bluuebunny/crossref_metadata_2025 huggingface dataset:
Long-Term Maximum and Minimum Temperature Projections Over Metro Vancouver, Canada
Authors: Tian Chuyin , Huang Guohe , Liu Yanli , Yan Denghua , Wang Feng , Duan Ruixin
Published: September 2021

Evident climate change has been observed and projected in observation records and General Circulation Models (GCMs), respectively. This change is expected to reshape current seasonal variability; the degree varies between regions. High-resolution climate projections are thereby necessary to support further regional impact assessment. In this study, a gated recurrent unit-based recurrent neural network statistical downscaling model is developed to project future temperature change (both daily maximum temperature and minimum temperature) over Metro Vancouver, Canada. Three indexes (i.e., coefficient of determinant, root mean square error, and correlation coefficient) are estimated for model validation, indicating the developed model’s competitive ability to simulate the regional climatology of Metro Vancouver. Monthly comparisons between simulation and observation also highlight the effectiveness of the proposed downscaling method. The projected results (under one model set-up, WRF-MPI-ESM-LR, RCP 8.5) show that both maximum and minimum temperature will consistently increase between 2,035 and 2,100 over the 12 selected meteorological stations. By the end of this century, the daily maximum temperature and minimum temperature are expected to increase by an average of 2.91°C and 2.98°C. Nevertheless, with trivial increases in summer and significant rises in winter and spring, the seasonal variability will be reduced substantially, which indicates less energy requirement over Metro Vancouver. This is quite favorable for Metro Vancouver to switch from fossil fuel-based energy sources to renewable and clean forms of energy. Further, the cold extremes’ frequency of minimum temperature will be reduced as expected; however, despite evident warming trend, the hot extremes of maximum temperature will become less frequent.
Leanness and Low Plasma Leptin in GPR17 Knockout Mice Are Dependent on Strain and Associated With Increased Energy Intake That Is Not Suppressed by Exogenous Leptin
Authors: Wargent Edward T. , Ahmad Suhaib J. S. , Lu Qing Richard , Kostenis Evi , Arch Jonathan R. S. , Stocker Claire J.
Published: September 2021

Previous studies have shown that agonists of GPR17 stimulate, while antagonists inhibit feeding. However, whole body knockout of GPR17 in mice of the C57Bl/6 strain did not affect energy balance, whereas selective knockout in oligodendrocytes or pro-opiomelanocortin neurons provided protection from high fat diet-induced obesity and impaired glucose homeostasis. We reasoned that whole body knockout of GPR17 in mice of the 129 strain might elicit more marked effects because the 129 strain is more susceptible than the C57Bl/6 strain to increased sympathetic activity and less susceptible to high fat diet-induced obesity. Consistent with this hypothesis, compared to wild-type mice, and when fed on either a chow or a high fat diet, GPR17 -/- mice of the 129 strain displayed increased expression of uncoupling protein-1 in white adipose tissue, lower body weight and fat content, reduced plasma leptin, non-esterified fatty acids and triglycerides, and resistance to high fat diet-induced glucose intolerance. Not only energy expenditure, but also energy intake was raised. Administration of leptin did not suppress the increased food intake in GPR17 -/- mice of the 129 strain, whereas it did suppress food intake in GPR17 +/+ mice. The only difference between GPR17 +/- and GPR17 +/+ mice of the C57Bl/6 strain was that the body weight of the GPR17 -/- mice was lower than that of the GPR17 +/+ mice when the mice were fed on a standard chow diet. We propose that the absence of GPR17 raises sympathetic activity in mice of the 129 strain in response to a low plasma fuel supply, and that the consequent loss of body fat is partly mitigated by increased energy intake.
Guidelines for Biobanking of Bone Marrow Adipose Tissue and Related Cell Types: Report of the Biobanking Working Group of the International Bone Marrow Adiposity Society
Authors: Lucas Stephanie , Tencerova Michaela , von der Weid Benoit , Andersen Thomas Levin , Attané Camille , Behler-Janbeck Friederike , Cawthorn William P. , Ivaska Kaisa K. , Naveiras Olaia , Podgorski Izabela , Reagan Michaela R. , van der Eerden Bram C. J.
Published: September 2021

Over the last two decades, increased interest of scientists to study bone marrow adiposity (BMA) in relation to bone and adipose tissue physiology has expanded the number of publications using different sources of bone marrow adipose tissue (BMAT). However, each source of BMAT has its limitations in the number of downstream analyses for which it can be used. Based on this increased scientific demand, the International Bone Marrow Adiposity Society (BMAS) established a Biobanking Working Group to identify the challenges of biobanking for human BMA-related samples and to develop guidelines to advance establishment of biobanks for BMA research. BMA is a young, growing field with increased interest among many diverse scientific communities. These bring new perspectives and important biological questions on how to improve and build an international community with biobank databases that can be used and shared all over the world. However, to create internationally accessible biobanks, several practical and legislative issues must be addressed to create a general ethical protocol used in all institutes, to allow for exchange of biological material internationally. In this position paper, the BMAS Biobanking Working Group describes similarities and differences of patient information (PIF) and consent forms from different institutes and addresses a possibility to create uniform documents for BMA biobanking purposes. Further, based on discussion among Working Group members, we report an overview of the current isolation protocols for human bone marrow adipocytes (BMAds) and bone marrow stromal cells (BMSCs, formerly mesenchymal), highlighting the specific points crucial for effective isolation. Although we remain far from a unified BMAd isolation protocol and PIF, we have summarized all of these important aspects, which are needed to build a BMA biobank. In conclusion, we believe that harmonizing isolation protocols and PIF globally will help to build international collaborations and improve the quality and interpretation of BMA research outcomes.
NLRP3 Inflammasome: A New Target for Prevention and Control of Osteoporosis?
Authors: Jiang Na , An Jinyang , Yang Kuan , Liu Jinjin , Guan Conghui , Ma Chengxu , Tang Xulei
Published: September 2021

