bluuebunny/crossref_metadata_2025 huggingface dataset:
Piecewise Polynomial Fitting with Trend Item Removal and Its Application in a Cab Vibration Test
Authors: Ren Wu , Ren Qiongqiong , Han Lin , Liu Ying , Peng Bo
Published: April 2018

The trend item of a long-term vibration signal is difficult to remove. This paper proposes a piecewise integration method to remove trend items. Examples of direct integration without trend item removal, global integration after piecewise polynomial fitting with trend item removal, and direct integration after piecewise polynomial fitting with trend item removal were simulated. The results showed that direct integration of the fitted piecewise polynomial provided greater acceleration and displacement precision than the other two integration methods. A vibration test was then performed on a special equipment cab. The results indicated that direct integration by piecewise polynomial fitting with trend item removal was highly consistent with the measured signal data. However, the direct integration method without trend item removal resulted in signal distortion. The proposed method can help with frequency domain analysis of vibration signals and modal parameter identification for such equipment.
Utility of Neck Circumference for Identifying Metabolic Syndrome by Different Definitions in Chinese Subjects over 50 Years Old: A Community-Based Study
Authors: Lin Shuo , Hu Li , Li Ping , Li Xiaofeng , Lin Keyi , Zhu Bilian , Mu Panwei , Zeng Longyi
Published: April 2018

Aims. Whether neck circumference (NC) could be used as a valuable tool for identifying metabolic syndrome (MS) by different criteria in Chinese is still unclear. Methods. We conducted a cross-sectional survey from October 2010 to January 2011 in Shipai community, Guangzhou, Guangdong Province, China. A total of 1473 subjects aged over 50 years were investigated. We measured height, weight, NC, waist circumference, blood pressure, blood glucose, and lipids in all subjects. MS was identified by criteria of the National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATP III), Chinese Diabetes Society (CDS), and International Diabetes Federation (IDF). Results. Mean NC was 38.0 ± 2.7 cm in men and 34.2 ± 2.5 cm in women. By using receiver operating characteristic curves, the area under the curve (AUC) of NC for identifying MS (IDF) was 0.823 in men and 0.777 in women, while for identifying MS (CDS), it was 0.788 in men and 0.762 in women. The AUC of NC for diagnosing MS (ATP III) was 0.776 in men and 0.752 in women. The optimal cut points of NC for MS were 38.5 cm by three definitions in men, while those were 34.2 cm, 33.4 cm, and 34.0 cm in women by IDF, ATP III, and CDS definitions, respectively. No significant difference was observed between the AUC of NC and BMI for diagnosing MS by using different criteria (all p>0.05). Conclusions. NC is associated with MS by different definitions in Chinese subjects over 50 years old. It may be a useful tool to identify MS in a community population.
Parallel Excitatory and Inhibitory Neural Circuit Pathways Underlie Reward‐Based Phasic Neural Responses
Authors: Zhou Huanyuan , Wong-Lin KongFatt , Wang Da-Hui
Published: April 2018

Phasic activity of dopaminergic (DA) neurons in the ventral tegmental area or substantia nigra compacta (VTA/SNc) has been suggested to encode reward‐prediction error signal for reinforcement learning. Recent studies have shown that the lateral habenula (LHb) neurons exhibit a similar response, but for nonrewarding or punishment signals. Hence, the transient signaling role of LHb neurons is opposite that of DA neurons and also that of several other brain nuclei such as the border region of the globus pallidus internal segment (GPb) and the rostral medial tegmentum (RMTg). Previous theoretical models have investigated the neural circuit mechanism underlying reward‐based phasic activity of DA neurons, but the feasibility of a larger neural circuit model to account for the observed reward‐based phasic activity in other brain nuclei such as the LHb has yet to be shown. Here, we propose a large‐scale neural circuit model and show that parallel excitatory and inhibitory pathways underlie the learned neural responses across multiple brain regions. Specifically, the model can account for the phasic neural activity observed in the GPb, LHb, RMTg, and VTA/SNc. Based on sensitivity analysis, the model is found to be robust against changes in the overall neural connectivity strength. The model also predicts that striosomes play a key role in the phasic activity of VTA/SNc and LHb neurons by encoding previous and expected rewards. Taken together, our model identifies the important role of parallel neural circuit pathways in accounting for phasic activity across multiple brain areas during reward and punishment processing.
A Literature Survey on Wireless Power Transfer for Biomedical Devices
Authors: Shadid Reem , Noghanian Sima
Published: April 2018

This paper provides a review and survey of research on power transfer for biomedical applications based on inductive coupling. There is interest in wireless power transfer (WPT) for implantable and wearable biomedical devices, for example, heart pacemaker or implantable electrocardiogram (ECG) recorders. This paper concentrates on the applications based on near-field power transfer methods, summarizes the main design features in the recent literature, and provides some information about the system model and coil optimization.
Applications of Parameterized Nonlinear Ordinary Differential Equations and Dynamic Systems: An Example of the Taiwan Stock Index
Authors: Li Meng-Rong , Chiang-Lin Tsung-Jui , Lee Yong-Shiuan
Published: April 2018

