levels of biological heterogeneity found in GC. Indeed, GC is a highly heterogeneous disease from morphological and molecular standpoints. The numerous histological and molecular classifications currently available reflect such heterogeneity. Although recent high-throughput studies cluster the molecular data obtained into subgroups with clinical relevance, we still need a practical, prognostic, and predictive classification system, integrating morphological and molecular features, towards the identification of novel therapeutic targets. It is noteworthy that GC heterogeneity encompasses not only interpatient variability (intertumour heterogeneity), but also variations within the same tumour (intratumour heterogeneity). The latter encompasses spatial heterogeneity (in different tumour areas) and temporal heterogeneity (along progression from primary to recurrent and/or metastatic disease). In this review, we analyse the morphological, immunophenotypic, and molecular heterogeneity in GC as the basis for a better understanding of the disease, and discuss the practical implications for diagnostic pathology, prognostic evaluation, and precision therapy.
Gastric Ulcer Complications after the Introduction of Proton Pump Inhibitors into Clinical Routine: 20-Year Experience
Authors: Eisner Friederike , Hermann Diana , Bajaeifer Khaled , Glatzle Jörg , Königsrainer Alfred , Küper Markus A.
Published: June 2017

Background: The aim of this study was to analyze the admissions and the management of peptic ulcer disease (PUD) in a tertiary care surgical center. Methods: We evaluated the medical records of all patients admitted to the University Hospital of Tübingen, Germany, for treatment of PUD during 1989-2008. Patients were included into the study if the diagnosis was verified endoscopically or surgically. Annual number of admissions, length of hospitalization, mortality rate, age, rate of non-steroidal anti-inflammatory drugs (NSAIDs) and proton pump inhibitor (PPI) medication, rate of Helicobacter pylori infection, and complications of PUD and surgery performed were recorded. Data were analyzed by descriptive analyses, Pearson's chi-square test, and regression analysis. Results: This study included 614 admissions. The number of annual admissions (31 ± 12), the length of hospitalization (9 ± 3 days), and the mortality rate (5 ± 4% per year) remained constant, whereas the age increased (1989: 52 ± 14 years vs. 2008: 67 ± 16 years). The rates of patients with H. pylori infection (47 ± 28% per year), NSAIDs treatment (29 ± 15% per year), and PPI treatment (31 ± 27% per year) remained constant. The most frequent PUD complication was hemorrhage (42 ± 16% per year), followed by perforation (9 ± 8% per year). During 1999-2008, more hemorrhages (125 vs. 121; p < 0.05) and perforations (40 vs. 21; p < 0.05) were registered than during 1989-1998. The rate of emergency surgery increased from 70% during 1989-1998 to 87% during 1999-2008. In contrast, elective surgery decreased from 21% during 1989-1998 to 7% during 1999-2008. Ulcer excision and oversewing was the most frequent surgical procedure performed (59%), with decreasing rates of acid-reducing surgery. Conclusion: Despite recent advances in PUD management, ulcer hemorrhage and perforation remain a significant health burden and a surgical disease.
Upregulation of Circulating miR-195-3p in Heart Failure
Authors: He Xia , Ji Jun , Wang Tao , Wang Ming-Bang , Chen Xiao-Ling
Published: June 2017

Objectives: Many circulating microRNAs (miRs) have been shown to have potential biomarker effects in cardiovascular disease. We studied the dysregulation of circulating miR-195-3p in patients with heart failure (HF) to elucidate its value as a potential biomarker for HF. Methods: Eight ischemic HF (IHF) patients, 8 nonischemic HF patients (NIHF), and 8 healthy volunteers (matched by age and sex - normal controls [NCs]) were chosen for miR sequencing. The plasma RNA was extracted, and a small RNA library of HF was established and then sequenced using next-generation sequencing (NGS) technology. The miR-195-3p was selected for a second clinical study in 60 IHF, 48 NIHF patients, and 35 NCs for qRT-PCR validation. Results: The expression of circulating miR-195-3p in the IHF group was increased 69.5-fold compared with the NC group using NGS technique, and it was the most elevated in all upregulated miRs. MiR-195-3p was ranked in the top 1 of all upregulated miRs in contribution to HF based on a random forest model analysis. The upregulation of circulating miR-195-3p was also validated with the qRT-PCR method, and receiver operating characteristic curve analysis showed that the area under the curve (AUC) was 0.831. Conclusions: The circulating miR-195-3p was upregulated in IHF and NIHF patients and could be a potential biomarker for HF.
Deletion of the Inflammasome Sensor Aim2 Mitigates Aβ Deposition and Microglial Activation but Increases Inflammatory Cytokine Expression in an Alzheimer Disease Mouse Model
Authors: Wu Pei-Jung , Hung Yun-Fen , Liu Hsin-Yu , Hsueh Yi-Ping
Published: June 2017