Osteoporosis is a systemic bone metabolism disease that often causes complications, such as fractures, and increases the risk of death. The nucleotide-binding oligomerization domain-like-receptor family pyrin domain-containing 3 (NLRP3) inflammasome is an intracellular multiprotein complex that regulates the maturation and secretion of Caspase-1 dependent proinflammatory cytokines interleukin (IL)-1β and IL-18, mediates inflammation, and induces pyroptosis. The chronic inflammatory microenvironment induced by aging or estrogen deficiency activates the NLRP3 inflammasome, promotes inflammatory factor production, and enhances the inflammatory response. We summarize the related research and demonstrate that the NLRP3 inflammasome plays a vital role in the pathogenesis of osteoporosis by affecting the differentiation of osteoblasts and osteoclasts. IL-1β and IL-18 can accelerate osteoclast differentiation by expanding inflammatory response, and can also inhibit the expression of osteogenic related proteins or transcription factors.In vivoandin vitroexperiments showed that the overexpression of NLRP3 protein was closely related to aggravated bone resorption and osteogenesis deficiency. In addition, abnormal activation of NLRP3 inflammasome can not only produce inflammation, but also lead to pyroptosis and dysfunction of osteoblasts by upregulating the expression of Caspase-1 and gasdermin D (GSDMD). In conclusion, NLRP3 inflammasome overall not only accelerates bone resorption, but also inhibits bone formation, thus increasing the risk of osteoporosis. Thus, this review highlights the recent studies on the function of NLRP3 inflammasome in osteoporosis, provides information on new strategies for managing osteoporosis, and investigates the ideal therapeutic target to treat osteoporosis.
Lower Limb Deformity and Gait Deviations Among Adolescents and Adults With X-Linked Hypophosphatemia
Authors: Mindler Gabriel T. , Kranzl Andreas , Stauffer Alexandra , Kocijan Roland , Ganger Rudolf , Radler Christof , Haeusler Gabriele , Raimann Adalbert
Published: September 2021

Background

X-linked hypophosphatemia (XLH) is a rare genetic disorder characterized by lower limb deformity, gait and joint problems, and pain. Hence, quality of life is substantially impaired. This study aimed to assess lower limb deformity, specific radiographic changes, and gait deviations among adolescents and adults with XLH.

Design

Data on laboratory examination and gait analysis results were analyzed retrospectively. Deformities, osteoarthritis, pseudofractures, and enthesopathies on lower limb radiographs were investigated. Gait analysis findings were compared between the XLH group and the control group comprising healthy adults.

Patients and Controls

Radiographic outcomes were assessed retrospectively in 43 patients with XLH (28 female, 15 male). Gait analysis data was available in 29 patients with confirmed XLH and compared to a healthy reference cohort (n=76).

Results

Patients with XLH had a lower gait quality compared to healthy controls (Gait deviation index GDI 65.9% +/- 16.2). About 48.3% of the study population presented with a greater lateral trunk lean, commonly referred to as waddling gait. A higher BMI and mechanical axis deviation of the lower limbs were associated with lower gait scores and greater lateral trunk lean. Patients with radiologic signs of enthesopathies had a lower GDI.

Conclusions

This study showed for the first time that lower limb deformity, BMI, and typical features of XLH such as enthesopathies negatively affected gait quality among adolescents and adults with XLH.
Electrochemical Characterization and Modelling of Anode and Electrolyte Supported Solid Oxide Fuel Cells
Authors: Padinjarethil Aiswarya Krishnakumar , Bianchi Fiammetta Rita , Bosio Barbara , Hagen Anke
Published: September 2021

Solid Oxide Fuel Cells (SOFCs) have emerged as an attractive alternative for efficient cogeneration of electricity and heat with reduced emissions during operation. High working temperatures result in optimized kinetics and higher efficiencies in comparison to other fuel cell types. Among different designs, Anode Supported Cells (ASCs) and Electrolyte Supported Cells are currently the most promising configurations on a commercial scale. This work analyses these two designs with a focus on electrochemical features as the main performance marker. The study was carried out using both theoretical and experimental approaches on planar single cells. A detailed test campaign at different operating conditions in terms of temperature, fuel and oxidant composition was designed. Electrochemical Impedance Spectroscopy and current-voltage (I-V) measurements were used to identify the contributions of different cell components. The electrochemical kinetics derived from the individual resistance terms was implemented in a 2D simulation tool (SIMFC-SIMulation of Fuel Cells) to obtain the detailed global cell behaviour and to understand local occurring mechanisms on anodic and cathodic cell planes. The model was validated for an anode supported cell consisting of Ni-YSZ/YSZ/LSCF-CGO and an electrolyte supported cell consisting of Ni-CGO/YSZ/LSCF-CGO, showing the possibility to tune the parameters depending on analysed cells.
Local Ancestry to Identify Selection in Response to Trypanosome Infection in Baoulé x Zebu Crossbred Cattle in Burkina Faso
Authors: Yougbaré Bernadette , Ouédraogo Dominique , Tapsoba Arnaud S. R. , Soudré Albert , Zoma Bienvenue L. , Orozco-terWengel Pablo , Moumouni Sanou , Ouédraogo-Koné Salifou , Wurzinger Maria , Tamboura Hamidou H. , Traoré Amadou , Mwai Okeyo Ally , Sölkner Johann , Khayatzadeh Negar , Mészáros Gábor , Burger Pamela A.
Published: September 2021