Considering the phenomenon of the mean reversion and the different speeds of stock prices in the bull market and in the bear market, we propose four dynamic models each of which is represented by a parameterized ordinary differential equation in this study. Based on existing studies, the models are in the form of either the logistic growth or the law of Newton’s cooling. We solve the models by dynamic integration and apply them to the daily closing prices of the Taiwan stock index, Taiwan Stock Exchange Capitalization Weighted Stock Index. The empirical study shows that some of the models fit the prices well and the forecasting ability of the best model is acceptable even though the martingale forecasts the prices slightly better. To increase the forecasting ability and to broaden the scope of applications of the dynamic models, we will model the coefficients of the dynamic models in the future. Applying the models to the market without the price limit is also our future work.
An Equal‐Strain Analytical Solution for the Radial Consolidation of Unsaturated Soils by Vertical Drains considering Drain Resistance
Authors: Zhou Feng , Chen Zheng , Wang Xudong
Published: April 2018

Developing an analytical solution for the consolidation of unsaturated soils remains a challenging task due to the complexity of coupled governing equations for air and water phases. This paper presents an equal‐strain model for the radial consolidation of unsaturated soils by vertical drains, and the effect of drain resistance is also considered. Simplified governing equations are established, and an analytical solution to calculate the excess pore‐air and pore‐water pressures is derived by using the methods of matrix analysis and eigenfunction expansion. The average degrees of consolidation for air and water phases and the ground surface settlement are also given. The solutions of the equal‐strain model are verified by comparing the proposed free‐strain model with the equal‐strain model, and reasonably good agreement is obtained. Moreover, parametric studies regarding the drain resistance effect are graphically presented.
A Longitudinal Study of Functional Outcomes in Patients with Limb Salvage Surgery for Soft Tissue Sarcoma
Authors: Oh Eunsun , Seo Sung Wook , Han Kwang Joon
Published: April 2018

Background. Many studies have reported on the surgical outcomes of soft tissue sarcoma. However, there was no longitudinal cohort study. Because time is the most valuable factor for functional recovery, adjusting time value was the key for finding the causal relationship between other risk factors and postoperative function. Therefore, existing cross-sectional studies can neither fully explain the causal relationship between the risk factors and the functional score nor predict functional recovery. The aim of this study was to determine important predictive factors that affect postoperative functional outcomes and longitudinal changes in functional outcomes in patients who had undergone limb-sparing surgery (LSS) for soft tissue sarcoma (STS). Methods. Between January 2008 and December 2014, we retrospectively enrolled 150 patients who had undergone LSS for STS and had been assessed for postoperative functional outcomes with questionnaires. To evaluate functional outcomes, we used the Musculoskeletal Tumor Society (MSTS) score and Toronto Extremity Salvage Score (TESS). Multivariate generalized estimating equation (GEE) analysis was used to identify the predictive factors, including size, stage, and anatomic location of tumor, bone resection, flap reconstruction, age, and time after surgery. Each continuous variable such as age and time after surgery was explored for statistically significant cutoff points using the Wilcoxon rank sum test. Results. Functional scores significantly improved until the second year after surgery and plateaued for the rest of the 5-year period. Age p<0.0001, bone resection p=0.0004, and time after surgery p<0.0001 were identified as significant predictive factors. The functional score was significantly higher in patients younger than 47 years old. Conclusions. Functional outcomes can improve until the second year after surgery. Patients who were older than 47 and underwent bone resection may have poor final functional outcomes.
Study on Attenuation Properties of Surface Wave of AE Simulation Source Based on OPCM Sensor Element
Authors: Wang Ziping , Xue Xian , Li Xingjia , Jiang Zhengxuan , Reddy Karthik
Published: April 2018

It is of great significance to grasp the ultrasonic attenuation characteristics of materials for the nondestructive testing of materials. The dynamic properties of a piezoelectric composite material (OPCM) with self-developed transverse anisotropy have been analyzed using the experiment in this work. The OPCM sensor is attached to the surface of the iron plate and concrete structures to sense the surface waves generated by acoustic emission (AE). The experiment results show that OPCM sensor elements have unique advantages compared to piezoelectric ceramic materials (PZT). Further, by comparing the signals of isotropic and anisotropic materials, the attenuation characteristics of surface waves propagating in different materials are studied, and a new method for measuring the attenuation coefficient of surface waves is demonstrated.
Specific Mechanical Energy and Thermal Degradation of Poly(lactic acid) and Poly(caprolactone)/Date Pits Composites
Authors: Mohamed A. A. , Hussain S. , Alamri M. S. , Ibraheem M. A. , Abdo Qasem Akram A.
Published: April 2018

The compatibility of date pits (DP) with polylactic acid (PLA) or polycaprolactone (PCL) is investigated. Composites were prepared by compounding PLA or PCL with date pits at 10, 20, 30, and 40% wt/wt and extruded. Wheat vital gluten (VG) was also used as a filler and in combination with DP. The specific mechanical energy (SME) was calculated and the composites thermal properties were tested using DSC (peak temperature, enthalpic relaxation, and glass transition) and TGA (degradation temperature and mechanism and degradation kinetics). Because DP is hard filler, the SME of PCL-DP composites increased as the amount of filler increased. At 40% fill, the SME decreased due to the lubricating effect of oil found naturally in DP. As illustrated by lower SME, PLA composites exhibited softer texture because PLA is harder than DP. The DSC melting peak temperature of both polymers has increased at higher DP; however, PLA exhibited enthalpic relation between 66 and 68°C. The TGA profile of the composites displayed two distinct peaks versus one peak for the pure polymer. The degradation kinetics showed multistep process for the composites and one-step process for the pure polymer. The utilization of date pits as a hard filler in developing biodegradable plastics is good for the environment and a value added for the date industry.
The Role of Saikosaponins in Therapeutic Strategies for Age‐Related Diseases
Authors: Kim Byeong Mo
Published: April 2018

