bluuebunny/crossref_metadata_2025 huggingface dataset:
Calorie Restriction and Aging in Humans
Authors: Flanagan Emily W. , Most Jasper , Mey Jacob T. , Redman Leanne M.
Published: June 2020

Calorie restriction (CR), the reduction of dietary intake below energy requirements while maintaining optimal nutrition, is the only known nutritional intervention with the potential to attenuate aging. Evidence from observational, preclinical, and clinical trials suggests the ability to increase life span by 1–5 years with an improvement in health span and quality of life. CR moderates intrinsic processes of aging through cellular and metabolic adaptations and reducing risk for the development of many cardiometabolic diseases. Yet, implementation of CR may require unique considerations for the elderly and other specific populations. The objectives of this review are to summarize the evidence for CR to modify primary and secondary aging; present caveats for implementation in special populations; describe newer, alternative approaches that have comparative effectiveness and fewer deleterious effects; and provide thoughts on the future of this important field of study.
Abortive Infection: Bacterial Suicide as an Antiviral Immune Strategy
Authors: Lopatina Anna , Tal Nitzan , Sorek Rotem
Published: June 2020

Facing frequent phage challenges, bacteria have evolved numerous mechanisms to resist phage infection. A commonly used phage resistance strategy is abortive infection (Abi), in which the infected cell commits suicide before the phage can complete its replication cycle. Abi prevents the phage epidemic from spreading to nearby cells, thus protecting the bacterial colony. The Abi strategy is manifested by a plethora of mechanistically diverse defense systems that are abundant in bacterial genomes. In turn, phages have developed equally diverse mechanisms to overcome bacterial Abi. This review summarizes the current knowledge on bacterial defense via cell suicide. It describes the principles of Abi, details how these principles are implemented in a variety of natural defense systems, and discusses phage counter-defense mechanisms.
Electrochemistry and Thermal Behavior of SiOxMade by Reactive Gas Milling
Authors: Cao Yidan , Dunlap R. A. , Obrovac M. N.
Published: June 2020

SiOxwith various oxygen contents were synthesized from Si powder by a simple room-temperature ball milling method by controlling the air exposure time during milling. The resulting SiOxconsists of nano and amorphous Si dispersed in an amorphous silicon oxide matrix. The oxygen saturated composition of SiO0.37is thermally stable up to 800 °C and has improved cycling performance after annealing. The 1st irreversible capacity is reduced by high temperature annealing due to defect healing, while the high reversible capacity (1500–2000 mAh g−1or 1600–1800 Ah l−1) is well maintained. This work demonstrates the thermal properties of SiOxmade by reactive gas milling and how internal defects directly influence its electrochemistry.
LncRNA-SMILR modulates RhoA/ROCK signaling by targeting miR-141 to regulate vascular remodeling in pulmonary arterial hypertension
Authors: Lei Si , Peng Fei , Li Mei-Lei , Duan Wen-Bing , Peng Cai-Qin , Wu Shang-Jie
Published: June 2020

Smooth muscle-enriched long noncoding RNA (SMILR), as a long noncoding RNA (lncRNA), was increased in pulmonary arterial hypertension (PAH) patients and in vitro and in vivo models. SMILR activated RhoA/ROCK signaling by targeting miR-141 to disinhibit its downstream target RhoA. SMILR knockdown or miR-141 overexpression inhibited hypoxia-induced cell proliferation and migration via repressing RhoA/ROCK signaling in pulmonary arterial smooth muscle cells (PASMCs), which was confirmed in vivo experiments that knockdown of SMILR inhibited vascular remodeling and alleviated PAH in rats. SMILR may be a promising and novel therapeutic target for the treatment and drug development of PAH.
GLP-1/GLP-1R Signaling Regulates Ovarian PCOS-Associated Granulosa Cells Proliferation and Antiapoptosis by Modification of Forkhead Box Protein O1 Phosphorylation Sites
Authors: Sun Zhihua , Li Peiyi , Wang Xiao , Lai Shuchang , Qiu Hong , Chen Zhi , Hu Shidi , Yao Jie , Shen Jie
Published: June 2020

As the major cause of female anovulatory infertility, polycystic ovary syndrome (PCOS) affects a great proportion of women at childbearing age. Although glucagon-like peptide 1 receptor agonists (GLP-IRAs) show therapeutic effects for PCOS, its target and underlying mechanism remains elusive. In the present study, we identified that, both in vivo and in vitro, GLP-1 functioned as the regulator of proliferation and antiapoptosis of MGCs of follicle in PCOS mouse ovary. Furthermore, forkhead box protein O1 (FoxO1) plays an important role in the courses. Regarding the importance of granulosa cells (GCs) in oocyte development and function, the results from the current study could provide a more detailed illustration on the already known beneficial effects of GLP-1RAs on PCOS and support the future efforts to develop more efficient GLP-1RAs for PCOS treatment.
Myristica lowiana Phytochemicals as Inhibitor of Plasmid Conjugation in Escherichia coli
Authors: Kwapong Awo Afi , Soares Sarah , Teo Stephen Ping , Stapleton Paul , Gibbons Simon
Published: June 2020

