bluuebunny/crossref_metadata_2025 huggingface dataset:
Dual-Class Firms and Innovation after NAFTA
Authors: Gao Lei , Zagorchev Andrey
Published: May 2020

We examine the effect of dual-class shares on U.S. firm innovation after the exogenous shock of the 1994 North American Free Trade Agreement (NAFTA), which intensified international competition. Using difference-in-differences models, we find that dual-class structure firms become less innovative but improve operating efficiency following NAFTA. We show that dual-class firms in many manufacturing industries reduce innovation, but marginally increase capital expenditures after the agreement, and thus substitute risky innovation with safer, long-term investments. The findings indicate that firms with dual-class structures facing lower competition decrease their stock market related innovation activities. We find that dual-class firms with entrenched managers decrease innovation and improve operating efficiency following NAFTA. Based on the robust results, agency costs and managerial entrenchment could explain these changes in innovations, efficiency, and investments.
Organisational Structure and Project Success: The Mediating Role of Knowledge Sharing
Authors: Raziq Muhammad Mustafa , Ahmad Mansoor , Iqbal Muhammad Zahid , Ikramullah Malik , David Maha
Published: May 2020

This paper looks at the relationship among elements of an organisational structure (i.e. formalisation, centralisation and integration) with project success, and examines whether the relationships are mediated by knowledge sharing. There is limited understanding with regard to how various elements of organisational structure relate to knowledge sharing and project success. Taking a contingency approach and grounding our argument in the resource-based view of the firm, we show that certain elements of organisational structures have positive implications for the project organisation. We draw on survey data from 220 respondents serving in (public and private) project-based telecom service provider firms in Pakistan. Our results show that formalisation and integration are conducive to project success, but centralisation is negatively related to project success. Knowledge sharing mediates the relationship between integration and project success for both the public and private telecom firms, but in case of formalisation, knowledge sharing mediation exists only for the public firms. Based on these results, we draw some implications for theory and practice.
An asymmetric dynamic multiparty quantum secret sharing against active attacks
Authors: Wang Ming-Ming , Kong Xing-Yu
Published: May 2020

We propose a dynamic quantum secret sharing (DQSS) protocol based on traveling single-qubits where any number of players can join or leave the protocol according to the dealer’s and players’ will. The protocol can resist collusion attacks of dishonest players by using an honesty test based on some unambiguous unitary operations. Specifically, the proposed protocol is secure against active attacks from dishonest players, which is different from existing protocols that consider only passive attacks based on the assumption that players are honest but curious. By using the asymmetric strategy, the efficiency of our DQSS protocol can be made asymptotically close to 100%. Compared with previous DQSS protocols, our protocol is securer, more efficient and more practical.
Relationship Between AST/ALT Ratio and Peripheral Nerve Function in Type 2 Diabetes Mellitus
Authors: Zhang Yinan , Zhang Lizhi , Li Fengwen , Liu Bo , Chu Chen , Lu Jingyi , Jiang Lan , Wu Jingwen , Wang Congrong , Bao Yuqian , Jia Weiping
Published: May 2020

Background: The aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio is suggested to be related to the increased risks of many metabolic diseases, whereas its association with neurological function in type 2 diabetes mellitus (T2DM) has not been understood. In this study, we aim to investigate the relationships between serum liver enzymes (ALT, AST, the AST/ALT ratio, gamma-glutamyl transferase (GGT)) and peripheral nerve function in patients with T2DM. Methods: In Group 1, we analyzed the associations between parameters of nerve function and liver enzymes in 460 T2DM patients from rural area of Shanghai. Besides, the same methods were applied to another group of 828 T2DM subjects from urban area of Shanghai. Results: In Group 1, the AST/ALT ratio was significantly higher in patients with abnormal nerve conduction [Formula: see text]. The peripheral nerve function significantly declined with increasing tertiles of AST/ALT ratio ([Formula: see text]). After adjustment for all potential confounders, the ratio of AST/ALT was still negatively correlated with the composite Z-scores of conduction velocity (CV). In Group 2, similar significant associations were found between the AST/ALT ratio and peripheral nerve function after adjustment for covariates. Conclusions: In two independent T2DM populations, the AST/ALT ratio was independently and consistently related to peripheral nerve function. The AST/ALT ratio might be helpful to highlight T2DM patients at high risk for diabetic peripheral neuropathy.
Application of analytical techniques to petroleum systems: an introduction
Authors: Dowey Patrick J. , Osborne Mark , Volk Herbert
Published: May 2020

Cutting-edge techniques have always been utilized in petroleum exploration and production to reduce costs and improve efficiencies. Innovations in analytical methods will continue to play a key role in the industry moving forwards, as society shifts towards lower carbon energy systems. This volume brings together new analytical approaches and describes how they can be applied to the study of petroleum systems. The papers within this volume cover a wide range of topics and case studies, in the fields of fluid and isotope geochemistry, organic geochemistry, imaging and sediment provenance. The work illustrates how the current, state-of-the-art technology can be effectively utilized to address ongoing challenges in petroleum geoscience.
Si Doped GaAs (001) Films
Authors: Shu
Published: May 2020

The short research of optimization of the growth method to obtain p-type GaAs (001) layers using Si as the dopant was reported in this work. Atomic force microscopy was used to analyze the surface morphology and low-temperature photoluminescence also used to confirm the p-type of the layers.
Effect of luminal flow on doming of mpkCCD cells in a 3D perfusable kidney cortical collecting duct model
Authors: Rein Joshua L. , Heja Szilvia , Flores Daniel , Carrisoza-Gaytán Rolando , Lin Neil Y. C. , Homan Kimberly A. , Lewis Jennifer A. , Satlin Lisa M.
Published: May 2020

