bluuebunny/crossref_metadata_2025 huggingface dataset:
Distributed representations of temporal stimulus associations across regular-firing and fast-spiking neurons in rat medial prefrontal cortex
Authors: Xing Bohan , Morrissey Mark D. , Takehara-Nishiuchi Kaori
Published: December 2019

The prefrontal cortex has been implicated in various cognitive processes, including working memory, executive control, decision making, and relational learning. One core computational requirement underlying all these processes is the integration of information across time. When rodents and rabbits associate two temporally discontiguous stimuli, some neurons in the medial prefrontal cortex (mPFC) change firing rates in response to the preceding stimulus and sustain the firing rate during the subsequent temporal interval. These firing patterns are thought to serve as a mechanism to buffer the previously presented stimuli and signal the upcoming stimuli; however, how these critical properties are distributed across different neuron types remains unknown. We investigated the firing selectivity of regular-firing, burst-firing, and fast-spiking neurons in the prelimbic region of the mPFC while rats associated two neutral conditioned stimuli (CS) with one aversive stimulus (US). Analyses of firing patterns of individual neurons and neuron ensembles revealed that regular-firing neurons maintained rich information about CS identity and CS-US contingency during intervals separating the CS and US. Moreover, they further strengthened the latter selectivity with repeated conditioning sessions over a month. The selectivity of burst-firing neurons for both stimulus features was weaker than that of regular-firing neurons, indicating the difference in task engagement between two subpopulations of putative excitatory neurons. In contrast, putative inhibitory, fast-spiking neurons showed a stronger selectivity for CS identity than for CS-US contingency, suggesting their potential role in sensory discrimination. These results reveal a fine-scaled functional organization in the prefrontal network supporting the formation of temporal stimulus associations.

NEW & NOTEWORTHY To associate stimuli that occurred separately in time, the brain needs to bridge the temporal gap by maintaining what was presented and predicting what would follow. We show that in rat medial prefrontal cortex, the former function is associated with a subpopulation of putative inhibitory neurons, whereas the latter is supported by a subpopulation of putative excitatory neurons. Our results reveal a distinct contribution of these microcircuit components to neural representations of temporal stimulus associations.
Aerodynamic Performance of a Passive Pitching Model on Bionic Flapping Wing Micro Air Vehicles
Authors: Hao Jinjing , Wu Jianghao , Zhang Yanlai
Published: December 2019

Reducing weight and increasing lift have been an important goal of using flapping wing micro air vehicles (FWMAVs). However, FWMAVs with mechanisms to limit the angle of attack (α) artificially by active force cannot meet specific requirements. This study applies a bioinspired model that passively imitates insects’ pitching wings to resolve this problem. In this bionic passive pitching model, the wing root is equivalent to a torsional spring.αobtained by solving the coupled dynamic equation is similar to that of insects and exhibits a unique characteristic with two oscillated peaks during the middle of the upstroke/downstroke under the interaction of aerodynamic, torsional, and inertial moments. Excess rigidity or flexibility deteriorates the aerodynamic force and efficiency of the passive pitching wing. With appropriate torsional stiffness, passive pitching can maintain a high efficiency while enhancing the average lift by 10% than active pitching. This observation corresponds to a clear enhancement in instantaneous force and a more concentrated leading edge vortex. This phenomenon can be attributed to a vorticity moment whose component in the lift direction grows at a rapid speed. A novel bionic control strategy of this model is also proposed. Similar to the rest angle in insects, the rest angle of the model is adjusted to generate a yaw moment around the wing root without losing lift, which can assist to change the attitude and trajectory of a FWMAV during flight. These findings may guide us to deal with various conditions and requirements of FWMAV designs and applications.
Cryptic Early Gastric Carcinoma in Gastric Stump: Challenges in Diagnostic Evaluation
Authors: Sakaleshpura Mallikarjunappa Subramanya , Jakate Shriram
Published: December 2019

Partial gastrectomy, performed for any indication, is a well-recognized risk factor for carcinoma developing in the gastric remnant (so-called “gastric stump carcinoma”). In symptomatic patients with gastro-enteric anastomosis, it is a common practice to endoscopically evaluate the patency and the status of the anastomosis and procure biopsy samples when endoscopic abnormalities are noted. We describe a case with Billroth I gastroduodenal anastomosis with oozing and friability at the anastomosis site which was biopsied. The biopsies showed invasive intestinal-type adenocarcinoma. Subsequent completion gastrectomy showed no grossly visible tumor and required extensive initial and additional sampling of the anastomosis and the surrounding stomach to locate a small focus of invasive adenocarcinoma limited to the mucosa (“early gastric carcinoma”). This case illustrates a known complication of partial gastrectomy and highlights challenges in diagnostic evaluation of early gastric carcinoma after gastrectomy.
CandidaBloodstream Infection: Changing Pattern of Occurrence and Antifungal Susceptibility over 10 Years in a Tertiary Care Saudi Hospital
Authors: Alkharashi Nawaf , Aljohani Sameera , Layqah Laila , Masuadi Emad , Baharoon Waleed , AL-Jahdali Hamdan , Baharoon Salim
Published: December 2019