Hexane extract and methanol fraction from the stem bark of Myristica lowiana specifically and significantly inhibited the conjugal transfer of the IncW plasmid R7K, a plasmid which harbors ampicillin‐, streptomycin‐, and spectinomycin‐resistant genes. The transfer of this plasmid via the conjugative pilli of Escherichia coli was reduced by 76.5 ± 2.0% and 79.0 ± 1.2% by hexane extract and methanol fraction of M. lowiana, respectively. The hexane extract exhibited significant anti‐conjugant activity at a non‐cytotoxic concentration of 100 mg/L as assessed against adult human dermal fibroblast cells. The hexane extract and methanol fraction were screened using phytochemical tests, NMR spectroscopy, IR spectroscopy, and high‐resolution electrospray ionization mass spectrometry (HRESIMS) and were found to contain terpenoids, sterols, and fatty acids.
Use of Intraoperative Radioguidance in Recurrent Merkel Carcinoma
Authors: Beniey Michèle , Destrempes Naomie , Coulombe Geneviève , El Khoury Mona , Nassif Edgard
Published: June 2020

Merkel cell carcinoma is a rapidly progressive nonmelanoma skin cancer with a high risk of recurrence. When recurrence occurs, it is associated with poor prognosis and there is a lack of guidelines for the management of such cases. This article describes a challenging case in which the innovative use of iodine-125 radioactive seeds permitted us to precisely identify and resect two nonpalpable recurrent nodules. The safety and accuracy of the surgical procedure were compromised by the presence of scar tissue following two past resections and two courses of radiotherapy. Radioactive seed localization is a well-known procedure in breast cancer, demonstrating potential for an extended application in other cancer types and in complex clinical situations.
Convergence Analysis of a Trust-Region Multidimensional Filter Method for Nonlinear Complementarity Problems
Authors: Wu C. W. , Cao J. P. , Wang L. F.
Published: June 2020

For solving nonlinear complementarity problems, a new algorithm is proposed by using multidimensional filter techniques and a trust-region method. The algorithm is shown to be globally convergent under the reasonable assumptions and does not depend on any extra restoration procedure. In particular, it shows that the subproblem is a convex quadratic programming problem, which is easier to be solved. The results of numerical experiments show its efficiency.
Finite Element Failure Analysis of GFRP Laminates in Plate-Cone Reticulated Shell
Authors: Wang Xing , Jiang Yu , Huang Yonghui , Huang Yue , Wang Fan
Published: June 2020

Plate-cone reticulated shell is a new type of spatial structures with good mechanical behavior, technical economy, and architectural appearance. In this paper, using ANSYS software, the strength failure analysis model of composite laminates is established in cooperation with the Strength Criterion of Hoffman. The effects of layer number, laying direction, and thickness of laminates on the ultimate strength of laminates are studied by detailed parametric analysis, which provides a theoretical basis for the design of composite plate-cone reticulated shell and GFRP laminated plates. Some important conclusions are obtained and can be applied to engineering practice.
UFM1-Specific Ligase 1 Ligating Enzyme 1 Mediates Milk Protein and Fat Synthesis-Related Gene Expression via the JNK Signaling Pathway in Mouse Mammary Epithelial Cells
Authors: Kuang Meiqian , Yang Min , Li Lian , Li Chengmin , Wang Genlin
Published: June 2020

Ubiquitin-like modifier 1 ligating enzyme 1 (UFL1) has been characterized as a ubiquitin-like (Ubl) protein that affects a range of cellular processes across various pathways. In this study, mouse mammary epithelial cells (HC11 cell line) and UFL1 knockout (KO) mice were used to establish UFL1 knockdown models to explore the influence of UFL1 on milk protein and fat synthesis in the mouse mammary gland and the underlying mechanisms. This is the first study to show UFL1 localization in mouse mammary epithelial cells. UFL1 depletion by transfected UFL1 siRNA (siUFL1) caused aggravated apoptosis. In addition, UFL1 depletion suppressed milk protein synthesis-related protein level in vivo and in vitro. Conversely, ACACA and FASN expressions increased in UFL1-deficient mice. Moreover, UFL1 depletion increased triglyceride synthesis levels and inhibited the p-JNK expression. Importantly, the expression of proteins related to milk protein synthesis was decreased in JNK- and UFL1-deficient cells, whereas proteins related to milk fat synthesis showed the opposite trend, indicating that UFL1 affects milk protein and fat synthesis via the suppression of JNK activation. Overall, our findings indicate that UFL1 plays a key role in mammary milk and fat synthesis via JNK activation.
Hypoxia Impairs NK Cell Cytotoxicity through SHP-1-Mediated Attenuation of STAT3 and ERK Signaling Pathways
Authors: Teng Rui , Wang Yanmeng , Lv Nan , Zhang Dan , Williamson Ramone A. , Lei Lei , Chen Ping , Lei Li , Wang Baiyan , Fu Jiaqi , Liu Xuna , He Aili , O’Dwyer Michael , Hu Jinsong
Published: June 2020

Natural killer (NK) cells are innate immune effectors with potent antitumor activity. However, tumor cells can create an immunosuppressive microenvironment to escape immune surveillance. Although accumulating evidence indicates that microenvironmental hypoxia plays an important role in favoring tumor development and immune evasion, it remains unclear by what means hypoxia directly impairs NK cell antitumor activity. In this study, we confirmed that hypoxic NK cells showed significantly lower cytotoxicity against tumor cells. Consistent with this finding, we found that the reduction in NK cell cytotoxicity resulting from hypoxia correlated to the lower expression of granzyme B, IFN-γ, and degranulation marker CD107a, as well as activating receptors including NKp30, NKp46, and NKG2D expressed on the surface of NK cells. More importantly, we further demonstrated that a reduction in the phosphorylation levels of ERK and STAT3 secondary to hypoxia was strongly associated with the attenuated NK cell cytotoxicity. Focusing on the mechanism responsible for reduced phosphorylation levels of ERK and STAT3, we reveal that the activation of protein tyrosine phosphatase SHP-1 (Src homology region 2 domain-containing phosphatase-1) following hypoxia might play an essential role in this process. By knocking down SHP-1 or blocking its activity using a specific inhibitor TPI-1, we were able to partially restore NK cell cytotoxicity under hypoxia. Taken together, we demonstrate that hypoxia could impair NK cell cytotoxicity by decreasing the phosphorylation levels of ERK and STAT3 in a SHP-1-dependent manner. Therefore, targeting SHP-1 could provide an approach to enhance NK cell-based tumor immunotherapy.
Quantum Influence of Topological Defects on a Relativistic Scalar Particle with Cornell-Type Potential in Cosmic String Space-Time with a Spacelike Dislocation
Authors: Ahmed Faizuddin
Published: June 2020