The genomes of crossbred (admixed) individuals are a mosaic of ancestral haplotypes formed by recombination in each generation. The proportion of these ancestral haplotypes in certain genomic regions can be responsible for either susceptibility or tolerance against pathogens, and for performances in production traits. Using a medium-density genomic marker panel from the Illumina Bovine SNP50 BeadChip, we estimated individual admixture proportions for Baoulé x Zebu crossbred cattle in Burkina Faso, which were tested for trypanosome infection by direct ELISA from blood samples. Furthermore, we calculated local ancestry deviation from average for each SNP across 29 autosomes to identify potential regions under selection in the trypanotolerant Baoulé cattle and their crossbreds. We identified significant deviation from the local average ancestry (above 5 and 10% genome-wide thresholds) on chromosomes 8 and 19 in the positive animals, while the negative ones showed higher deviation on chromosomes 6, 19, 21, and 22. Some candidate genes on chromosome 6 (PDGFRA) and chromosome 19 (CDC6) have been found associated to trypanotolerance in West African taurines. Screening for FST outliers in trypanosome positive/negative animals we detected seven variants putatively under selection. Finally, we identified a minimum set of highly ancestry informative markers for routine admixture testing. The results of this study contribute to a better understanding of the genetic basis of trypanotolerance in Baoulé cattle and their crossbreeds. Furthermore, we provide a small informative marker set to monitor admixture in this valuable indigenous breed. As such, our results are important for conserving the genetic uniqueness and trypanotolerance of Baoulé cattle, as well as for the improvement of Baoulé and Zebu crossbreds in specific community-based breeding programs.
Effects of Mesenchymal Stem Cell-Derived Exosomes on Autoimmune Diseases
Authors: Shen Ziwei , Huang Wei , Liu Jun , Tian Jie , Wang Shengjun , Rui Ke
Published: September 2021

Recent years, the immunosuppressive properties of mesenchymal stem cells (MSCs) have been demonstrated in preclinical studies and trials of inflammatory and autoimmune diseases. Emerging evidence indicates that the immunomodulatory effect of MSCs is primarily attributed to the paracrine pathway. As one of the key paracrine effectors, mesenchymal stem cell-derived exosomes (MSC-EXOs) are small vesicles 30-200 nm in diameter that play an important role in cell-to-cell communication by carrying bioactive substances from parental cells. Recent studies support the finding that MSC-EXOs have an obvious inhibitory effect toward different effector cells involved in the innate and adaptive immune response. Moreover, substantial progress has been made in the treatment of autoimmune diseases, including multiple sclerosis (MS), systemic lupus erythematosus (SLE), type-1 diabetes (T1DM), uveitis, rheumatoid arthritis (RA), and inflammatory bowel disease (IBD). MSC-EXOs are capable of reproducing MSC function and overcoming the limitations of traditional cell therapy. Therefore, using MSC-EXOs instead of MSCs to treat autoimmune diseases appears to be a promising cell-free treatment strategy. In this review, we review the current understanding of MSC-EXOs and discuss the regulatory role of MSC-EXOs on immune cells and its potential application in autoimmune diseases.
Vertical Fine-Scale Distribution of Calanus sinicus in the Yellow Sea Cold Water Mass During the Over-Summering Process
Authors: Pan Jun , Cheng Fangping , Yu Fei , Shi Yongqiang , Sun Fan , Si Guangcheng , Wei Chuanjie , Diao Xinyuan , Zhao Yongfang
Published: September 2021

Calanus sinicus, a temperate copepod with a lethal temperature >27°C, is one of the key species in Chinese coastal marine ecosystems. The C. sinicus population increases in spring and declines in early summer annually due to increasing water temperature. Numerous C. sinicus individuals then congregate in the Yellow Sea Cold Water Mass (YSCWM) and remain under the thermocline from early summer to early autumn. Development and reproduction is halted in this cold and foodless bottom water and they avoid ascending to the hot surface water, which is regarded as an over-summering strategy. Based on discrete water sampling approaches, previous studies demonstrated that higher chlorophyll a (Chl a) levels appeared in the mixed hot surface water layer; however, the subsurface chlorophyll a maximum layer (SCML) has seldom been described. In the present study, various probes and a visual plankton recorder (VPR) were used to determine the fine vertical distributions of environmental factors and C. sinicus. VPR observations showed the ecological responses in fine scale and indicated that few C. sinicus individuals ascend at night, the main population preferred to remain below the SCML all day long. The results demonstrated that a constant thin SCML existed in the YSCWM area, and that the SCML location coincided with or was beneath the thermocline and halocline layers, where the temperature was suitable for C. sinicus. The relationship between abundance and Chl a, showed the diel vertical migration trend of C. sinicus to feed at night in the YSCWM area. In addition to temperature as a main influencing factor, dissolved oxygen concentrations and column depth were also influencing factors. Therefore, in addition to avoiding high surface temperature, energy supplement may be an important driving force confining the diel vertical migration of C. sinicus in the Yellow Sea in summer.
A Cross-Reactive Monoclonal Antibody Against Neuraminidases of Both H9N2 and H3N2 Influenza Viruses Shows Protection in Mice Challenging Models
Authors: Wang Fei , Wan Zhimin , Wu Jinsen , Wang Yajuan , Fu Hui , Shao Hongxia , Qian Kun , Gao Wei , Ye Jianqiang , Qin Aijian
Published: September 2021