The cortical collecting duct (CCD) of the mammalian kidney plays a major role in the maintenance of total body electrolyte, acid/base, and fluid homeostasis by tubular reabsorption and excretion. The mammalian CCD is heterogeneous, composed of Na+-absorbing principal cells (PCs) and acid-base-transporting intercalated cells (ICs). Perturbations in luminal flow rate alter hydrodynamic forces to which these cells in the cylindrical tubules are exposed. However, most studies of tubular ion transport have been performed in cell monolayers grown on or epithelial sheets affixed to a flat support, since analysis of transepithelial transport in native tubules by in vitro microperfusion requires considerable expertise. Here, we report on the generation and characterization of an in vitro, perfusable three-dimensional kidney CCD model (3D CCD), in which immortalized mouse PC-like mpkCCD cells are seeded within a cylindrical channel embedded within an engineered extracellular matrix and subjected to luminal fluid flow. We find that a tight epithelial barrier composed of differentiated and polarized PCs forms within 1 wk. Immunofluorescence microscopy reveals the apical epithelial Na+ channel ENaC and basolateral Na+/K+-ATPase. On cessation of luminal flow, benzamil-inhibitable cell doming is observed within these 3D CCDs consistent with the presence of ENaC-mediated Na+ absorption. Our 3D CCD provides a geometrically and microphysiologically relevant platform for studying the development and physiology of renal tubule segments.
Lung-resident mesenchymal stromal cells are tissue-specific regulators of lung homeostasis
Authors: Sveiven Stefanie Noel , Nordgren Tara M.
Published: May 2020

Until recently, data supporting the tissue-resident status of mesenchymal stromal cells (MSC) has been ambiguous since their discovery in the 1950–60s. These progenitor cells were first discovered as bone marrow-derived adult multipotent cells and believed to migrate to sites of injury, opposing the notion that they are residents of all tissue types. In recent years, however, it has been demonstrated that MSC can be found in all tissues and MSC from different tissues represent distinct populations with differential protein expression unique to each tissue type. Importantly, these cells are efficient mediators of tissue repair, regeneration, and prove to be targets for therapeutics, demonstrated by clinical trials ( phase 1– 4) for MSC-derived therapies for diseases like graft-versus-host-disease, multiple sclerosis, rheumatoid arthritis, and Crohn’s disease. The tissue-resident status of MSC found in the lung is a key feature of their importance in the context of disease and injuries of the respiratory system, since these cells could be instrumental to providing more specific and targeted therapies. Currently, bone marrow-derived MSC have been established in the treatment of disease, including diseases of the lung. However, with lung-resident MSC representing a unique population with a different phenotypic and gene expression pattern than MSC derived from other tissues, their role in remediating lung inflammation and injury could provide enhanced efficacy over bone marrow-derived MSC methods. Through this review, lung-resident MSC will be characterized, using previously published data, by surface markers, gene expression patterns, and compared with bone-marrow MSC to highlight similarities and, importantly, differences in these cell types.
Urgent reconsideration of lung edema as a preventable outcome in COVID-19: inhibition of TRPV4 represents a promising and feasible approach
Authors: Kuebler Wolfgang M. , Jordt Sven-Eric , Liedtke Wolfgang B.
Published: May 2020

Lethality of coronavirus disease (COVID-19) during the 2020 pandemic, currently still in the exponentially accelerating phase in most countries, is critically driven by disruption of the alveolo-capillary barrier of the lung, leading to lung edema as a direct consequence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We argue for inhibition of the transient receptor potential vanilloid 4 (TRPV4) calcium-permeable ion channel as a strategy to address this issue, based on the rationale that TRPV4 inhibition is protective in various preclinical models of lung edema and that TRPV4 hyperactivation potently damages the alveolo-capillary barrier, with lethal outcome. We believe that TRPV4 inhibition has a powerful prospect at protecting this vital barrier in COVID-19 patients, even to rescue a damaged barrier. A clinical trial using a selective TRPV4 inhibitor demonstrated a benign safety profile in healthy volunteers and in patients suffering from cardiogenic lung edema. We argue for expeditious clinical testing of this inhibitor in COVID-19 patients with respiratory malfunction and at risk for lung edema. Perplexingly, among the currently pursued therapeutic strategies against COVID-19, none is designed to directly protect the alveolo-capillary barrier. Successful protection of the alveolo-capillary barrier will not only reduce COVID-19 lethality but will also preempt a distressing healthcare scenario with insufficient capacity to provide ventilator-assisted respiration.
Healthy active older adults have enhanced K+channel-dependent endothelial vasodilatory mechanisms
Authors: Serviente Corinna , Berry Craig W. , Kenney W. Larry , Alexander Lacy M.
Published: May 2020