As life expectancy increases, elderly populations tend to spend an increasing number of years in poor health, with chronic age‐related diseases and disability. Therefore, the development of therapeutic strategies to treat or prevent multiple pathophysiological conditions in the elderly may improve health‐adjusted life expectancy and alleviate the potential economic and social burdens arising from age‐related diseases. Bioactive natural products might represent promising new drug candidates for the treatment of many chronic age‐related diseases, including cancer, Alzheimer’s disease, cardiovascular disease, obesity, and liver disease. Here, we discuss a therapeutic option using saikosaponins, which are triterpene saponins isolated from Bupleurum, against a variety of age‐related diseases. Understanding the underlying mechanisms of natural products like saikosaponins in the treatment of age‐related diseases may help in the development of diverse natural product‐derived compounds that may be effective against a number of chronic health problems.
Complex Scaling Approach for Stability Analysis and Stabilization of Multiple Time-Delayed Systems
Authors: Zhou Jun , Gao Ketian , Lu Xinbiao
Published: April 2018

Based on complex scaling, the paper copes with stability analysis and stabilization of linear time-invariant continuous-time systems with multiple time delays in state, control input, and measured output, under state and/or output feedback. More specifically, the paper establishes stability criteria for exponential/asymptotical stability with Hurwitz complex scaling being applied to the related characteristic polynomials. The stability conditions are necessary and sufficient, delay-dependent, and independent of feedback structures and open-loop poles distribution. The criteria can be implemented graphically with locus plotting or numerically without it; moreover, no prior frequency sweeping is involved, and the contour and locus encirclement orientations can be self-defined. Exploiting the complex scaling approach and embracing its technical merits, it is considered to design static state feedback control for robustly stabilizing time-delayed systems. A small-gain interpretation for the suggested stabilization is also elaborated. Examples are included to illustrate the main results.
Seismic Performance of CAP1400 Nuclear Power Station considering Foundation Uplift
Authors: Peng Ling-Yun , Kang Ying-Jie , Tang Zhen-Yun , Chen Hua-Ting
Published: April 2018

Under earthquake action, the reinforced concrete structure at the edge of the CAP1400 nuclear power plant foundation slab will be uplifted. In order to determine the seismic performance of this structure, a 1 : 12 scale shaking table test model was fabricated using gypsum as simulated concrete in order to meet scaled design requirements. By testing this model, the seismic response of the structure with consideration of the foundation uplift was obtained. Numerical analyses of the test model and the prototype structure were conducted to gain a better understanding of the structural seismic performance. When subjected to earthquakes, the foundation slab of the nuclear power plant experiences a slight degree of uplift but remains in the elastic stage due to the weight of the structure above, which provides an antioverturning moment. The numerical simulation is in general agreement with the test results, suggesting numerical simulations could be accurately employed in place of physical tests. The superstructure displacement response was found not to affect the safety of adjacent structures, and the seismic performance of the structure was shown to meet the relevant design requirements, demonstrating that this approach to modelling can serve as a design basis for the CAP1400 nuclear power demonstration project.
Stability Analysis of Partially Submerged Landslide with the Consideration of the Relationship between Porewater Pressure and Seepage Force
Authors: Wang Yang , Yu Le , Yin Tianci , Yu Lanbing , Huo Zhitao
Published: April 2018

For partially submerged landslides, hydrostatic and hydrodynamic pressures, related to water level fluctuation and rainfall, are usually expressed in the form of porewater pressure, seepage force, and buoyancy. There are some connections among them, but it is very easy to confuse one force with another. This paper presents a modified mathematical expression for stability analysis of partially submerged landslide and builds the relationship between porewater pressures and buoyancy acting on the underwater zone of partially submerged landslide and the relationship among porewater pressures, seepage force, and buoyancy acting on partially submerged zone. The porewater pressures acting on the underwater slice are calculated using hydrostatic forces, and the porewater pressures acting on the partially submerged slice are estimated by an approximation of equipotential lines and flow lines under the steady state seepage condition. The resultant of the porewater pressures acting on the underwater slice equals the buoyancy, and that acting on the partially submerged slice is equivalent to the vector sum of seepage force and the buoyancy. The result shows there are two equivalent approaches for considering the effect of water on landslide stability in the limit equilibrium method. One is based on total unit weight and porewater pressures, and the other is in terms of the buoyant weight and the seepage force. The study provides a modified model for simplifying the complex boundary porewater pressures in limit equilibrium analysis for the stability of the partially submerged landslide.
Shortening of the Pittsburgh Sleep Quality Index Survey Using Factor Analysis
Authors: Famodu Oluremi A. , Barr Makenzie L. , Holásková Ida , Zhou Wenjun , Morrell Jesse S. , Colby Sarah E. , Olfert Melissa D.
Published: April 2018

