bluuebunny/crossref_metadata_2025 huggingface dataset:
Immune Challenge Alters Reactivity of Hippocampal Noradrenergic System in Prenatally Stressed Aged Mice
Authors: Grigoryan Gayane , Lonnemann Niklas , Korte Martin
Published: January 2019

Prenatal stress (PS) has long-term sequelae for the morphological and functional status of the central nervous system of the progeny. A PS-induced proinflammatory status of the organism may result in an impairment of both hippocampal synaptic plasticity and hippocampus-dependent memory formation in adults. We addressed here the question of how PS-induced alterations in the immune response in young and old mice may contribute to changes in hippocampal function in aging. Immune stimulation (viaLPS injection) significantly affected the ability of the hippocampal CA3-CA1 synapse of PS mice to undergo long-term potentiation (LTP). Elevated corticosterone level in the blood of aged PS mice that is known to influence LTP magnitude indicates a chronic activation of the HPA axis due to thein uterostress exposure. We investigated the contribution of adrenergic receptors to the modulation of hippocampal synaptic plasticity of aged mice and found that impaired LTP in the PS-LPS group was indeed rescued by application of isoproterenol (a nonspecific noradrenergic agonist). Further exploration of the mechanisms of the observed phenomena will add to our understanding of the interaction between PS and proinflammatory immune activation and its contribution to the functional and structural integrity of the aging brain.
A Proposal of a Personalized Surveillance Strategy for Gastric Cancer: A Retrospective Analysis of 9191 Patients
Authors: Pan Si-wei , Wang Peng-liang , Huang Han-wei , Luo Lei , Wang Xin , Wang Tao , Liu Fu-nan , Xu Hui-mian
Published: January 2019

Background. In gastric cancer, various surveillance strategies are suggested in international guidelines. The current study is intended to evaluate the current strategies and provide more personalized proposals for personalized cancer medicine. Materials and Methods. In the aggregate, 9191 patients with gastric cancer after gastrectomy from 1998 to 2009 were selected from the Surveillance, Epidemiology, and End Results database. Disease-specific survival was analyzed by Kaplan-Meier method and the log-rank test. Cox proportional hazards regression analyses were used to confirm the independent prognostic factors. As well, hazard ratio (HR) curves were used to compare the risk of death over time. Conditional survival (CS) was applied to dynamically assess the prognosis after each follow-up. Results. Comparisons from HR curves on different stages showed that earlier stages had distinctly lower HR than advanced stages. The curve of stage IIA was flat and more likely the same as that of stage I while that of stage IIB is like that of stage III with an obvious peak. After estimating CS at intervals of three months, six months, and 12 months in different periods, stages I and IIA had high levels of CS all along, while there were visible differences among CS levels of stages IIB and III. Conclusions. The frequency of follow-up for early stages, like stages I and IIA, could be every six months or longer in the first three years and annually thereafter. And those with unfavorable conditions, such as stages IIB and III, could be followed up much more frequently and sufficiently than usual.
Thickness and Ratio of Noncompacted and Compacted Layers of the Left Ventricular Myocardium Evaluated in 56 Normal Fetuses by Two-Dimensional Echocardiography
Authors: Sun Lei , Zhao Enfa , Wei Yajuan , Kang Chunmiao , Liu Baomin
Published: January 2019

The thickness and ratio of noncompacted and compacted layers of the left ventricular (LV) myocardium in the normal fetus were investigated by fetal echocardiography. We aimed to investigate the compaction process of the LV myocardium during the normal gestation period and provide reference for echocardiographic diagnosis of a fetus with ventricular myocardium noncompaction. A total of 56 pregnant women in the gestational period of 23–30 weeks were included. Complete fetal echocardiography was performed with system ultrasonographic examination to exclude congenital heart malformation or extracardiac malformation. All 56 fetuses showed normal development. In the short-axis view of the fetal heart, the LV wall was divided into an upper and lower section at the level of the papillary muscle. Each section was then further divided into four segments, namely, anterior, posterior, lateral, and inferior wall. Thus, the LV wall was divided into eight segments. The thickness of the ventricular noncompacted and compacted layers and the ratio of the ventricular noncompacted to compacted layers of these segments at end-systole were measured and calculated. In echocardiography, the fetal LV myocardium is a two-layered structure: the endocardial noncompact myocardium (NC) with higher echo and the epicardium compact myocardium (C) with lower echo. The noncompacted layer is thinner than the compacted layer in the anterior wall, but thicker than the compacted layers in the posterior, lateral, and inferior wall. With respect to the upper and lower sections of the LV myocardium, the noncompacted layer in each segment of the upper section is thinner than that in each segment of the lower section, whereas the compacted layer of the upper section is thicker than that of the lower section. This study suggests that the densification of the fetal LV myocardium occurs gradually from base to apex and from the anterior to lateral, posterior, and inferior walls. This finding aids in further understanding the process of myocardial densification and provides a diagnostic reference for noncompaction of noncompaction cardiomyopathy (NCCM).
Curcumin Induces Neural Differentiation of Human Pluripotent Embryonal Carcinoma Cells through the Activation of Autophagy
Authors: Heebkaew Nudjanad , Rujanapun Narawadee , Kunhorm Phongsakorn , Jaroonwitchawan Thiranut , Chaicharoenaudomrung Nipha , Promjantuek Wilasinee , Noisa Parinya
Published: January 2019

