bluuebunny/crossref_metadata_2025 huggingface dataset:
Novel Tumor-Specific Antigens for Immunotherapy Identified From Multi-omics Profiling in Thymic Carcinomas
Authors: Fang Wentao , Wu Chia-Hsin , Sun Qiang-Ling , Gu Zhi-Tao , Zhu Lei , Mao Teng , Zhang Xue-Fei , Xu Ning , Lu Tzu-Pin , Tsai Mong-Hsun , Chen Li-Han , Lai Liang-Chuan , Chuang Eric Y.
Published: November 2021

Thymic carcinoma (TC) is the most aggressive thymic epithelial neoplasm. TC patients with microsatellite instability, whole-genome doubling, or alternative tumor-specific antigens from gene fusion are most likely to benefit from immunotherapies. However, due to the rarity of this disease, how to prioritize the putative biomarkers and what constitutes an optimal treatment regimen remains largely unknown. Therefore, we integrated genomic and transcriptomic analyses from TC patients and revealed that frameshift indels in KMT2C and CYLD frequently produce neoantigens. Moreover, a median of 3 fusion-derived neoantigens was predicted across affected patients, especially the CATSPERB-TC2N neoantigens that were recurrently predicted in TC patients. Lastly, potentially actionable alterations with early levels of evidence were uncovered and could be used for designing clinical trials. In summary, this study shed light on our understanding of tumorigenesis and presented new avenues for molecular characterization and immunotherapy in TC.
Construction of Genomic Library and Screening of Edwardsiella tarda Immunogenic Proteins for Their Protective Efficacy Against Edwardsiellosis
Authors: Bothammal Palanisamy , Ganesh Mohan , Vigneshwaran Vellaisamy , Anbarasu Kumarasamy , Ponmurugan Karuppiah , Al-Dhabi Naif Abdullah , Natarajaseenivasan Kalimuthusamy
Published: November 2021

Edwardsiella tarda is a severe aquaculture pathogen that can infect many hosts including humans, animals, and fish. Timely diagnosis and treatment are crucial for the control of edwardsiellosis in the aqua industry. By using rabbit polyclonal antibody, an expression gene library of virulent Edwardsiella tarda strain ED-BDU 1 isolated in south India was constructed and screened. The identified immune expressive proteins were characterized, and the corresponding coding sequences were cloned, expressed, and the purified recombinant proteins were used as antigens. The identified immunoreactive proteins namely HflC, HflK, and YhcI were studied for their immune protective potential in vivo by challenge experiments. The protective efficacy of HflC, HflK, and YhcI showed that the clearance of Edwardsiella from the host with ~ 60% survivability. Further, the immunoreactive proteins induce a strong immune response upon infection and elicit the significant production of IL-10, IFN-γ, Th1, and Th2 mediated mRNA expression and were therefore effective in vaccine production for edwardsiellosis.
Potential Applications of Fluorescence-Activated Cell Sorting (FACS) and Droplet-Based Microfluidics in Promoting the Discovery of Specific Antibodies for Characterizations of Fish Immune Cells
Authors: Fei Chenjie , Nie Li , Zhang Jianhua , Chen Jiong
Published: November 2021

Akin to their mammalian counterparts, teleost fish possess a complex assortment of highly specialized immune cells that are capable of unleashing potent innate immune responses to eradicate or mitigate incoming pathogens, and also differentiate into memory lymphocytes to provide long-term protection. Investigations into specific roles and functions of fish immune cells depend on the precise separation of each cell type. Commonly used techniques, for example, density gradient centrifugation, rely on immune cells to have differing sizes or densities and thus fail to separate between similar cell types (e.g. T and B lymphocytes). Furthermore, a continuously growing database of teleost genomic information has revealed an inventory of cellular markers, indicating the possible presence of immune cell subsets in teleost fish. This further complicates the interpretation of results if subsets of immune cells are not properly separated. Consequently, monoclonal antibodies (mAbs) against specific cellular markers are required to precisely identify and separate novel subsets of immune cells in fish. In the field of fish immunology, mAbs are largely generated using the hybridoma technology, resulting in the development of mAbs against specific cellular markers in different fish species. Nevertheless, this technology suffers from being labour-intensive, time-consuming and most importantly, the inevitable loss of diversities of antibodies during the fusion of antibody-expressing B lymphocytes and myeloma cells. In light of this, the focus of this review is to discuss the potential applications of fluorescence-activated cell sorting and droplet-based microfluidics, two emerging technologies capable of screening and identifying antigen-specific B lymphocytes in a high-throughput manner, in promoting the development of valuable reagents for fish immunology studies. Our main goal is to encourage the incorporation of alternative technologies into the field of fish immunology to promote the production of specific antibodies in a high-throughput and cost-effective way, which could better allow for the precise separation of fish immune cells and also facilitate the identification of novel immune cell subsets in teleost fish.
Characterization of Host lncRNAs in Response to Vibrio splendidus Infection and Function as Efficient miRNA Sponges in Sea Cucumber
Authors: Zhang Siyuan , Shao Yina , Li Chenghua
Published: November 2021

Long non-coding RNAs (lncRNAs) have been reported to play critical roles during pathogen infection and innate immune response in mammals. Such observation inspired us to explore the expression profiles and functions of lncRNAs in invertebrates upon bacterial infection. Here, the lncRNAs of sea cucumber (Apostichopus japonicus) involved in Vibrio splendidus infection were characterized. RNA-seq obtained 2897 differentially expressed lncRNAs from Vibrio splendidus infected coelomocytes of sea cucumbers. The potential functions of the significant differentially expressed lncRNAs were related to immunity and metabolic process based on the gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. Moreover, we identify a lncRNA (XLOC_028509), which is downregulated with Vibrio splendidus challenged, further study indicated that XLOC_028509 adsorb miR-2008 and miR-31 as competing endogenous RNAs (ceRNAs) through base complementarity, which in turn decreased the amount of miRNAs (microRNAs) bound to the 3’UTRs (untranslated regions) of mRNAs to reduce their inhibition of target gene translation. These data demonstrated that the lncRNAs of invertebrates might be important regulators in pathogen-host interactions by sponging miRNAs.
Subtle Differences in the Representation of Consumer Dynamics Have Large Effects in Marine Food Web Models
Authors: Flynn Kevin J. , Speirs Douglas C. , Heath Michael R. , Mitra Aditee
Published: November 2021