Background.Candidahas emerged as one of the most important pathogens that cause bloodstream infection (BSI).Understanding the currentCandidaBSI trends, the dominant species causing disease and the mortality associated with this infection are crucial to optimize therapeutic and prophylaxis measures.Objectives. To study the epidemiology and to evaluate the risk factors, prognostic factors, and mortality associated with candidemia and to compare these findings with previously published studies from Saudi Arabia.Design. A retrospective medical record review.Setting. Tertiary hospital in Riyadh.Patients and Methods. The analysis included all cases ofCandidablood stream infection who are >18 years old over the period from 2013 to 2018. Continuous variables were compared using the parametricT-test while categorical variables were compared using the Chi-squared test.Main Outcome Measure. Incidence, resistance, and hospital outcomes inCandidablood stream infection.Sample Size. 324 patients.Results. Three hundred and twenty-four episodes ofCandidablood stream infections were identified. Median age of patients was 49.7 SD ± 28.1 years, and 53% of patients were males. More than half of the patients had an underlying disease involving the abdomen or laparotomy, 78% had an indwelling intravenous catheter, and 62% had suffered a bacterial infection within 2 weeks prior to candidemia.Candida albicansrepresents 33% of all isolates with decreasing trend overtime. There was an increase in the number of nonalbicans Candidaovertime withCandida tropicalisin the lead (20%). Use of broad spectrum antibiotics (82%), prior ICU admission (60%) and use of central venous catheters (58%) were the most prevalent predisposing factors of candidemia. Azole resistance was variable overtime. Resistance to caspofungin remained very low (1.9%). Fourteen days crude mortality was 37% for ICU patients and 26.7% in non-ICU patients, while hospital crude mortality was 64.4% and 46.7%, respectively.Conclusion. There is an increasing trend of nonalbicans Candidablood stream infection. Fluconazole resistance remained low toC. albicans. Most isolates remain susceptible to caspofungin, voriconazole, and amphotericin B.Candidabloodstream infection is associated with high 14-day hospital mortality.
Effect of Threshold Pressure Gradients on Control Areas Determination of Production Well in CBM Reservoirs
Authors: Wang Ruifei , Yang Jiaosheng , Wang Meizhu , Zhao Yang , Chen Weiqing
Published: December 2019

Understanding the mechanism of water drainage and gas recovery is the burning issue for Coalbed Methane (CBM) reservoir development. In the process of exploitation, threshold pressure gradients (TPG) is an important factor affecting the control areas, which related to the low-permeability and complex water saturation of CBM reservoirs. In this paper, a new flow model of CBM has been established considering the TPG and gas desorption. Then we carried out a series of experiments and fitted out a new relational expression between TPG and permeability and water saturation, which shows that TPG is negatively correlated with permeability and positively correlated with water saturation. After that, we analyzed the influence of TPG and desorption on the control radius and illustrated a case study. The results show that TPG and desorption effect both can slow down the rate of pressure reduction. The case study indicates that the control radius of target well groups ranges from 55 m to 136.7 m The average control radius and gas TPG are 91.3 m 0.0082 MPa/m respectively. Furthermore, we classify the wells into 5 categories, which are mainly distributed in III (80∼100 m). Finally, we suggest using well pattern infilling in region II and III and hydraulic fracturing method for region IV to increase the utilization area and the sustainability for the target area. This study provides a quick and reasonable prediction of control radius in CBM reservoir with different water saturation for further adjustment suggestion and sustainable development.
Investigation of Interaction between Vitamin D Receptor Gene Polymorphisms and Environmental Factors in Early Childhood Caries in Chinese Children
Authors: Qin Xiurong , Shao Linqin , Zhang Lixia , Ma Long , Xiong Shijiang
Published: December 2019

Background. Early childhood caries is a multifactorial disease involving interactions between genetic and environmental risk factors. The aim of this study was to examine the effects of vitamin D receptor (VDR) gene polymorphisms and gene-environment interactions on the etiology of, and susceptibility to, caries in Chinese children aged 3–5 years. Methods. Children (n = 549) were divided into three groups according to caries risk: high (decayed, missing, filled teeth (dmft) index > 4; n = 148), moderate (dmft = 1–4; n = 156), and caries-free (n = 245). A questionnaire was designed to collect demographic information, dietary habits, and oral hygiene practices, and dental plaque samples were collected to test acidogenic activity of bacteria. Genomic DNA was extracted from the buccal mucosa, and the VDR polymorphisms rs7975232, rs1544410, rs11568820, rs10735810, and rs731236 were genotyped using TaqMan assays. Results. There were no differences among the caries risk groups in frequencies of the rs7975232, rs731236, rs1544410, or rs11568820 polymorphisms (χ2 test, P>0.05); however, the frequency of the rs10735810 CC genotype was clearly higher in the high caries risk group than in the control and moderate caries risk groups (39.2%, 25.6%, and 30.6%, respectively; χ2 test, P=0.028). In multivariate analysis of genotypes and behavioral factors, rs7975232, rs731236, rs1544410, rs11568820, and rs10735810 were not associated with deciduous tooth decay (χ2 test, P>0.05). Conclusion. We conclude that these VDR polymorphisms cannot be used as markers for identification of Chinese children at increased risk of dental caries, when combined with environmental factors. Future studies are needed to replicate these initial findings and better assess the risk of caries in deciduous teeth.
Forecast Customization System (FOCUS): A Multimodel Ensemble-Based Seasonal Climate Forecasting Tool for the Homogeneous Climate Zones of Myanmar
Authors: Dash Itesh , Nagai Masahiko , Pal Indrajit
Published: December 2019