Objective/Introduction. Lengthy surveys have the potential to burden users and can lead to inaccuracies. Conducting analyses to shorten existing validated surveys is beneficial. The objective, therefore, was to shorten the Pittsburgh Quality Sleep Index (PSQI) for young adults.Methods. PSQI data from 1246 college students were used. An exploratory factor analysis (FA) was utilized to shorten survey after dropping select items. Nonparametric correlation analysis (Spearman’s rho) was conducted between the global sleep scores of the shortened and original surveys. Agreements tests (Kappa and McNemar’s test) measured the agreement of the surveys and sensitivity and specificity were evaluated.Results. Six factors were examined using maximum likelihood factoring method, applying squared multiple correlations with Promax rotation to allow for correlated variables. FA with six factors explained 100% of shared variance based on eigenvalues and accounted for 61% of variability based on variables. The FA resulted in 13 selected questions (“shortPSQI”), corresponding to 5 of the 7 components of the original survey. High correlation was found between the global scores of the original survey and the “shortPSQI” (rho = 0.94,p<0.001). When the global score was converted to the categorical variable of good or poor sleepers, the agreement test indicated strong agreement (Kappa 0.83, 95% CI 0.79–0.86,p<0.0001).Conclusion. The validated, 19-item PSQI survey was shortened to 13 items. Tests of correlation and agreement indicate the “shortPSQI” may be an acceptable alternative to the original survey for young adults.Clinical Trial Registration. Data for this study was taken from the Get Fruved study, registered on October 21, 2016, on clinicaltrials.gov (NCT02941497).
Serum Exosomal Long Noncoding RNAs ENSG00000258332.1 and LINC00635 for the Diagnosis and Prognosis of Hepatocellular Carcinoma
Authors: Xu Hong , Chen Yueming , Dong Xueyan , Wang Xianjun
Published: April 2018

Background: Increasing studies suggest that long noncoding RNAs (lncRNAs) are involved in carcinogenesis of human cancers and might be used as diagnostic biomarkers for cancers.

Methods: A total of 301 participants were recruited in the first part of the study, including a hepatocellular carcinoma (HCC) group (n = 60), liver cirrhosis (LC) group (n = 85), chronic hepatitis B (CHB) group (n = 96), and healthy subjects (n = 60). In the second part, we collected 55 HCC patients, 60 CHB patients, and 60 healthy subjects as an independent cohort to validate the ability of the experiential lncRNAs for identifying HCC from CHB. A commercial kit was used to isolate serum exosomes and total RNA. The relative levels of lnRNAs and GAPDH mRNA were measured with TaqMan PCR.

Results: The results showed that the levels of ENSG00000258332.1 and LINC00635 in the HCC group were significantly higher than those in the other groups (all P < 0.05). A high ENSG00000258332.1 level in HCC was associated with portal vein tumor emboli, lymph node metastasis, TNM stage, and overall survival (OS; all P < 0.05), and a high LINC00635 level was related to lymph node metastasis, TNM stage, and OS (all P < 0.05). ENSG00000258332.1 discriminated HCC from CHB, gaining an area under the ROC curve (AUC) of 0.719 (cutoff value of 1.345); LINC00635 gained an AUC of 0.750 (cutoff value of 1.690). Furthermore, the AUC for the combination of the 2 lncRNAs and serum AFP (cutoff value of 20 μg/L) was 0.894. The abilities of the 2 lncRNAs for identifying HCC from CHB were validated by an independent cohort.

Conclusions: The results suggested that the combination of serum exosomal ENSG00000258332.1, LINC00635, and AFP may be a valuable assay in diagnosis and prognosis of HCC.

Impact: Our data will shed light on exosomal lncRNAs as biomarkers for HCC. Cancer Epidemiol Biomarkers Prev; 27(6); 710–6. ©2018 AACR.
Reparameterization of PAM50 Expression Identifies Novel Breast Tumor Dimensions and Leads to Discovery of a Genome-Wide Significant Breast Cancer Locus at 12q15
Authors: Madsen Michael J. , Knight Stacey , Sweeney Carol , Factor Rachel , Salama Mohamed , Stijleman Inge J. , Rajamanickam Venkatesh , Welm Bryan E. , Arunachalam Sasi , Jones Brandt , Rachamadugu Rakesh , Rowe Kerry , Cessna Melissa H. , Thomas Alun , Kushi Lawrence H. , Caan Bette J. , Bernard Philip S. , Camp Nicola J.
Published: April 2018

Background: Breast tumor subtyping has failed to provide impact in susceptibility genetics. The PAM50 assay categorizes breast tumors into: Luminal A, Luminal B, HER2-enriched and Basal-like. However, tumors are often more complex than simple categorization can describe. The identification of heritable tumor characteristics has potential to decrease heterogeneity and increase power for gene finding.

Methods: We used 911 sporadic breast tumors with PAM50 expression data to derive tumor dimensions using principal components (PC). Dimensions in 238 tumors from high-risk pedigrees were compared with the sporadic tumors. Proof-of-concept gene mapping, informed by tumor dimension, was performed using Shared Genomic Segment (SGS) analysis.

Results: Five dimensions (PC1-5) explained the majority of the PAM50 expression variance: three captured intrinsic subtype, two were novel (PC3, PC5). All five replicated in 745 TCGA tumors. Both novel dimensions were significantly enriched in the high-risk pedigrees (intrinsic subtypes were not). SGS gene-mapping in a pedigree identified a 0.5 Mb genome-wide significant region at 12q15. This region segregated through 32 meioses to 8 breast cancer cases with extreme PC3 tumors (P = 2.6 × 10−8).

Conclusions: PC analysis of PAM50 gene expression revealed multiple independent, quantitative measures of tumor diversity. These tumor dimensions show evidence for heritability and potential as powerful traits for gene mapping.