Objective: Inflammation is clearly associated with Alzheimer disease (AD). Knockout of Nlrp3, a gene encoding an inflammasome sensor, has been shown to ameliorate AD pathology in a mouse model. Because AIM2 is the most dominant inflammasome sensor expressed in mouse brains, here we investigate whether Aim2 deletion also influences the phenotype of a 5XFAD AD mouse model. Methods: Quantitative RT-PCR, immunostaining, immunoblotting, and behavioral analyses were applied to compare wild-type, Aim2-/-, 5XFAD, and Aim2-/-;5XFAD mice. Results: We found that Aim2 knockout mitigates Aβ deposition in the cerebral cortex and hippocampus of 5XFAD mice. The activation of microglial cells is also reduced in Aim2-/-;5XFAD brains compared with 5XFAD brains. However, Aim2 knockout does not improve memory and anxiety phenotypes of 5XFAD mice in an open field, cued Y-maze, or Barnes maze. Compared with 5XFAD mice, Il-1 expression levels are not reduced in Aim2-/-;5XFAD mice. Unexpectedly, Il-6 and Il-18 expression levels in 5XFAD brains were further increased when Aim2 was deleted. Thus, inflammatory cytokine expression in 5XFAD brains is upregulated by Aim2 deletion through an unknown mechanism. Conclusion: Although Aim2 knockout mitigates Aβ deposition and microglial activation, Aim2 deletion does not have a beneficial effect on the spatial memory or cytokine expression of 5XFAD mice. Our findings suggest that Aβ aggregation and microglial activation may not always be correlated with the expression of inflammatory cytokines or cognitive function of 5XFAD mice. Our study also implies that different inflammasomes likely perform distinct roles in different physiological and/or pathological events.
Genetic Testing in a Cohort of Complex Esophageal Atresia
Authors: Beauregard-Lacroix Eliane , Tardif Jessica , Lemyre Emmanuelle , Kibar Zoha , Faure Christophe , Campeau Philippe M.
Published: June 2017

The objective of the present study is to describe a cohort of complex esophageal atresia and the yield of genetic tests performed for such patients. We selected 45 patients with complex esophageal atresia (EA), namely those having at least one associated anomaly. We reviewed their medical records to assess clinical features, other diagnoses, and genetic investigations. Most of the patients had a diagnosis of VACTERL association (56%) with no genetic variant identified. Interestingly, 5 patients in the cohort (11%) had a right pulmonary hypoplasia or agenesis. A majority of our cohort (73%) had genetic testing; 60% were karyotyped (abnormal in 4 of the 27 patients tested), 31% had aCGH (abnormal in 1 of the 14 patients tested), and 31% had diepoxybutane (DEB) testing for Fanconi anemia (abnormal in 2 of the 14 patients tested). One patient had exome sequencing studies, but no candidate gene was identified. Various anomalies were associated with EA, and overall a genetic variant could be identified in 7 of the 33 patients tested. Chromosomal studies such as aCGH and chromosomal breakage studies should be considered, and their yield varied between 7 and 14%. Other genetic investigations such as exome sequencing could possibly have even higher yields but will need to be assessed in a large cohort. Improved genetic diagnoses in EA may improve the management of these patients by directing specific surveillance and management schemes.
Identification of 8 Novel Mutations in Nephrogenesis-Related Genes in Chinese Han Patients with Unilateral Renal Agenesis
Authors: Wu Hangdi , Xu Qian , Xie Jingyuan , Ma Jun , Qiao Panpan , Zhang Wen , Yu Haijin , Wang Weiming , Qian Ying , Zhang Qianying , Guo Yiqing , Tang Yonghua , Chen Xiao-nong , Wang Zhaohui , Chen Nan
Published: June 2017