We study the relativistic quantum of scalar particles in the cosmic string space-time with a screw dislocation (torsion) subject to a uniform magnetic field including the magnetic quantum flux in the presence of potential. We solve the Klein-Gordon equation with a Cornell-type scalar potential in the considered framework and obtain the energy eigenvalues and eigenfunctions and analyze a relativistic analogue of the Aharonov-Bohm effect for bound states.
Evolution and Influencing Factors of Township Spatial Form: A Two-Dimensional Perspective
Authors: Gao Yanpeng , Chen Wenjun
Published: June 2020

The countryside is the habitat of food, ecology, and culture, and the indispensable basis for human survival and development. Assessing the spatial and temporal evolution of rural settlements contributes to the promotion of rural scientific developments. This study used the fractal theory, center-of-gravity model, and spatial syntax to analyze the spatial and temporal evolution of Shenyang Ciyutuo Subdistrict and its influencing factors based on geospatial data from 2009‒2019, from the perspectives of internal characteristics and external morphological changes. In terms of the external characteristics, from 2009‒2019, the compactness index increased from 0.414 to 0.454, the expansion rate increased from 1.17% to 3.11%, and the expansion intensity increased from 0.05% to 0.15%. From 2014‒2019, the western part of the subdistrict experienced the maximum expansion rate and expansion intensity. The center-of-gravity of the construction land shifted to the west and southwest. The internal characteristics of land use depended on geographical conditions. Clusters of rural settlements were formed in a north-south direction due to the topography and along the riverside in a band-like manner. From 2009‒2019, the integration level of the subdistrict improved and the scale and number of integration axis increased, forming a multicore tree-shaped structure. Pearson’s correlation analysis showed that urbanization is the main factor affecting the spatial and temporal land-use evolution, with transportation convenience, industrial park, and proximity to the river having little effects. This study provides a theoretical basis for the development of Ciyutuo Subdistrict and provides a reference for the development of similar commercial towns.
Natural Scene Text Detection and Segmentation Using Phase-Based Regions and Character Retrieval
Authors: Diaz-Escobar Julia , Kober Vitaly
Published: June 2020

Multioriented text detection and recognition in natural scene images are still challenges in the document analysis and computer vision communities. In particular, character segmentation plays an important role in the complete end-to-end recognition system performance. In this work, a robust multioriented text detection and segmentation method based on a biological visual system model is proposed. The proposed method exploits the local energy model instead of a common approach based on variations of local image pixel intensities. Features such as lines and edges are obtained by searching for the maximum local energy utilizing the scale-space monogenic signal framework. The candidate text components are extracted from maximally stable extremal regions of the local phase information of the image. The candidate regions are filtered by their phase congruency and classified as text and nontext components by the AdaBoost classifier. Finally, misclassified characters are restored, and all final characters are grouped into words. Experimental results show that the proposed text detection and segmentation method is invariant to scale and rotation changes and robust to perspective distortions, blurring, low resolution, and illumination variations (low contrast, high brightness, shadows, and nonuniform illumination). Besides, the proposed method achieves often a better performance compared with state-of-the-art methods on typical natural scene datasets.
Improvement of Osteoporosis Screening among Inflammatory Bowel Disease Patients at Gastroenterology Fellows’ Clinics
Authors: Wehbeh Antonios , Phatharacharukul Parkpoom , Fayad Nabil F.
Published: June 2020

Introduction. Individuals with inflammatory bowel disease (IBD) have an increased risk of osteoporosis compared to the general population. We aimed to improve the osteoporosis screening rate in the IBD patient population of the gastroenterology (GI) fellows’ continuity clinics. Methods. Baseline preintervention data were collected on patients seen from July through September of 2018. Four simplified criteria for osteoporosis screening were extrapolated from 3 national guidelines. Among patients who met any of these criteria, we determined the baseline screening rate. Fellows were then educated with a didactic session and handout material, and a standardized template was incorporated into clinic notes. Following this intervention, screening rates were reassessed from December 2018 through February 2019. Results. During the preintervention phase, fellows saw 80 patients with IBD. Dual-energy X-ray absorptiometry (DEXA) scan was obtained in 44% of IBD patients who qualify for screening at the county hospital clinic compared to 21% of veterans’ clinic IBD patients. In the postintervention period, screening rates remarkably improved to 100% in the county hospital clinic and to 75% in the veterans’ clinic. Overall, the screening rate increased by 56% (P<0.001). Conclusions. A large percentage of IBD patients at risk for osteoporosis did not have appropriate bone mass density testing. Educating GI fellows and adding a template to clinic notes were effective in significantly improving the number of patients at risk of osteoporosis to receive appropriate screening test, a DEXA scan. Similar educational interventions should be considered for providers caring for IBD patients to prevent complications of osteoporosis in these patients.
The Late-Gestational Triglyceride to High-Density Lipoprotein Cholesterol Ratio Is Associated with Neonatal Macrosomia in Women without Diabetes Mellitus
Authors: Yu Mengru , Wang Wenting , Wang Hong
Published: June 2020

