Bioequivalence Study of Atenolol Tablets in Healthy Chinese Subjects Under Fasting and Fed Conditions.

Atenolol, a cardioselective ß1-blocker, exhibits efficacy in treating cardiovascular diseases. We conducted a single-center, randomized, open, single-dose, 2-preparation, 2-cycle, 2-sequence, double-crossover trial with a 7-day washout period to investigate the pharmacokinetics, bioequivalence (BE), and safety of test and reference atenolol tablets (25 mg) in healthy Chinese volunteers. Forty-eight healthy participants were randomized into the fasting and fed arms. After administering a single oral dose of the test or reference formulation (25 mg), plasma atenolol concentrations were measured using liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were obtained from concentration-time profiles. In total, 23 and 24 individuals were included in the fasting and fed arms, respectively. The mean concentration-time profiles for both formulations were similar, and Cmax, AUC0-t, and AUC0-∞ were within the BE range of 80%-125%. Thirteen adverse events (AEs) were observed in 7 participants in the fasting arm; 1 withdrew from the trial early owing to an AE. In the fed arm, 20 AEs were observed in 8 participants, and none withdrew from the trial. All adverse reactions were grade I, with no serious AEs or deaths. Therefore, the 2 tablets are bioequivalent in healthy Chinese individuals under fasting and fed conditions, supporting their further clinical development.

Identification of crucial anoikis-related genes as novel biomarkers and potential therapeutic targets for lung adenocarcinoma via bioinformatic analysis and experimental verification.

Lung adenocarcinoma (LUAD) is a malignant tumor of the respiratory system that has a poor 5-year survival rate. Anoikis, a type of programmed cell death, contributes to tumor development and metastasis. The aim of this study was to develop an anoikis-based stratified model, and a multivariable-based nomogram for guiding clinical therapy for LUAD. Through differentially expressed analysis, univariate Cox, LASSO Cox regression, and random forest algorithm analysis, we established a 4 anoikis-related genes-based stratified model, and a multivariable-based nomogram, which could accurately predict the prognosis of LUAD patients in the TCGA and GEO databases, respectively. The low and high-risk score LUAD patients stratified by the model showed different tumor mutation burden, tumor microenvironment, gemcitabine sensitivity and immune checkpoint expressions. Through immunohistochemical analysis of clinical LUAD samples, we found that the 4 anoikis-related genes (PLK1, SLC2A1, ANGPTL4, CDKN3) were highly expressed in the tumor samples from clinical LUAD patients, and knockdown of these genes in LUAD cells by transfection with small interfering RNAs significantly inhibited LUAD cell proliferation and migration, and promoted anoikis. In conclusion, we developed an anoikis-based stratified model and a multivariable-based nomogram of LUAD, which could predict the survival of LUAD patients and guide clinical treatment.

Magnetically controlled nanorobots induced oriented and rapid clearance of the cytokine storm for acute lung injury therapy.

Cytokine storms characterized by excessive secretion of circulating cytokines and immune-cell hyperactivation are life-threatening systemic inflammatory syndromes. The new strategy is in great demand to inhibit the cytokine storm. Here, we designed a type of magnetically controlled nanorobots (MAGICIAN) by fusing neutrophil membranes onto Fe3O4 nanoparticles (Fe3O4NPs). In our study, the receptors of neutrophil membranes were successfully coated to the surface of Fe3O4NPs. The associated membrane functions of neutrophils were highly preserved. MAGICIAN could in vitro neutralize the inflammatory cytokines including interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), and interferon γ (IFN-γ). Interestingly, MAGICIAN could be navigated to the liver sites under magnetic control and accelerated the cytokine clearance by the liver. Administration of MAGICIAN could efficiently relieve the inflammation in the acute lung injury mouse model. In addition, MAGICIAN displayed good biosafety in systemic administration. The present study provides a safe and convenient approach for the clearance of cytokine storms, indicating the potential for clinical application in acute lung injury therapy.

Ephrin-A4 Ligand (EFNA4) Predicts Poor Prognosis of Hepatocellular Carcinoma and Promotes Tumor Proliferation.

Background/Aims: Primary hepatocellular carcinoma (HCC) is one of the most lethal tumor diseases in the world. Receptor tyrosine kinases (RTKs) are thought to play a vital role in HCC and Ephrin-A4 ligand (EFNA4) is a membrane-bound molecule that can activate RTKs through erythropoietin-producing hepatocellular (Eph) receptors. However, the specific role of EFNA4 remains unknown. The aim of our study was to explore the prognostic value of EFNA4 expression in HCC. Methods: Bioinformatics analyses were conducted to probe the expression levels and prognostic value of EFNA4 in HCC. The quantitative real-time polymerase chain reaction, immunohistochemical and western blot were used to confirm the expression of EFNA4 in paired clinical specimens of HCC. Colony formation assay was used to confirm the proliferation of tumor cell. Results: The expression of EFNA4 is generally elevated in various cancers. Especially, EFNA4 was upregulated in tumor tissue and associated with clinical stage in HCC patients. HCC patients with lower levels of EFNA4 possessed better survival and progression-free survival times. Colony formation assay indicated that the overexpression of EFNA4 promoted tumor cell proliferation. Conclusion: These results demonstrated that EFNA4 played as an oncogenic gene and a prognostic biomarker for HCC patients.