Impact: Our study suggests a new approach to describe tumor expression diversity, provides new avenues for germline studies, and proposes a new breast cancer locus. Similar reparameterization of expression patterns may inform other studies attempting to model the effects of tumor heterogeneity. Cancer Epidemiol Biomarkers Prev; 27(6); 644–52. ©2018 AACR.
Sequential ALK Inhibitors Can Select for Lorlatinib-Resistant Compound ALK Mutations in ALK-Positive Lung Cancer
Authors: Yoda Satoshi , Lin Jessica J. , Lawrence Michael S. , Burke Benjamin J. , Friboulet Luc , Langenbucher Adam , Dardaei Leila , Prutisto-Chang Kylie , Dagogo-Jack Ibiayi , Timofeevski Sergei , Hubbeling Harper , Gainor Justin F. , Ferris Lorin A. , Riley Amanda K. , Kattermann Krystina E. , Timonina Daria , Heist Rebecca S. , Iafrate A. John , Benes Cyril H. , Lennerz Jochen K. , Mino-Kenudson Mari , Engelman Jeffrey A. , Johnson Ted W. , Hata Aaron N. , Shaw Alice T.
Published: April 2018

The cornerstone of treatment for advanced ALK-positive lung cancer is sequential therapy with increasingly potent and selective ALK inhibitors. The third-generation ALK inhibitor lorlatinib has demonstrated clinical activity in patients who failed previous ALK inhibitors. To define the spectrum of ALK mutations that confer lorlatinib resistance, we performed accelerated mutagenesis screening of Ba/F3 cells expressing EML4–ALK. Under comparable conditions, N-ethyl-N-nitrosourea (ENU) mutagenesis generated numerous crizotinib-resistant but no lorlatinib-resistant clones harboring single ALK mutations. In similar screens with EML4–ALK containing single ALK resistance mutations, numerous lorlatinib-resistant clones emerged harboring compound ALK mutations. To determine the clinical relevance of these mutations, we analyzed repeat biopsies from lorlatinib-resistant patients. Seven of 20 samples (35%) harbored compound ALK mutations, including two identified in the ENU screen. Whole-exome sequencing in three cases confirmed the stepwise accumulation of ALK mutations during sequential treatment. These results suggest that sequential ALK inhibitors can foster the emergence of compound ALK mutations, identification of which is critical to informing drug design and developing effective therapeutic strategies.

Significance: Treatment with sequential first-, second-, and third-generation ALK inhibitors can select for compound ALK mutations that confer high-level resistance to ALK-targeted therapies. A more efficacious long-term strategy may be up-front treatment with a third-generation ALK inhibitor to prevent the emergence of on-target resistance. Cancer Discov; 8(6); 714–29. ©2018 AACR.

This article is highlighted in the In This Issue feature, p. 663
Gibt es Fortschritte in der Routinebehandlung von Patienten mit fortgeschrittenem Pankreaskarzinom?
Authors: Stahl Michael
Published: April 2018

Background: Randomized clinical trials do not reflect the day-to-day reality of patient care; hence, the treatment of patients with advanced pancreatic cancer in oncology group practices was evaluated. Patients and Methods: All consecutive patients with advanced pancreatic cancer who were treated between 01/2012 and 12/2015 in 4 oncology group practices were analyzed retrospectively using SPSS software. Results: 324 patients with a median age of 70 years (range 32-94 years) were analyzed. The majority were male (56%) and had distant metastases (74%). Chemotherapy was the major modality of treatment (86%) with a median overall survival (OS) of 33.3 weeks (range 1.7-245.4 weeks). Chemotherapy significantly (p < 0.001) improved OS in comparison to best supportive care only (37.6 vs. 13.9 weeks). Patients with locally advanced disease had a better prognosis compared to patients with metastases (median OS 49.6 vs. 30.4 weeks; p < 0.001). An age-adjusted Charlson comorbidity score of ≥ 9 was found to influence the OS significantly (p = 0.004). Conclusion: Chemotherapy remains the main modality of treatment for patients with advanced pancreatic cancer with an OS comparable to prospective randomized trials. The OS of this patient cohort has remained the same over the last 20 years despite advances in treatment modalities.
Rituximab in Refractory Chronic Spontaneous Urticaria: An Encouraging Therapeutic Approach
Authors: Combalia Andrea , Losno Ricardo A. , Prieto-González Sergio , Mascaró J. Manuel
Published: April 2018

Background: Chronic spontaneous urticaria (CSU) is a frequent mast cell-driven disease that affects approximately 0.5–1% of the population. Antihistamines are currently the drugs of choice in patients with CSU. Omalizumab has been shown to be very effective in CSU and has been recently approved as second-line therapy. However, although its introduction has markedly improved the therapeutic possibilities for CSU, there is still a hard core of patients who do not respond and require effective treatment. Methods: We report the case of a patient who achieved an 8-month remission of refractory CSU following the use of rituximab, and perform a review of the literature regarding the use of rituximab in CSU. Results: There was a remarkable improvement in her CSU after the administration of rituximab maintained over time. Conclusion: Rituximab is a chimeric murine/human monoclonal antibody directed against CD20, which depletes memory B-lymphocytes that are necessary for autoantibody production. The abrogation of the autoantibody production is the proposed mechanism by which it may alleviate the symptoms of CSU.
In vitro Antichlamydial Activity of 1,2,3,5-Tetrasubstituted Pyrrole Derivatives
Authors: Ji Hongzhang , Wu Changyue , Ni Min , Feng Nannan , Wang Chan , Zhao Yu , Liu Lingyan , Yang Shengju , Bao Xiaofeng
Published: April 2018