Background: Few genetic studies have focused on unilateral renal agenesis (URA), which is a disorder with insidious clinical manifestations and a tendency to result in renal failure. We aimed to detect pathogenic mutations in nephrogenesis-related genes, which were identified by a literature review conducted among a large cohort of Chinese Han patients with URA. Methods: Totally, 86 unrelated URA patients were included. All URA patients were diagnosed by employing radiological methods. Patients with a solitary kidney owing to nephrectomy or renal atrophy due to secondary factors were excluded. Nine (10.5%) patients had a family history of abnormal nephrogenesis. Fifteen (17.4%) had other malformations in the urogenital system. All coding exons and adjacent intron regions of 25 genes were analyzed using next-generation sequencing and validated by Sanger sequencing and 100 ethnically matched healthy controls. Results: Ten conserved mutations (9 missense mutations and 1 deletion mutation) were identified in SALL1, EYA1, RET, HNF1B, DSTYK, WNT4, and SIX5. All mutations were novel or rare (frequency <0.1%) in the public databases and absent from the 100 healthy controls. Nine patients carried mutations in candidate genes. Most of the patients carried one single heterozygous mutation, except for 2, who respectively carried compound heterozygous mutations and 2 single heterozygous mutations. In addition, 2 patients shared the same mutation in DSTYK. Conclusion: A total of 10.5% of our URA cases could be explained by mutations in our candidate genes. The mutations in nephrogenesis-related genes in the Chinese Han patients with URA had a decentralized distribution without any hotspot mutations.
Matrix Metalloproteases in Arterial Hypertension and their Trend after Antihypertensive Treatment
Authors: Hopps Eugenia , Lo Presti Rosalia , Caimi Gregorio
Published: June 2017

Background/Aims: Arterial hypertension is characterized by vascular remodelling, atherosclerosis and cardiovascular complications. Matrix metalloproteases (MPPs) are endopeptidases produced by all the cells present in the vascular wall and are involved in the regulation of the extracellular matrix protein turnover. MMPs contribute to blood vessel formation, remodelling, angiogenesis; whereas an altered expression or activity of MMPs or their tissue inhibitors (TIMPs) results correlated with the development and progression of cardiovascular complications. Methods: We examined the literature data regarding the role of MMPs in human hypertension, including their involvement in vascular remodelling, and the effects of some antihypertensive molecules on these MMP/TIMP profile. Results: The expression and the activity of some MMPs and TIMPs are impaired in human hypertension. An altered MMPs/TIMPs balance plays an important role in the vascular wall rearrangement, in response to hemodynamic changes which may induce myocardial hypertrophy and fibrosis leading to ventricular remodelling. Several studies have examined the effects of some antihypertensive molecules, such as ACE inhibitors, angiotensin receptor blockers, calcium-channel blockers, and aldosterone antagonists, on the MMPs/TIMPs profile by obtaining positive results. Conclusion: Considering the data taken into consideration, the authors believe that in clinical practice a strategic antihypertensive therapy directed to the MMPs profile, may be useful to decrease the risk of cardiovascular complications.
Induction of Apoptosis in HepaRG Cell Line by Aloe-Emodin through Generation of Reactive Oxygen Species and the Mitochondrial Pathway
Authors: Dong Xiaoxv , Fu Jing , Yin Xingbin , Qu Changhai , Yang Chunjing , He Huyiligeqi , Ni Jian
Published: June 2017

Background/Aims: Aloe-emodin (1,8-dihydroxy-3-hydroxymethyl-anthraquinone), an anthraquinone active compounds, is isolated from some traditional medicinal plants such as Rheum palmatum L. and Cassia occidentalis, which induce hepatotoxicity in rats. The aim of this study was to determine potential cytotoxic effects of aloe-emodin on HepaRG cells and to define the underlying mechanism. Methods: MTT was used to evaluate cell viability. Apoptotic cell death was analyzed via Annexin V-FITC/PI double staining. Intracellular reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) were determined by flow cytometry, while the expression of apoptosis-related proteins was determined by Western blot analysis. Results: Treatment with aloe-emodin significantly reduced cell viability and induced apoptosis in HepaRG cells in a dose- and time-dependent manner. It provoked ROS generation and depolarization of MMP in HepaRG cells when compared with controls. Aloe-emodin dose-dependently increased release of mitochondrial cytochrome c, and levels of Fas, p53, p21, Bax/Bcl-2 ratio, as well as activation of caspase-3, caspase-8, caspase-9, and subsequent cleavage of poly(ADP-ribose)polymerase (PARP). It also induced S-phase cell cycle arrest by increasing the expression of p21 and cyclin E proteins while significantly decreasing the expression of cyclin A and CDK2. Conclusion: These results suggest that aloe-emodin inhibits cell proliferation and induces apoptosis in HepaRG cells, most probably through a mechanism involving both Fas death pathway and the mitochondrial pathway by generation of ROS. These findings underscore the need for risk assessment of human exposure to aloe-emodin.
Disconnections of Cortico-Subcortical Pathways Related to Cognitive Impairment in Patients with Leukoaraiosis: A Preliminary Diffusion Tensor Imaging Study
Authors: Yuan Jun-Liang , Wang Shuang-Kun , Guo Xiao-Juan , Teng Lei-lei , Jiang Hua , Gu Hua , Hu Wen-Li
Published: June 2017