Study on the migration characteristics of bioaerosols and optimization of ventilation patterns in a negative pressure isolation ward considering different patient postures.

Due to the serious global harm caused by the outbreak of various viral infectious diseases, how to improve indoor air quality and contain the spread of infectious bioaerosols has become a popular research subject. Negative pressure isolation ward is a key place to prevent the spread of aerosol particles. However, there is still limited knowledge available regarding airflow patterns and bioaerosol diffusion behavior in the ward, which is not conducive to reducing the risk of cross-infection between health care workers (HCWs) and patients. In addition, ventilation layout and patient posture have important effects on aerosol distribution. In this study, the spatial and temporal characteristics as well as dispersion patterns of bioaerosols under different ventilation patterns in the ward were investigated using the computational fluid dynamics (CFD) technique. It is concluded that changes in the location of droplet release source due to different body positions of the patient have a significant effect on the bioaerosol distribution. After optimizing the layout arrangements of exhaust air, the aerosol concentration in the ward with the patient in both supine and sitting positions is significantly reduced with particle removal efficiencies exceeding 95%, that is, the ventilation performance is improved. Meanwhile, the proportion of aerosol deposition on all surfaces of the ward is decreased, especially the deposition on both the patient's body and the bed is less than 1%, implying that the risk of HCWs being infected through direct contact is reduced.

Pharmacokinetic and Bioequivalence Evaluation of Two Cefprozil Dispersible Tablets in Healthy Chinese Volunteers.

This study aimed to assess the bioequivalence of 2 cefprozil dispersible tablet formulations (250 mg) in healthy Chinese volunteers under fasting and fed conditions and to determine the pharmacokinetics of cefprozil. A randomized, single-dose, open-label, 2-formulation, 2-period study was conducted. The elimination period for this study was 7 days. Forty-eight healthy volunteers received 250-mg cefprozil dispersible tablets in each study period under both test and reference conditions. The test and the reference cefprozil were bioequivalent in healthy Chinese volunteers, and there was no significant food effect in individuals receiving either formulation. No serious adverse event was recorded, and no volunteers withdrew from the study.

Bibliometric Analysis of Exercise and Chronic Obstructive Pulmonary Disease.

Background: Chronic Obstructive Pulmonary Disease (COPD) is the leading cause of death in the world. Pulmonary rehabilitation includes, but is not limited to, exercise training and education, which aim to improve the physical and psychological conditions of patients with chronic respiratory diseases through self-management interventions. Objective: The aim of this study was to perform a bibliometric analysis of studies on exercise and COPD published from 2000 to 2021 using VOSviewer and CiteSpace. Methods: All included literature was obtained from the Web of Science core collection. VOSviewer was used to analyze country or region, institution, major co-cited journals, and keywords. CiteSpace was used to analyze centrality, author and co-cited authors, journals, the strongest citation bursts of references, and keywords. Results: A total of 1889 articles meeting the criteria were obtained. The United States has the largest number of publications. The American Journal of Respiratory and Critical Care Medicine is the most influential in this field, and the most published research institution is Queen's University. Denis E. O'Donnell has made significant contributions to exercise and COPD research. Association, impact, and statement are hot spots of research in this field. Conclusion: A bibliometric analysis of exercise interventions for COPD over the past 22 years provides direction for future research.

Cell Membrane-Camouflaged Nanoparticles Mediated Nucleic Acids Delivery.

Nucleic acids have emerged as promising therapeutic agents for many diseases because of their potential in modulating gene expression. However, the delivery of nucleic acids remains a significant challenge in gene therapy. Although viral vectors have shown high transfection efficiency, concerns regarding teratogenicity or carcinogenicity have been raised. Non-viral vehicles, including cationic polymers, liposomes, and inorganic materials possess advantages in terms of safety, ease of preparation, and low cost. Nevertheless, they also face limitations related to immunogenicity, quick clearance in vivo, and lack of targeting specificity. On the other hand, bioinspired strategies have shown increasing potential in the field of drug delivery, yet there is a lack of comprehensive reviews summarizing the rapid development of bioinspired nanoparticles based on the cell membrane camouflage to construct the nucleic acids vehicles. Herein, we enumerated the current difficulties in nucleic acid delivery with various non-viral vehicles and provided an overview of bioinspired strategies for nucleic acid delivery.