A Multi-Model Ensemble (MME) based seasonal rainfall forecast customization tool called FOCUS was developed for Myanmar in order to provide improved seasonal rainfall forecast to the country. The tool was developed using hindcast data from 7 Global Climate Models (GCMs) and observed rainfall data from 49 meteorological surface observatories for the period of 1982 to 2011 from the Department of Meteorology and Hydrology. Based on the homogeneity in terms of the rainfall received annually, the country was divided into six climatological zones. Three different operational MME techniques, namely, (a) arithmetic mean (AM-MME), (b) weighted average (WA-MME), and (c) supervised principal component regression (PCR-MME), were used and built-in to the tool developed. For this study, all 7 GCMs were initialized with forecast data of May month to predict the rainfall during June to September (JJAS) period, which is the predominant rainfall season for Myanmar. The predictability of raw GCMs, bias-corrected GCMs, and the MMEs was evaluated using RMSE, correlation coefficients, and standard deviations. The probabilistic forecasts for the terciles were also evaluated using the relative operating characteristics (ROC) scores, to quantify the uncertainty in the GCMs. The results suggested that MME forecasts have shown improved performance (RMSE = 1.29), compared to the raw individual models (ECMWF, which is comparatively better among the selected models) with RMSE = 4.4 and bias-corrected RMSE = 4.3, over Myanmar. Specifically, WA-MME (CC = 0.64) and PCR-MME (CC = 0.68) methods have shown significant improvement in the high rainfall (delta) zone compared with WA-MME (CC = 0.57) and PCR-MME (CC = 0.56) techniques for the southern zone. The PCR method suggests higher predictability skill for the upper tercile (ROC = 0.78) and lower tercile categories (ROC = 0.85) for the delta region and is less skillful over lower rainfall zones like dry zones with ROC = 0.6 and 0.63 for upper and lower terciles, respectively. The model is thus suggested to perform relatively well over the higher rainfall (Wet) zones compared to the lower (Dry) zone during the JJAS period.
Research on Coupling Degree Model of Safety Risk System for Tunnel Construction in Subway Shield Zone
Authors: Pan Haize , Gou Jing , Wan Zihong , Ren Chuxuan , Chen Mengjie , Gou Tangqiao , Luo Zhenhua
Published: December 2019

Due to the complexity of construction technology and the seriousness of the safety situation in subway tunnels, it is urgent to find a risk‐control method to monitor and evaluate the construction safety risk system of the subway shield tunnel and to avoid the occurrence of safety risk accidents. Based on the fuzzy entropy theory, this paper establishes a comprehensive index system for the construction safety risk system of shield tunnels. Also, in order to quantitatively analyze the coupling degree among various factors in the safety risk system, the calculation model of coupling degree is established based on the theory of coupling degree in physics. Taking Tianjin subway project as an example, the coupling degree of its safety risk system is calculated. The result shows that the coupling degree of the safety risk system is 0.6997, which indicates that the whole safety risk system is in high‐risk coupling level. Due to the system in an unbalanced development stage, the coupling movement between various factors has a great destructive effect on the construction safety risk system of the subway shield tunnel. This model can not only identify the main risk factors affecting the safety risk system but also monitor the coupling status of the safety risk system in real time and master its development stage. By controlling the main risk factors affecting the safety risk system, the coupling degree of the safety risk system and the probability of the safety risk accident occurrence can be reduced.
ADAMTS-5 Decreases in Coronary Arteries and Plasma from Patients with Coronary Artery Disease
Authors: Wang Zhen , Ye Di , Ye Jing , Wang Menglong , Liu Jianfang , Jiang Huimin , Xu Yao , Zhang Jishou , Chen Jiangbin , Wan Jun
Published: December 2019

The current study demonstrates that a disintegrin and metalloproteinase with thrombospondin type 1 motif- (ADAMTS-) 5 is a key extracellular matrix protease and associated with cardiovascular diseases. However, the plasma ADAMTS-5 levels and relevance of coronary artery disease (CAD) remain largely unknown. This study is aimed at examining the relationship between the plasma ADAMTS-5 levels and the severity of coronary stenosis in patients with CAD. In the present study, the expression of ADAMTS-5 was analyzed in coronary artery samples and blood. The results showed that the plasma ADAMTS-5 levels were lower in the CAD group than in the control group. In addition, significantly higher matrix metalloproteinase- (MMP-) 2 and MMP-9 levels were also observed in the patients with CAD, and the ADAMTS-5 levels were negatively correlated with the MMP-2 and MMP-9 levels. Spearman’s correlation analysis showed that the Gensini score was negatively correlated with the ADAMTS-5 levels but was positively correlated with the MMP-2 and MMP-9 levels. Receiver-operating characteristic (ROC) analysis revealed that ADAMTS-5, MMP-2, and MMP-9 may have a certain diagnostic value in CAD and that the combination of all three metalloproteinases had a higher diagnostic value. The findings provided a better understanding of the role of ADAMTS-5 in the diagnosis of CAD.
Clinical Features of Liver Injury Induced by Immune Checkpoint Inhibitors in Japanese Patients
Authors: Imoto Koji , Kohjima Motoyuki , Hioki Tomonobu , Kurashige Tomoyuki , Kurokawa Miho , Tashiro Shigeki , Suzuki Hideo , Kuwano Akifumi , Tanaka Masatake , Okada Seiji , Kato Masaki , Ogawa Yoshihiro
Published: December 2019