Projecting ocean biogeochemistry and fisheries resources under climate change requires confidence in simulation models. Core to such models is the description of consumer dynamics relating prey abundance to capture, digestion efficiency and growth rate. Capture is most commonly described as a linear function of prey encounter or by rectangular hyperbola. Most models also describe consumers as eating machines which “live-to-eat,” where growth (μ) is limited by a maximum grazing rate (Gmax). Real consumers can feed much faster than needed to support their maximum growth rate (μmax); with feeding modulated by satiation, they “eat-to-live.” A set of strategic analyses were conducted of these alternative philosophies of prey consumption dynamics and testing of their effects in the StrathE2E end-to-end marine food web and fisheries model. In an experiment where assimilation efficiencies were decreased by 10%, such as might result from a change in temperature or ocean acidity, the different formulation resulted in up to 100% variation in the change in abundances of food web components, especially in the mid-trophic levels. Our analysis points to a need for re-evaluation of some long-accepted principles in consumer-resource modeling.
Antiviral Electrospun Polymer Composites: Recent Advances and Opportunities for Tackling COVID-19
Authors: Li Jinghang , Wang Wenzhao , Jiang Rui , Guo Chengchen
Published: November 2021

The ongoing COVID-19 pandemic caused by SARS-CoV-2 has significantly affected the world, creating a global health emergency. For controlling the virus spread, effective and reliable diagnostic and therapeutic measures are highly expected. Using proper biomedical materials to produce detection kits/devices and personal protective equipment (PPE), such as swabs and masks, has become the focus since they play critical roles in virus diagnostics and prevention. Electrospun polymer composites have garnered substantial interest due to their potential to provide antiviral healthcare solutions. In this review, we summarized the recent efforts in developing advanced antiviral electrospun polymer composites for virus detection and prevention. We highlighted some novel strategies for developing effective antiviral personal protective equipment (PPE), including self-sterilization, reusability, and potential antiviral drug encapsulation. Besides, we discussed the current challenges and future perspectives for improving the materials’ performance to achieve better virus detection, antiviral, prevention, and therapeutics.
Impact of Positive Interferon-Gamma Release Assay on IVF-ET Pregnancy Outcomes in Infertile Patients With Untreated Prior Tuberculosis: A Prospective Cohort Study
Authors: Gai Xiaoyan , Chi Hongbin , Zeng Lin , Cao Wenli , Chen Lixue , Zhang Chen , Li Rong , Sun Yongchang , Qiao Jie
Published: November 2021

Introduction: Tuberculosis (TB) is a major infectious disease that seriously endangers human health and female reproduction. In our previous study, 10.4% of infertile patients preparing for In vitro fertilization and embryo transfer (IVF-ET) had prior pulmonary TB (PTB) as detected on chest X-ray (CXR) screening. Among them, 81.8% did not receive anti-TB treatment. It remains unclear whether infertile women with untreated prior PTB have latent TB infection (LTBI) and whether LTBI affects IVF-ET outcomes. In this study, we aim to analyze the relationship between LTBI and pregnancy outcomes following IVF-ET in patients with untreated prior PTB.

Methods and Analysis: We designed a prospective cohort study of 1,200 infertile women with CXR findings suggestive of old-healed untreated TB, who are preparing for IVF-ET. Patients with a history of active TB and anti-TB treatment will be excluded. Interferon-gamma release assay (IGRA) will be used in patients with CXR findings suggestive of old-healed untreated TB to construct a cohort of IGRA-positive and IGRA-negative patients. Participants will undergo IVF-ET. General information, including age, body mass index, infertility causes, and controlled ovarian hyperstimulation protocol, will be recorded. Participants will be followed up during pregnancy. The primary outcome is live birth. Secondary outcomes include the numbers of retrieved oocytes, high-quality embryo rate, clinical pregnancy, number of active TB cases during pregnancy, and miscarriage.

Ethics and Dissemination: The study was approved by the Ethics Committee of Peking University Third Hospital [approval number (2020)218-01; approval date: June 19, 2020]. The research results will be disseminated through scientific/medical conferences and published in academic journals.

Trial Registration:ClinicalTrials.gov; identifier: NCT04443283.
Different Effects of Thermophilic Microbiological Inoculation With and Without Biochar on Physicochemical Characteristics and Bacterial Communities in Pig Manure Composting
Authors: Sun Likun , Long Min , Li Jianshu , Wu Renfei , Ma Lin , Tang Defu , Lu Yongli , Wang Ziyu
Published: November 2021