Objective. To investigate the associations between late-gestational dyslipidemia, expressed as the ratio between triglycerides (TGs) and high-density lipoprotein cholesterol (HDL), and the risk of macrosomia among nondiabetic pregnant women. Methods. In this case-control study, 171 pregnant women who delivered macrosomia newborns were recruited from a total of 1856 nondiabetic pregnant women who delivered a singleton, nonanomalous newborn. A total of 684 normal controls were one-to-four matched by age. Logistic regression analysis was used to analyze the association between the TG/HDL ratio and the neonatal body weight as well as the risk of macrosomia. Results. The maternal serum TG and TG/HDL levels were much higher in the macrosomia group, while the maternal serum HDL-C levels were much lower in the macrosomia group than those in the control group. However, the serum total cholesterol (TC) and LDL-C levels were not significantly different between the two groups. Furthermore, maternal TG/HDL levels were positively associated with neonatal body weight. The confounding factors including maternal age, maternal height, gestational age, maternal body mass index (BMI), FPG, SBP, and neonatal sex were adjusted. A positive association between TG/HDL and neonatal body weight was still found. Moreover, the prevalence of macrosomia increased markedly in a dose-dependent manner as with maternal TG/HDL levels increased. Conclusions. Maternal serum TG/HDL levels at late gestation are positively associated with neonatal body weight and the risk of macrosomia in women without DM. Maintaining maternal lipid levels in an appropriate range is important in the context of fetal overgrowth and primary prevention of macrosomia.
Implementing Surrogate Safety Measures in Driving Simulator and Evaluating the Safety Effects of Simulator-Based Training on Risky Driving Behaviors
Authors: Ka Eunhan , Kim Do-Gyeong , Hong Jooneui , Lee Chungwon
Published: June 2020

Human errors cause approximately 90 percent of traffic accidents, and drivers with risky driving behaviors are involved in about 52 percent of severe traffic crashes. Driver education using driving simulators has been used extensively to obtain a quantitative evaluation of driving behaviors without causing drivers to be at risk for physical injuries. However, since many driver education programs that use simulators have limits on realistic interactions with surrounding vehicles, they are limited in reducing risky driving behaviors associated with surrounding vehicles. This study introduces surrogate safety measures (SSMs) into simulator-based training in order to evaluate the potential for crashes and to reduce risky driving behaviors in driving situations that include surrounding vehicles. A preliminary experiment was conducted with 31 drivers to analyze whether the SSMs could identify risky driving behaviors. The results showed that 15 SSMs were statistically significant measures to capture risky driving behaviors. This study used simulator-based training with 21 novice drivers, 16 elderly drivers, and 21 commercial drivers to determine whether a simulator-based training program using the SSMs is effective in reducing risky driving behaviors. The risky driving behaviors by novice drivers were reduced significantly with the exception of erratic lane-changing. In the case of elderly drivers, speeding was the only risky driving behavior that was reduced; the others were not reduced because of their difficulty with manipulating the pedals in the driving simulator and their defensive driving. Risky driving behaviors by commercial drivers were reduced overall. The results of this study indicated that the SSMs can be used to enhance drivers’ safety, to evaluate the safety of traffic management strategies as well as to reduce risky driving behaviors in simulator-based training.
Taxonomic Distribution of Medicinal Plants for Alzheimer’s Disease: A Cue to Novel Drugs
Authors: Kamran Muhammad , Kousar Rehana , Ullah Shakir , Khan Siraj , Umer Muhammad Farooq , Rashid Haroon Ur , Khan Zakir , Khattak Muhammad Ijaz Khan , Rehman Mujeeb Ur
Published: June 2020

Alzheimer’s disease (AD) is a neurodegenerative disorder manifested by decline in memory and mild cognitive impairment leading to dementia. Despite global occurrence of AD, the severity and hence onset of dementia vary among different regions, which was correlated with the customary use of medicinal herbs and exposure level to the causatives. In spite of execution of versatile therapeutic strategies to combat AD and other neurodegenerative diseases, success is only limited to symptomatic treatment. The role of natural remedies remained primitive and irreplaceable in all ages. In some examples, the extracted drugs failed to show comparable results due to lack of micro ingredients. Micro ingredients impart a peerless value to natural remedies which are difficult to isolate and/or determine their precise role during treatment. A variety of plants have been used for memory enhancement and other dementia-related complications since ages. Acetyl choline esterase inhibition, antioxidant potential, neuroprotection, mitochondrial energy restoration, and/or precipitated protein clearance put a vast taxonomic variety into a single group of anti-AD plants. Secondary metabolites derived from these medicinal plants have the potential to treat AD and other brain diseases of common pathology. This review summarizes the potential of taxonomically diverse medicinal plants in the treatment of AD serving as a guide to further exploration.
A Comparative Study of Antibacterial Activity of CuO/Ag and ZnO/Ag Nanocomposites
Authors: Asamoah R. B. , Annan E. , Mensah B. , Nbelayim P. , Apalangya V. , Onwona-Agyeman B. , Yaya A.
Published: June 2020