Microvascular endothelial dysfunction, a precursor to atherosclerotic cardiovascular disease, increases with aging. Endothelium-derived hyperpolarizing factors (EDHFs), which act through K+channels, regulate blood flow and are important to vascular health. It is unclear how EDHFs change with healthy aging. To evaluate microvascular endothelial reliance on K+channel-mediated dilation as a function of age in healthy humans. Microvascular function was assessed using intradermal microdialysis in healthy younger (Y; n = 7; 3 M/4 W; 26 ± 1 yr) and older adults (O; n = 12; 5 M/7 W; 64 ± 2 yr) matched for V̇o2peak(Y: 39.0 ± 3.8, O: 37.6 ± 3.1 mL·kg−1·min−1). Participants underwent graded local infusions of: the K+channel activator Na2S (10−6to 10−1M), acetylcholine (ACh, 10−10to 10−1M), ACh + the K+channel inhibitor tetraethylammonium (TEA; 25 or 50 mM), and ACh + the nitric oxide synthase-inhibitor l-NAME (15 mM). Red blood cell flux was measured with laser-Doppler flowmetry and used to calculate cutaneous vascular conductance (CVC; flux/mean arterial pressure) as a percentage of each site-specific maximum (%CVCmax, 43°C+28 mM sodium nitroprusside). The %CVCmaxresponse to Na2S was higher in older adults (mean, O: 51.7 ± 3.9% vs. Y: 36.1 ± 5.3%; P = 0.03). %CVCmaxwas lower in the ACh+TEA vs. the ACh site starting at 10−5M (ACh: 34.0 ± 5.7% vs. ACh+TEA: 19.4 ± 4.5%; P = 0.002) in older and at 10−4M (ACh: 54.5 ± 9.4% vs. ACh+TEA: 31.2 ± 6.7%; P = 0.0002) in younger adults. %CVCmaxwas lower in the ACh+l-NAME vs. the ACh site in both groups starting at 10−4M ACh (Y: P < 0.001; O: P = 0.02). Healthy active older adults have enhanced K+channel-dependent endothelial vasodilatory mechanisms, suggesting increased responsiveness to EDHFs with age.
A New Two-Lane Lattice Hydrodynamic Model considering the Traffic Interruption Probability under Honk Environment
Authors: Wang Qingying , Ge Hongxia , Cheng Rongjun
Published: May 2020

By accounting for the traffic interruption probability on two-lane highway under honk environment, an extended lattice hydrodynamic model is presented in the paper. In view of the novel model, a series of researches are carried out. The neutral stability condition and the stable condition can be derived through linear analysis. Then, the mKdV equation near the critical point can be obtained by applying nonlinear analysis, which describes the traffic jams according to the kink-antikink density waves. In addition, numerical simulation is performed, which confirms that traffic interruption probability on two-lane highway under honk environment can develop traffic jams by the change of density waves. Also, the phenomenon is consistent with the results of previous theoretical analysis. It shows that accounting for the traffic interruption probability on two-lane highway under honk environment can stabilize the traffic flow efficiently.
Fuzheng Huayu Capsule Attenuates Hepatic Fibrosis by Inhibiting Activation of Hepatic Stellate Cells
Authors: Wu Mei , Zhou Yang , Qin Sheng-Lan , Lin Li-Jing , Ping Jian , Tao Zhang , Zhang Jing , Xu Lie-Ming , Wu Jian
Published: May 2020

Aim. To investigate the mechanisms of Fuzheng Huayu (FZHY) Capsule in the treatment of hepatitis B (HBV)‐ associated fibrosis, HBV patients were divided into two groups, 50 cases were in the nucleotide analogues (NAs) group, while additional 50 cases were in the NAs + FZHY group. Methods. We assessed the curative effects of antifibrosis through liver function, FibroScan test, and liver biopsy and detected the ratio of lymphocyte subsets by flow cytometry. Peripheral blood lymphocyte and CD8+T, CD4+T, and natural killer cell subsets collected from patients were cocultured with LX‐2 cells. Activation of LX‐2 cells, production of the extracellular matrix, apoptosis, and proliferation of LX‐2 cells were determined. Chronic liver injury models were established by ConA treatment. Results. It is evident that FZHY treatment significantly increased the percentage of NK cells, the rate of death, and apoptosis of LX‐2 cells and decreased the FibroScan liver stiffness measurement value. The expressions of α‐SMA and procollagen type I mRNA in LX‐2 cells of the FZHY treatment group as downregulated when they were cocultured with lymphocytes compared to those from the NAs group. The proliferation of LX‐2 cells in the FZHY treatment group was inhibited compared to that in the NAs group. In a mouse model of hepatic fibrosis, PBLs and IHLs from ConA exposure plus FZHY treatment inhibited the ability of JS‐1 cells to express α‐SMA. Conclusions. FZHY Capsule improved the disordered cellular immunity and postponed liver fibrosis possibly through inhibiting the interaction between lymphocyte and hepatic stellate cells.
Hematological Indexes Can Be Used to Predict the Incidence of Hypothyroidism in Nasopharyngeal Carcinoma Patients after Radiotherapy
Authors: Zhou Ling , Chen Jia , Tao Chang-Juan , Huang Shuang , Zhang Jiang , Shen Wei , Zhu Chao-Nan , Chen Ming , Yu Zhong-Hua , Chen Yuan-Yuan
Published: May 2020

Background. This study explored the relationship between thyroid‐associated antibodies, immune cells, and hypothyroidism to establish a predictive model for the incidence of hypothyroidism in patients with nasopharyngeal carcinoma (NPC) after radiotherapy. Methods. A total of 170 patients with NPC treated at the Cancer Hospital of University of Chinese Academy of Sciences between January 2015 and August 2018 were included. The complete blood count, biochemical, coagulation function, immune cells, and thyroid‐associated antibodies tested before radiotherapy were evaluated. A logistic regression model was performed to elucidate which hematological indexes were related to hypothyroidism development. A predictive model for the incidence of hypothyroidism was established. Internal verification of the multifactor model was performed using the tenfold cross‐validation method. Results. The univariate analysis showed that immune cells had no statistically significant differences among the patients with and without hypothyroidism. Sex, N‐stage, antithyroid peroxidase antibody (TPO‐Ab), antithyroglobulin antibody (TG‐Ab), thyroglobulin (TG), and fibrinogen (Fb) were associated with hypothyroidism. Males and early N‐stage were protective factors of thyroid function, whereas increases in TPO‐Ab, TG‐Ab, TG, and Fb counts were associated with an increased rate of hypothyroidism incidence. The multivariate analysis showed that TPO‐Ab, TG‐Ab, TG, and Fb were independent predictors of hypothyroidism. The comprehensive effect of the significant model, including TPO‐Ab, TG‐Ab, TG, and Fb counts, represented the optimal method of predicting the incidence of radiation‐induced hypothyroidism (AUC = 0.796). Tenfold cross‐validation methods were applied for internal validation. The AUCs of the training and testing sets were 0.792 and 0.798, respectively. Conclusion. A model combining TPO‐Ab, TG‐Ab, TG, and Fb can be used to screen populations at a high risk of developing hypothyroidism after radiotherapy.
A Low Creatinine to Body Weight Ratio Predicts the Incident Nonalcoholic Fatty Liver Disease in Nonelderly Chinese without Obesity and Dyslipidemia: A Retrospective Study
Authors: Lin Jianxiong , Zheng Jiehua , Lin Xiaoqing , Chen Yexi , Li Zhiyang
Published: May 2020