This study evaluated the effects of thermophilic microbiological inoculation alone (TA) and integrated with biochar (TB) on the physicochemical characteristics and bacterial communities in pig manure (PM) composting with wheat straw. Both TA and TB accelerated the rate of temperature increase during the PM composting. TA significantly reduced total nitrogen loss by 18.03% as opposed to TB which significantly accelerated total organic carbon degradation by 12.21% compared with the control.Firmicutes,Bacteroidetes,Actinobacteria, andProteobacteriawere the major phyla in composting. Variation of the relative abundance of genera depended on the composting period and treatment. The generaLactobacillus(26.88–46.71%) andClostridium_sensu_stricto(9.03–31.69%) occupied a superior position in the temperature rise stage, andBacillus(30.90–36.19%) was outstanding in the cooling stage. Temperature, total nitrogen (TN), and ammonium nitrogen significantly influenced the bacterial phyla composition. TN, water content, and nitrite nitrogen were the main drivers of the bacterial community genera. Furthermore, our results demonstrated that microbiological consortia were resistant to high temperatures and could fix nitrogen for enrichedPseudomonas; however, when interacted with biochar, total organic carbon (TOC) degradation was accelerated for higher bacterial richness and diversity as well as overrepresentedCorynebacterium.
Comprehensive Analysis of Hepatitis Delta Virus Assembly Determinants According to Genotypes: Lessons From a Study of 526 Hepatitis Delta Virus Clinical Strains
Authors: Gerber Athenaïs , Le Gal Frédéric , Dziri Samira , Alloui Chakib , Roulot Dominique , Dény Paul , Sureau Camille , Brichler Ségolène , Gordien Emmanuel
Published: November 2021

Human hepatitis Delta virus (HDV) infection is associated to the most severe viral hepatic disease, including severe acute liver decompensation and progression to cirrhosis, and hepatocellular carcinoma. HDV is a satellite of hepatitis B virus (HBV) that requires the HBV envelope proteins for assembly of HDV virions. HDV and HBV exhibit a large genetic diversity that extends, respectively to eight (HDV-1 to -8) and to ten (HBV/A to/J) genotypes. Molecular determinants of HDV virion assembly consist of a C-terminal Proline-rich domain in the large Hepatitis Delta Antigen (HDAg) protein, also known as the Delta packaging domain (DPD) and of a Tryptophan-rich domain, the HDV matrix domain (HMD) in the C-terminal region of the HBV envelope proteins. In this study, we performed a systematic genotyping of HBV and HDV in a cohort 1,590 HDV-RNA-positive serum samples collected between 2001 to 2014, from patients originated from diverse parts of the world, thus reflecting a large genetic diversity. Among these samples, 526 HBV (HBV/A, B, C, D, E, and G) and HDV (HDV-1, 2, 3, and 5 to -8) genotype couples could be obtained. We provide results of a comprehensive analysis of the amino-acid sequence conservation within the HMD and structural and functional features of the DPD that may account for the yet optimal interactions between HDV and its helper HBV.
Antiviral Activity of CD437 Against Mumps Virus
Authors: Kato Fumihiro , Nakatsu Yuichiro , Murano Keiko , Wakata Aika , Kubota Toru , Hishiki Takayuki , Yamaji Toshiyuki , Kidokoro Minoru , Katoh Hiroshi , Takeda Makoto
Published: November 2021

Many efforts have been dedicated to the discovery of antiviral drug candidates against the mumps virus (MuV); however, no specific drug has yet been approved. The development of efficient screening methods is a key factor for the discovery of antiviral candidates. In this study, we evaluated a screening method using an Aequorea coerulescens green fluorescent protein-expressing MuV infectious molecular clone. The application of this system to screen for active compounds against MuV replication revealed that CD437, a retinoid acid receptor agonist, has anti-MuV activity. The point of antiviral action was a late step(s) in the MuV life cycle. The replication of other paramyxoviruses was also inhibited by CD437. The induction of retinoic acid-inducible gene (RIG)-I expression is a reported mechanism for the antiviral activity of retinoids, but our results indicated that CD437 did not stimulate RIG-I expression. Indeed, we observed antiviral activity despite the absence of RIG-I, suggesting that CD437 antiviral activity does not require RIG-I induction.
Characterization and Comparative Genomics Analysis of lncFII Multi-Resistance Plasmids Carrying blaCTX–M and Type1 Integrons From Escherichia coli
Authors: Zhou Wei , Zhang Enbao , Zhou Jinzhi , He Ze , Zhou Yuqiao , Han Jianzhong , Qu Daofeng
Published: November 2021

This research aimed to investigate the presence and transferability of the extended-spectrum β-lactamase resistance genes to identify the genetic context of multi-drug resistant (MDR) loci in two Escherichia coli plasmids from livestock and poultry breeding environment. MICs were determined by broth microdilution. A total of 137 E. coli resistant to extended-spectrum β-lactam antibiotics were screened for the presence of the ESBL genes by PCR. Only two E. coli out of 206 strains produced carbapenemases, including strain 11011 that produced enzyme A, and strain 417957 that produced enzyme B. The genes were blaKPC and blaNDM, respectively. The plasmids containing blaCTX–M were conjugatable, and the plasmids containing carbapenem resistance gene were not conjugatable. Six extended-spectrum β-lactamase resistance genes were detected in this research, including blaTEM, blaCTX–M, blaSHV, blaOAX–1, blaKPC, and blaNDM, and the detection rates were 94.89% (130/137), 92.7% (127/137), 24.81% (34/137), 20.43% (28/137), 0.72% (1/137), and 0.72% (1/137), respectively. Two conjugative lncFII multi-resistance plasmids carrying blaCTX–M, p11011-fosA and p417957-CTXM, were sequenced and analyzed. Both conjugative plasmids were larger than 100 kb and contained three accessory modules, including MDR region. The MDR region of the two plasmids contained many antibiotic resistance genes, including blaCTX–M, mph (A), dfrA17, aadA5, sul1, etc. After transfer, both the transconjugants displayed elevated MICs of the respective antimicrobial agents. A large number of resistance genes clusters in specific regions may contribute to the MDR profile of the strains. The presence of mobile genetic elements at the boundaries can possibly facilitate transfer among Enterobacteriaceae through inter-replicon gene transfer. Our study provides beta-lactam resistance profile of bacteria, reveals the prevalence of β-lactamase resistance genes in livestock and poultry breeding environment in Zhejiang Province, and enriches the research on IncFII plasmids containing blaCTX–M.
Systematic Evaluation of Whole-Genome Sequencing Based Prediction of Antimicrobial Resistance in Campylobacter jejuni and C. coli
Authors: Hodges Lisa M. , Taboada Eduardo N. , Koziol Adam , Mutschall Steven , Blais Burton W. , Inglis G. Douglas , Leclair Daniel , Carrillo Catherine D.
Published: November 2021