Aim. Immune checkpoint inhibitors (ICIs) have improved the survival rate of patients carrying various malignant neoplasms. Despite their efficacy, ICIs occasionally induce liver injury as an immune-related adverse event (irAE). This study aimed to reveal the clinical features of the hepatic irAE in Japanese patients. Methods. Among 387 patients treated with ICIs, those who developed drug-induced liver injury were investigated. We also describe the histological findings and clinical courses of four patients with hepatic irAE who underwent liver biopsy. Results. Among the 56 patients with all-grade liver injury, only 11 (19.6%) showed hepatocellular-type liver injury, which resembled autoimmune hepatitis. Thirty-four patients (60.7%) developed cholestatic or mixed-type liver injury, although only one patient showed abnormal image findings in the bile duct. Most patients with grade ≤2 liver injury improved spontaneously, while two patients with biliary dysfunction required ursodeoxycholic acid or prednisolone. Among eight patients with grade ≥3 liver injury, three required no immunosuppressants and five were treated with prednisolone (three of five patients required other types of immunosuppressants). Four patients in the case series showed diverse clinical features in terms of hepatotoxic pattern, symptoms, and the interval time between the initiation of immunotherapy and the onset of the hepatic irAE. Conclusions. Our findings suggest that ICIs could cause microscopic biliary disorder without any abnormal image finding. Because the hepatic irAE presents diverse clinical features, liver biopsy is recommended to provide appropriate treatments.
Prevalence of APOL1 Risk Variants in Afro-Descendant Patients with Chronic Kidney Disease in a Latin American Country
Authors: Duran Carlos E. , Ramírez Alejandro , Posada Juan G. , Schweineberg Johanna , Mesa Liliana , Pachajoa Harry , Estacio Mayra , Manzi Eliana , Aros Vanessa , Díaz Lorena , Garcia Victor H.
Published: December 2019

Introduction. In Colombia, the genetic background of the populations was shaped by different levels of admixture between Natives, European, and Africans. Approximately 35.363 patients have diagnosed chronic kidney disease and according to population studies, 10.4% of these patients are Afro-descendant. We aim to assess the frequency of APOL1 variants G1 and G2 in Afro-descendant patients with ESRD treated at la Fundacion Valle del Lili University Hospital in Cali, Colombia. Methods. This is an observational cross-sectional study. Afro-descendant patients with ESRD in waitlist or recipients of kidney transplant were evaluated. Clinical data were collected from the electronic medical records. Genotyping was carried out by amplification of the exon 7 of the APOL1 gene. For the identification of risk genotypes, the bioinformatics tool BLAST was used. Results. We enrolled 102 participants. The frequency of APOL1 risk variants was 67.2%, in which 24.5% (n = 25) were G1 heterozygous and 5.8% (n = 6) were G2 heterozygous and 37% of the patients had high-risk status with two alleles in homozygous (G1/G1 = 21 and G2/G2 = 3) or compound heterozygote (G1/G2 = 14) form.
Controlling Effects of Residual Deformation on Pore Pressure: A Loess Soil Case
Authors: Liu Kun , Wang Lanmin , Tian Wentong , Wang Zhenming , Li Na , Sun Yu , Sun Junjie
Published: December 2019

What the role of each phase medium plays and how their interactions do work should be essential problems to understand dynamic behaviours of soils. In order to disclose interactions between solid, water, and air phases of soils, we applied loess samples to analyse controlling effects of residual deformation on pore pressure based on three kinds of laboratory tests. We obtained the similarity and difference of mechanical behaviors of soil samples under different water contents and loading. Both process and cause of pore air/water pressures are independent of initial stress conditions or loadings. However, absolute values of pore water pressure depend on the confining pressure, whereas the pore air pressure is contrary. The uniformity of responding process and cause of pore pressure depend upon the interaction mechanism between solid particles and air/water media, but the different absolute values depend upon the permeability and compressibility of air/water.
Thyroxine Alleviates Energy Failure, Prevents Myocardial Cell Apoptosis, and Protects against Doxorubicin-Induced Cardiac Injury and Cardiac Dysfunction via the LKB1/AMPK/mTOR Axis in Mice
Authors: Wang Yuan , Zhu Shan , Liu Hongtao , Wei Wen , Tu Yi , Chen Chuang , Song Junlong , Li Juanjuan , Sun Shengrong , Wang Changhua , Xu Zhiliang
Published: December 2019

Background. Previous studies have demonstrated that energy failure is closely associated with cardiac injury. Doxorubicin (DOX) is a commonly used clinical chemotherapy drug that can mediate cardiac injury through a variety of mechanisms. Thyroxine is well known to play a critical role in energy generation; thus, this study is aimed at investigating whether thyroxine can attenuate DOX-induced cardiac injury by regulating energy generation. Methods. First, the effect of DOX on adenosine diphosphate (ADP) and adenosine triphosphate (ATP) ratios in mice was assessed. In addition, thyroxine was given to mice before they were treated with DOX to investigate the effects of thyroxine on DOX-induced cardiac injury. Furthermore, to determine whether the liver kinase b1 (LKB1)/adenosine 5′-monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) axis mediated the effect of thyroxine on DOX-induced cardiac injury, thyroxine was given to DOX-treated LKB1 knockout (KO) mice. Results. DOX treatment time- and dose-dependently increased the ADP/ATP ratio. Thyroxine treatment also reduced lactate dehydrogenase (LDH) and creatine kinase myocardial band (CK-MB) levels in both serum and heart tissue and alleviated cardiac dysfunction in DOX-treated mice. Furthermore, thyroxine reversed DOX-induced reductions in LKB1 and AMPK phosphorylation; mitochondrial complex I, III, and IV activity; and mitochondrial swelling and reversed DOX-induced increases in mTOR pathway phosphorylation and myocardial cell apoptosis. These effects of thyroxine on DOX-treated mice were significantly attenuated by LKB1 KO. Conclusions. Thyroxine alleviates energy failure, reduces myocardial cell apoptosis, and protects against DOX-induced cardiac injury via the LKB1/AMPK/mTOR axis in mice. Thyroxine may be a new agent for the clinical prevention of cardiac injury in tumor patients undergoing chemotherapy with DOX.
The Impact of Preconceptional Serum TSH Levels between 2.5 and 4.0 mIU/L on Infertile Women Going through Their First IUI Treatment Cycle
Authors: Zhang Yuchao , Wu Wenbin , Liu Yanli , Wang Xingling , Jia Liting
Published: December 2019