Aim. A lower ratio of creatinine to body weight (Cr/BW) is considered the independent risk factor for incident nonalcoholic fatty liver disease (NAFLD). However, the relationship between the Cr/BW ratio and NAFLD among individuals without obesity and dyslipidemia and how this relationship is impacted by age are still ambiguous. Therefore, we explored the effect of the Cr/BW ratio on the incident NAFLD among Chinese without obesity and dyslipidemia of different age groups. Methods. A total of 9756 participants without NAFLD at baseline were included and grouped by the median value (1.32) of the Cr/BW ratio. Then, a further analysis was stratified by age (60 years old). The primary outcome was new-onset NAFLD. Results. After a median follow-up of 2.76 years, 844 (8.7%) participants developed NAFLD. The elderly had a higher person-years incidence rate and cumulative incidence rate than the nonelderly. A high Cr/BW ratio showed a lower cumulative incidence compared to a low Cr/BW ratio for the whole population (P=0.039) and the nonelderly group (P=0.008). After being adjusted for multivariate variables, the lower Cr/BW ratio was the independent risk factor for incident NAFLD in the nonelderly (HR 0.718, 95% CI 0.548-0.942), instead of the elderly. Conclusions. The Cr/BW ratio has a negative relationship with incident NAFLD among nonobese Chinese without dyslipidemia before the age of 60.
The Analysis of PTPN6 for Bladder Cancer: An Exploratory Study Based on TCGA
Authors: Shen Chengquan , Liu Jing , Wang Jirong , Yang Xiaokun , Niu Haitao , Wang Yonghua
Published: May 2020

PTPN6(protein tyrosine phosphatase nonreceptor type 6), a tyrosine phosphatase, is known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. Previous studies have demonstrated thatPTPN6expression is relatively elevated in several malignancies. However, the role ofPTPN6in bladder cancer (BC) remains unclear. The purpose of this study was to explore the prognostic value ofPTPN6in BC. RNA-seq data from The Cancer Genome Atlas (TCGA) was used to identify the expression level ofPTPN6in BC. The relationship between clinical pathologic features andPTPN6were analyzed with the Wilcoxon signed-rank test. The prognostic and predictive value ofPTPN6was evaluated by survival analysis and nomogram. Gene Set Enrichment Analysis (GSEA) was conducted to explore the potential molecular mechanisms ofPTPN6in BC. Finally, Tumor Immune Estimation Resource (TIMER) was applied to investigate the relationship betweenPTPN6and immune cell infiltration in the tumor microenvironment. Results indicated thatPTPN6was overexpressed in BC tissues compared with normal bladder tissues and was significantly correlated with grade, stage, T, and N. Survival analysis showed that low expression ofPTPN6was significantly related to the poor overall survival (OS) in BC patients. Coexpression analysis showed thatPTPN6andTNFRSF14(Tumor necrosis factor receptor superfamily member 14) have a close correlation in BC. GSEA showed that multiple cancer-associated signaling pathways are differentially enriched in thePTPN6high expression phenotype. Moreover, the expression level ofPTPN6was positively associated with the infiltration of B cells, CD4+T cells, dendritic cells, and neutrophils and negatively associated with CD8+ T cells and macrophages in BC. In conclusion, we identified thatPTPN6may be a novel prognostic biomarker in BC based on the TCGA database. Further clinical trials are needed to confirm our observations and mechanisms underlying the prognostic value ofPTPN6in BC also deserve further experimental exploration.
JMJD1A Represses the Development of Cardiomyocyte Hypertrophy by Regulating the Expression of Catalase
Authors: Zang Rongjia , Tan Qingyun , Zeng Fanrong , Wang Dongwei , Yu Shuang , Wang Qingdong
Published: May 2020

The histone demethylase JMJD family is involved in various physiological and pathological functions. However, the roles of JMJD1A in the cardiovascular system remain unknown. Here, we studied the function of JMJD1A in cardiac hypertrophy. The mRNA and protein levels of JMJD1A were significantly downregulated in the hearts of human patients with hypertrophic cardiomyopathy and the hearts of C57BL/6 mice underwent cardiac hypertrophy induced by transverse aortic constriction (TAC) surgery or isoproterenol (ISO) infusion. In neonatal rat cardiomyocytes (NRCMs), siRNA‐mediated JMJD1A knockdown facilitated ISO or angiotensin II‐induced increase in cardiomyocyte size, protein synthesis, and expression of hypertrophic fetal genes, including atrial natriuretic peptide (Anp), brain natriuretic peptide (Bnp), and Myh7. By contrast, overexpression of JMJD1A with adenovirus repressed the development of ISO‐induced cardiomyocyte hypertrophy. We observed that JMJD1A reduced the production of total cellular and mitochondrial levels of reactive oxygen species (ROS), which was critically involved in the effects of JMJD1A because either N‐acetylcysteine or MitoTEMPO treatment blocked the effects of JMJD1A deficiency on cardiomyocyte hypertrophy. Mechanism study demonstrated that JMJD1A promoted the expression and activity of Catalase under basal condition or oxidative stress. siRNA‐mediated loss of Catalase blocked the protection of JMJD1A overexpression against ISO‐induced cardiomyocyte hypertrophy. These findings demonstrated that JMJD1A loss promoted cardiomyocyte hypertrophy in a Catalase and ROS‐dependent manner.
The Feasibility of All‐Blastocyst‐Culture and Single Blastocyst Transfer Strategy in Elderly Women: A Retrospective Analysis
Authors: Su Weijue , Xu Jialing , Arhin Samuel Kofi , Liu Chang , Zhao Junzhao , Lu Xiaosheng
Published: May 2020