The synergistic effects of transition metal based nanocomposites are known to possess enhanced antibacterial activities. However, in‐depth analysis of the relative antibacterial performance of some of the prominent nanocomposites remains unavailable. This study compares the antibacterial activity of two separate nanocomposites, which are copper oxide with silver (CuO/Ag) and zinc oxide with silver (ZnO/Ag). The individual CuO/Ag and ZnO/Ag nanocomposites were synthesised by a mixed wet‐chemical method. The resulting particles were analysed by XRD, XRF, TEM, UV‐Vis spectrophotometer, BET, and FTIR. The antibacterial activity of the nanoparticles were tested on Gram‐negative and Gram‐positive bacteria, Escherichia coli (ATCC25922) and Staphylococcus aureus (ATCC25923), respectively, using the Kirby–Bauer disc diffusion and the microdilution methods. The Kirby–Bauer disc diffusion test results had the same minimum inhibition concentration (MIC) value for both CuO/Ag and ZnO/Ag against E. coli and S. aureus, which was 0.25 mg/ml. The applied nanocomposites using microdilution showed that CuO/Ag had approximately 98.8% and 98.7% efficiency on the respective Gram‐positive and Gram‐negative bacterial species, while ZnO/Ag achieved 91.7% and 89.3% efficiency, respectively, against the Gram‐positive and Gram‐negative bacterial species. This study presents a novel approach for relative analysis of the performance efficiency of transition metal based nanocomposites.
Ethnopharmacological Potential of Aspilia africana for the Treatment of Inflammatory Diseases
Authors: Okello Denis , Lee Jun , Kang Youngmin
Published: June 2020

Inflammatory diseases are major health concerns affecting millions of people worldwide. Aspilia africana has been used for centuries by many African communities in the treatment of a wide range of health conditions, including inflammatory diseases, osteoporosis, rheumatic pains, and wounds. Analysis of the phytochemical composition of A. africana indicated that the plant is rich in a broad range of secondary metabolites, including flavonoids, alkaloids, tannins, saponins, terpenoids, sterols, phenolic compounds, and glycosides. This explains the efficacy of the plant in treating inflammation‐related diseases, as well as several other health conditions affecting different African communities. The mechanisms of action of the anti‐inflammatory phytochemical compounds in A. africana include inhibition of a number of physiological processes involved in the inflammatory process and synthesis or action of proinflammatory enzymes. The phytochemicals enhance anti‐inflammatory biological responses such as inhibition of a number of chemical mediators including histamine, prostanoids and kinins, 5‐lipoxygenase. and cyclooxygenase and activation of phosphodiesterase and transcriptase. Currently used anti‐inflammatory medications are associated with several disadvantages such as drug toxicity and iatrogenic reactions, thereby complicating the treatment process. The adverse effects related to the use of these conventional synthetic drugs have been the driving force behind consideration of natural remedies, and efforts are being made toward the development of anti‐inflammatory agents based on natural extracts. A. africana is rich in secondary metabolites, and its use as a traditional medicine for treating inflammatory diseases has been validated through in vitro and in vivo studies. Therefore, the plant could be further explored for potential development of novel anti‐inflammatory therapeutics.
[Retracted] Overexpression of 14‐3‐3δ Predicts Poor Prognosis in Extrahepatic Cholangiocarcinoma Patients
Authors: Wu Qiao , Fan Hua , Lang Ren , Li Xianliang , Zhang Xingmao , Lv Shaocheng , He Qiang
Published: June 2020

The protein 14‐3‐3δ interacts with Trp53 to maintain G2 arrest and thus regulates the cell cycle. Though dysfunction of 14‐3‐3δ caused by hyper‐methylation of CpG islands was reported in several carcinomas, the exact role of this protein in the development of extrahepatic cholangiocarcinoma has not been fully elucidated. Here, we aim at investigating the clinical relevance between 14‐3‐3δ and human extrahepatic cholangiocarcinoma. We collected extrahepatic cholangiocarcinoma specimens of 65 patients in Beijing Chao Yang Hospital and evaluated their 14‐3‐3δ expression using immunohistochemistry. We categorized the patients into different subgroups according to clinic pathological factors, such as sex, age, tumor size, pathological classification, lymph node metastasis status, tumor stage, and serum markers including CEA, CA‐242, or CA19‐9, and further evaluated the correlation between 14‐3‐3δ expression and these potential prognostic factors. As a result, we detected 14‐3‐3δ expression in 53 out of 65 specimens (81.5%), and the expression was positively correlated with TNM stage, lymph node metastasis, and overall survival. Our results suggest that 14‐3‐3δ serves as an oncogenic driver in extrahepatic cholangiocarcinoma tumorigenesis rather than a cell cycle regulator; the overexpression of 14‐3‐3δ might be frequently acquired by tumor cells to escape appropriate cell cycle regulation. Thus, 14‐3‐3δ could be a potential target for extrahepatic cholangiocarcinoma diagnosis and therapy.
Seroprevalence and Risk Factors for Hepatitis B Virus Infection in Adolescent Blood Donors within Selected Counties of Western Kenya
Authors: Awili Hilary O. , Gitao George C. , Muchemi Gerald M.
Published: June 2020