Curcumin is a natural polyphenolic compound, isolated from Curcuma longa, and is an important ingredient of Asian foods. Curcumin has revealed its strong activities of anti-inflammatory, antioxidant, and anticancer. The efficient amount of curcumin could induce differentiation of stem cells and promoted the differentiation of glioma-initiating cells; however, the mechanisms underlying neural induction of curcumin have not yet been revealed. In this study, neural-inducing ability of curcumin was explored by using human pluripotent embryonal carcinoma cells, NTERA2 cells. The cells were induced toward neural lineage with curcumin and were compared with a standard neutralizing agent (retinoic acid). It was found that, after 14 days of the induction by curcumin, NTERA2 cells showed neuronal morphology and expressed neural-specific genes, includingNeuroD,TUJ1, andPAX6. Importantly, curcumin activated neurogenesis of NTERA2 cells via the activation of autophagy, since autophagy-related genes, such asLC3,LAMP1, andATG5, were upregulated along with the expression of neural genes. The inhibition of autophagy by chloroquine suppressed both autophagy and neural differentiation, highlighting the positive role of autophagy during neural differentiation. This autophagy-mediated neural differentiation of curcumin was found to be an ROS-dependent manner; curcumin induced ROS generation and suppressed antioxidant gene expression. Altogether, this study proposed the neural-inducing activity of curcumin via the regulation of autophagy within NTERA2 cells and underscored the health beneficial effects of curcumin for neurodegenerative disorders, such as Alzheimer’s disease and Parkinson’s disease.
The Role of Fiber in Energy Balance
Authors: Hervik Astrid Kolderup , Svihus Birger
Published: January 2019

Excessive energy intake is linked with obesity and subsequent diet-related health problems, and it is therefore a major nutritional challenge. Compared with the digestible carbohydrates starch and sugars, fiber has a low energy density and may have an attenuating effect on appetite. This narrative review attempts to clarify the net energy contributions of various fibers, and the effect of fiber on satiety and thus appetite regulation. Fibers, broadly defined as nonstarch polysaccharides, are a varied class of substances with vastly different physicochemical properties depending on their chemical arrangement. Thus, net energy content can vary from more than 10 kJ/g for soluble, nonviscous, and easily fermentable fibers such as those in many fruits, to less than zero for viscous fibers with anti-nutritive properties, such as certain types of fibers found in rye and other cereals. Likewise, some fibers will increase satiety by being viscous or contribute to large and/or swollen particles, which may facilitate mastication and increase retention time in the stomach, or potentially through fermentation and an ensuing satiety-inducing endocrine feedback from the colon. Thus, fibers may clearly contribute to energy balance. The metabolizable energy content is very often considerably lower than the commonly used level of 8 kJ per g fiber, and some fibers may reduce energy intake indirectly through satiety-inducing effects. A more precise characterization of fiber and its physicochemical effects are required before these beneficial effects can be fully exploited in human nutrition.
Modified Posterior Scleral Reinforcement as a Treatment for High Myopia in Children and Its Therapeutic Effect
Authors: Miao Zequn , Li Luojia , Meng Xiaoli , Guo Lili , Cao Di , Jia Yanlei , He Dongmei , Huang Lvzhen , Wang Lejin
Published: January 2019

Purpose. To investigate the safety and therapeutic effect of a modified posterior scleral reinforcement (PSR) in treating high myopia.Methods. A total of 85 highly myopic eyes in 47 children (6.3±3.6 years of age, range from 3 years to 15 years) who underwent this modified PSR were included in this study. Axial length, refractive error, best-corrected visual acuity (BCVA), macular scans, and adverse events were recorded before the operation (as a baseline) and in postoperative reviews taken yearly for 5 years.Results. This was a 5-year research: 50% of the children (20 children, 40 eyes) participated in the 6-month review, 41% of the children (17 children, 33 eyes) participated in the 1-year review, 26% of the children (11 children, 21 eyes) participated in the 2-year review, 16% of the children (7 children, 13 eyes) participated in the 3-year review, 13% of the children (5.3 children, 11 eyes) participated in the 4-year review, and 8% of the children (3.3 children, 7 eyes) participated in the 5-year review. Compared with the baseline, axial elongation was significantly changed (P<0.05) over the 5-year period in all of the children: 6-month (P=0.003), 1-year (P=0), 2-year (P=0), 3-year (P=0), 4-year (P=0), and 5-year (P=0). The axial length was extended. No significant difference was found in refractive error between measurements taken at baseline and at the 5-year postoperative visit in all of the children: 6-month (P=0.51), 1-year (P=0.50), 2-year (P=0.46), 3-year (P=0.56), 4-year (P=0.30), and 5-year (P=0.16). There were significant differences in BCVA between measurements taken at baseline and at the postoperative 5-year visit in all the children: 6-month (P=0), 1-year (P=0), 2-year (P=0), 3-year (P=0), 4-year (P=0), and 5-year (P=0). BCVA improved in 71 eyes (83.52%), remained stable in 14 eyes (16.47%), and declined in none of the children. No serious adverse events occurred before the operation and during the 5-year follow-up period.Conclusion. This modified PSR could be a therapeutic treatment for high myopia.
Optimization of Microwave-Assisted Extraction Saponins from Sapindus mukorossi Pericarps and an Evaluation of Their Inhibitory Activity on Xanthine Oxidase
Authors: Deng Baoqin , Liu Zaizhi , Zou Zhengrong
Published: January 2019