Objective. To evaluate the impact of preconceptional serum TSH levels on the clinical outcomes of infertile patients undergoing their first IUI treatment cycle. Method. This was a retrospective study. Euthyroid patients undergoing the first cycle of IUI treatment from Jan 2017 to Aug 2018 were included. The patients were divided into a normal high TSH level (2.5–4.0 mIU/L) group and a low TSH level (0.4–2.5 mIU/L) group. Then, different factors were included separately to compare the outcomes between normal high and low TSH levels. The primary outcomes were clinical pregnancy rates, implantation rates, and miscarriage rates. The secondary outcomes were obstetric outcomes such as single live birth rates, birth length, birth weight, and duration of gestation. Results. Initially, 1856 patients were included, and 371 patients were excluded for different reasons. A total of 1485 patients were finally included in the analysis. The general parameters between normal high and low TSH levels were similar except for infertile duration and female BMI, which were, however, significantly different between AID-IUI patients and AIH-IUI patients (P=0.005 and P=0016). No significant differences were found in terms of either primary outcomes or secondary outcomes. Conclusion. Normal high-serum TSH levels within the reference range (0.4–4.0 mIU/L) measured before treatment seemed to have no adverse impact on the clinical outcomes of patients undergoing their first IUI treatment cycle.
Association of Estimated Insulin Resistance with N-Terminal B-Type Natriuretic Peptide Concentration in Men with Metabolic Syndrome
Authors: Krzesiński Paweł , Piechota Wiesław , Piotrowicz Katarzyna , Gielerak Grzegorz , Woźniak-Kosek Agnieszka
Published: December 2019

Background. The diagnostic and prognostic role of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in heart failure is well established. However, additional factors may influence its concentration. One of them is obesity, which in general is accompanied by reduced NT-proBNP levels. However, specific data concerning metabolic syndrome (MS) are equivocal. The aim of the present study was to evaluate the association of NT-proBNP with estimated insulin resistance (eIR) in men with MS. Methods. In 86 male patients with MS (78 of them hypertensive), blood pressure, anthropometric measures, NT-proBNP, creatinine, glucose, and insulin were assessed and eIR was calculated using homeostatic model assessment (HOMA-IR). Results. Both eIR and age were independently associated with NT-proBNP concentrations (b = 0.2248, p=0.019; b = 0.0102, p=0.049, respectively). Blood pressure, anthropometric measures, and eGFR were not correlated with NT-proBNP. Patients without eIR had higher NT-proBNP than those with eIR (32.2 ± 26.4 vs 21.4 ± 25.4 pg/mL, p=0.014). The difference was even higher in the younger subgroup of patients reaching nearly 50%. Conclusions. Insulin resistance and, to a lesser degree, age were associated with NT-proBNP levels in men with MS. In younger subjects with eIR, mean NT-proBNP level was lower than in corresponding healthy age males.
Efficient One-Step Induction of Human Umbilical Cord-Derived Mesenchymal Stem Cells (UC-MSCs) Produces MSC-Derived Neurospheres (MSC-NS) with Unique Transcriptional Profile and Enhanced Neurogenic and Angiogenic Secretomes
Authors: Peng Chunyang , Li Yajiao , Lu Li , Zhu Jianwen , Li Huiyu , Hu Jingqiong
Published: December 2019

Cell therapy has emerged as a promising strategy for treating neurological diseases such as stroke, spinal cord injury, and various neurodegenerative diseases, but both embryonic neural stem cells and human induced Pluripotent Stem Cell- (iPSC-) derived neural stem cells have major limitations which restrict their broad use in these diseases. We want to find a one-step induction method to transdifferentiate the more easily accessible Umbilical Cord-Derived Mesenchymal Stem Cells (UC-MSCs) into neural stem/progenitor cells suitable for cell therapy purposes. In this study, UC-MSCs were induced to form neurospheres under a serum-free suspension culture with Epidermal Growth Factor- (EGF-) and basic Fibroblast Growth Factor- (bFGF-) containing medium within 12 hours. These MSC-derived neurospheres can self-renew to form secondary neurospheres and can be readily induced to become neurons and glial cells. Real-time PCR showed significantly upregulated expression of multiple stemness and neurogenic genes after induction. RNA transcriptional profiling study showed that UC-MSC-derived neurospheres had a unique transcriptional profile of their own, with features of both UC-MSCs and neural stem cells. RayBio human growth factor cytokine array analysis showed significantly upregulated expression levels of multiple neurogenic and angiogenic growth factors, skewing toward a neural stem cell phenotype. Thus, we believe that these UC-MSC-derived neurospheres have amenable features of both MSCs and neural stem/progenitor cells and have great potential in future stem cell transplantation clinical trials targeting neurological disorders.
Safety and Efficacy in Relapsed or Refractory Classic Hodgkin’s Lymphoma Treated with PD-1 Inhibitors: A Meta-Analysis of 9 Prospective Clinical Trials
Authors: Zhang Xueyan , Chen Li , Zhao Yawei , Yin Huiru , Ma He , He Miao
Published: December 2019