Background: Chlamydia is a group of bacterial pathogens distributed worldwide that can lead to serious reproductive and other health problems. The rise of antibiotic-resistant pathogens promotes the development of novel antichlamydial agents. The aim of this study is to assess in vitro antichlamydial activity of our previously synthesized 1,2,3,5- tetrasubstituted pyrroles. Methods: The derivatives were screened for their antichlamydial activity against three Chlamydia strains by calculating IC50 values using concentration-response inhibition data between 1 and 32 μM. The action of the compounds on Chlamydia elementary body (EB) infectivity and the impact of the chemicals’ administration time on their antichlamydial effect were evaluated to reveal the inhibitory mechanism. Results: Some of the compounds moderately inhibited the Chlamydia strains. Compound 10 exhibited the strongest inhibitory activity, with IC50 values from 4.34 to 5.83 μM. These pyrrole derivatives inhibited Chlamydia infection by reducing EB infectivity during the early stage and disturbing Chlamydia growth by targeting the early-to-middle stage prior to 12 h of the chlamydial life cycle. Conclusion: Our findings highlight the potential of 1,2,3,5-tetrasubstituted pyrrole derivatives as promising lead molecules for the development of antichlamydial agents.
Lymphatic Vasculature Requires Estrogen Receptor-α Signaling to Protect From Lymphedema
Authors: Morfoisse Florent , Tatin Florence , Chaput Benoit , Therville Nicole , Vaysse Charlotte , Métivier Raphael , Malloizel-Delaunay Julie , Pujol Francoise , Godet Anne-Claire , De Toni Fabienne , Boudou Frederic , Grenier Katia , Dubuc David , Lacazette Eric , Prats Anne-Catherine , Guillermet-Guibert Julie , Lenfant Francoise , Garmy-Susini Barbara
Published: April 2018

Objective—

Estrogens exert beneficial effect on the blood vascular system. However, their role on the lymphatic system has been poorly investigated. We studied the protective effect of the 17β estradiol—the most potent endogenous estrogen—in lymphedema—a lymphatic dysfunction, which results in a massive fluid and fat accumulation in the limb.

Approach and Results—

Screening of DNA motifs able to mobilize ERs (estrogen receptors) and quantitative real-time polymerase chain reaction analysis revealed that estradiol promotes transcriptional activation of lymphangiogenesis-related gene expression including VEGF (vascular endothelial growth factor)-D, VEGFR (VEGF receptor)-3, lyve-1, and HASs (hyaluronan synthases). Using an original model of secondary lymphedema, we observed a protective effect of estradiol on lymphedema by reducing dermal backflow—a representative feature of the pathology. Blocking ERα by tamoxifen—the selective estrogen modulator—led to a remodeling of the lymphatic network associated with a strong lymphatic leakage. Moreover, the protection of lymphedema by estradiol treatment was abrogated by the endothelial deletion of the receptor ERα in Tie2-Cre; ERα
lox/lox
mice, which exhibit dilated lymphatic vessels. This remodeling correlated with a decrease in lymphangiogenic gene expression. In vitro, blocking ERα by tamoxifen in lymphatic endothelial cells decreased cell–cell junctions, inhibited migration and sprouting, and resulted in an inhibition of Erk but not of Akt phosphorylation.

Conclusions—

Estradiol protection from developing lymphedema is mediated by an activation of its receptor ERα and is antagonized by tamoxifen. These findings reveal a new facet of the estrogen influence in the management of the lymphatic system and provide more evidence that secondary lymphedema is worsened by hormone therapy.
Cardiovascular Genetic Risk Testing for Targeting Statin Therapy in the Primary Prevention of Atherosclerotic Cardiovascular Disease
Authors: Jarmul Jamie , Pletcher Mark J. , Hassmiller Lich Kristen , Wheeler Stephanie B. , Weinberger Morris , Avery Christy L. , Jonas Daniel E. , Earnshaw Stephanie , Pignone Michael
Published: April 2018

Background:

It is unclear whether testing for novel risk factors, such as a cardiovascular genetic risk score (cGRS), improves clinical decision making or health outcomes when used for targeting statin initiation in the primary prevention of atherosclerotic cardiovascular disease (ASCVD). Our objective was to estimate the cost-effectiveness of cGRS testing to inform clinical decision making about statin initiation in individuals with low-to-intermediate (2.5%–7.5%) 10-year predicted risk of ASCVD.

Methods and Results:

We evaluated the cost-effectiveness of testing for a 27-single-nucleotide polymorphism cGRS comparing 4 test/treat strategies: treat all, treat none, test/treat if cGRS is high, and test/treat if cGRS is intermediate or high. We tested a set of clinical scenarios of men and women, aged 45 to 65 years, with 10-year ASCVD risks between 2.5% and 7.5%. Our primary outcome measure was cost per quality-adjusted life-year gained. Under base case assumptions for statin disutility and cost, the preferred strategy is to treat all patients with ASCVD risk >2.5% without cGRS testing. For certain clinical scenarios, such as a 57-year-old man with a 10-year ASCVD risk of 7.5%, cGRS testing can be cost-effective under a limited set of assumptions; for example, when statins cost $15 per month and statin disutility is 0.013 (ie, willing to trade 3 months of life in perfect health to avoid 20 years of statin therapy), the preferred strategy (using a willingness-to-pay threshold of $50 000 per quality-adjusted life-year gained) is to test and treat if cGRS is intermediate or high. Overall, the results were not sensitive to assumptions about statin efficacy and harms.