A microwave-assisted extraction (MAE) method was applied to separate saponins from Sapindus mukorossi pericarps. The most important factors of the six extraction parameters were selected using Plackett–Burman designs; therefore, the further extraction procedure was optimized using the Box–Behnken designs; meanwhile, the optimum processing parameters and well-pleasing saponins extraction rate were inferred. The final operation conditions were the ethanol concentration of 40%, soaking time of 3 h, particle size of 80–100 meshes, extraction time of 13 min, solvent-solid ratio of 19 mL/g, and microwave power of 425 W. Based on the optimal extraction parameters, the extraction rate of the saponins by means of MAE technique reached 280.55 ± 6.81 mg/g, which exceeds yields acquired using conventional manners. Saponins from S. mukorossi have obvious xanthine oxidase inhibitory properties in vitro compared with allopurinol. The saponins displayed a type of competitive inhibition of xanthine oxidase. In conclusion, a MAE technique in association with a response surface design provides an efficient extraction tactics, which could sufficiently isolate saponins from S. mukorossi pericarps; further, this technique could be applied to the dissociation of other bioactive substances from plant sources. In addition, the saponins may be a promising alternative to conventional medicine to treat gout and other inflammation-associated disorders to mitigate the side effects of traditional drugs.
Potential Antiglycation and Hypoglycaemic Effects ofToona ciliataM. Roem. andSchkuhria pinnataLam. Thell. Crude Extracts in Differentiated C2C12 Cells
Authors: Beseni Brian K. , Matsebatlela Thabe M. , Bagla Victor P. , Njanje Idris , Poopedi Kgomotso , Mbazima Vusi , Mampuru Leseilane , Mokgotho Matlou P.
Published: January 2019

Medicinal plants have been identified as a feasible avenue for the development of new potent antidiabetic agents. The phytoconstituent compositions of differentToona ciliataandSchkuhria pinnataextracts were determined and quantified using standard chemical methods after exhaustive extraction. Thereafter, their antioxidant and antiglycation potentials were spectrophotometrically determined. The cytotoxicity profiles of the extracts on C2C12 cells were determined using the MTT assay.Toona ciliatamethanol extract resulted in the highest percentage yield (20.83%) and high total phenols and flavonoids content in the methanol and acetone extracts compared toS. pinnataextracts. The acetone extract ofT. ciliatashowed good activity in the DPPH scavenging and FRAP assays with EC50values of 1.90 mg/ml and 5.26 mg/ml, respectively. Arbutin’s antiglycation ability was outperformed by treatments with the methanol, acetone, and hexane extract ofT. ciliatawhich resulted in 2.49%, 2.79%, and 2.56% glycation, respectively. The hexane extract ofT. ciliatawas less toxic to C2C12 cells as compared to the other extracts with CC50value of 402.16μg/ml. Only the hexane extract ofS. pinnataresulted in glucose utilisation of 28.56% which was higher than that of insulin (26.06%) after 6 hours and is therefore considered as the most potent extract with hypoglycaemic potential in this study. Studies are ongoing aimed at identifying drug candidates in this extract that may be employed in the development of hypoglycaemic, antioxidant, and antiglycation agents.
The XinJiang Astronomical Observatory NSRT Pulsar Data Archive
Authors: Zhang Hailong , Demleitner Markus , Wang Jie , Wang Na , Nie Jun , Yuan Jianping
Published: January 2019

The sensitivity of our pulsar observation system with typical integration time of 16 minutes has reached 0.4 mJy after we have upgraded the receiver cooling system of NanShan 25-m radio telescope (NSRT) at Xinjiang Astronomical Observatory (XAO) in 2002. About 280 pulsars were observed after the upgrade. The NanShan station pulsar data is transmitted to the data center at XAO headquarters via a 300Mb/s dedicated data link for long-term storage, and the remote backup is realized by synchronous data transmission between NanShan station and XAO headquarters. Metadata extraction, archiving, and releasing are completed by the data release servers which are located in XAO headquarters. At present, more than 84000 pulsar observation data files in the PSRFITS format have been released with a maximum file size of 1GB. XAO pulsar data online service provides cone search and multiobject constraint query. We have published our data based on Virtual Observatory (VO) standards. The online pulsar data service is registered in the International Virtual Observatory Alliance’s Registry. Users can access the data through common VO tools.
Patellar Transskeletal Traction for the Treatment of Chronic Patellar Pseudoarthrosis
Authors: de Faria José Leonardo Rocha , Portella Dieno Mol Souza , Titonelli Victor Elias , Cavanellas Naasson Trindade , e Albuquerque Rodrigo Pires , de Sousa Eduardo Branco , Barretto João Maurício
Published: January 2019

Patellar fractures, which constitute approximately 1% of bone lesions, may lead to severe impairment of the extensor mechanism. When conservative or surgical treatment fails, the patella may develop pseudoarthrosis. Neglect or delayed treatment of this type of injury may lead to significant diastasis between the patellar fragments. There is no consensus regarding the best treatment for such cases. This study is aimed at describing a rare case of patellar pseudoarthrosis in a patient who underwent two-step surgical treatment comprising transskeletal patellar traction followed by osteosynthesis with a tension band. A 17-year-old male patient presented with a left patellar fracture that resulted from a fall from a standing height 8 years ago. He did not undergo any type of surgical treatment during that time, but the fracture was immobilized for only 2 weeks. The two-step surgical treatment with transskeletal patellar traction and patellar osteosynthesis was performed and provided satisfactory functional clinical results in this patient. This two-step surgical treatment can be performed in cases similar to ours with satisfactory results.
Fine Tuning of Hepatocyte Differentiation from Human Embryonic Stem Cells: Growth Factor vs. Small Molecule-Based Approaches
Authors: Varghese Divya S. , Alawathugoda Thilina Thejinda , Ansari Suraiya A.
Published: January 2019