The increasing prevalence of antimicrobial resistance (AMR) in Campylobacter spp. is a global concern. This study evaluated the use of whole-genome sequencing (WGS) to predict AMR in Campylobacter jejuni and C. coli. A panel of 271 isolates recovered from Canadian poultry was used to compare AMR genotype to antimicrobial susceptibility testing (AST) results (azithromycin, ciprofloxacin, erythromycin, gentamicin, tetracycline, florfenicol, nalidixic acid, telithromycin, and clindamycin). The presence of antibiotic resistance genes (ARGs) was determined for each isolate using five computational approaches to evaluate the effect of: ARG screening software, input data (i.e., raw reads, draft genome assemblies), genome coverage and genome assembly software. Overall, concordance between the genotype and phenotype was influenced by the computational pipelines, level of genome coverage and the type of ARG but not by input data. For example, three of the pipelines showed a 99% agreement between detection of a tet(O) gene and tetracycline resistance, whereas agreement between the detection of tet(O) and TET resistance was 98 and 93% for two pipelines. Overall, higher levels of genome coverage were needed to reliably detect some ARGs; for example, at 15X coverage a tet(O) gene was detected in >70% of the genomes, compared to <60% of the genomes for bla(OXA). No genes associated with florfenicol or gentamicin resistance were found in the set of strains included in this study, consistent with AST results. Macrolide and fluoroquinolone resistance was associated 100% with mutations in the 23S rRNA (A2075G) and gyrA (T86I) genes, respectively. A lower association between a A2075G 23S rRNA gene mutation and resistance to clindamycin and telithromycin (92.8 and 78.6%, respectively) was found. While WGS is an effective approach to predicting AMR in Campylobacter, this study demonstrated the impact that computational pipelines, genome coverage and the genes can have on the reliable identification of an AMR genotype.
An Overview of Glycosylation and its Impact on Cardiovascular Health and Disease
Authors: Loaeza-Reyes Karen Julissa , Zenteno Edgar , Moreno-Rodríguez Adriana , Torres-Rosas Rafael , Argueta-Figueroa Liliana , Salinas-Marín Roberta , Castillo-Real Lizet Monserrat , Pina-Canseco Socorro , Cervera Yobana Pérez
Published: November 2021

The cardiovascular system is a complex and well-organized system in which glycosylation plays a vital role. The heart and vascular wall cells are constituted by an array of specific receptors; most of them are N- glycosylated and mucin-type O-glycosylated. There are also intracellular signaling pathways regulated by different post-translational modifications, including O-GlcNAcylation, which promote adequate responses to extracellular stimuli and signaling transduction. Herein, we provide an overview of N-glycosylation and O-glycosylation, including O-GlcNAcylation, and their role at different levels such as reception of signal, signal transduction, and exogenous molecules or agonists, which stimulate the heart and vascular wall cells with effects in different conditions, like the physiological status, ischemia/reperfusion, exercise, or during low-grade inflammation in diabetes and aging. Furthermore, mutations of glycosyltransferases and receptors are associated with development of cardiovascular diseases. The knowledge on glycosylation and its effects could be considered biochemical markers and might be useful as a therapeutic tool to control cardiovascular diseases.
Mechanical Learning for Prediction of Sepsis-Associated Encephalopathy
Authors: Zhao Lina , Wang Yunying , Ge Zengzheng , Zhu Huadong , Li Yi
Published: November 2021

Objective: The study aims to develop a mechanical learning model as a predictive model for predicting the appearance of sepsis-associated encephalopathy (SAE).

Materials and Methods: The prediction model was developed in a primary cohort of 2,028 sepsis patients from June 2001 to October 2012, retrieved from the Medical Information Mart for Intensive Care (MIMIC III) database. Least absolute shrinkage and selection operator (LASSO) regression model was used for data dimension reduction and feature selection. The model was developed using multivariable logistic regression analysis. The performance of the nomogram has been evaluated in terms of calibration, discrimination, and clinical utility.

Results: There were nine particular features in septic patients that were significantly associated with SAE. Predictors of individualized prediction nomograms included age, rapid sequential evaluation of organ failure (qSOFA), and drugs including carbapenem antibiotics, quinolone antibiotics, steroids, midazolam, H2-antagonist, diphenhydramine hydrochloride, and heparin sodium injection. The area under the curve (AUC) was 0.743, indicating good discrimination. The prediction model showed calibration curves with minor deviations from the ideal predictions. Decision curve analysis (DCA) suggested that the nomogram was clinically useful.

Conclusion: We propose a nomogram for the individualized prediction of SAE with satisfactory performance and clinical utility, which could aid the clinician in the early detection and management of SAE.
Cerebral Autoregulation in Non-Brain Injured Patients: A Systematic Review
Authors: Longhitano Yaroslava , Iannuzzi Francesca , Bonatti Giulia , Zanza Christian , Messina Antonio , Godoy Daniel , Dabrowski Wojciech , Xiuyun Li , Czosnyka Marek , Pelosi Paolo , Badenes Rafael , Robba Chiara
Published: November 2021

Introduction: Cerebral autoregulation (CA) plays a fundamental role in the maintenance of adequate cerebral blood flow (CBF). CA monitoring, through direct and indirect techniques, may guide an appropriate therapeutic approach aimed at improving CBF and reducing neurological complications; so far, the role of CA has been investigated mainly in brain-injured patients. The aim of this study is to investigate the role of CA in non-brain injured patients.