Neuraminidases (NAs) of H9N2 avian influenza virus (AIV) and H3N2 human seasonal influenza virus (HSIV) share similar antigenic structures. However, there are few reports on epitopes shared by these two NAs. We previously reported a monoclonal antibody (mAb) 1G8 against the NA of H9N2 AIV with neuraminidase inhibition (NI) ability. In this study, 1G8 was shown to cross-react with and inhibit the NA of H3N2 HSIV. In a passive transfer experiment, 1G8 provided protection to mice challenged with rescued H1N2 viruses carrying H9N2 NA or H3N2 NA. Mutation at amino acid position 199 was also selected and proved to be crucial for H3N2 HSIV to escape from mAb 1G8. Moreover, we found that residue 199 contributed to inducing broad protective antibodies without the influence of the N-linked glycosylation at amino acid position 200 in NAs. Residues as residue 199, which are not shielded by glycosylation modification, would form ideal epitopes for developing universal vaccine and protective antibodies.
Ursolic Acid Targets Glucosyltransferase and Inhibits Its Activity to Prevent Streptococcus mutans Biofilm Formation
Authors: Liu Yucui , Huang Yanxin , Fan Cong , Chi Zhongmei , Bai Miao , Sun Luguo , Yang Li , Yu Chunlei , Song Zhenbo , Yang Xiaoguang , Yi Jingwen , Wang Shuyue , Liu Lei , Wang Guannan , Zheng Lihua
Published: September 2021

Streptococcus mutans (S. mutans), the prime pathogen of dental caries, can secrete glucosyltransferases (GTFs) to synthesize extracellular polysaccharides (EPSs), which are the virulence determinants of cariogenic biofilms. Ursolic acid, a type of pentacyclic triterpene natural compound, has shown potential antibiofilm effects on S. mutans. To investigate the mechanisms of ursolic acid-mediated inhibition of S. mutans biofilm formation, we first demonstrated that ursolic acid could decrease the viability and structural integrity of biofilms, as evidenced by XTT, crystal violet, and live/dead staining assays. Then, we further revealed that ursolic acid could compete with the inherent substrate to occupy the catalytic center of GTFs to inhibit EPS formation, and this was confirmed by GTF activity assays, computer simulations, site-directed mutagenesis, and capillary electrophoresis (CE). In conclusion, ursolic acid can decrease bacterial viability and prevent S. mutans biofilm formation by binding and inhibiting the activity of GTFs.
Identification of Mast Cell-Based Molecular Subtypes and a Predictive Signature in Clear Cell Renal Cell Carcinoma
Authors: Liu Hanxiang , Yang Yi
Published: September 2021

Background: Kidney renal clear cell carcinoma (KIRC) is a common malignant tumor of the urinary system. Surgery is the preferred treatment option; however, the rate of distant metastasis is high. Mast cells in the tumor microenvironment promote or inhibit tumorigenesis depending on the cancer type; however, their role in KIRC is not well-established. Here, we used a bioinformatics approach to evaluate the roles of mast cells in KIRC.

Methods: To quantify mast cell abundance based on gene sets, a single-sample gene set enrichment analysis (ssGSEA) was utilized to analyze three datasets. Weighted correlation network analysis (WGCNA) was used to identify the genes most closely related to mast cells. To identify new molecular subtypes, the nonnegative matrix factorization algorithm was used. GSEA and least absolute shrinkage and selection operator (LASSO) Cox regression were used to identify genes with high prognostic value. A multivariate Cox regression analysis was performed to establish a prognostic model based on mast cell-related genes. Promoter methylation levels of mast cell-related genes and relationships between gene expression and survival were evaluated using the UALCAN and GEPIA databases.

Results: A prolonged survival in KIRC was associated with a high mast cell abundance. KIRC was divided into two molecular subtypes (cluster 1 and cluster 2) based on mast cell-related genes. Genes in Cluster 1 were enriched for various functions related to cancer development, such as the TGFβ signaling pathway, renal cell carcinoma, and mTOR signaling pathway. Based on drug sensitivity predictions, sensitivity to doxorubicin was higher for cluster 2 than for cluster 1. By a multivariate Cox analysis, we established a clinical prognostic model based on eight mast cell-related genes.

Conclusion: We identified eight mast cell-related genes and constructed a clinical prognostic model. These results improve our understanding of the roles of mast cells in KIRC and may contribute to personalized medicine.
Case Report: A Novel GNB1 Mutation Causes Global Developmental Delay With Intellectual Disability and Behavioral Disorders
Authors: Da Silva Jorge Diogo , Costa Marta Daniela , Almeida Bruno , Lopes Fátima , Maciel Patrícia , Teixeira-Castro Andreia
Published: September 2021

Diseases of neurodevelopment mostly exhibit neurological and psychiatric symptoms that go from very mild to extremely severe. While the etiology of most cases of neurodevelopmental disease is still unknown, the discovery of underlying genetic causes is rapidly increasing, with hundreds of genes being currently implicated as disease-causing. Here, we report a clinical case of a patient with a previously undiagnosed syndrome comprising severe global developmental delay, intellectual disability, and behavioral disorders (such as attention-deficit/hyperactivity disorder, autism spectrum disorder and recurrent bouts of aggressive behavior). After genetic testing, a pathogenic variant was detected in the GNB1 gene, which codes for the G-protein subunit β1. The detected variant (c.217G>A, p.A73T) has not been previously reported in any of the 58 published cases of GNB1 encephalopathy. However, it localizes to the mutational hotspot in exons 6 and 7 in which 88% of all missense mutations occur. An in silico model predicts that this mutation is likely to disrupt the WD40 domain of the GNB1 protein, which is required for its interaction with other G-proteins and, consequently, for downstream signal transduction. In conclusion, we reported an additional GNB1 encephalopathy patient, bearing a novel mutation, taking another step toward a better understanding of its clinical presentation and prospective development of treatments for the disease.
Baroreflex Curve Fitting Using a WYSIWYG Boltzmann Sigmoidal Equation
Authors: Heusser Karsten , Heusser Ramona , Jordan Jens , Urechie Vasile , Diedrich André , Tank Jens
Published: September 2021