Human embryonic stem cells (hESCs) are being utilized in diverse areas of studies such as development and disease modeling, cell replacement therapy, or drug toxicity testing because of their potential to be differentiated into any cell type in the body. The directed differentiation of hESCs into hepatocytes could provide an invaluable source of liver cells for various liver-based applications. Therefore, several protocols have been established in the past for hESC-hepatocyte differentiation based on the knowledge of signaling pathways and growth factors involved in different stages of embryonic hepatogenesis. Although successful derivation of hepatocytes has been achieved through these protocols, the efficiency is not always ideal. Herein, we have tested several combinations of published protocols, for example, growth factor vs. small molecule and different time durations of treatment for definitive endoderm (DE) induction and further hepatocyte differentiation to develop an efficient DE induction and hepatocyte differentiation in a highly reproducible manner based on the stage-specific marker expression and functional analysis.
Influence Analysis of Underground Excavation on the Adjacent Buildings and Surrounding Soil Based on Scale Model Test
Authors: Yu Suhui , Geng Yongchang
Published: January 2019

In urban areas, it is common to construct underground structure nearby existing buildings. To investigate the impact of excavation construction on the adjacent existing buildings and surrounding soil, eight parallel scale model tests that considered the process of cut and cover construction are carried out with two kinds of the diameter of support piles, two kinds of the adjacent structure, and two kinds of the relative horizontal distance from the excavation in the laboratory. And, the variations of horizontal and vertical displacements of adjacent buildings and the soil pressure surrounding the excavation and the foundations of existing buildings with different parameters are presented and discussed. Then, the experimental data and the results of eight prototype finite element models are compared and analyzed.
Screening and Antifungal Activity of a β-Carboline Derivative against Cryptococcus neoformans and C. gattii
Authors: Cruz Kátia Santana , Lima Emerson Silva , Silva Marcia de Jesus Amazonas da , Souza Erica Simplício de , Montoia Andreia , Pohlit Adrian Martin , Souza João Vicente Braga de
Published: January 2019

Background. Cryptococcosis is a fungal disease of bad prognosis due to its pathogenicity and the toxicity of the drugs used for its treatment. The aim of this study was to investigate the medicinal potential of carbazole and β-carboline alkaloids and derivatives against Cryptococcus neoformans and C. gattii. Methods. MICs were established in accordance with the recommendations of the Clinical and Laboratory Standards Institute for alkaloids and derivatives against C. neoformans and C. gattii genotypes VNI and VGI, respectively. A single active compound was further evaluated against C. neoformans genotypes VNII, VNIII, and VNIV, C. gattii genotypes VGI, VGIII, and VGIV, Candida albicans ATCC 36232, for cytotoxicity against the MRC-5 lineage of human fibroblasts and for effects on fungal cells (cell wall, ergosterol, and leakage of nucleic acids). Results. Screening of 11 compounds revealed 8-nitroharmane as a significant inhibitor (MIC 40 μg/mL) of several C. neoformans and C. gattii genotypes. It was not toxic to fibroblasts (IC50 > 50 µg/mL) nor did it alter fungal cell walls or the concentration of ergosterol in C. albicans or C. neoformans. It increased leakage of substances that absorb at 260 nm. Conclusions. The synthetic β-carboline 8-nitroharmane significantly inhibits pathogenic Cryptococcus species and is interesting as a lead compound towards new therapy for Cryptococcus infections.
Implementation of Process‐Based and Data‐Driven Models for Early Prediction of Construction Time
Authors: Petruseva Silvana , Zileska-Pancovska Valentina , Car-Pušić Diana
Published: January 2019

The need of respecting the construction time as one of the construction contract elements points out that early prediction of construction time is of crucial importance for the construction project participants’ business. Thus, having a model for early prediction of construction time is useful not only for the participants involved in the construction contracting process, but also for other participants in the construction project realization. Regarding that, this paper aims to present a hybrid method for predicting construction time in the early project phase, which is a combination of process‐based and data‐driven models. Five hybrid models have been developed, and the most accurate one was the BTC‐GRNN model, which uses Bromilow’s time‐cost (BTC) model as a process‐based model and the general regression neural network (GRNN) as a data‐driven model. For evaluating the quality of the models, the 10‐fold cross‐validation method has been used. The mean absolute percentage error (MAPE) of the BTC‐GRNN is 3.34% and the coefficient of determination R2, which reflects the global fit of the model, is 93.17%. These results show a drastic improvement of the accuracy in comparison to the model when only data‐driven model (GRNN) has been used, where MAPE was 31.8% and R2 was 75.64%. This model can be useful to the investors, the contractors, the project managers, and other project participants for construction time prediction in the early project phases, especially in the phases of bidding and contracting, when many factors, that can determine the construction project realization, are unknown.
Vagus Nerve Stimulation (VNS) in Super Refractory New Onset Refractory Status Epilepticus (NORSE)
Authors: Kurukumbi Mohankumar , Leiphart James , Asif Anam , Wang Jing
Published: January 2019