Background: We aimed to explore the relation between the microstructural integrity of white matter using the technique of diffusion tensor imaging (DTI) and changes of cognition in leukoaraiosis (LA). Methods: Fifty patients with LA and 50 age- and gender-matched controls were recruited consecutively. The average values of mean diffusivity (MD) and fractional anisotropy (FA) were quantified both within white matter lesions (WMLs) and normal-appearing white matter (NAWM) from the regions of interest (ROIs). Results: We found significantly decreased FA and increased MD in WMLs at the 5 ROIs than that in NAWM and controls (p < 0.05). The values of FA in NAWM were significantly lower at centrum semiovale and posterior periventricular white matter than those of controls (p < 0.05). The values of MD in NAWM were significantly higher at the anterior periventricular white matter and corpus callosum than those of controls (p < 0.05). The values of FA in NAWM located at anterior periventricular white matter correlated inversely with the Z scores of executive function (r = -0.420, p = 0.028). Conclusions: DTI may provide some important information about the cognitive dysfunction in patients with LA, which may largely attribute to the “disconnection” of cortico-subcortical pathways, with the evidence of reduced FA and increased MD.
Management of Helicobacter pylori Infection: What Should the Surgeon Know
Authors: Selgrad Michael , Malfertheiner Peter
Published: June 2017

Infection with Helicobacter pylori continues to represent a major global health care burden, and various national and international consensus reports and guidelines have aimed at tracking recent developments for their translation into an optimized clinical management. The most important ‘innovation' is the definition of H. pylori gastritis as an infectious disease. This does imply the consideration of therapy of this condition even before the development of clinical manifestations including non-malignant and malignant gastroduodenal diseases, such as peptic ulcer disease, gastric cancer, and gastric mucosa-associated lymphoid tissue lymphoma. Treatment of H. pylori is facing an increasing number of failures, with the main reason being an increasing antibiotic resistance to some of the previously most effective antibiotics, i.e. clarithromycin and levofloxacin, for H. pylori strains. Several new treatment options or modifications of already established regimens have been introduced to overcome bacterial resistance and treatment failure. In this review, we provide an update on the current recommendations for a successful management of H. pylori infection, and in this context a special reference is made to the role of visceral surgeons.
Tracing the Development of the Nuclear Taboo: The Eisenhower Administration and Four Crises in East Asia
Authors: Hanania Richard
Published: June 2017

Many scholars have argued that a taboo on the use of nuclear weapons became widely accepted in the 1960s, spurred on by the Cuban missile crisis and the subsequent growth of U.S. and Soviet long-range nuclear missile forces. The Eisenhower administration, in contrast, has been seen as relatively more willing to use nuclear diplomacy to achieve its military objectives. This article examines the Eisenhower administration's attitudes toward nuclear weapons during four crises in East Asia: the end of the Korean War, the siege of Dien Bien Phu, and the shelling of Quemoy and Matsu in 1954–1955 and 1958. U.S. officials at first acted almost as if nuclear weapons were simply “bigger bombs,” but as the decade progressed, nuclear weapons were increasingly seen as all but unusable. Much of the confusion regarding Dwight Eisenhower's attitude toward this issue resulted from changes over time and the complex interactions he had with members of his administration who argued for a more aggressive stance toward foreign enemies.
To “Keep the Genie Bottled Up”: U.S. Diplomacy, Nuclear Proliferation, and Gas Centrifuge Technology, 1962–1972
Authors: Burr William
Published: June 2017