Objective. To investigate the feasibility and clinical outcome of the all‐blastocyst‐culture and single blastocyst transfer strategy in women aged ≥35 years. Methods. A retrospective analysis of patients aged ≥35 years undergoing IVF/ICSI was performed from January 2017 to April 2019 in the reproductive center of the Second Affiliated Hospital of Wenzhou Medical University. A total of 155 cases treated with ovarian hyperstimulation by prolonged protocol and implemented single (84 cases) or double (71 cases) blastocyst transfer were collected. Then, patients were further divided into <38 yr. group and ≥38 yr. group, and the laboratory and clinical outcomes were compared between the groups. Results. The double‐blastocyst‐transfer (DBT) group showed higher clinical pregnancy rate and multiple pregnancy rate and lower neonatal birth weight than those in the single‐blastocyst‐transfer (SBT) group (P < 0.05). However, there were no statistically significant differences between the groups in the embryo implantation rate, biochemical pregnancy rate, miscarriage rate, preterm delivery rate, and term birth rate. For patients < 38 yr., SBT significantly reduced the multiple pregnancy rate and increased the neonate birth weight without significant reduction in the clinical pregnancy rate. While in the ≥38 yr. group, there are no differences in pregnancy outcomes between SBT and DBT. Logistic regression analysis showed that the number of MII oocytes was positively correlated with the live birth rate (OR = 1.18) and negatively correlated with the miscarriage rate (OR = 0.844), suggesting that elderly patients with relatively normal ovarian reserve would obtain better prospect in pregnancy. The number of fetal heart beat in pregnancy was negatively correlated with the live birth rate (OR = 0.322) and positively correlated with the preterm birth rate (OR = 7.16). Conclusion. The strategy of all‐blastocyst‐culture and single blastocyst transfer is feasible, safe, and effective for elderly patients with normal ovarian reserve, which would reduce the multiple pregnancy rate.
The Therapeutic Effects of Extracorporeal Shock Wave Therapy (ESWT) on the Rotator Cuff Lesions with Shoulder Stiffness: A Prospective Randomized Study
Authors: Ko Jih-Yang , Siu Kai-Kit , Wang Feng-Sheng , Wang Ching-Jen , Chou Wen-Yi , Huang Chung-Cheng , Kuo Shu-Jui
Published: May 2020

Aim. We wish to investigate the therapeutic potential of a single‐session high‐energy extracorporeal shock wave therapy (ESWT) on the rotator cuff lesions with shoulder stiffness. Patients and Methods. Thirty‐seven patients afflicted with rotator cuff lesions with shoulder stiffness were randomized to receive either shockwave or sham treatment based on statistical randomization. In the shockwave group, we used Orthospec™ Extracorporeal Shock Wave Therapy 3000 impulse 24 kV (0.32 mJ/mm2) focused at two points as one session. The sham intervention entailed the use of the device in which the silicone pad was removed from the stand‐off device. The visual analogue scale (VAS), muscle power of the shoulder, Constant and Murley score (CMS), and range of motion (ROM) of the shoulder were assessed for all patients. Ten milliliters of peripheral venous blood was obtained from every participant for the measurements of markers for inflammation, tissue regeneration, angiogenesis, and substance P before and at 1 week and 4 weeks after intervention. Results. The ESWT group has significantly better VAS, muscle power, CMS, and ROM at 6 and 12 months after intervention. No between‐group differences were observed before as well as 1 and 4 weeks after intervention in the selected biomarkers. Conclusion. ESWT may be a good adjuvant for the treatment of rotator cuff lesions with shoulder stiffness.
A Dynamic Territorializing Approach for Multiagent Task Allocation
Authors: Islam Mohammad , Dadvar Mehdi , Zargarzadeh Hassan
Published: May 2020

In this paper, we propose a dynamic territorializing approach for the problem of distributing tasks among a group of robots. We consider the scenario in which a task comprises two subtasks—detection and completion; two complementary teams of agents, hunters and gatherers, are assigned for the subtasks. Hunters are assigned with the task of exploring the environment, i.e., detection, whereas gatherers are assigned with the latter subtask. To minimize the workload among the gatherers, the proposed algorithm utilizes the center of mass of the known targets to form territories among the gatherers. The concept of center of mass has been adopted because it simplifies the task of territorial optimization and allows the system to dynamically adapt to changes in the environment by adjusting the assigned partitions as more targets are discovered. In addition, we present a game-theoretic analysis to justify the agents’ reasoning mechanism to stay within their territory while completing the tasks. Moreover, simulation results are presented to analyze the performance of the proposed algorithm. First, we investigate how the performance of the proposed algorithm varies as the frequency of territorializing is varied. Then, we examine how the density of the tasks affects the performance of the algorithm. Finally, the effectiveness of the proposed algorithm is verified by comparing its performance against an alternative approach.
Network Pharmacology‐Based Approach to Investigate the Mechanisms of Mahai Capsules in the Treatment of Cardiovascular Diseases
Authors: Shi Minjuan , Li Bo , Yuan Qiuzhen , Gan Xuefeng , Ren Xiao , Jiang Shanshan , Liu Zhuo
Published: May 2020