The treatment protocol of status epilepticus has many associated toxicities so there is interest in alternate nonmedicinal therapies for managing New Onset Refractory Status Epilepticus (NORSE) patients. Vagus nerve stimulation (VNS) is an FDA-approved therapy for refractory epilepsy that has been shown to decrease the frequency and severity of seizures. We present the case of a patient with new-onset refractory status epilepticus (NORSE) whose seizures were successfully treated with vagus nerve stimulation. A 25-year-old male with no history of epilepsy or other neurological disorders presented with altered mental status and generalized tonic-clonic seizures following a two-week history of an upper respiratory tract infection. Lumbar puncture showed neutrophilic pleocytosis, and he was treated for bacterial and viral meningoencephalitis. In spite of treatment, his seizures began increasing in frequency. On day three, the patient entered status epilepticus (SE) refractory to intensive pharmacotherapy with maximal doses of valproate, levetiracetam, and propofol. On day four, SE remained refractory, so pentobarbital was introduced with targeted burst suppression pattern on electroencephalography (EEG). Patient continued to be refractory to these measures, so a vagus nerve stimulator (VNS) was implanted (day eight). Following VNS implantation, EEG demonstrated significant reduction of seizure activity and subsequent magnet swiping continued aborting electrographic seizures. No SE or electrographic seizures were reported for seventy-two hours, but few occasional discharges were reported. Seizures eventually recurred on day fourteen and the patient succumbed to his multiple comorbidities on day seventeen. Due to the efficacy of VNS in refractory epilepsy, there was interest in using it in refractory status epilepticus. Multiple case reports have described a benefit from implantation of VNS in the treatment of SE. The successful use of VNS to acutely terminate status epilepticus for seventy-two hours in this critically ill patient adds to current evidence that there is utility in using VNS for refractory status epilepticus.
Adaptive Path Following and Locomotion Optimization of Snake‐Like Robot Controlled by the Central Pattern Generator
Authors: Cao Zhengcai , Zhang Dong , Hu Biao , Liu Jinguo
Published: January 2019

This work investigates locomotion efficiency optimization and adaptive path following of snake‐like robots in a complex environment. To optimize the locomotion efficiency, it takes energy consumption and forward velocity into account to investigate the optimal locomotion parameters of snake‐like robots controlled by a central pattern generator (CPG) controller. A cuckoo search (CS) algorithm is applied to optimize locomotion parameters of the robot for environments with variable fractions and obstacle distribution. An adaptive path following method is proposed to steer the snake‐like robot forward and along a desired path. The efficiency and accuracy of the proposed path following method is researched. In addition, a control framework that includes a CPG network, a locomotion efficiency optimization algorithm, and an adaptive path following method is designed to control snake‐like robots move in different environments. Simulation and experimental results are presented to illustrate the performance of the proposed locomotion optimization method and adaptive path following controller for snake‐like robots in complexity terrains.
Observation and Real-Time Simulation of a Tornado Event in Hong Kong on 29 August 2018
Authors: Hon K. K. , Tse S. M. , Chan P. W. , Li Q. S.
Published: January 2019

An observational and simulation study of a tornado event in Hong Kong that occurred in the morning of 29 August 2018 is documented in this paper. Rotating airflow associated with the tornado is well captured by the Doppler velocity from a Terminal Doppler Weather Radar (TDWR) in Hong Kong. The Doppler velocity patterns show the typical signature of a velocity couplet associated with a meso/microcyclone, and for most part of its lifetime, it captures clearly the evolution with time. Weather radar echoes of those thunderstorms inducing the current tornado, as well as the meso/microcyclone itself, are also successfully reproduced in a real-time simulation by a fine-resolution numerical weather prediction (NWP) model initialised 3 hours earlier, albeit with a time lag of about 15 minutes when compared to the actual event. The model simulation displays some interesting features of the cyclone, including the vertical structure of horizontal and vertical velocities and cloud liquid water content, which are consistent with literature that accounts in other parts of the world. The vertical profile of maximum radial velocity associated with the velocity couplet also compares well between the actual weather radar observation and numerical simulation. The results in this paper could serve as an interesting reference for both meteorologists and wind engineers, also demonstrating the power of very high-resolution NWP in predicting such events in a real-time fashion.
Nonalcoholic Fatty Liver Disease Aggravated the Severity of Acute Pancreatitis in Patients
Authors: Wu Dacheng , Zhang Min , Xu Songxin , Wu Keyan , Wang Ningzhi , Wang Yuanzhi , Wu Jian , Lu Guotao , Gong Weijuan , Ding Yanbing , Xiao Weiming
Published: January 2019

Background and Aim. The incidence of nonalcoholic fatty liver disease (NAFLD) as a metabolic disease is increasing annually. In the present study, we aimed to explore the influence of NAFLD on the severity of acute pancreatitis (AP). Methods. The severity of AP was diagnosed and analyzed according to the 2012 revised Atlanta Classification. Outcome variables, including the severity of AP, organ failure (all types of organ failure), and systemic inflammatory response syndrome (SIRS), were compared for patients with and without NAFLD. Results. Six hundred and fifty-six patients were enrolled in the study and were divided into two groups according to the presence or absence of NAFLD. The non-NAFLD group contained 278 patients and the main etiology in this group was gallstone. The NAFLD group consisted of 378 patients and the main etiology was hyperlipidemia. The incidence of mild AP, moderately severe AP, and severe AP was 77.30%, 18.3%, and 4.3% in the non-NAFLD group and 58.2%, 33.9%, and 7.9% in the NAFLD group, respectively. There were significant differences between the two groups according to the severity of AP (P ≤ 0.001). In addition, the Ranson and BISAP scores as well as the incidence of SIRS and organ failure in the NAFLD group were higher than those in the non-NAFLD group (all P < 0.05). The patients were further divided into non-NAFLD, mild-NAFLD, and moderate-severe NAFLD (M+S-NAFLD) groups. The results showed that the severity of AP increased gradually from the non-NAFLD group to the M+S-NAFLD group. In addition, the incidence rates of SIRS and organ failure showed an upward trend with the aggravation of fatty liver severity. Multivariate logistic analysis showed that patients with NAFLD, especially those with M+S-NAFLD, had higher risks of SIRS and organ failure. Conclusions. Compared with non-NAFLD, NAFLD has a clinically relevant impact on the severity of AP and may be an early prognostic parameter for patients with AP.
Digit Tip Injuries: Current Treatment and Future Regenerative Paradigms
Authors: Miller Travis J. , Deptula Peter L. , Buncke Gregory M. , Maan Zeshaan N.
Published: January 2019