Background. Classic Hodgkin’s lymphoma (cHL) is characterized by the unique biology in which rare Hodgkin-Reed-Sternberg cells propagate an immunosuppressive microenvironment. Checkpoint inhibitors that target the interaction of PD-1 immune checkpoint receptors have demonstrated remarkable activities in various cancers, such as cHL. This study aims to evaluate the safety and efficacy of PD-1 inhibitors in treating relapsed or refractory cHL (rrHL). Methods. We searched PubMed, MEDLINE, Embase, Cochrane Central Register of Controlled Trials, China National Knowledge Infrastructure, Wanfang, Chinese Biological Medical Literature, and Abstracts of Conference proceedings of annual meetings without any language restrictions to limit language bias (up to January 2019) for prospective clinical trials that evaluate PD-1 inhibitors in treating relapsed or refractory cHL. Results. A total of 9 prospective clinical trials with 731 patients were included in the meta-analysis. The pooled risks of all-grade and grade ≥3 adverse events (AEs) were 0.86 (95% CI: 0.66–0.98) and 0.21 (95% CI: 0.17–0.24), respectively. The pooled response, complete response, partial response, and stable disease rates were 0.74 (95% CI: 0.70–0.79), 0.24 (95% CI: 0.18–0.34), 0.48 (95% CI: 0.41–0.55), and 0.15 (95% CI: 0.12–0.17), respectively. The pooled 6-month progression-free survival and 1-year overall survival rates were 0.76 (95% CI: 0.72–0.79) and 0.93 (95% CI: 0.90–0.96), correspondingly. Conclusions. Our meta-analysis suggested that anti-PD1 monoclonal antibodies improve the outcomes of response and survival rates with tolerable AEs in cHL. However, evidence of immune checkpoint inhibitors for patients with cHL remained insufficient. Well-designed randomized controlled trials or at least nonrandomized trials with a control group should be conducted to confirm the findings of this meta-analysis.
hsa_circ0021347 as a Potential Target Regulated by B7-H3 in Modulating the Malignant Characteristics of Osteosarcoma
Authors: Wang Ling , Zhang Guo-chuan , Kang Fu-Biao , Zhang Long , Zhang Ying-ze
Published: December 2019

In our previous study, we showed that B7-H3 played crucial roles in osteosarcoma (OS) development and might serve as a negative regulator of in osteoimmunology and help tumor cells escape immune surveillance. However, little is known about B7-H3 deficiency and its corresponding circRNA alteration or their relationship with osteosarcoma progression. Therefore, we established stable silencing of B7-H3 in OS cells and validated our results with western blotting and real-time PCR detection. Then, we performed a circRNA array to analyze the differential expression of circRNAs between the control and B7-H3 knockdown cells. The association between target circRNA expression and the clinicopathological features of patients with OS was further analyzed. As a result, hsa_circ0021347 was selected and validated to be significantly downregulated in OS tissues and cell lines and showed a strong negative relationship with B7-H3 expression in OS. In addition, clinicopathological features showed that hsa_circ0021347 in OS tissues was negatively associated with Enneking stage and positively associated with patients’ survival. Finally, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and PANTHER pathway analyses were performed to predict a network of hsa_circ0021347/miRNAs interactions to help us develop potential biomarkers for clinical diagnosis and design therapeutic strategies for OS.
Cell-free Circulating Tumor DNA Variant Allele Frequency Associates with Survival in Metastatic Cancer
Authors: Pairawan Seyed , Hess Kenneth R. , Janku Filip , Sanchez Nora S. , Mills Shaw Kenna R. , Eng Cathy , Damodaran Senthilkumar , Javle Milind , Kaseb Ahmed O. , Hong David S. , Subbiah Vivek , Fu Siqing , Fogelman David R. , Raymond Victoria M. , Lanman Richard B. , Meric-Bernstam Funda
Published: December 2019

Purpose:

Physicians are expected to assess prognosis both for patient counseling and for determining suitability for clinical trials. Increasingly, cell-free circulating tumor DNA (cfDNA) sequencing is being performed for clinical decision making. We sought to determine whether variant allele frequency (VAF) in cfDNA is associated with prognosis.

Experimental Design:

We performed a retrospective analysis of 298 patients with metastatic disease who underwent clinical comprehensive cfDNA analysis and assessed association between VAF and overall survival.

Results:

cfDNA mutations were detected in 240 patients (80.5%). Median overall survival (OS) was 11.5 months. cfDNA mutation detection and number of nonsynonymous mutations (NSM) significantly differed between tumor types, being lowest in appendiceal cancer and highest in colon cancer. Having more than one NSM detected was associated with significantly worse OS (HR = 2.3; P < 0.0001). VAF was classified by quartiles, Q1 lowest, Q4 highest VAF. Higher VAF levels were associated with a significantly worse overall survival (VAF Q3 HR 2.3, P = 0.0069; VAF Q4 HR = 3.8, P < 0.0001) on univariate analysis. On multivariate analysis, VAF Q4, male sex, albumin level <3.5 g/dL, number of nonvisceral metastatic sites >0 and number of prior therapies >4 were independent predictors of worse OS.