Conclusions:

Testing for a 27-single-nucleotide polymorphism cGRS is generally not a cost-effective approach for targeting statin therapy in the primary prevention of ASCVD for low- to intermediate-risk patients.
Regulation of Blood Pressure by Targeting Ca
V
1.2-Galectin-1 Protein Interaction
Authors: Hu Zhenyu , Li Guang , Wang Jiong-Wei , Chong Suet Yen , Yu Dejie , Wang Xiaoyuan , Soon Jia Lin , Liang Mui Cheng , Wong Yuk Peng , Huang Na , Colecraft Henry M. , Liao Ping , Soong Tuck Wah
Published: April 2018

Background:

L-type Ca
V
1.2 channels play crucial roles in the regulation of blood pressure. Galectin-1 (Gal-1) has been reported to bind to the I-II loop of Ca
V
1.2 channels to reduce their current density. However, the mechanistic understanding for the downregulation of Ca
V
1.2 channels by Gal-1 and whether Gal-1 plays a direct role in blood pressure regulation remain unclear.

Methods:

In vitro experiments involving coimmunoprecipitation, Western blot, patch-clamp recordings, immunohistochemistry, and pressure myography were used to evaluate the molecular mechanisms by which Gal-1 downregulates Ca
V
1.2 channel in transfected, human embryonic kidney 293 cells, smooth muscle cells, arteries from
Lgasl1
−/−
mice, rat, and human patients. In vivo experiments involving the delivery of Tat-e9c peptide and AAV5-Gal-1 into rats were performed to investigate the effect of targeting Ca
V
1.2-Gal-1 interaction on blood pressure monitored by tail-cuff or telemetry methods.

Results:

Our study reveals that Gal-1 is a key regulator for proteasomal degradation of Ca
V
1.2 channels. Gal-1 competed allosterically with the Ca
V
β subunit for binding to the I-II loop of the Ca
V
1.2 channel. This competitive disruption of Ca
V
β binding led to Ca
V
1.2 degradation by exposing the channels to polyubiquitination. It is notable that we demonstrated that the inverse relationship of reduced Gal-1 and increased Ca
V
1.2 protein levels in arteries was associated with hypertension in hypertensive rats and patients, and Gal-1 deficiency induces higher blood pressure in mice because of the upregulated Ca
V
1.2 protein level in arteries. To directly regulate blood pressure by targeting the Ca
V
1.2-Gal-1 interaction, we administered Tat-e9c, a peptide that competed for binding of Gal-1 by a miniosmotic pump, and this specific disruption of Ca
V
1.2-Gal-1 coupling increased smooth muscle Ca
V
1.2 currents, induced larger arterial contraction, and caused hypertension in rats. In contrasting experiments, overexpression of Gal-1 in smooth muscle by a single bolus of AAV5-Gal-1 significantly reduced blood pressure in spontaneously hypertensive rats.

Conclusions:

We have defined molecularly that Gal-1 promotes Ca
V
1.2 degradation by replacing Ca
V
β and thereby exposing specific lysines for polyubiquitination and by masking I-II loop endoplasmic reticulum export signals. This mechanistic understanding provided the basis for targeting Ca
V
1.2-Gal-1 interaction to demonstrate clearly the modulatory role that Gal-1 plays in regulating blood pressure, and offering a potential approach for therapeutic management of hypertension.
Plasma Concentrations and Dietary Intakes of Choline and Betaine in Association With Atrial Fibrillation Risk: Results From 3 Prospective Cohorts With Different Health Profiles
Authors: Zuo Hui , Svingen Gard F. T. , Tell Grethe S. , Ueland Per M. , Vollset Stein E. , Pedersen Eva R. , Ulvik Arve , Meyer Klaus , Nordrehaug Jan E. , Nilsen Dennis W. T. , Bønaa Kaare H. , Nygård Ottar
Published: April 2018

Background

Although choline metabolism has been associated with atherosclerotic heart disease, less research attention has been paid to the associations of choline and its oxidative metabolite betaine with cardiac arrhythmias.

Methods and Results

We evaluated associations of plasma concentrations and dietary intakes of choline and betaine with long‐term atrial fibrillation (
AF
) risk in a community‐based cohort, HUSK ([the Hordaland Health Study] n=6949), and validated the findings in 2 patient cohorts: the Western Norway Coronary Angiography Cohort (n=4164) and the NORVIT (Norwegian B‐Vitamin) Trial (n=3733). Information on
AF
was obtained from the
CVDNOR
(Cardiovascular Disease in Norway) project. In
HUSK
,
WECAC
(Western Norway Coronary Angiography Cohort), and
NORVIT
, 552, 411, and 663
AF
cases were identified during a median follow‐up time of 10.9, 7.3, and, 8.7 years, respectively. Plasma concentrations of choline and betaine were significantly positively associated with later
AF
risk after multivariable adjustments in
HUSK
. Such associations were independently replicated in the 2 external prospective patient cohorts. The pooled hazard ratio was 1.13 (95% confidence interval 1.08‐1.19,
P
<0.001) and 1.16 (95% confidence interval 1.10‐1.22,
P
<0.001) per
SD
increment for log‐transformed choline and betaine, respectively. Moreover, dietary intake of choline was marginally associated with
AF
risk (pooled hazard ratio 1.29, 95% confidence interval 1.01‐1.66, fifth versus first quintile), whereas no significant association was observed between dietary betaine and
AF
risk.

Conclusions

Our findings indicate that plasma concentrations as well as dietary intake of choline, but not betaine, are associated with subsequent risk of
AF
, suggesting a potential role of choline metabolism in the pathogenesis of
AF
.