Over the past several decades there has been a profound increase in the understanding of tissue regeneration, driven largely by the observance of the tremendous regenerative capacity in lower order life forms, such as hydra and urodeles. However, it is known that humans and other mammals retain the ability to regenerate the distal phalanges of the digits after amputation. Despite the increased knowledge base on model organisms regarding regenerative paradigms, there is a lack of application of regenerative medicine techniques in clinical practice in regard to digit tip injury. Here, we review the current understanding of digit tip regeneration and discuss gaps that remain in translating regenerative medicine into clinical treatment of digit amputation.
Expression Profiles of Long Noncoding RNAs in Intranasal LPS-Mediated Alzheimer’s Disease Model in Mice
Authors: Tang Liang , Liu Lan , Li Guangyi , Jiang Pengcheng , Wang Yan , Li Jianming
Published: January 2019

Alzheimer’s disease (AD), characterized by memory loss, cognitive decline, and dementia, is a progressive neurodegenerative disease. Although the long noncoding RNAs (lncRNAs) have recently been identified to play a role in the pathogenesis of AD, the specific effects of lncRNAs in AD remain unclear. In present study, we have investigated the expression profiles of lncRNAs in hippocampal of intranasal LPS-mediated Alzheimer’s disease models in mice by microarray method. A total of 395 lncRNAs and 123 mRNAs was detected to express differently in AD models and controls (>2.0 folds,p<0.05). The microarray expression was validated by Quantitative Real-Time-PCR (qRT-PCR). The pathway analysis showed the mRNAs that correlated with lncRNAs were involved in inflammation, apoptosis, and nervous system related pathways. The lncRNA-TFs network analysis suggested the lncRNAs were mostly regulated by HMGA2, ONECUT2, FOXO1, and CDC5L. Additionally, lncRNA-target-TFs network analysis indicated the FOXL1, CDC5L, ONECUT2, and CDX1 to be the TFs most likely to regulate the production of these lncRNAs. This is the first study to investigate lncRNAs expression pattern in intranasal LPS-mediated Alzheimer’s disease model in mice. And these results may facilitate the understanding of the pathogenesis of AD targeting lncRNAs.
A DNA Repair and Cell-Cycle Gene Expression Signature in Primary and Recurrent Glioblastoma: Prognostic Value and Clinical Implications
Authors: Gobin Matthieu , Nazarov Petr V. , Warta Rolf , Timmer Marco , Reifenberger Guido , Felsberg Joerg , Vallar Laurent , Chalmers Anthony J. , Herold-Mende Christel C. , Goldbrunner Roland , Niclou Simone P. , Van Dyck Eric
Published: January 2019

Inevitable tumor recurrence and a poor median survival are frustrating reminders of the inefficacy of our current standard of care for patients with newly diagnosed glioblastoma (GBM), which includes surgery followed by radiotherapy and chemotherapy with the DNA alkylating agent temozolomide. Because resistance to genotoxic damage is achieved mainly through execution of the DNA damage response (DDR) and DNA repair pathways, knowledge of the changes in DNA repair and cell-cycle gene expression that occur during tumor development might help identify new targets and improve treatment. Here, we performed a gene expression analysis targeting components of the DNA repair and cell-cycle machineries in cohorts of paired tumor samples (i.e., biopsies from the same patient obtained at the time of primary tumor operation and at recurrence) from patients treated with radiotherapy or radiotherapy plus temozolomide. We identified and validated a 27-gene signature that resulted in the classification of GBM specimens into three groups, two of which displayed inverse expression profiles. Each group contained primary and recurrent samples, and the tumor at relapse frequently displayed a gene expression profile different from that of the matched primary biopsy. Within the groups that exhibited opposing gene expression profiles, the expression pattern of the gene signature at relapse was linked to progression-free survival. We provide experimental evidence that our signature exposes group-specific vulnerabilities against genotoxicants and inhibitors of the cell cycle and DDR, with the prospect of personalized therapeutic strategies.