Conclusions:

Higher levels of cfDNA VAF and a higher number of NSMs were associated with worse OS in patients with metastatic disease. Further study is needed to determine optimal VAF thresholds for clinical decision making and the utility of cfDNA VAF as a prognostic marker in different tumor types.
5-Hydroxymethylcytosine Profiles in Circulating Cell-Free DNA Associate with Disease Burden in Children with Neuroblastoma
Authors: Applebaum Mark A. , Barr Erin K. , Karpus Jason , West-Szymanski Diana C. , Oliva Meritxell , Sokol Elizabeth A. , Zhang Sheng , Zhang Zhou , Zhang Wei , Chlenski Alexandre , Salwen Helen R. , Wilkinson Emma , Dobratic Marija , Grossman Robert L. , Godley Lucy A. , Stranger Barbara E. , He Chuan , Cohn Susan L.
Published: December 2019

Purpose:

5-Hydroxymethylcytosine (5-hmC) is an epigenetic marker of open chromatin and active gene expression. We profiled 5-hmC with Nano-hmC-Seal technology using 10 ng of plasma-derived cell-free DNA (cfDNA) in blood samples from patients with neuroblastoma to determine its utility as a biomarker.

Experimental Design:

For the Discovery cohort, 100 5-hmC profiles were generated from 34 well children and 32 patients (27 high-risk, 2 intermediate-risk, and 3 low-risk) at various time points during the course of their disease. An independent Validation cohort encompassed 5-hmC cfDNA profiles (n = 29) generated from 21 patients (20 high-risk and 1 intermediate-risk). Metastatic burden was classified as high, moderate, low, or none per Curie metaiodobenzylguanidine scores and percentage of tumor cells in bone marrow. Genes with differential 5-hmC levels between samples according to metastatic burden were identified using DESeq2.

Results:

Hierarchical clustering using 5-hmC levels of 347 genes identified from the Discovery cohort defined four clusters of samples that were confirmed in the Validation cohort and corresponded to high, high-moderate, moderate, and low/no metastatic burden. Samples from patients with increased metastatic burden had increased 5-hmC deposition on genes in neuronal stem cell maintenance and epigenetic regulatory pathways. Further, 5-hmC cfDNA profiles generated with 1,242 neuronal pathway genes were associated with subsequent relapse in the cluster of patients with predominantly low or no metastatic burden (sensitivity 65%, specificity 75.6%).

Conclusions:

cfDNA 5-hmC profiles in children with neuroblastoma correlate with metastatic burden and warrants development as a biomarker of treatment response and outcome.
Comparison of Two Numerical Parameters to Assess Detrusor Contractility in Prognosing Short-Term Outcome after Transurethral Resection of the Prostate
Authors: Zhong Ping , Zhao Yao-Rui , Qiao Bao-Min , Yang Fu-Jiang , Zhu Yan , Yang Zhi-Qiang , Niu Yuan-Jie
Published: December 2019

Objective: To investigate and compare the influence of two numerical detrusor contractility parameters, the bladder contractility index (BCI) and the maximum Watts factor (WFmax), on transurethral resection of the prostate (TURP) outcome. Methods: A retrospective study was conducted on 236 patients who had undergone urodynamic assessment preoperatively and TURP for benign prostatic obstruction. They were evaluated by International Prostate Symptom Score (IPSS) and uroflowmetry preoperatively and 3 months postoperatively. Related criteria were established to determine the overall efficacy of TURP. Logistic regression analysis and receiver operating characteristic curves were made to investigate the influence of the BCI and WFmax on TURP efficacy. Results: Among the 236 patients, 195 treatments were effective and 41 ineffective. Multivariate analysis showed that both the BCI (OR 1.038) and the WFmax (OR 1.291) could influence TURP efficacy. For predicting TURP efficacy, the optimal cut-off values of the BCI and WFmax were 98.7 and 10.27 W/m2, respectively. The AUC, sensitivity and specificity of the BCI were 0.722, 78.5% and 61.0%; those of the WFmax were 0.761, 73.9% and 73.2%, with no significant difference (p > 0.05). Conclusions: To some extent, the BCI and the WFmax can predict TURP efficacy equally well. A discrimination level of 10.27 W/m2 may be a threshold value for detrusor underactivity (DU); as regards the BCI, the current threshold value is appropriate to diagnose DU.
A Comparison of Intradialytic versus Out-of-Clinic Exercise Training Programs for Hemodialysis Patients
Authors: Fang Hsin-Yu , Burrows Brett T. , King Alexis C. , Wilund Kenneth R.
Published: December 2019

Background: Physical inactivity is prevalent and linked with a variety of unfavorable clinical outcomes in hemodialysis patients. To increase physical activity (PA) and improve quality of life in this population, intradialytic and out-of-clinic exercise interventions have been implemented in many studies. However, there is still a lack of consensus in the literature on which type of exercise intervention is more feasible and effective. Summary: This review provides a brief overview of intradialytic and out-of-clinic exercise protocols utilized in previous studies. We also examine data related to the feasibility of each approach, and their efficacy for improving cardiovascular health, muscle mass, strength, and physical function. Key Messages: The benefits from most intradialytic and out-of-center exercise training interventions published to date have been modest or inconsistent. Furthermore, neither appears to provide a significant advantage over the other in terms of benefits for cardiovascular health, muscle mass, strength, and physical function. A significant concern is that most intradialytic and out-of-center exercise interventions are mandated exercise prescriptions that include either endurance or resistance training exercises, performed at low-moderate intensities, for a total of 60–135 min of exercise/week. This volume, intensity, and variety of exercise are far less than what is recommended in most PA guidelines. This type of structured activity is also boring for most patients. To enhance the effectiveness of exercise interventions, we suggest using the intradialytic period to provide patients guidance on how they can best incorporate more activity into their lives, based on their individual needs and barriers.
The Synergistic Value of Time-Averaged Serum Albumin and Globulin in Predicting the First Peritonitis in Incident Peritoneal Dialysis Patients
Authors: Zhang Wenyu , Wang Xichao , Liu Ying , Han Yingying , Li Jinping , Sun Na , Tu Yangke , Chang Wenxiu
Published: December 2019