Clinical Trial Registration

URL:
https://www.clinicaltrials.gov.Unique
identifier:
NCT
00671346.
Graph theory approaches to functional network organization in brain disorders: A critique for a brave new small-world
Authors: Hallquist Michael N. , Hillary Frank G.
Published: April 2018

Over the past two decades, resting-state functional connectivity (RSFC) methods have provided new insights into the network organization of the human brain. Studies of brain disorders such as Alzheimer’s disease or depression have adapted tools from graph theory to characterize differences between healthy and patient populations. Here, we conducted a review of clinical network neuroscience, summarizing methodological details from 106 RSFC studies. Although this approach is prevalent and promising, our review identified four challenges. First, the composition of networks varied remarkably in terms of region parcellation and edge definition, which are fundamental to graph analyses. Second, many studies equated the number of connections across graphs, but this is conceptually problematic in clinical populations and may induce spurious group differences. Third, few graph metrics were reported in common, precluding meta-analyses. Fourth, some studies tested hypotheses at one level of the graph without a clear neurobiological rationale or considering how findings at one level (e.g., global topology) are contextualized by another (e.g., modular structure). Based on these themes, we conducted network simulations to demonstrate the impact of specific methodological decisions on case-control comparisons. Finally, we offer suggestions for promoting convergence across clinical studies in order to facilitate progress in this important field.
Subject specificity of the correlation between large-scale structural and functional connectivity
Authors: Zimmermann J. , Griffiths J. , Schirner M. , Ritter P. , McIntosh A. R.
Published: April 2018

Structural connectivity (SC), the physical pathways connecting regions in the brain, and functional connectivity (FC), the temporal coactivations, are known to be tightly linked. However, the nature of this relationship is still not understood. In the present study, we examined this relation more closely in six separate human neuroimaging datasets with different acquisition and preprocessing methods. We show that using simple linear associations, the relation between an individual’s SC and FC is not subject specific for five of the datasets. Subject specificity of SC-FC fit is achieved only for one of the six datasets, the multimodal Glasser Human Connectome Project (HCP) parcellated dataset. We show that subject specificity of SC-FC correspondence is limited across datasets due to relatively small variability between subjects in SC compared with the larger variability in FC.
Christus unicus ille episcopus universalis
Authors: de Boer Erik A.
Published: April 2018

In their critique of the hierarchy in the Roman Catholic Church most reformers in the sixteenth century did not argue for retaining the office of bishop. In the English Reformation, led by the king, the bishopric was reformed, and in Hungary, too, the office of bishop survived. Did reformers like John Calvin fundamentally reject this office, or did they primarily attack its abuse? Investigation of the early work of Calvin shows a focus on the meaning of the biblical term ‘overseer’ and on preaching as the primary function of the episcopacy. While the title of bishop is reserved for the one head of the church, the office of the preacher is brought to a higher level. As moderator of the Company of Pastors in Geneva, Calvin would have a standing in the city comparable to the ousted bishop.
A revision of Welfia (Arecaceae)
Authors: HENDERSON ANDREW , VILLALBA ISABEL
Published: April 2018

A taxonomic revision of the neotropical palm genus Welfia based on morphological data and morphometric methods was carried out. One hundred and five herbarium specimens were scored for one qualitative variable and 19 quantitative variables. Based on the qualitative variable, fruit shape, two species are recognized. One (W. regia) is widely distributed in Central America and northwestern South America from Nicaragua to Colombia and Ecuador; the second, described here (W. alfredii) is restricted to a small area of central Peru. Nomenclature, descriptions, and distribution maps are provided for each species, and images of the type specimen of the new species are also provided.
Liparis wenshanensis, a new orchid species from China: Evidence from morphological and molecular analyses
Authors: SU YONG-YU , HUANG YI-LANG , CHEN LI-JUN , ZHANG PEI-WEN , Liu Zhong-Jian , ZHANG GUO-QIANG
Published: April 2018

A new orchid species, Liparis wenshanensis, discovered in Yunnan, China is described and illustrated in this study based on morphological and molecular analyses. A detailed comparison between the newly discovered orchid and other members of the genus, Liparis, was conducted. The new plant is characterized by the combination of the following features: a long rachis with 45 to 55 flowers; white sepals, petals and column; a greenish lip with a purplish center; strongly recurved and revolute dorsal sepals and petals; strongly recurved, oblong lateral sepals; a cordate lip that is strongly deflexed below the middle, with a two-lobed apex and a two-lobed callus at the base; an arcuate column with a lamella extending along the center almost to the stigma, and with a pair of broad wings toward the apex. These features distinguish the new orchid from all other known species of Liparis. We proceeded to a phylogenetic analysis to ascertain the systematic position of this enigmatic species. Molecular analyses based on nuclear ribosomal ITS and plastid matK DNA sequence data supports the recognition of L. wenshanensis as a distinct species.
A new species of Pestalotiopsis from leaf spots of Licuala grandis from Hainan, China
Authors: GENG KUN , ZHANG BIN , SONG YU , HYDE KEVIN D. , KANG JI-CHUAN , WANG YONG
Published: April 2018

A new species, Pestalotiopsis licualacola, was isolated from grey leafspots of Licuala grandis (ruffled fan palm). It is morphologically distinct in having relatively small, greyish brown conidia (16–20 × 3–5 μm), and 1–3 short apical appendages without knobs. Phylogenetic analysis based on combination of ITS, β-tubulin and tef1 gene sequence data clearly distinguishes P. licualacola from other species in this genus, with ex-type sequence data in GenBank. Based on morphology and molecular phylogeny we describe it as a new species.