Methods: A systematic consultation of literature was carried out. Search terms included: “CA and sepsis,” “CA and surgery,” and “CA and non-brain injury.”

Results: Our research individualized 294 studies and after screening, 22 studies were analyzed in this study. Studies were divided in three groups: CA in sepsis and septic shock, CA during surgery, and CA in the pediatric population. Studies in sepsis and intraoperative setting highlighted a relationship between the incidence of sepsis-associated delirium and impaired CA. The most investigated setting in the pediatric population is cardiac surgery, but the role and measurement of CA need to be further elucidated.

Conclusion: In non-brain injured patients, impaired CA may result in cognitive dysfunction, neurological damage, worst outcome, and increased mortality. Monitoring CA might be a useful tool for the bedside optimization and individualization of the clinical management in this group of patients.
Delayed FDG PET Provides Superior Glioblastoma Conspicuity Compared to Conventional Image Timing
Authors: Johnson Jason Michael , Chen Melissa M. , Rohren Eric M. , Prabhu Sujit , Chasen Beth , Mawlawi Osama , Liu Ho-Ling , Gule-Monroe Maria Kristine
Published: November 2021

Background: Glioblastomas are malignant, often incurable brain tumors. Reliable discrimination between recurrent disease and treatment changes is a significant challenge. Prior work has suggested glioblastoma FDG PET conspicuity is improved at delayed time points vs. conventional imaging times. This study aimed to determine the ideal FDG imaging time point in a population of untreated glioblastomas in preparation for future trials involving the non-invasive assessment of true progression vs. pseudoprogression in glioblastoma.

Methods: Sixteen pre-treatment adults with suspected glioblastoma received FDG PET at 1, 5, and 8 h post-FDG injection within the 3 days prior to surgery. Maximum standard uptake values were measured at each timepoint for the central enhancing component of the lesion and the contralateral normal-appearing brain.

Results: Sixteen patients (nine male) had pathology confirmed IDH-wildtype, glioblastoma. Our results revealed statistically significant improvements in the maximum standardized uptake values and subjective conspicuity of glioblastomas at later time points compared to the conventional (1 h time point). The tumor to background ratio at 1, 5, and 8 h was 1.4 ± 0.4, 1.8 ± 0.5, and 2.1 ± 0.6, respectively. This was statistically significant for the 5 h time point over the 1 h time point (p > 0.001), the 8 h time point over the 1 h time point (p = 0.026), and the 8 h time point over the 5 h time point (p = 0.036).

Conclusions: Our findings demonstrate that delayed imaging time point provides superior conspicuity of glioblastoma compared to conventional imaging. Further research based on these results may translate into improvements in the determination of true progression from pseudoprogression.
Tissue Engineering Strategies for Peripheral Nerve Regeneration
Authors: Li Yin , Ma Zhenjiang , Ren Ya , Lu Dezhi , Li Tao , Li Wentao , Wang Jinwu , Ma Hui , Zhao Jie
Published: November 2021

A peripheral nerve injury (PNI) has severe and profound effects on the life of a patient. The therapeutic approach remains one of the most challenging clinical problems. In recent years, many constructive nerve regeneration schemes are proposed at home and abroad. Nerve tissue engineering plays an important role. It develops an ideal nerve substitute called artificial nerve. Given the complexity of nerve regeneration, this review summarizes the pathophysiology and tissue-engineered repairing strategies of the PNI. Moreover, we discussed the scaffolds and seed cells for neural tissue engineering. Furthermore, we have emphasized the role of 3D printing in tissue engineering.
Similar Metabolic Health in Overweight/Obese Individuals With Contrasting Metabolic Flexibility to an Oral Glucose Tolerance Test
Authors: Fernández-Verdejo Rodrigo , Malo-Vintimilla Lorena , Gutiérrez-Pino Juan , López-Fuenzalida Antonio , Olmos Pablo , Irarrazaval Pablo , Galgani Jose E.
Published: November 2021

Background: Low metabolic flexibility (MetF) may be an underlying factor for metabolic health impairment. Individuals with low MetF are thus expected to have worse metabolic health than subjects with high MetF. Therefore, we aimed to compare metabolic health in individuals with contrasting MetF to an oral glucose tolerance test (OGTT).

Methods: In individuals with excess body weight, we measured MetF as the change in respiratory quotient (RQ) from fasting to 1 h after ingestion of a 75-g glucose load (i.e., OGTT). Individuals were then grouped into low and high MetF (Low-MetF n = 12; High-MetF n = 13). The groups had similar body mass index, body fat, sex, age, and maximum oxygen uptake. Metabolic health markers (clinical markers, insulin sensitivity/resistance, abdominal fat, and intrahepatic fat) were compared between groups.

Results: Fasting glucose, triglycerides (TG), and high-density lipoprotein (HDL) were similar between groups. So were insulin sensitivity/resistance, visceral, and intrahepatic fat. Nevertheless, High-MetF individuals had higher diastolic blood pressure, a larger drop in TG concentration during the OGTT, and a borderline significant (P = 0.05) higher Subcutaneous Adipose Tissue (SAT). Further, compared to Low-MetF, High-MetF individuals had an about 2-fold steeper slope for the relationship between SAT and fat mass index.