Arterial baroreflex assessment using vasoactive substances enables investigators to collect data pairs over a wide range of blood pressures and reflex reactions. These data pairs relate intervals between heartbeats or sympathetic neural activity to blood pressure values. In an X-Y plot the data points scatter around a sigmoidal curve. After fitting the parameters of a sigmoidal function to the data, the graph’s characteristics represent a rather comprehensive quantitative reflex description. Variants of the 4-parameter Boltzmann sigmoidal equation are widely used for curve fitting. Unfortunately, their ‘slope parameters’ do not correspond to the graph’s actual slope which complicates the analysis and bears the risk of misreporting. We propose a modified Boltzmann sigmoidal function with preserved goodness of fit whose parameters are one-to-one equivalent to the sigmoidal curve’s characteristics.
Relationship Between Dietary Knowledge, Socioeconomic Status, and Stroke Among Adults Involved in the 2015 China Health and Nutrition Survey
Authors: Xiang Ruojun , Zhai Xiaoya , Zhang Qiujin , Wang Zhihua
Published: September 2021

Stroke is a public health threat that requires urgent attention in China. Nutrients have individual significant impacts on the prevalence of stroke. However, little research has been conducted on the impact of dietary knowledge on stroke and whether the impact is potentially heterogeneous under the effect of socioeconomic status. This study used the 2015 Chinese Health and Nutrition Survey to explore the impact of dietary knowledge and socioeconomic factors on populations suffering from stroke. Results indicated that risk of stroke decreased significantly with increasing dietary knowledge score. Additionally, the impact of dietary knowledge scores on the prevalence of stroke has obvious heterogeneity. First, dietary knowledge scores significantly influenced low-income groups and individuals with low educational levels. Second, the risk of stroke in females is more affected by dietary knowledge. Third, for people living in different areas, dietary knowledge determines whether rural populations suffer from stroke.
Efficacy and Safety of Tumor Treating Fields (TTFields) in Elderly Patients with Newly Diagnosed Glioblastoma: Subgroup Analysis of the Phase 3 EF-14 Clinical Trial
Authors: Ram Zvi , Kim Chae-Yong , Hottinger Andreas F. , Idbaih Ahmed , Nicholas Garth , Zhu Jay-Jiguang
Published: September 2021

Background

Understudied elderly patients comprise a large segment of high-risk patients with glioblastoma (GBM) that are challenging to treat. Tumor Treating Fields (TTFields) is a locoregional, noninvasive, antimitotic therapy delivering low-intensity, intermediate-frequency alternating electric fields to the tumor. In the phase 3 EF-14 clinical trial, TTFields (200 kHz) improved median progression-free survival (PFS) and median overall survival (OS) in patients with newly diagnosed GBM (ndGBM) when added concomitantly to maintenance temozolomide (TMZ). This EF-14 subgroup analysis evaluated the safety and efficacy of TTFields in elderly patients.

Methods

All 134 patients who are ≥65 years of age were included (TTFields/TMZ combination, n=89; TMZ monotherapy, n=45; 2:1 ratio of randomization). PFS and OS were analyzed using Kaplan–Meier methodology (α=0.05). Health-related quality-of-life (HRQoL) was assessed using the European Organisation for Research and Treatment of Cancer (EORTC) quality-of-life questionnaire QLQ-C30 supplemented with the brain tumor module (QLQ-BN20). Adverse events (AEs) were evaluated using Common Terminology Criteria for AEs (CTCAE) v4.0.

Results

The PFS was 6.5 months in patients randomized to the treatment group with TTFields/TMZ combination versus 3.9 months in patients treated with TMZ monotherapy (HR, 0.47; 95% CI, 0.30–0.74; P=0.0236). The OS was 17.4 months in patients treated with TTFields/TMZ combination versus 13.7 months in patients treated with TMZ monotherapy (HR, 0.51; 95% CI, 0.33–0.77; P=0.0204). Annual survival rates with TTFields/TMZ versus TMZ monotherapy were 39% (95% CI, 29–50%) versus 27% (95% CI, 15–41%; P=0.072) at 2 years, 19% (95% CI, 11–29%) versus 11% (95% CI, 4–23%; P=0.135) at 3 years, and 15% (95% CI, 7–25%) versus 0% at 5 years, respectively. There were no significant differences between groups in the preselected items of HRQoL assessment. Grade ≥3 systemic AEs were 46% in the TTFields/TMZ group versus 40% in the TMZ monotherapy group, without statistically significant difference between the two groups. The only TTFields-related AEs were reversible scalp skin reactions, with grades 1–2 and grade 3 skin reactions reported by 51% and 2% of patients, respectively.

Conclusions

Combining TTFields with maintenance TMZ significantly improved PFS and OS in elderly patients with ndGBM in the phase 3 EF-14 clinical trial, without significant increases in systemic toxicity or negatively affecting patient HRQoL. TTFields-related skin AEs were low-grade and manageable.