Significance: These findings suggest that classification of GBM tumors based on a DNA repair and cell-cycle gene expression signature exposes vulnerabilities to standard-of-care therapies and offers the potential for personalized therapeutic strategies.
An Orally Active Galectin-3 Antagonist Inhibits Lung Adenocarcinoma Growth and Augments Response to PD-L1 Blockade
Authors: Vuong Lynda , Kouverianou Eleni , Rooney Claire M. , McHugh Brian J. , Howie Sarah E.M. , Gregory Christopher D. , Forbes Stuart J. , Henderson Neil C. , Zetterberg Fredrik R. , Nilsson Ulf J. , Leffler Hakon , Ford Paul , Pedersen Anders , Gravelle Lise , Tantawi Susan , Schambye Hans , Sethi Tariq , MacKinnon Alison C.
Published: January 2019

A combination therapy approach is required to improve tumor immune infiltration and patient response to immune checkpoint inhibitors that target negative regulatory receptors. Galectin-3 is a β-galactoside-binding lectin that is highly expressed within the tumor microenvironment of aggressive cancers and whose expression correlates with poor survival particularly in patients with non–small cell lung cancer (NSCLC). To examine the role of galectin-3 inhibition in NSCLC, we tested the effects of galectin-3 depletion using genetic and pharmacologic approaches on syngeneic mouse lung adenocarcinoma and human lung adenocarcinoma xenografts. Galectin-3−/− mice developed significantly smaller and fewer tumors and metastases than syngeneic C57/Bl6 wild-type mice. Macrophage ablation retarded tumor growth, whereas reconstitution with galectin-3-positive bone marrow restored tumor growth in galectin-3−/− mice, indicating that macrophages were a major driver of the antitumor response. Oral administration of a novel small molecule galectin-3 inhibitor GB1107 reduced human and mouse lung adenocarcinoma growth and blocked metastasis in the syngeneic model. Treatment with GB1107 increased tumor M1 macrophage polarization and CD8+ T-cell infiltration. Moreover, GB1107 potentiated the effects of a PD-L1 immune checkpoint inhibitor to increase expression of cytotoxic (IFNγ, granzyme B, perforin-1, Fas ligand) and apoptotic (cleaved caspase-3) effector molecules. In summary, galectin-3 is an important regulator of lung adenocarcinoma progression. The novel galectin-3 inhibitor presented could provide an effective, nontoxic monotherapy or be used in combination with immune checkpoint inhibitors to boost immune infiltration and responses in lung adenocarcinoma and potentially other aggressive cancers.

Significance:

A novel and orally active galectin-3 antagonist inhibits lung adenocarcinoma growth and metastasis and augments response to PD-L1 blockade.
GARP Dampens Cancer Immunity by Sustaining Function and Accumulation of Regulatory T Cells in the Colon
Authors: Salem Mohammad , Wallace Caroline , Velegraki Maria , Li Anqi , Ansa-Addo Ephraim , Metelli Alessandra , Kwon Hyunwoo , Riesenberg Brian , Wu Bill , Zhang Yongliang , Guglietta Silvia , Sun Shaoli , Liu Bei , Li Zihai
Published: January 2019

Activated regulatory T (Treg) cells express the surface receptor glycoprotein-A repetitions predominant (GARP), which binds and activates latent TGFβ. How GARP modulates Treg function in inflammation and cancer remains unclear. Here we demonstrate that loss of GARP in Treg cells leads to spontaneous inflammation with highly activated CD4+ and CD8+ T cells and development of enteritis. Treg cells lacking GARP were unable to suppress pathogenic T-cell responses in multiple models of inflammation, including T-cell transfer colitis. GARP−/− Treg cells were significantly reduced in the gut and exhibited a reduction in CD103 expression, a colon-specific migratory marker. In the colitis-associated colon cancer model, GARP on Treg cells dampened immune surveillance, and mice with GARP−/− Treg cells exhibited improved antitumor immunity. Thus, GARP empowers the functionality of Treg cells and their tissue-specific accumulation, highlighting the importance of cell surface TGFβ in Treg function and GARP as a potential therapeutic target for colorectal cancer therapy.

Significance: These findings uncover functions of membrane-bound TGFβ and GARP that tune the activity of Treg cells, highlighting a potential treatment strategy in autoimmune diseases and cancer.
The CD98 Heavy Chain Is a Marker and Regulator of Head and Neck Squamous Cell Carcinoma Radiosensitivity
Authors: Digomann David , Kurth Ina , Tyutyunnykova Anna , Chen Oleg , Löck Steffen , Gorodetska Ielizaveta , Peitzsch Claudia , Skvortsova Ira-Ida , Negro Giulia , Aschenbrenner Bertram , Eisenhofer Graeme , Richter Susan , Heiden Stephan , Porrmann Joseph , Klink Barbara , Schwager Christian , Dowle Adam A. , Hein Linda , Kunz-Schughart Leoni A. , Abdollahi Amir , Lohaus Fabian , Krause Mechthild , Baumann Michael , Linge Annett , Dubrovska Anna
Published: January 2019

Purpose:

The heavy chain of the CD98 protein (CD98hc) is encoded by the SLC3A2 gene. Together with the light subunit LAT1, CD98hc constitutes a heterodimeric transmembrane amino acid transporter. High SLC3A2 mRNA expression levels are associated with poor prognosis in patients with head and neck squamous cell carcinoma (HNSCC) treated with radiochemotherapy. Little is known regarding the CD98hc protein–mediated molecular mechanisms of tumor radioresistance.

Experimental Design:

CD98hc protein expression levels were correlated with corresponding tumor control dose 50 (TCD50) in HNSCC xenograft models. Expression levels of CD98hc and LAT1 in HNSCC cells were modulated by siRNA or CRISPR/Cas9 gene editing. HNSCC cell phenotypes were characterized by transcription profiling, plasma membrane proteomics, metabolic analysis, and signaling pathway activation. Expression levels of CD98hc and LAT1 proteins were examined by IHC analysis of tumor tissues from patients with locally advanced HNSCC treated with primary radiochemotherapy (RCTx). Primary endpoint was locoregional tumor control (LRC).