Background. Mahai capsules (MHC) have been deemed to be an effective herb combination for treatment of cardiovascular diseases (CVD) development and improvement of the life quality of CVD patients. To systematically explore the mechanisms of MHC in CVD, a network pharmacology approach mainly comprising target prediction, network construction, biological process and pathway analysis, and related diseases was adopted in this study. Methods. We collected the bioactive compounds and potential targets of MHC through the TCMSP servers. Candidate targets related to CVD were collected from Therapeutic Targets Database and PharmGkb database and analyzed using ClueGO plugin in Cytoscape. KEGG pathway was enriched and analyzed through the EnrichR platform, and protein‐protein interaction networks were calculated by STRING platform. The compound‐target, target‐disease, and compound‐target‐disease networks were constructed using Cytoscape. Results. A total of 303 targets of the 57 active ingredients in MHC were obtained. The network analysis showed that PTGS2, PTGS1, HSP90, Scn1a, estrogen receptor, calmodulin, and thrombin were identified as key targets of MHC in the treatment of CVD. The functional enrichment analysis indicated that MHC probably produced the therapeutic effects against CVD by synergistically regulating many biological pathways, such as PI3K‐Akt, TNF, HIF‐1, FoxO, apoptosis, calcium, T‐cell receptor, VEGF, and NF‐kappa B signaling pathway. Conclusions. In summary, the analysis of the complete profile of the pharmacological properties, as well as the elucidation of targets, networks, and pathways, can further illuminate that the underlying mechanisms of MHC in CVD might be strongly associated with its synergic regulation of inflammation, apoptosis, and immune function, and provide new clues for its future development of therapeutic strategies and basic research.
Fine Particulate Matter Air Pollution and Mortality among Pediatric, Adolescent, and Young Adult Cancer Patients
Authors: Ou Judy Y. , Hanson Heidi A. , Ramsay Joemy M. , Kaddas Heydon K. , Pope Clive Arden , Leiser Claire L. , VanDerslice James , Kirchhoff Anne C.
Published: May 2020

Background:

Air pollution is a carcinogen and causes pulmonary and cardiac complications. We examined the association of fine particulate matter pollution (PM2.5) and mortality from cancer and all causes among pediatric, adolescent, and young adult (AYA) patients with cancer in Utah, a state with considerable variation in PM2.5.

Methods:

We followed 2,444 pediatric (diagnosed ages 0–14) and 13,459 AYA (diagnosed ages 15–39) patients diagnosed in 1986–2015 from diagnosis to 5 and 10 years postdiagnosis, death, or emigration. We measured average monthly PM2.5 by ZIP code during follow-up. Separate pediatric and AYA multivariable Cox models estimated the association of PM2.5 and mortality. Among AYAs, we examined effect modification of PM2.5 and mortality by stage while controlling for cancer type.

Results:

Increases in PM2.5 per 5 μg/m3 were associated with cancer mortality in pediatric lymphomas and central nervous system (CNS) tumors at both time points, and all cause mortality in lymphoid leukemias [HR5-year = 1.32 (1.02–1.71)]. Among AYAs, PM2.5 per 5 μg/m3 was associated with cancer mortality in CNS tumors and carcinomas at both time points, and all cause mortality for all AYA cancer types [HR5-year = 1.06 (1.01–1.13)]. PM2.5 ≥12 μg/m3 was associated with cancer mortality among breast [HR5-year = 1.50 (1.29–1.74); HR10-year = 1.30 (1.13–1.50)] and colorectal cancers [HR5-year = 1.74 (1.29–2.35); HR10-year = 1.67 (1.20–2.31)] at both time points. Effect modification by stage was significant, with local tumors at highest risk.

Conclusions:

PM2.5 was associated with mortality in pediatric and AYA patients with specific cancers.

Impact:

Limiting PM2.5 exposure may be important for young cancer patients with certain cancers.

See all articles in this CEBP Focus section, “Environmental Carcinogenesis: Pathways to Prevention.”
Combinatorial Inhibition of Focal Adhesion Kinase and BCL-2 Enhances Antileukemia Activity of Venetoclax in Acute Myeloid Leukemia
Authors: Wang Xiangmeng , Mak Po Yee , Mu Hong , Tao Wenjing , Rao Arvind , Visweswaran Ravikumar , Ruvolo Vivian , Pachter Jonathan A. , Weaver David T. , Andreeff Michael , Xu Bing , Carter Bing Z.
Published: May 2020