Clinical Trial Registration

https://clinicaltrials.gov/ct2/show/NCT00916409, identifier: NCT00916409.
RETRACTED: OTUB2 Facilitates Tumorigenesis of Gastric Cancer Through Promoting KDM1A-Mediated Stem Cell-Like Properties
Authors: Liu Guangming , Guo Wei , Qin Junjie , Lin Zhiliang
Published: September 2021

Otubain 2 (OTUB2), a deubiquitinating enzyme, overexpression is considered to predict poor outcome in various cancers. However, the function and potential regulatory mechanisms of OTUB2 in gastric cancer (GC) progression remains unclear. To determine how OTUB2 participate in GC progression, the gain and loss of-function experiments were conducted in vivo and in vitro. We found that OTUB2 was upregulated in GC samples (n=140) and cells. Moreover, the overall, first progression and post progression survival rates of GC patients with high OTUB2 expression showed a poorer prognosis than that in those patients with low OTUB2 expression. Down-regulation of OTUB2 suppressed sphere formation and reduced expression of stem cell markers in GC cells. Furthermore, OTUB2-silenced GC cells also showed a decreased proliferation, invasion, migration, and in vivo tumorigenic ability. However, OTUB2 overexpression showed the opposite effects. Notably, we demonstrated that OTUB2 increased lysine-specific histone demethylase 1A (KDM1A) expression through deubiquitination. KDM1A, a demethylase known to promote demethylation of downstream genes, was identified to promote the maintenance of cancer stem cell characteristics. Moreover, the alterations caused by OTUB2 overexpression were partly inversed by KDM1A knockdown and in turn KDM1A overexpression reversed the changes induced by OTUB2 shRNA. Taken together, we demonstrate that OTUB2 may serve as a vital driver in GC tumorigenesis by enhancing KDM1A-mediated stem cell-like properties.
Potential Molecular Biomarkers of Vestibular Schwannoma Growth: Progress and Prospects
Authors: Zhang Yu , Long Jianfei , Ren Junwei , Huang Xiang , Zhong Ping , Wang Bin
Published: September 2021

Vestibular schwannomas (VSs, also known as acoustic neuromas) are relatively rare benign brain tumors stem from the Schwann cells of the eighth cranial nerve. Tumor growth is the paramount factor for neurosurgeons to decide whether to choose aggressive treatment approach or careful follow-up with regular magnetic resonance imaging (MRI), as surgery and radiation can introduce significant trauma and affect neurological function, while tumor enlargement during long-term follow-up will compress the adjacent nerves and tissues, causing progressive hearing loss, tinnitus and vertigo. Recently, with the deepening research of VS biology, some proteins that regulate merlin conformation changes, inflammatory cytokines, miRNAs, tissue proteins and cerebrospinal fluid (CSF) components have been proposed to be closely related to tumor volume increase. In this review, we discuss advances in the study of biomarkers that associated with VS growth, providing a reference for exploring the growth course of VS and determining the optimal treatment strategy for each patient.
Revisiting the Immunological Aspects of Temozolomide Considering the Genetic Landscape and the Immune Microenvironment Composition of Glioblastoma
Authors: Di Ianni Natalia , Maffezzini Martina , Eoli Marica , Pellegatta Serena
Published: September 2021

The microenvironment (ME) plays a critical role in causing glioblastoma (GBM) to be a moving and incurable target. The main features governing the interaction between cancer cells and the ME include dependency, promotion, and in rare cases, even competition. In the original Stupp protocol, the alkylating agent temozolomide (TMZ) is the first-line chemotherapy drug to treat GBM, and it is broadly used together or after radiotherapy. Some studies have described TMZ as an adjuvant to other therapeutic approaches including immunotherapy because of its ability to induce an immunogenic death of cancer cells. TMZ also exerts immunomodulatory effects on the tumor and immune ME. These findings support the coexistence of two circuits, i.e., one that subverts local immunosuppressive mechanisms and another that exerts a harmful influence on the peripheral immune response. A bias toward the latter can drive the failure of treatments based on the combination of chemotherapy and immunotherapy approaches. In this review, we will reanalyze how intrinsic and acquired resistance to TMZ impacts the immunomodulatory effects previously described by way of inducing a functional alteration of local immune cells and promoting immunosuppression and how different components of the immune ME, with particular attention to tumor-associated macrophages and microglia, can cause TMZ resistance to circumvent potential local immunogenic mechanisms.
β2-and β3-Adrenergic Receptors Contribute to Cancer-Evoked Pain in a Mouse Model of Osteosarcoma via Modulation of Neural Macrophages
Authors: Bruno Gennaro , De Logu Francesco , Souza Monteiro de Araujo Daniel , Subbiani Angela , Lunardi Federica , Rettori Sofia , Nassini Romina , Favre Claudio , Calvani Maura
Published: September 2021

The mechanisms involved in the development and maintenance of cancer pain remain largely unidentified. Recently, it has been reported that β-adrenergic receptors (β-ARs), mainly β2-and β3-ARs, contribute to tumor proliferation and progression and may favor cancer-associated pain and neuroinflammation. However, the mechanism underlying β-ARs in cancer pain is still unknown. Here, we investigated the role of β1-, β2-and β3-ARs in a mouse model of cancer pain generated by the para-tibial injection of K7M2 osteosarcoma cells. Results showed a rapid tumor growth in the soft tissue associated with the development of mechanical allodynia in the hind paw ipsilateral to the injected site. In addition to reduce tumor growth, both propranolol and SR59230A, β1-/β2-and β3-AR antagonists, respectively, attenuated mechanical allodynia, the number of macrophages and an oxidative stress by-product accumulated in the ipsilateral tibial nerve. The selective β1-AR antagonist atenolol was able to slightly reduce the tumor growth but showed no effect in reducing the development of mechanical allodynia. Results suggest that the development of the mechanical allodynia in K7M2 osteosarcoma-bearing mice is mediated by oxidative stress associated with the recruitment of neural macrophages, and that antagonism of β2-and β3-ARs contribute not solely to the reduction of tumor growth, but also in cancer pain. Thus, the targeting of the β2-and β3-ARs signaling may be a promising therapeutic strategy against both tumor progression and the development of cancer-evoke pain in osteosarcoma.
Effects of Fluoride on Submandibular Glands of Mice: Changes in Oxidative Biochemistry, Proteomic Profile, and Genotoxicity
Authors: Lima Leidiane Alencar de Oliveira , Miranda Giza Hellen Nonato , Aragão Walessa Alana Bragança , Bittencourt Leonardo Oliveira , dos Santos Sávio Monteiro , de Souza Michel Platini Caldas , Nogueira Lygia S. , de Oliveira Edivaldo Herculano Corrêa , Monteiro Marta Chagas , Dionizio Aline , Leite Aline Lima , Pessan Juliano Pelim , Buzalaf Marília Afonso Rabelo , Lima Rafael Rodrigues
Published: September 2021