In the 1960s and early 1970s, U.S. policymakers maintained a complex effort to limit the dissemination of gas centrifuge technology for enriching uranium, which they saw as an inherent nuclear proliferation risk. Recognizing that controls could not stop scientific research and development, U.S. officials nevertheless believed the overseas development of gas centrifuge technology could be slowed. To prevent further dissemination overseas, the United States supported cooperation with European allies that were already developing the technology. Cooperation involved implementation of secrecy and export controls, although a U.S. initiative to include Japan failed because nuclear secrecy was incompatible with Japanese law. The United States tried to deflect Japan's interest in the gas centrifuge by offering to share an alternative technology, gaseous diffusion, for enrichening uranium. That initiative failed, but the U.S. government remained committed to keeping enrichment technologies under secrecy controls.
Reinhold Niebuhr and Catholic Social Teaching on ‘Why Nations Fail’: Constructing a Common Christian Ethical Analysis of a New Theory of Political Economy
Authors: O’Sullivan James P.
Published: June 2017

In this paper the author undertakes a Christian ethical analysis of a prominent new theory of political economy by Daron Acemoglu and James Robinson. The analysis utilizes two commonly juxtaposed Christian sources, Reinhold Niebuhr and Catholic social teaching (cst), which allow for a common Christian analysis while also highlighting the nuance and variations of the Christian view. The author first makes the case for the compatibility of the understanding of basic social justice in Niebuhr and cst. Subsequently, the author expounds Acemoglu and Robinson’s account of the roots of development, poverty, and prosperity and then applies the insights of Niebuhr and cst. The aim is not to argue for the accuracy of Acemoglu and Robinson’s theory, but rather to show that Niebuhr and cst reveal deeper theological and ethical dimensions of this highly regarded empirical account, and that these dimensions compel greater action by the developed nations of the world.
Offshore Coral Reef Damage, Overfishing, and Paths to Peace in the South China Sea
Authors: McManus John W.
Published: June 2017

Offshore coral reefs of the South China Sea are subject to complex overlapping sovereignty claims by up to six regional nations. Escalating tensions have led to widespread structural reinforcement of military outposts on many reefs via dredging and filling. Satellite images indicated at least 160 km2 of coral reef damage, including 17 km2 of essentially permanent damage from filling and channel/harbour dredging, and 143 km2 of decadal-scale damage from dredging for building materials and giant clam harvesting. This damage will exacerbate the growing regional overfishing problem. Options to lessen tensions include (1) the establishment of a Greater Spratly Islands Peace Park, and (2) the collaborative management of fisheries, the environment and mineral resources across the entire Sea. Both options require freezes on extant claims and activities in support of claims. No matter how it is achieved, regional peace would greatly enhance fisheries stability and economic growth among all claimant nations.
On the Origin and Development of an Embedded v-Initial Construction in Frisian
Authors: Hoekstra Eric
Published: June 2017

Frisian features an embeddedv-First construction, which is semantically equivalent to an infinitival clause. The construction comes in two varieties. The coordinated variety involves a clause functioning as a second clause of a coordination in the scope of a modal verb. It used to feature an infinitival verb until it started to appear in the 18th century with (unambiguously) imperative verbs. The subordinated variety involves a clause functioning as a verbal argument. It developed out of the coordinated variety in the 18th century. The grammatical properties of both varieties of this construction in present-day Frisian are presented and understood as a result of their origin and subsequent development out of a coordinate construction in Old Frisian. To the extent that the analysis is successful, it provides support for the notion ‘construction’ and for examining the origin and evolution of constructions, as is customary in construction grammar (Goldberg 2006, Givon 2009).
Old Frisian krocha: Setting Fire with a Coal Pan
Authors: Lendinara Patrizia
Published: June 2017

TheBrokmerbrefand the Emsigo Compensation Tariff concerning arson provide a number of occurrences of the wordkrocha, otherwise unrecorded in Old Frisian, in the meaning ‘coal pan’. Yet the Modern Frisian dialect words denote different sorts of cooking pots, either earthen or metal, and apparently do not support the specialized meaning of the Old Frisian. Coal pans were quite common in medieval times, however, and the legal provisions under examination provide both homely and lively descriptions of arson, possibly based on actual cases. Medieval iconography of the devil as an arsonist—portrayed with a coal pan in his hand—assists the interpretation ofkrocha, which goes back to Richthofen, and adds a further negative tinge to the crime of arson, harshly sanctioned by Old Frisian laws.
Zu den Einwohnerbezeichnungen mit dem ja-Suffix im Altniederländischen
Authors: Quak Arend
Published: June 2017