Conclusion: Individuals with contrasting MetF to an OGTT had similar metabolic health. Yet High-MetF appears related to enhanced circulating TG clearance and enlarged subcutaneous fat.
Changes in the Fermentation and Bacterial Community by Artificial Saliva pH in RUSITEC System
Authors: Guo Tongqing , Guo Tao , Cao Yurong , Guo Long , Li Fei , Li Fadi , Yang Guo
Published: November 2021

The purpose of the study was to assess the artificial saliva (AS) pH on ruminal fermentation and rumen bacteria community in the rumen simulation technique (RUSITEC) system. The experiment was performed in two treatments (low AS pH vs. high AS pH) with four replicates. The low AS pH was sustained by altering the composition of the AS (NaHCO3 from 9.8 to 1.96 g/L, Na2HPO4 from 9.3 to 1.86 g/L) according to McDougall's method. The diets were supplemented with 16 g basic diets with forage to the concentrate ratio of 50:50. The experiments were conducted over 13-day incubation periods, with 9 days adaption and 4 days sample collection. The results showed low AS pH decreased dry matter (DM) degradability (64.37 vs. 58.67%), organic matter (OM) degradability (64.38 vs. 59.32%), neutral detergent fiber (NDF) degradability (46.87 vs. 39.94%), acid detergent fiber (ADF) degradability (38.16 vs. 31.13%), and crude protein (CP) degradability (70.33 vs. 62.99%), respectively. Compared with the high AS pH, the low AS pH increased the proportion of butyrate (P = 0.008) and decreased the proportion of propionate (P < 0.001). At the bacteria community, the low AS pH increased the abundances of Spirochaetes (P = 0.001) and Synergistetes (P = 0.004) and decreased the Verrucomicrobia abundance (P = 0.004) in solid-associated bacteria. At the genus level, the low AS pH increased the abundance of Lactobacillus (P = 0.050) and decreased the abundance of Schwartzia (P = 0.002) in solid-associated bacteria. The abundances of Prevotellaceae_YAB2003_group (P = 0.040), Schwartzia (P = 0.002), and Ruminobacter (P = 0.043) were lower in the low AS pH group compared with the high AS pH group in liquid-associated bacteria. Low AS pH decreased the number of Ruminococcus albus, Ruminococcus flavefaciens, Fibrobacter succinogenes (P < 0.001) both in the solid- and liquid-associated bacteria, respectively. The results of the present study included three groups of bacteria communities according to the different sensitives to rumen pH: the abundances of Lactobacillus, Succinivibrio, and Prevotella_7 are increased with decreasing AS pH; the amounts of R. albus, R. flavefaciens, F. succinogenes as well as the abundances of Schwartzia and Ruminobacter decreased with the reducing AS pH; the abundances of Selenomonas_1, Rikenellaceae_RC9_gut_group, and Succiniclasticum were not affected by the AS pH in RUSTITEC.
Early Death and Survival of Patients With Acute Promyelocytic Leukemia in ATRA Plus Arsenic Era: A Population-Based Study
Authors: Zhu Hong-Hu , Ma Ya-Fang , Yu Kang , Ouyang Gui-Fang , Luo Wen-Da , Pei Ren-Zhi , Xu Wei-Qun , Hu Hui-Xian , Mo Shu-Ping , Xu Xiao-Hua , Lan Jian-Ping , Shen Jian-Ping , Shou Li-Hong , Qian Shen-Xian , Feng Wei-Ying , Zhao Pu , Jiang Jin-Hong , Hu Bei-Li , Zhang Jin , Qian Su-Ying , Wu Gong-Qiang , Wu Wen-Ping , Qiu Lei , Li Lin-Jie , Lang Xiang-Hua , Chen Sai , Chen Li-Li , Guo Jun-Bin , Cao Li-Hong , Jiang Hui-Fang , Xia Yong-Ming , Le Jing , Zhao Jian-Zhi , Huang Jian , Zhang Yue-Feng , Lv Ya-Li , Hua Jing-Sheng , Hong Yong-Wei , Zheng Cui-Ping , Wang Ju-Xiang , Hu Bin-Fei , Chen Xiao-Hui , Zhang Li-Ming , Tao Shi , Xie Bing-Shou , Kuang Yue-Min , Luo Wen-Ji , Su Ping , Guo Jun , Wu Xiao , Jiang Wei , Zhang Hui-Qi , Zhang Yun , Chen Chun-Mei , Xu Xiao-Feng , Guo Yan , Tu Jin-Ming , Hu Shao , Yan Xiao-Yan , Yao Chen , Lou Yin-Jun , Jin Jie ,   the APL Cooperative Group of Zhejiang Province
Published: November 2021

Most randomized trials for acute promyelocytic leukemia (APL) have investigated highly selected patients under idealized conditions, and the findings need to be validated in the real world. We conducted a population-based study of all APL patients in Zhejiang Province, China, with a total population of 82 million people, to assess the generalization of all-trans retinoic acid (ATRA) and arsenic as front-line treatment. The outcomes of APL patients were also analyzed. Between January 2015 and December 2019, 1,233 eligible patients were included in the final analysis. The rate of ATRA and arsenic as front-line treatment increased steadily from 66.2% in 2015 to 83.3% in 2019, with no difference among the size of the center (≥5 or <5 patients per year, p = 0.12) or age (≥60 or <60 years, p = 0.35). The early death (ED) rate, defined as death within 30 days after diagnosis, was 8.2%, and the 3-year overall survival (OS) was 87.9% in the whole patient population. Age (≥60 years) and white blood cell count (>10 × 109/L) were independent risk factors for ED and OS in the multivariate analysis. This population-based study showed that ATRA and arsenic as front-line treatment are widely used under real-world conditions and yield a low ED rate and a high survival rate, which mimic the results from clinical trials, thereby supporting the wider application of APL guidelines in the future.
Identification of Prognostic Biomarkers Originating From the Tumor Stroma of Betel Quid-Associated Oral Cancer Tissues
Authors: Liu Yi-Hong , Chen Yu-Lian , Lai Ting-Yu , Ko Ying-Chieh , Chou Yu-Fu , Chen Peir-Rong , Hsiao Jenn-Ren , Chang Jang-Yang , Shiah Shine-Gwo , Lee Jeng-Woei , Yang Jia-Ling , Lin Su-Fang
Published: November 2021

Background

Partial epithelial-mesenchymal transition (p-EMT) is a distinct clinicopathological feature prevalent in oral cavity tumors of The Cancer Genome Atlas. Located at the invasion front, p-EMT cells require additional support from the tumor stroma for collective cell migration, including track clearing, extracellular matrix remodeling and immune evasion. The pathological roles of otherwise nonmalignant cancer-associated fibroblasts (CAFs) in cancer progression are emerging.