Although fluoride (F) is well-known to prevent dental caries, changes in cell processes in different tissues have been associated with its excessive exposure. Thus, this study aimed to evaluate the effects of F exposure on biochemical, proteomic, and genotoxic parameters of submandibular glands. Twenty one old rats (n = 30) were allocated into three groups: 60 days administration of drinking water containing 10 mgF/L, 50 mgF/L, or only deionized water (control). The submandibular glands were collected for oxidative biochemistry, protein expression profile, and genotoxic potential analyses. The results showed that both F concentrations increased the levels of thiobarbituric acid–reactive substances (TBARS) and reduced glutathione (GSH) and changed the proteomic profile, mainly regarding the cytoskeleton and cellular activity. Only the exposure to 50 mgF/L induced significant changes in DNA integrity. These findings reinforce the importance of continuous monitoring of F concentration in drinking water and the need for strategies to minimize F intake from other sources to obtain maximum preventive/therapeutic effects and avoid potential adverse effects.
Evaluation of a Clinically Relevant Drug–Drug Interaction Between Rosuvastatin and Clopidogrel and the Risk of Hepatotoxicity
Authors: Ning Chen , Su Shengdi , Li Jiaming , Kong Dexuan , Cai Hui , Qin Zhiying , Xing Han , Chen Xijing , He Jiake
Published: September 2021

Purpose: The combination therapy of rosuvastatin (RSV) and the platelet inhibitor clopidogrel (CP) is widely accepted in the management of cardiovascular diseases. The objective of the present study was to identify the mechanism of RSV–CP DDI and evaluate the risk of hepatotoxicity associated with the concomitant use of CP.

Methods: We first studied the effect of CP and its major circulating metabolite, carboxylic acid metabolite (CPC), on RSV transport by overexpressing cells and membrane vesicles. Second, we investigated whether a rat model could replicate this DDI and then be used to conduct mechanistic studies and assess the risk of hepatotoxicity. Then, cytotoxicity assay in hepatocytes, biochemical examination, and histopathology were performed to measure the magnitude of liver injury in the presence and absence of DDI.

Results: CP inhibited OATP1B1-mediated transport of RSV with an IC50 value of 27.39 μM. CP and CPC inhibited BCRP-mediated RSV transport with IC50 values of <0.001 and 5.96 μM, respectively. The CP cocktail (0.001 μM CP plus 2 μM CPC) significantly inhibited BCRP-mediated transport of RSV by 26.28%. Multiple p.o. doses of CP significantly increased intravenous RSV plasma AUC0-infinity by 76.29% and decreased intravenous RSV CL by 42.62%. Similarly, multiple p.o. doses of CP significantly increased p.o. RSV plasma AUC0-infinity by 87.48% and decreased p.o. RSV CL by 43.27%. CP had no effect on cell viability, while RSV exhibited dose-dependent cytotoxicity after 96 h incubation. Co-incubation of 100 μM CP and RSV for 96 h significantly increased intracellular concentrations and cell-to-medium concentration ratios of RSV and reduced hepatocyte viability. Histological evaluation of liver specimens showed patterns of drug-induced liver injury. Cholestasis was found in rats in the presence of DDI.

Conclusion: CP is not a clinically relevant inhibitor for OATP1B1 and OATP1B3. The primary mechanism of RSV–CP DDI can be attributed to the inhibition of intestinal BCRP by CP combined with the inhibition of hepatic BCRP by CPC. The latter is likely to be more clinically relevant and be a contributing factor for increased hepatotoxicity in the presence of DDI.
Upregulation of Thymidylate Synthase Induces Pemetrexed Resistance in Malignant Pleural Mesothelioma
Authors: Sato Yuzo , Tomita Masaru , Soga Tomoyoshi , Ochiai Atsushi , Makinoshima Hideki
Published: September 2021

Malignant pleural mesothelioma (MPM) is an invasive malignancy that develops in the pleural cavity, and antifolates are used as chemotherapeutics for treating. The majority of antifolates, including pemetrexed (PMX), inhibit enzymes involved in purine and pyrimidine synthesis. MPM patients frequently develop drug resistance in clinical practice, however the associated drug-resistance mechanism is not well understood. This study was aimed to elucidate the mechanism underlying resistance to PMX in MPM cell lines. We found that among the differentially expressed genes associated with drug resistance (determined by RNA sequencing), TYMS expression was higher in the established resistant cell lines than in the parental cell lines. Knocking down TYMS expression significantly reduced drug resistance in the resistant cell lines. Conversely, TYMS overexpression significantly increased drug resistance in the parental cells. Metabolomics analysis revealed that the levels of dTMP were higher in the resistant cell lines than in the parental cell lines; however, resistant cells showed no changes in dTTP levels after PMX treatment. We found that the nucleic acid-biosynthetic pathway is important for predicting the efficacy of PMX in MPM cells. The results of chromatin immunoprecipitation-quantitative polymerase chain reaction (ChIP-qPCR) assays suggested that H3K27 acetylation in the 5′-UTR of TYMS may promote its expression in drug-resistant cells. Our findings indicate that the intracellular levels of dTMP are potential biomarkers for the effective treatment of patients with MPM and suggest the importance of regulatory mechanisms of TYMS expression in the disease.
Associations Between Lipoprotein Subfractions and Area and Density of Abdominal Muscle and Intermuscular Adipose Tissue: The Multi-Ethnic Study of Atherosclerosis
Authors: Marron Megan M. , Allison Matthew , Kanaya Alka M. , Larsen Britta , Wood Alexis C. , Herrington David , Greenland Philip , Miljkovic Iva
Published: September 2021