Focal adhesion kinase (FAK) promotes cancer cell growth and metastasis. We previously reported that FAK inhibition by the selective inhibitor VS-4718 exerted antileukemia activities in acute myeloid leukemia (AML). The mechanisms involved, and whether VS-4718 potentiates efficacy of other therapeutic agents, have not been investigated. Resistance to apoptosis inducted by the BCL-2 inhibitor ABT-199 (venetoclax) in AML is mediated by preexisting and ABT-199–induced overexpression of MCL-1 and BCL-XL. We observed that VS-4718 or silencing FAK with siRNA decreased MCL-1 and BCL-XL levels. Importantly, VS-4718 antagonized ABT-199–induced MCL-1 and BCL-XL. VS-4718 markedly synergized with ABT-199 to induce apoptosis in AML cells, including primary AML CD34+ cells and AML cells overexpressing MCL-1 or BCL-XL. In a patient-derived xenograft (PDX) model derived from a patient sample with NPM1/FLT3-ITD/TET2/DNMT3A/WT1 mutations and complex karyotype, VS-4718 statistically significantly reduced leukemia tissue infiltration and extended survival (72 vs. control 36 days, P = 0.0002), and only its combination with ABT-199 effectively decreased systemic leukemia tissue infiltration and circulating blasts, and prolonged survival (65.5 vs. control 36 days, P = 0.0119). Furthermore, the combination decreased NFκB signaling and induced the expression of IFN genes in vivo. The combination also markedly extended survival of a second PDX model developed from an aggressive, TP53-mutated complex karyotype AML sample. The data suggest that the combined inhibition of FAK and BCL-2 enhances antileukemia activity in AML at least in part by suppressing MCL-1 and BCL-XL and that this combination may be effective in AML with TP53 and other mutations, and thus benefit patients with high-risk AML.
Autocrine CCL5 Effect Mediates Trastuzumab Resistance by ERK Pathway Activation in HER2-Positive Breast Cancer
Authors: Zazo Sandra , González-Alonso Paula , Martín-Aparicio Ester , Chamizo Cristina , Luque Melani , Sanz-Álvarez Marta , Mínguez Pablo , Gómez-López Gonzalo , Cristóbal Ion , Caramés Cristina , García-Foncillas Jesús , Eroles Pilar , Lluch Ana , Arpí Oriol , Rovira Ana , Albanell Joan , Madoz-Gúrpide Juan , Rojo Federico
Published: May 2020

HER2-positive breast cancer is currently managed with chemotherapy in combination with specific anti-HER2 therapies, including trastuzumab. However, a high percentage of patients with HER2-positive tumors do not respond to trastuzumab (primary resistance) or either recur (acquired resistance), mostly due to molecular alterations in the tumor that are either unknown or undetermined in clinical practice. Those alterations may cause the tumor to be refractory to treatment with trastuzumab, promoting tumor proliferation and metastasis. Using continued exposure of a HER2-positive cell line to trastuzumab, we generated a model of acquired resistance characterized by increased expression of several cytokines. Differential gene expression analysis indicated an overexpression of 15 genes, including five different chemokines, and highlighting CCL5/RANTES as the most overexpressed one. Functional studies, either by in vitro gene silencing or by in vitro and in vivo pharmacologic inhibition of the CCL5/CCR5 interaction with maraviroc, confirmed that CCL5 overexpression was implicated in acquired resistance to trastuzumab, which was mediated by ERK activation. In patient samples, increased CCL5 expression significantly correlated with lower rates of complete response after neoadjuvant therapy, confirmed by detection of high serum CCL5 levels by ELISA. Overexpression of CCL5 correlated with ERK phosphorylation in tumor cells and was statistically associated with worse disease-free survival and overall cancer survival in patients with early HER2-positive breast cancer.
Development of a MUC16-Targeted Near-Infrared Fluorescent Antibody Conjugate for Intraoperative Imaging of Pancreatic Cancer
Authors: Olson Madeline T. , Wojtynek Nicholas E. , Talmon Geoffrey A. , Caffrey Thomas C. , Radhakrishnan Prakash , Ly Quan P. , Hollingsworth Michael A. , Mohs Aaron M.
Published: May 2020

Surgical resection is currently the only potentially curative option for patients with pancreatic cancer. However, the 5-year survival rate after resection is only 25%, due in part to high rates of R1 resections, in which cells are left behind at the surgical margin, resulting in disease recurrence. Fluorescence-guided surgery (FGS) has emerged as a method to reduce incomplete resections and improve intraoperative assessment of cancer. Mucin-16 (MUC16), a protein biomarker highly overexpressed in pancreatic cancer, is a potential target for FGS. In this study, we developed a fluorescent MUC16-targeted antibody probe, AR9.6-IRDye800, for image-guided resection of pancreatic cancer. We demonstrated the efficacy of this probe to bind human pancreatic cancer cell lines in vitro and in vivo. In an orthotopic xenograft model, AR9.6-IRDye800 exhibited superior fluorescence enhancement of tumors and lower signal in critical background organs in comparison to a nonspecific IgG control. The results of this study suggest that AR9.6-IRDye800 has potential for success as a probe for FGS in pancreatic cancer patients, and MUC16 is a feasible target for intraoperative imaging.
Golgi Alpha-Mannosidase II as a Novel Biomarker Predicts Prognosis in Clear Cell Renal Cell Carcinoma
Authors: Li Chenglong , Guo Linjie , Chen Fan , Yu Weiming , Rao Ting , Ruan Yuan
Published: May 2020