Background: The prognostic value of serum time-averaged albumin (TA-Alb) and time-averaged globulin (TA-Glo) combination on the peritonitis in peritoneal dialysis (PD) patients is unknown. Methods: The patients who started PD treatment between July 2013 and 2018 were included. Serum Alb and globulin (Glo) were tested at baseline and monthly during follow-up. TA-Alb and TA-Glo were calculated until first peritonitis occurred or the end of the study. PD patients were divided into 4 groups based on the medians of TA-Alb and TA-Glo separately. Cox regression was conducted to identify the hazard ratios (HRs) of peritonitis among categorical groups. Results: Three hundred and sixty-three patients were included and among them 109 patients experienced first peritonitis. Peritonitis patients had lower baseline Alb, TA-Alb, and TA-Glo levels and ultrafiltration volume. Multivariate cox regression analysis revealed that TA-Alb, TA-Glo, and baseline Alb were significantly associated with first peritonitis. The highest HR existed in Group 1 with lower Alb and lower Glo (HR 4.57, 95% CI 2.36–8.87, p < 0.001) compared with Group 4 with higher Alb and higher Glo. Conclusion: Lower TA-Glo is an independent risk factor for the first peritonitis in PD patients. Combined with lower TA-Alb will increase the predictive effect than separate factor alone.
Association between Dialysis Modality and Cardiovascular Diseases: A Comparison between Peritoneal Dialysis and Hemodialysis
Authors: Banshodani Masataka , Kawanishi Hideki , Moriishi Misaki , Shintaku Sadanori , Tsuchiya Shinichiro
Published: December 2019

Introduction: In patients with end-stage kidney disease (ESKD), cardiovascular diseases (CVDs) are the most common causes of hospitalization and death. Objective: We aimed to determine the association between dialysis modality and CVDs. Methods: This retrospective observational cohort study compared the emergency hospitalization and mortality of patients with CVDs who underwent peritoneal dialysis (PD) versus hemodialysis (HD). After propensity score matching, the risk factors were evaluated using Cox proportional hazards regression models. Results: A total of 260 patients were matched: 130 of 135 PD (75 men; age, 65.4 years; dialysis vintage, 3.3 years) and 130 of 706 HD (70 men [p = 0.5]; 66.6 years [p = 0.4]; dialysis vintage, 3.1 years [p = 0.5]) patients. Emergency hospitalization rates (hospitalizations/person-years) for overall CVDs (0.138 vs. 0.066, p = 0.002) and pulmonary edema (0.048 vs. 0.019, p = 0.03) were significantly higher in patients who underwent PD than those who underwent HD. The log-rank test revealed that all-cause and CVD mortalities were significantly higher in PD (both p < 0.001). Mortality rates (deaths/person-years) for overall CVDs (0.058 vs. 0.015, p < 0.002), cerebrovascular disease (0.019 vs. 0.004, p = 0.03), and ischemic heart disease (0.010 vs. 0, p = 0.02) were significantly higher in PD. The Cox proportional hazards regression model showed that PD and age were significant predictors of emergency hospitalization (hazard ratio [HR] 2.70; 95% CI 1.53–4.77; p = 0.001) and mortality (HR 4.41; 95% CI 1.66–11.72; p = 0.003) for CVDs. Conclusions: PD is a risk factor for emergency hospitalization and mortality associated with CVDs in dialysis patients with ESKD. Strict control of body fluid balance may prevent cardiovascular events in patients undergoing PD.
Feeding Tolerance, Intestinal Motility, and Superior Mesenteric Artery Blood Flow in Infants with Gastroschisis
Authors: Williams Sadie L. , Tkach Jean A. , Rattan Mantosh S. , South Andrew P. , Wessel Jacqueline , Kingma Paul S.
Published: December 2019

Objective:The aim of this study was to determine the relationship of superior mesenteric artery (SMA) blood flow and intestinal motility with feeding tolerance in infants with gastroschisis. Study Design: This was a prospective observational cohort study of 23 infants with gastroschisis. Magnetic resonance images were obtained at abdominal wall closure, initiation of feeds, and full feeds. Motility and SMA flow data were correlated with feeding tolerance. Result:All infants had abnormal motility, and most continued with abnormal motility despite achieving full feeds. Increased SMA flow at the time of abdominal wall closure was found to be significantly related to the earlier achievement of full feeds (ρ = –0.45, p = 0.05) and trended towards earlier initiation of feeds (ρ = –0.36, p = 0.13), shorter parenteral nutrition days (ρ = –0.42, p = 0.07), and earlier discharge (ρ = –0.41, p = 0.08). Conclusion: Increased SMA blood flow at the time of abdominal wall closure is positively correlated with feeding tolerance, suggesting the importance of initial intestinal perfusion in the pathophysiology for feeding intolerance and intestinal dysmotility in gastroschisis.