Hepatitis B virus is a widespread public health menace approximated to have infected 257 million people chronically by 2015. Data on the prevalence of HBV is important in formulating public health policies on HBV control like safe blood transfusion. Adolescents aged 15 to 24 years, known to engage in risky activities associated with HBV spread, constitute major blood donors in Kenya. Notwithstanding current blood donation safety measures, HBV still remain hazardous transfusion‐transmissible infections in donated blood. This study therefore was to determine the prevalence of HBsAg and related risk factors among this donor group. A cross‐sectional study was conducted from April 2019 to August 2019 in Siaya, Kisumu, and Homa Bay counties. One thousand (1000) voluntary blood donors 18 to 25 years old were recruited. A predonation questionnaire was used to record their sociodemographic features and prior risk exposures. Blood samples were initially tested for HBsAg using Murex HBsAg Version 3 (DiaSorin, UK) and positives confirmed using ARCHITECT HBsAg Qualitative Confirmatory assay (Abbott Ireland) as per the manufacturer’s instructions. A result was considered positive if the first and confirmatory tests were all reactive. Generally, the prevalence of HBV was 3.4%, with no significant association between various sociodemographic variables and HBsAg positivity. Nevertheless, scarification and risky sexual behavior were significantly linked to HBV infections (odds ratio (OR) = 8.533, 95%confidence interval (CI) = 3.128‐23.275, p value of 0.001 and OR = 5.471, 95%CI = 1.925‐15.547, p value of 0.002, respectively). This study revealed a prevalence of 3.4% HBsAg among adolescent blood donors, with perilous sexual behaviors being the most significant risk factor, evidence that sexual contact still plays a major role in transmission of HBV among this donor group despite blood transfusion safety measures put in place. These study findings should therefore be put into consideration while framing health policies to mitigate effects of HBV infection on safe blood transfusion.
A Novel Aerodynamic Force and Flutter of the High-Aspect-Ratio Cantilever Plate in Subsonic Flow
Authors: Ma Li , Yao Minghui , Zhang Wei , Lou Kai , Cao Dongxing , Niu Yan
Published: June 2020

This paper focuses on the derivation of the aerodynamic force for the cantilever plate in subsonic flow. For the first time, a new analytical expression of the quasi-steady aerodynamic force related to the velocity and the deformation for the high-aspect-ratio cantilever plate in subsonic flow is derived by utilizing the subsonic thin airfoil theory and Kutta-Joukowski theory. Results show that aerodynamic force distribution obtained theoretically is consistent with that calculated by ANSYS FLUENT. Based on the first-order shear deformation and von Karman nonlinear geometric relationship, nonlinear partial differential dynamical equations of the high-aspect-ratio plate subjected to the aerodynamic force are established by using Hamilton’s principle. Galerkin approach is applied to discretize the governing equations to ordinary differential equations. Numerical simulation is utilized to investigate the relation between the critical flutter velocity and some parameters of the system. Results show that when the inflow velocity reaches the critical value, limit cycle oscillation occurs. The aspect ratio, the thickness, and the air damping have significant impact on the critical flutter velocity of the thin plate.
Association between Interleukin-10 Gene Polymorphisms and Behcet’s Disease Susceptibility: Evidence from a Meta-Analysis
Authors: Li Xue-Feng , Huang Zhi-Zhen , Hu Yuan-Yuan , Niu Yu-Ming , Cai Jun-Wei
Published: June 2020

Epidemiological studies have demonstrated that interleukin-10 (IL-10) polymorphisms may be associated with the development of Behcet’s disease (BD). However, the published results were inconsistent. Therefore, this meta-analysis was conducted to derive a more precise relationship between IL-10 polymorphisms and BD susceptibility. Online databases (PubMed, Embase, Science Citation Index (SCI), CNKI, and WanFang) were searched to identify eligible studies. Odds ratio (OR) and a 95% confidence interval (CI) were applied to assess the relationship strength between IL-10 -1082A>G (rs1800896), -819T>C (rs1800871), and -592A>C (rs1800872) polymorphisms and BD susceptibility. Publication bias, sensitivity, and cumulative analyses were conducted to measure the robustness of our findings. Finally, fifteen articles (36 independent case-control studies) involving 5,971 patients and 8,913 controls were included. Overall, significant associations between -819T>C polymorphisms and BD risk were observed in the total population (C vs. T: OR=0.72, 95%CI=0.67‐0.77, P<0.01, I2=36.6%; TC vs. TT: OR=0.73, 95%CI=0.66‐0.80, P<0.01, I2=23.0%; CC vs. TT: OR=0.52, 95%CI=0.39‐0.70, P<0.01, I2=53.7%; TC+CC vs. TT: OR=0.67, 95%CI=0.61‐0.71, P<0.01, I2=22.1%; and CC vs. TT+TC: OR=0.66, 95%CI=0.53‐0.82, P<0.01, I2=57.8%). Moreover, the IL-10 -592 A>C polymorphism and the ACC haplotype exhibited a significant, protective effect against BD susceptibility. In summary, our meta-analysis suggested that IL-10 gene polymorphisms may play a salient role for BD development.
Efficacy and Safety Exposure–Response Relationships of Apalutamide in Patients with Nonmetastatic Castration-Resistant Prostate Cancer
Authors: Perez-Ruixo Carlos , Ackaert Oliver , Ouellet Daniele , Chien Caly , Uemura Hiroji , Olmos David , Mainwaring Paul , Lee Ji Youl , Yu Margaret K. , Perez-Ruixo Juan Jose , Smith Matthew R. , Small Eric J.
Published: June 2020

Purpose:

To evaluate the relationship between exposure of apalutamide and its active metabolite, N-desmethyl-apalutamide, and selected clinical efficacy and safety parameters in men with high-risk nonmetastatic castration-resistant prostate cancer.

Patients and Methods:

An exploratory exposure–response analysis was undertaken using data from the 1,207 patients (806 apalutamide and 401 placebo) enrolled in the SPARTAN study, including those who had undergone dose reductions and dose interruptions. Univariate and multivariate Cox regression models evaluated the relationships between apalutamide and N-desmethyl-apalutamide exposure, expressed as area under the concentration–time curve at steady state, and metastasis-free survival (MFS). Univariate and multivariate logistic regression models assessed the relationship between apalutamide and N-desmethyl-apalutamide exposure and common treatment-emergent adverse events including fatigue, fall, skin rash, weight loss, and arthralgia.