Objective: Golgi alpha-mannosidase II (GM II) is one of the crucial enzymes in the process of N-glycan processing. The aim of our study was to examine the clinical significance of GM II in patients with clear cell renal cell carcinoma (ccRCC). Methods: Quantitative reverse transcription polymerase chain reaction analysis and immunohistochemical staining were used to analyze GM II expression in patients with ccRCC. The clinical data of 62 patients with ccRCC were collected to analyze the clinical significance of GM II. The clinical significance among GM II expression, clinicopathological staging, and histological grade of ccRCC was explored. Survival analyses were performed to identify the relevance between the expression of GM II and the overall survival of patients with ccRCC. A uni-/multivariate Cox regression model was used to detect risk factors affecting the prognosis of patients with ccRCC. Subsequently, the proliferation and migration of ccRCC cells were detected after transfecting with GM II-short hairpin RNA (shRNA). Results: The results of these comparisons suggested that GM II expression of ccRCC tissues was dramatically higher than that of para-carcinoma tissues (p < 0.05). GM II expression in the high-differentiation group was lower than that in the median- and low-differentiation groups (p < 0.05). GM II expression in stage I and II tissues was lower than that in stage III and IV tissues (p < 0.05). The expression levels of GM II in the group without lymph node metastasis were lower than those in the group with lymph node metastasis (p < 0.05). Survival analysis indicated that patients with ccRCC with high GM II expression generally had decreased overall survival. Uni-/multivariate Cox model analyses further suggested an association between GM II expression and prognosis of patients with breast cancer. High GM II expression is a potential and independent prognostic biomarker in ccRCC. The inhibition of GM II by transfecting with GM II-shRNA could reduce the proliferation and migration of ccRCC. Conclusion: GM II expression in human ccRCC tissues was upregulated compared with that found in normal human renal tissue, and GM II may promote the progression and migration of ccRCC. Furthermore, the GM II gene may be used as a promising tumor marker for the diagnosis and prognosis of ccRCC.
Weight-Based Assessment of Fluid Overload in Patients with Acute Kidney Injury
Authors: Chow Bing Lun , Poh Cheng Boon , Chionh Chang Yin
Published: May 2020

Introduction: Acute kidney injury (AKI) with fluid overload is associated with poor outcomes. While percentage fluid overload (PFO) using intake/output charts (PFOi/o) has been validated as a marker of overload, accurate PFOi/o measurements may not be possible in a general ward. We propose an alternative weight-based PFO calculation: PFOw = [(maximum weight − baseline weight) ÷ baseline weight] × 100%. Methods: This is a prospective, observational pilot study on general ward inpatients with AKI who were referred for nephrology consult. PFOw was compared with PFOi/o, and both were evaluated for associations with dialysis requirement, AKI stage 2 or 3, and 90-day mortality. Results: Fifty-eight patients with a median age of 67.5 years (interquartile range 18.0) were recruited. Of which, 33 (56.9%) were males and 41 (70.7%) had preexisting CKD 3 or higher. We found no correlation between PFOi/o and PFOw (R2 = 0.015, p = 0.531). A higher PFOw was observed in AKI stage 2 or 3 (p = 0.005) and in patients requiring dialysis (p = 0.001). On multivariate analysis, each percentage increase in PFOw was associated with increased odds of AKI stage 2 or 3 (odds ratio 1.37 [95% CI 1.05–1.78], p = 0.020) and dialysis need (odds ratio 1.69 [95% CI 1.20–2.39], p = 0.003). Twenty-nine patients had complete quantitative data to calculate PFOi/o. Multivariate analysis of these 29 patients showed that PFOw correlated with AKI stage 2 or 3 and dialysis requirement, while PFOi/o had no correlation with these events. The area under the curve receiver operating characteristics of PFOw was 0.706 for AKI stage 2 or 3 and 0.819 for AKI requiring dialysis. The optimal PFOw cutoff was determined at ≥1%. Three deaths occurred within 90 days, and all had PFOw ≥ 1%, although the log-rank test did not achieve statistical significance (p = 0.050). Conclusion: The proposed PFOw is a potential prognostic indicator for general ward patients with AKI. PFOw ≥ 1% is associated with poor renal outcomes.
Respiratory Muscle and Lung Function in Lung Allograft Recipients: Association with Exercise Intolerance
Authors: Spiesshoefer Jens , Henke Carolin , Kabitz Hans Joachim , Nofer Jerzy Roch , Mohr Michael , Evers Georg , Strecker Jan-Kolia , Brix Tobias , Randerath Winfried Johannes , Herkenrath Simon , Schmidt Lars Henning , Boentert Matthias
Published: May 2020

Background: In lung transplant recipients (LTRs), restrictive ventilation disorder may be present due to respiratory muscle dysfunction that may reduce exercise capacity. This might be mediated by pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). Objective: We investigated lung respiratory muscle function as well as circulating pro-inflammatory cytokines and exercise capacity in LTRs. Methods: Fifteen LTRs (6 female, age 56 ± 14 years, 63 ± 45 months post-transplantation) and 15 healthy controls matched for age, sex, and body mass index underwent spirometry, measurement of mouth occlusion pressures, diaphragm ultrasound, and recording of twitch transdiaphragmatic (twPdi) and gastric pressures (twPgas) following magnetic stimulation of the phrenic nerves and the lower thoracic nerve roots. Exercise capacity was quantified using the 6-min walking distance (6MWD). Plasma IL-6 and TNF-α were measured using enzyme-linked immunosorbent assays. Results: Compared with controls, patients had lower values for forced vital capacity (FVC; 81 ± 30 vs.109 ± 18% predicted, p = 0.01), maximum expiratory pressure (100 ± 21 vs.127 ± 17 cm H2O, p = 0.04), diaphragm thickening ratio (2.2 ± 0.4 vs. 3.0 ± 1.1, p = 0.01), and twPdi (10.4 ± 3.5 vs. 17.6 ± 6.7 cm H2O, p = 0.01). In LTRs, elevation of TNF-α was related to lung function (13 ± 3 vs. 11 ± 2 pg/mL in patients with FVC ≤80 vs. >80% predicted; p < 0.05), and lung function (forced expiratory volume after 1 s) was closely associated with diaphragm thickening ratio (r = 0.81; p < 0.01) and 6MWD (r = 0.63; p = 0.02). Conclusion: There is marked restrictive ventilation disorder and respiratory muscle weakness in LTRs, especially inspiratory muscle weakness with diaphragm dysfunction. Lung function impairment relates to elevated levels of circulating TNF-α and diaphragm dysfunction and is associated with exercise intolerance.