There are some compostive place-names which seem not to have a genitive element, like ODu. Godolfhem [802–7]. The question is, whether they were actual stem-compositions or lost their genitive element. Gysseling (1973) explained them as originally containing the suffix PGm. *-ja, which was lost in the course of time. In that case there must be remains of the suffix in some place-names. This article argues that remains are to be found in place-names with -e like Notleuenes [C12] and even -a and -o like Fengrimahuson [918–48] and *Baltremothorp [C9]. Most of them are derivations from personal names, but there are also derivations from place-names like Heslemaholt [918–48]. The majority of these names seem to occur in the coastal areas, although there are also instances in Germany. Weakening in unaccented syllables made the derivation unclear and led to the loss of vowels, or sometimes to replacement by clearer suffixes like -er.

Bei Ortsnamen findet man ab und zu solche, die scheinbar kein genitivisches Element besitzen wie etwa anl. Godolfhem [802–17]. Die Frage ist dann, ob es sich hier um Stammkomposition handelt oder ob doch irgendwann eine Genitivendung vorhanden war. Gysseling (1973) hat versucht, sie dadurch zu erklären, dass sie mit einem Suffix pgm. *-ja gebildet wurden, das im Laufe der Zeit verschwunden ist. Wenn das stimmt, sollten sich eventuell noch Spuren nachweisen lassen. Es erweist sich, dass es tatsächlich Spuren gibt. So bestehen Formen mit -e wie Notluenes [12.Jh.] und mit -o und -a: Fengrimahuson [918–48] und *Baltremothorp [9. Jh.], gebildet zu Personennamen und Heslemaholt [918–48] zu einem Ortsnamen. Obwohl es auch in Deutschland beispiele gibt, stammen die meisten Namen eher aus den Küstengebieten. Da durch die Abschwächung der Vokale in unbetonten Silben diese Bildung undeutlich wurde, dürfte sie in späterer Zeit verschwunden oder durch deutlichere Bildungen wie die mit -er ersetzt sein.

This article is in German.
John Ray’s A Compleat Collection of English Proverbs as a Source for J. H. Halbertsma’s Lexicon Frisicum
Authors: Roper Jonathan
Published: June 2017

J. H. Halbertsma’s Lexicon Frisicum is an extraordinary work which includes, amongst other things, a fair number of English proverbs and phrases. These are implicitly presented as parallels to the Frisian proverbs and phrases that the work features. Many of these are drawn from A Compleat Collection of English Proverbs by John Ray (1628–1705). This piece looks at some cases where Halbertsma draws on Ray, what he might be attempting to achieve by doing so, and how plausible, convincing and reliable his practice is.
Binna skelde: zur Deutung eines Ausdrucks des friesischen Fehdewesens
Authors: Vries Oebele
Published: June 2017

In this article we will try to clarify the expression binna skelde (literally ‘within the shield’ or ‘within the debt’), which features in Old Frisian juridical language, and which has not yet received a satisfactory explanation. We arrive at the following results. Firstly, the (inflected) form skelde undoubtedly means ‘shield’. Secondly, the context of most of the relevant passages—some being unclear—proves that the expression belongs to the field of Frisian feud terminology, which has its own specific characteristics. Finally, the data suggest that the best way to paraphrase binna skelde is ‘under the liability of the feud leader(s)’ or, alternatively ‘under his (or: their) liability as (a) feud leader(s)’.

In diesem Aufsatz wird der Versuch gewagt, einen bislang nicht befriedigend gedeuteten Begriff der altfriesischen Rechtssprache, und zwar die Wendung binna skelde (wortwörtlich ‚innerhalb des Schildes‘ oder ‚innerhalb der Schuld‘), zu klären. Es lässt sich Folgendes feststellen. Erstens ist mit skelde (flektierte Form) zweifelsohne ‚Schild‘ gemeint. Weiterhin lässt sich aus dem Kontext der meisten der vorhandenen Belegstellen – die übrigen sind unklar – schließen, dass der Ausdruck der teilweise ganz eigenständigen friesischen Fehdeterminologie zuzuordnen ist. Letztendlich wird aus den vorliegenden Daten gefolgert, dass eine angemessene Umschreibung der Bedeutung des Ausdruckes ‚unter der Haftung des Fehdeleiters‘ oder auch ‚unter seiner (bzw. ihrer) Haftung als Fehdeleiter‘ ist.

This article is in German.