Results:

High expression levels of CD98hc resulted in an increase in mTOR pathway activation, amino acid metabolism, and DNA repair as well as downregulation of oxidative stress and autophagy. High expression levels of CD98hc and LAT1 proteins were significantly correlated and associated with an increase in radioresistance in HNSCC in vitro and in vivo models. High expression of both proteins identified a poor prognosis subgroup in patients with locally advanced HNSCC after RCTx.

Conclusions:

We found that CD98hc-associated signaling mechanisms play a central role in the regulation of HNSCC radioresistance and may be a promising target for tumor radiosensitization.
Maternal Embryonic Leucine Zipper Kinase (MELK), a Potential Therapeutic Target for Neuroblastoma
Authors: Chlenski Alexandre , Park Chanyoung , Dobratic Marija , Salwen Helen R. , Budke Brian , Park Jae-Hyun , Miller Ryan , Applebaum Mark A. , Wilkinson Emma , Nakamura Yusuke , Connell Philip P. , Cohn Susan L.
Published: January 2019

Maternal embryonic leucine zipper kinase (MELK) activates pathways that mediate aggressive tumor growth and therapy resistance in many types of adult cancers. Pharmacologic and genomic inhibition of MELK impairs tumor growth and increases sensitivity to radiation and chemotherapy. On the basis of these promising preclinical studies, early-phase adult clinical trials testing the MELK inhibitor OTS167 are ongoing. To investigate whether MELK is also a therapeutic target in neuroblastoma, we analyzed MELK expression in primary tumors and cell lines, and examined the effects of OTS167 on neuroblastoma growth. In primary tumors, high levels of MELK were associated with advanced stage disease and inferior survival. Higher levels of MELK were also detected in tumorigenic versus nontumorigenic neuroblastoma cell lines, and cells with higher levels of MELK expression were more sensitive to OTS167 than low-MELK expressing cells. OTS167 suppressed the growth of neuroblastoma xenografts, and in a preclinical model of minimal residual disease, survival was prolonged with MELK inhibition. OTS167 treatment downregulated MELK and its target enhancer of zeste homolog 2 (EZH2), a component of the polycomb repressive complex 2 (PRC2) that is known to modulate the DNA damage response. We also show that OTS167 reduced the formation of collapsed replication forks induced by camptothecin or radiation. Taken together, our results indicate that MELK indirectly mediates efficient processing of replication-associated DNA lesions in neuroblastoma, and that OTS167 sensitizes cells to DNA-damaging agents by abrogating this process. Further studies evaluating the activity of combination treatment regimens with OTS167 in neuroblastoma are warranted.
Lack of Response to Imatinib in Melanoma Carrying Rare KIT Mutation р.T632I
Authors: Orlova Kristina V. , Yanus Grigory A. , Aleksakhina Svetlana N. , Venina Aigul R. , Iyevleva Aglaya G. , Demidov Lev V. , Imyanitov Evgeny N.
Published: January 2019

Approximately 15% of acral and mucous melanomas carry activating mutations in KIT oncogene. There is a diversity of spectrum of KIT mutations, with some of them rendering tumors responsive to imatinib, while others being imatinib-resistant or not studied yet. Here we present an acral melanoma patient with KIT р.T632I mutation, who failed to respond to imatinib.
European Practical and Patient-Centred Guidelines for Adult Obesity Management in Primary Care
Authors: Durrer Schutz Dominique , Busetto Luca , Dicker Dror , Farpour-Lambert Nathalie , Pryke Rachel , Toplak Hermann , Widmer Daniel , Yumuk Volkan , Schutz Yves
Published: January 2019

The first contact for patients with obesity for any medical treatment or other issues is generally with General Practitioners (GPs). Therefore, given the complexity of the disease, continuing GPs’ education on obesity management is essential. This article aims to provide obesity management guidelines specifically tailored to GPs, favouring a practical patient-centred approach. The focus is on GP communication and motivational interviewing as well as on therapeutic patient education. The new guidelines highlight the importance of avoiding stigmatization, something frequently seen in different health care settings. In addition, managing the psychological aspects of the disease, such as improving self-esteem, body image and quality of life must not be neglected. Finally, the report considers that achieving maximum weight loss in the shortest possible time is not the key to successful treatment. It suggests that 5–10% weight loss is sufficient to obtain substantial health benefits from decreasing comorbidities. Reducing waist circumference should be considered even more important than weight loss per se, as it is linked to a decrease in visceral fat and associated cardiometabolic risks. Finally, preventing weight regain is the cornerstone of lifelong treatment, for any weight loss techniques used (behavioural or pharmaceutical treatments or bariatric surgery).
Uterus Preserving Prolapse Repair: How Long does it Last?
Authors: Illiano Ester , Zucchi Alessandro , Giannitsas Konstantinos , Carbone Antonio , Pastore Antonio Luigi , Costantini Elisabetta
Published: January 2019

Background: The preservation of the uterus has an important role in the pelvic organ prolapse (POP) surgery. Objectives: The aim of this study is to assess the long-term anatomical and functional outcomes of abdominal hysterosacropexy. Methods: Prospective study. A series of women who underwent open abdominal hysterosacropexy for high-stage POP with a minimum 75-month follow-up were included. Results: Data on 51 patients were included. Median follow-up was 136.7 months (range 75.8–258 months). Apical prolapse cure rate was 100%. The success rate for anterior and posterior vaginal compartment was 96 and 94% respectively. Urinary and sexual symptoms significantly improved. Ninety-two percentage of the women were “extremely” or “very much improved” with the operation. Conclusion: This study confirms that abdominal hysterosacropexy is a good surgical option with durable results for the management of POP in women who wish to preserve their uterus.