Results:

A total of 21% of patients in the apalutamide arm experienced dose reductions diminishing the average daily dose to 209 mg instead of 240 mg. Within the relatively narrow exposure range, no statistically significant relationship was found between MFS and apalutamide and N-desmethyl-apalutamide exposure. Within apalutamide-treated subjects, skin rash and weight loss had a statistically significant association with higher apalutamide exposure.

Conclusions:

The use of apalutamide at the recommended dose of 240 mg once daily provided a similar delay in metastases across the SPARTAN patient population, regardless of exposure. The exploratory exposure–safety analysis supports dose reductions in patients experiencing adverse events.
Proteasome Subunits Differentially Control Myeloma Cell Viability and Proteasome Inhibitor Sensitivity
Authors: Shi Chang-Xin , Zhu Yuan Xiao , Bruins Laura A. , Bonolo de Campos Cecilia , Stewart William , Braggio Esteban , Stewart A. Keith
Published: June 2020

We generated eight multiple myeloma cell lines resistant to bortezomib; five acquired PSMB5 mutations. In 1,500 patients such mutations were rare clinically. To better understand disruption of proteasomes on multiple myeloma viability and drug sensitivity, we systematically deleted the major proteasome catalytic subunits. Multiple myeloma cells without PSMB5 were viable. Drug-resistant, PSMB5-mutated cell lines were resensitized to bortezomib by PSMB5 deletion, implying PSMB5 mutation is activating in its drug resistance function. In contrast, PSMB6 knockout was lethal to multiple myeloma cell lines. Depleting PSMB6 prevented splicing of the major catalytic subunits PSMB5, PSMB7, PSMB8, and PSMB10; however, PSMB6 engineered without splicing function or catalytic activity, also restored viability, inferring the contribution of PSMB6 to proteasome structure to be more important than functional activity. Supporting this, bortezomib sensitivity was restored in drug-resistant multiple myeloma cell lines by low level expression of mutated PSMB6 lacking splicing function. Loss of PSMB8 and PSMB9 was neither lethal nor restored bortezomib sensitivity. Significant codependency of PSMB5, PSMB6, and PSMB7 expression was observed. We demonstrated elevated levels of PSMB6 and 7, but not 8 and 9, in some, but not all, serial patient samples exposed to proteasome inhibitors. In summary, we show PSMB6 and PSMB7, but not PSMB5, to be essential for multiple myeloma cell survival, this dependency is structural and that upregulation or activating mutation of PSMB5, 6, and 7 confers proteasome inhibitor resistance, while depletion confers sensitivity.

Implications:

These findings support modulation of PSMB5, PSMB6, or PSMB7 expression as a new therapeutic strategy.
Identification of the Cryptic HLA-I Immunopeptidome
Authors: Erhard Florian , Dölken Lars , Schilling Bastian , Schlosser Andreas
Published: June 2020

The success of cancer immunotherapy relies on the ability of cytotoxic T cells to specifically recognize and eliminate tumor cells based on peptides presented by HLA-I. Although the peptide epitopes that elicit the corresponding immune response often remain unidentified, it is generally assumed that neoantigens, due to tumor-specific mutations, are the most common targets. Here, we used a mass spectrometric approach to show an underappreciated class of epitopes that accounts for up to 15% of HLA-I peptides for certain HLA alleles in various tumors and patients. These peptides are translated from cryptic open reading frames in supposedly noncoding regions in the genome and are mostly unidentifiable with conventional computational analyses of mass spectrometry (MS) data. Our approach, Peptide-PRISM, identified thousands of such cryptic peptides in tumor immunopeptidomes. About 20% of these HLA-I peptides represented the C-terminus of the corresponding translation product, suggesting frequent proteasome-independent processing. Our data also revealed HLA-I allele–dependent presentation of cryptic peptides, with HLA-A*03 and HLA-A*11 presenting the highest percentage of cryptic peptides. Our analyses refute the reported frequent presentation of HLA peptides generated by proteasome-catalyzed peptide splicing. Thus, Peptide-PRISM represents an important step toward comprehensive identification of HLA-I immunopeptidomes and reveals cryptic peptides as an abundant class of epitopes with potential relevance for novel immunotherapeutic approaches.
Players in Drug-Resistant Leukemia Stem/Initiating Cells and Immunity in Patients with CML in Context of Oxygen Levels: Would Collecting/Processing Cells in Hypoxia Offer Additional Information? A Next Frontier of Investigation
Authors: Broxmeyer Hal
Published: June 2020

Chronic myelogenous leukemia (CML) is a stem cell disorder once considered an eventual death sentence upon progression to the terminal acute/blastic cell phase, a terrible clinical outcome that has improved with the introduction of tyrosine kinase inhibitors. A major continuing problem with treating CML is the persistence of drug-resistant leukemia stem/initiating cells (LS/IC). In this issue of Blood Cancer Discovery, Silvestri and colleagues describe an incredibly in-depth mechanistic study using genetic and pharmacologic modulation of the miRNA MiR300 with and without treatment with activators of the serine-threonine protein phosphatase 2A (PP2A) in human cells. In vitro studies and in vivo mouse models of patient-derived xenografts were used to address the need to target LS/ICs and restore immunity of impaired natural killer cells for attenuation of CML progression.