Skeletal muscle quantity and quality decrease with older age, which is partly attributed to ectopic fat infiltration and has negative metabolic consequences. To inform efforts to preserve skeletal muscle with aging, a better understanding of biologic correlates of quantity and quality of muscle and intermuscular adipose tissue (IMAT) is needed. We used targeted lipidomics of lipoprotein subfractions among 947 Multi-Ethnic Study of Atherosclerosis participants to provide a detailed metabolic characterization of area and density of abdominal muscle and IMAT. Serum lipoprotein subfractions were measured at the first visit using 1H-Nuclear Magnetic Resonance spectroscopy. Muscle and IMAT area (cm2) and density (Hounsfield units) were estimated at visit 2 or 3 using computed tomography of the total abdominal, locomotion (psoas), and stabilization (paraspinal, oblique, rectus abdominis) muscles. We identified lipoprotein subfractions associated with body composition using linear regression adjusting for demographics, lifestyle, and multiple comparisons. Among 105 lipoprotein subfractions, 24 were associated with total muscle area (absolute standardized regression coefficient range: 0.07–0.10, p-values ≤ 0.002), whereas none were associated with total muscle density. When examining muscle subgroups, 25 lipoprotein subfractions were associated with stabilization muscle area, with associations strongest among the obliques. For total IMAT area, there were 27 significant associations with lipoprotein subfractions (absolute standardized regression coefficient range: 0.09–0.13, p-values ≤ 0.002). Specifically, 27 lipoprotein subfractions were associated with stabilization IMAT area, with associations strongest among the oblique and rectus abdominis muscles. For total IMAT density, there were 39 significant associations with lipoprotein subfractions (absolute standardized regression coefficient range: 0.10–0.19, p-values ≤ 0.003). Specifically, 28 and 33 lipoprotein subfractions were associated with IMAT density of locomotion and stabilization (statistically driven by obliques) muscles, respectively. Higher VLDL (cholesterol, unesterified cholesterol, phospholipids, triglycerides, and apolipoprotein B) and lower HDL (cholesterol and unesterified cholesterol) were associated with higher muscle area, higher IMAT area, and lower IMAT density. Several associations between lipoprotein subfractions and abdominal muscle area and IMAT area and density were strongest among the stabilization muscles, particularly the obliques, illustrating the importance of examining muscle groups separately. Future work is needed to determine whether the observed associations indicate a lipoprotein profile contributing to worse skeletal muscle with fat infiltration.
Robust Reductions of Body Weight and Food Intake by an Oxytocin Analog in Rats
Authors: Elfers Clinton T. , Blevins James E. , Lawson Elizabeth A. , Pittner Richard , Silva David , Kiselyov Alex , Roth Christian L.
Published: September 2021

Background: Oxytocin is a hypothalamic neuropeptide that participates in the network of appetite regulation. Recently the oxytocin signaling pathway has emerged as an attractive target for treating obesity. However, the short half-life limits its development as a clinical therapeutic. Here we provide results from testing a long-lasting, potent and selective oxytocin analog ASK1476 on its efficacy to reduce food intake and body weight in comparison to the native oxytocin peptide.

Methods: ASK1476 features two specific amino acid substitutions in positions 7 and 8 combined with a short polyethylene glycol spacer. Short time dose escalation experiments testing increasing doses of 3 days each were performed in diet-induced overweight (DIO) male rats assessing effects on body weight as well as changes in food intake. Furthermore, DIO rats were tested for changes in body weight, food intake, temperature, and locomotor activity over 28 days of treatment (oxytocin, ASK1476, or vehicle).

Results: In dose escalation experiments, significant reductions in food intake relative to baseline were detected beginning with doses of 15 nmol/kg ASK1476 (−15.2 ± 2.3 kcal/d, p = 0.0017) and 20 nmol/kg oxytocin (−11.2.9 ± 2.4 kcal/d, p = 0.0106) with corresponding significant changes in body weight (ASK1476: −5.2 ± 0.8 g, p = 0.0016; oxytocin: −2.6 ± 0.7 g, p = 0.0326). In long-term experiments, there was no difference on body weight change between 120 nmol/kg/d ASK1476 (−71.4 ± 34.2 g, p = 0.039) and 600 nmol/kg/d oxytocin (−91.8 ± 32.2 g, p = 0.035) relative to vehicle (706.9 ± 28.3 g), indicating a stronger dose response for ASK1476. Likewise, both ASK1476 and oxytocin at these doses resulted in similar reductions in 28-day cumulative food intake (ASK1476: −562.7 ± 115.0 kcal, p = 0.0001; oxytocin: −557.1 ± 101.3 kcal, p = 0.0001) relative to vehicle treatment (2716 ± 75.4 kcal), while no effects were detected on locomotor activity or body temperature.

Conclusion: This study provides proof-of-concept data demonstrating an oxytocin analog with extended in vivo stability and improved potency to reduce food intake and body weight in DIO animals which could mark a new avenue in anti-obesity drug interventions.