Methods

Gene set enrichment analysis was used to reveal differentially enriched genes and molecular pathways in OC3 and TW2.6 xenograft tissues, representing mesenchymal and p-EMT tumors, respectively. R packages of genomic data science were executed for statistical evaluations and data visualization. Immunohistochemistry and Alcian blue staining were conducted to validate the bioinformatic results. Univariate and multivariate Cox proportional hazards models were performed to identify covariates significantly associated with overall survival in clinical datasets. Kaplan–Meier curves of estimated overall survival were compared for statistical difference using the log-rank test.

Results

Compared to mesenchymal OC3 cells, tumor stroma derived from p-EMT TW2.6 cells was significantly enriched in microvessel density, tumor-excluded macrophages, inflammatory CAFs, and extracellular hyaluronan deposition. By translating these results to clinical transcriptomic datasets of oral cancer specimens, including the Puram single-cell RNA-seq cohort comprising ~6000 cells, we identified the expression of stromal TGFBI and HYAL1 as independent poor and protective biomarkers, respectively, for 40 Taiwanese oral cancer tissues that were all derived from betel quid users. In The Cancer Genome Atlas, TGFBI was a poor marker not only for head and neck cancer but also for additional six cancer types and HYAL1 was a good indicator for four tumor cohorts, suggesting common stromal effects existing in different cancer types.

Conclusions

As the tumor stroma coevolves with cancer progression, the cellular origins of molecular markers identified from conventional whole tissue mRNA-based analyses should be cautiously interpreted. By incorporating disease-matched xenograft tissue and single-cell RNA-seq results, we suggested that TGFBI and HYAL1, primarily expressed by stromal CAFs and endothelial cells, respectively, could serve as robust prognostic biomarkers for oral cancer control.
Dose Optimization of Aditoprim-Sulfamethoxazole Combinations Against Trueperella pyogenes From Patients With Clinical Endometritis by Using Semi-mechanistic PK/PD Model
Authors: Maan Muhammad Kashif , Chaudhry Tamoor Hamid , Sattar Adeel , Shabbir Muhammad Abu Bakr , Ahmed Saeed , Mi Kun , Ahmed Waqas , Xie Shuyu , Xin Li , Huang Lingli
Published: November 2021

Combinations of two and more drugs with different target sites are being used as a new treatment regimen for resistant clones of bacteria. Though, achieving the right combination of the drugs for optimal dosage regimen is challenging. In our study, we studied the antimicrobial effect of aditoprim, a novel dihydrofolate reductase inhibitor, and its synergistic effect with sulfamethoxazole. Synergy testing was performed by checkerboard micro dilution method and validation of different checkerboard ratios by static and dynamic time-kill analysis and in vitro pharmacokinetic/pharmacodynamics (PK/PD) model, and semi mechanistic PK/PD modeling was used to calculate and validate the synergistic effect of drug combination. Both checkerboard and static time-kill assays demonstrated the greater synergistic effect [fractional inhibitory concentration index (FICI) = 0.37] of the aditoprim [minimum inhibitory concentration (MIC) = 0.25 µg/ml]-sulfamethoxazole (MIC=>64 µg/ml) combination against all T. Pyogenes isolates. In the in vitro PK/PD model, the dosage proportion of sulfamethoxazole 4 mg/ml twice a day in combination with steady-state aditoprim 1 mg/ml efficiently repressed the growth of bacteria in 24 h with the ratio of 2-log10 decrease, related to the early inoculum against three T. Pyogenes isolates. The semi mechanistic PK/PD model projected that a combination of a high dose of aditoprim (2 mg/ml) with sulfamethoxazole (2 mg/day) was necessary to attain the killing of bacteria below the detection limit (limit of detection (LOD); i.e., 1 log10 CFU/ml) at 24 h with an MIC sulfamethoxazole (SMZ) of 64 µg/ml. However, it is anticipated that a combination of high dose of aditoprim with sulfamethoxazole is critical to attain the suppressed bacterial growth to < LOD. This study represents essential PK/PD modeling for optimization of combination of aditoprim and sulfamethoxazole to suppress growth of T. Pyogenens.
Underlying Mechanism and Active Ingredients of Tianma Gouteng Acting on Cerebral Infarction as Determined via Network Pharmacology Analysis Combined With Experimental Validation
Authors: Tang Xiaolei , Lu Jing , Chen Haoyuan , Zhai Lu , Zhang Yuxin , Lou Huijuan , Wang Yufeng , Sun Liwei , Song Bailin
Published: November 2021