See related article by Silvestri et al., p. 48.
SPC18 Expression Is an Independent Prognostic Indicator of Patients with Esophageal Squamous Cell Carcinoma
Authors: Yamamoto Yuji , Oue Naohide , Asai Ryuichi , Katsuya Narutaka , Uraoka Naohiro , Sakamoto Naoya , Sentani Kazuhiro , Tanabe Kazuaki , Ohdan Hideki , Yasui Wataru
Published: June 2020

Objectives: Esophageal cancer is the sixth most common malignancy worldwide. Signal peptidase complex 18 (SPC18) protein, which is encoded by the SEC11A gene, is one of the subunits of the signal peptidase complex and plays an important role in the secretion of proteins including transforming growth factor α (TGF-α). In this study, we investigated the significance of SPC18 expression in human esophageal squamous cell carcinoma (ESCC). Methods: SPC18 expression was examined by immunohistochemistry. RNA interference was used to inhibit SPC18 expression in ESCC cell lines. To examine cell viability, we performed 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays. The effects of SPC18 inhibition on epidermal growth factor receptor (EGFR) signaling were analyzed by Western blot. Results:In total, 46 (50%) of 92 ESCC cases were positive for SPC18. SPC18 staining was observed more frequently in stage II/III/IV cases than in stage I cases (p = 0.028). We found that SPC18 expression was significantly associated with increased cancer-specific mortality (p = 0.006, log-rank test). SPC18 expression was frequently found in EGFR-positive cases compared with EGFR-negative cases. Cell proliferation and EGFR signaling were inhibited by SPC18 knockdown. Conclusion: Specific inhibitors of SPC18 may be promising anticancer drugs for patients with ESCC.
Investigation of the Relationship between MR-Based Supraclavicular Fat Fraction and Thyroid Hormones
Authors: Junker Daniela , Syväri Jan , Weidlich Dominik , Holzapfel Christina , Drabsch Theresa , Waschulzik Birgit , Rummeny Ernst J. , Hauner Hans , Karampinos Dimitrios C.
Published: June 2020

Purpose: Brown adipose tissue (BAT) plays a potential role in energy and glucose metabolism in humans. Thyroid hormones (TH) are main regulators of BAT development and function. However, it remains unknown how the magnetic resonance (MR)-based proton density fat fraction (PDFF) of supraclavicular adipose tissue used as a surrogate marker for BAT presence relates to TH. Therefore, the purpose of this analysis was to investigate the relationship between supraclavicular PDFF and serum levels of TH. Methods: In total, 96 adult volunteers from a large cross-sectional study who underwent additional MR examination of the neck and pelvis were included in this analysis. Segmented PDFF maps of the supraclavicular and gluteal subcutaneous adipose tissue were generated. Delta PDFF was calculated as the difference between gluteal and supraclavicular PDFF and grouped as high (≥12%) or low (<12%) based on the median and the clinical rationale of a high versus low probability of BAT being present. Thyroid-stimulating hormone (mIU/L), free triiodothyronine (FT3, pg/mL) and free thyroxine (FT4, ng/dL) levels were determined in blood samples. Body mass index (BMI) was calculated as weight (kg)/height (m)2. Statistical analyses included the use of paired samples ttest, simple linear regression analysis and a multivariable linear regression analysis. Results: The median age of the subjects (77% female) was 33 years, BMI ranged from 17.2 to 43.1 kg/m2. Supraclavicular and gluteal PDFF differed significantly (76.5 ± 4.8 vs. 89.4 ± 3.5 %, p < 0.01). Supraclavicular PDFF was associated with FT3 in subjects with high delta PDFF (R2 = 0.17, p < 0.01), with higher FT3 being associated with lower supraclavicular PDFF (y = 85.2 + –3.6 x). In a multivariable linear regression analysis considering further potential prognostic factors, the interaction between the delta PDFF group and FT3 remained a predictor for supraclavicular PDFF (B = –4.65, p < 0.01). Discussion/Conclusions: Supraclavicular PDFF corresponds to the presence of BAT. In the present analysis, supraclavicular PDFF is correlated with FT3 in subjects with high delta PDFF. Therefore, the present findings suggest that biologically active T3 may be involved in the development of supraclavicular BAT.
White Tea Reduced Bone Loss by Suppressing the TRAP/CTX Pathway in Ovariectomy-Induced Osteoporosis Model Rats
Authors: Yıldırım Murat , Saral Sinan , Mercantepe Tolga , İskender Hatice , Tümkaya Levent , Atak Mehtap , Taşçı Filiz
Published: June 2020

Osteoporosis is an important skeletal disease characterized by bone weakness and high risk of fracture in postmenopausal women. Tea consumption is known to play an important role in the prevention or alleviation of osteoporosis. However, the therapeutic effects of aqueous extracts of white tea (WT) have not been evaluated in osteoporosis rat models. The aim of this study was to investigate the potential anti-osteoporotic role of WT in ovariectomized (OVX) rats. WT was given orally at 0.5% w/v doses for 12 weeks in OVX rats. Biochemical parameters in blood samples, bone tartrate-resistant acid phosphatase (TRAP), C-terminal telopeptide of type 1 collagen (CTX) and estradiol levels were evaluated. Bone mineral density and bone mineral content values were measured in the left femur. In addition to histopathological examination, osteolcalcin, osteopontin and TUNEL levels were determined. OVX group data demonstrated that bone loss occurred by thinning of the metaphyseal growth plates of the femur. Similarly, the levels of TRAP and CTX, markers of osteoclastic activity, were found to be high concurrently with a decrease in femoral bone mineral density. In addition, increased osteolcalcin and osteopontin levels were present in the metaphyseal growth zones. On the other hand, while TRAP and CTX levels were suppressed in the OVX-WT group, bone mineral content increased. In ad­dition, TUNEL, osteocalcin and osteopontin positivity decreased in the right femoral metaphysis growth zones, proliferating zone and resting zone cells. These results showed that chronic WT consumption has a protective effect by reducing bone resorption in OVX-induced osteoporotic rats.