Cerebral infarction (CI), a common cerebrovascular disease worldwide, is caused by unknown factors common to many diseases, including hypokalemia, respiratory diseases, and lower extremity venous thrombosis. Tianma Gouteng (TMGT), a traditional Chinese Medicine (TCM) prescription, has been used for the clinical treatment of CI. In this study, high-performance liquid chromatography (HPLC) fingerprint analysis was used to detect and identify major chemical constituents of TMGT. TCMSP and BATMAN-TCM databases were used to screen for active TMGT constituent compounds, while the GeneCards database was used to screen for protein targets associated with CI. Next, GO and KEGG enrichment analysis of these core nodes were performed to determine the identities of key associated biological processes and signal pathways. Meanwhile, a total of six possible gene targets of TMGT, including NFKBIA, PPARG, IL6, IL1B, CXCL8, and HIF1A, were selected for further study using two cellular models of CI. For one model, PC12 cells were treated under oxygen and glucose deprivation (OGD) conditions to generate an OGD cellular model of CI, while for the other model, BV2 cells were stimulated with lipopolysaccharide (LPS) to generate a cellular model of CI-associated inflammation. Ultimately TMGT treatment increased PPARγ expression and downregulated the expression of p-P65, p-IκBα, and HIF-1α in both OGD-induced and LPS-induced cell models of CI. In addition, molecular docking analysis showed that one TMGT chemical constituent, quercetin, may be a bioactive TMGT compound with activity that may be associated with the alleviation of neuronal damage and neuroinflammation triggered by CI. Moreover, additional data obtained in this work revealed that TMGT could inhibit neuroinflammation and protect brain cells from OGD-induced and LPS-induced damage by altering HIF-1α/PPARγ/NF-κB pathway functions. Thus, targeting this pathway through TMGT administration to CI patients may be a strategy for alleviating nerve injury and neuroinflammation triggered by CI.
Guideline Adherence of β-blocker Initiating Dose and its Consequence in Hospitalized Patients With Heart Failure With Reduced Ejection Fraction
Authors: Zhou Yiling , Zeng Yuping , Wang Si , Li Nan , Wang Miye , Mordi Ify R. , Ren Yan , Zhou Youlian , Zhu Ye , Tian Haoming , Sun Xin , Chen Xiaoping , An Zhenmei , Lang Chim C. , Li Sheyu
Published: November 2021

Background: We aim to investigate the guideline adherence of β-blocker (BB) initiating dose in Chinese hospitalized patients with heart failure with reduced ejection fraction (HFrEF) and whether the adherence affected the in-hospital outcomes.

Methods: This was a retrospective study of patients hospitalized with HFrEF who had initiated BBs during their hospitalization. We defined adherence to clinical practice guidelines as initiating BB with standard dose and non-adherence to guidelines if otherwise, and examined the association between adherence to guidelines and in-hospital BB-related adverse events. Subgroup analyses based on sex, age, coronary heart disease, and hypertension were performed.

Results: Among 1,104 patients with HFrEF initiating BBs during hospitalization (median length of hospitalization, 12 days), 304 (27.5%) patients received BB with non-adherent initiating dose. This non-adherence was related to a higher risk (hazard ratio [95% confidence interval]) of BB dose reduction or withdrawal (1.78 [1.42 to 2.22], P < 0.001), but not significantly associated with risks of profound bradycardia, hypotension, cardiogenic shock requiring intravenous inotropes, and severe bronchospasm requiring intravenous steroid during hospitalization.

Conclusion: This study identified that over a fourth of patients had received BBs with an initiating dose that was not adherent to guidelines in Chinese hospitalized patients with HFrEF, and this non-adherence was associated with BB dose reduction or withdrawal during hospitalization.
Supraphysiological Role of Melatonin Over Vascular Dysfunction of Pregnancy, a New Therapeutic Agent?
Authors: Valenzuela-Melgarejo Francisco J. , Lagunas Constanza , Carmona-Pastén Fabiola , Jara-Medina Kevins , Delgado Gustavo
Published: November 2021

Hypertension can be induced by the disruption of factors in blood pressure regulation. This includes several systems such as Neurohumoral, Renin-angiotensin-aldosterone, the Circadian clock, and melatonin production, which can induce elevation and non-dipping blood pressure. Melatonin has a supraphysiological role as a chronobiotic agent and modulates vascular system processes via pro/antiangiogenic factors, inflammation, the immune system, and oxidative stress regulation. An elevation of melatonin production is observed during pregnancy, modulating the placenta and fetus’s physiological functions. Their impairment production can induce temporal desynchronization of cell proliferation, differentiation, or invasion from trophoblast cells results in vascular insufficiencies, elevating the risk of poor fetal/placental development. Several genes are associated with vascular disease and hypertension during pregnancy via impaired inflammatory response, hypoxia, and oxidative stress, such as cytokines/chemokines IL-1β, IL-6, IL-8, and impairment expression in endothelial cells/VSMCs of HIF1α and eNOS genes. Pathological placentas showed differentially expressed genes (DEG), including vascular genes as CITED2, VEGF, PL-II, PIGF, sFLT-1, and sENG, oncogene JUNB, scaffolding protein CUL7, GPER1, and the pathways of SIRT/AMPK and MAPK/ERK. Additionally, we observed modification of subunits of NADPH oxidase and extracellular matrix elements, i.e., Glypican and Heparanase and KCa channel. Mothers with a low level of melatonin showed low production of proangiogenic factor VEGF, increasing the risk of preeclampsia, premature birth, and abortion. In contrast, melatonin supplementation can reduce systolic pressure, prevent oxidative stress, induce the activation of the antioxidants system, and lessen proteinuria and serum level of sFlt-1. Moreover, melatonin can repair the endothelial damage from preeclampsia at the placenta level, increasing PIGF, Nrf-2, HO-1 production and reducing critical markers of vascular injury during the pregnancy. Melatonin also restores the umbilical and uterine blood flow after oxidative stress and inhibits vascular inflammation and VCAM-1, Activin-A, and sEng production. The beneficial effects of melatonin over pathological pregnancies can be partially observed in normal pregnancies, suggesting the dual role of/over placental physiology could contribute to protection and have therapeutic applications in vascular pathologies of pregnancies in the future.