A bibliometric analysis of COVID-19 and physical activity.

BACKGROUND: Due to the huge impact of coronavirus disease 2019 (COVID-19) on a global scale, the level of physical activity during confinement has become a widespread concern. This study summarizes the development of performance and research trends in COVID-19 and physical activity over the last 3 years. METHODS: Research publications on COVID-19 and physical activity in the past 3 years were downloaded from the Web of Science database. CiteSpace and VOSviewer software were used to analyze the authors, published outputs, journals, cited authors, countries and institutions, co-cited journals, cited references, and keywords. Statistical and centrality analyses were used to identify the active authors, core journals, basic references, hot topics, and cutting-edge fields. RESULTS: A total of 1331 papers was retrieved. SMITH L was a prolific author in the field of exercise intervention in COVID-19 with 11 publications. International Journal of Environmental Research and Public Health was the most productive journal (179 publications) and the most cited journal (1324). The most productive countries and institutions in this field were the USA (322 publications) and Harvard Medical School (21 publications). The four hot keywords in COVID-19 and physical activity research were physical activity, exercise, health, and mental health. CONCLUSIONS: This study provides researchers with directions to intervene in changing levels of physical activity during the COVID-19 pandemic and valuable information for researchers in the field of sports medicine to identify potential collaborators, collaborating institutions, hot issues, and research frontiers.

Gender difference in effects of proprioceptive neuromuscular facilitation stretching on flexibility and stiffness of hamstring muscle.

Objective: This study investigated the acute effects of PNF stretching on hamstring flexibility and muscle stiffness of lower limbs between genders. Methods: 15 male and 15 female university students without any injury histories on lower limbs in the past 3 months were included in this study were selected. All subjects were measured by MyotonPRO before and after stretching to determine the muscle stiffness of the biceps femoris muscle (BF), semitendinosus muscle (ST) of the hamstring and the medial gastrocnemius muscles (MG), lateral gastrocnemius muscles (LG), and the soleus (SOL) of the triceps surae muscles. Additionally, their flexibility was measured using the sit-and-reach test (the SR test) and passive hip range of motion (ROM). Differences based on time (pre-stretching vs. post-stretching) and sex (females vs. males) were assessed using 2 × 2 repeated measures AVONA. Results: There was a significant decrease in the stiffness of the hamstring and triceps surae muscles after stretching (BF, MG, LG, and SOL: p < 0.001; ST: p = 0.003). The muscle stiffness of the hamstring and triceps surae muscles is larger in males than in females at all time points (p < 0.001). There was a significant increase in hip flexion angle and the SR test in males and females after PNF stretching (p < 0.001); However, there was no difference in the change in the muscle stiffness and the flexibility between genders (p > 0.05). Conclusion: PNF stretching helped improve hamstring flexibility and decrease muscle stiffness. Stretching the hamstrings can also contribute to a decrease in the stiffness of the triceps surae muscles. The muscle stiffness of males before and after stretching is always greater than that of females. However, there was no difference in the change of improvement in stretching between genders.

Gut Microbiome Signatures in the Progression of Hepatitis B Virus-Induced Liver Disease.

The gut microbiome is associated with hepatitis B virus (HBV)-induced liver disease, which progresses from chronic hepatitis B, to liver cirrhosis, and eventually to hepatocellular carcinoma. Studies have analyzed the gut microbiome at each stage of HBV-induced liver diseases, but a consensus has not been reached on the microbial signatures across these stages. Here, we conducted by a systematic meta-analysis of 486 fecal samples from publicly available 16S rRNA gene datasets across all disease stages, and validated the results by a gut microbiome characterization on an independent cohort of 15 controls, 23 chronic hepatitis B, 20 liver cirrhosis, and 22 hepatocellular carcinoma patients. The integrative analyses revealed 13 genera consistently altered at each of the disease stages both in public and validation datasets, suggesting highly robust microbiome signatures. Specifically, Colidextribacter and Monoglobus were enriched in healthy controls. An unclassified Lachnospiraceae genus was specifically elevated in chronic hepatitis B, whereas Bilophia was depleted. Prevotella and Oscillibacter were depleted in liver cirrhosis. And Coprococcus and Faecalibacterium were depleted in hepatocellular carcinoma. Classifiers established using these 13 genera showed diagnostic power across all disease stages in a cross-validation between public and validation datasets (AUC = 0.65-0.832). The identified microbial taxonomy serves as non-invasive biomarkers for monitoring the progression of HBV-induced liver disease, and may contribute to microbiome-based therapies.

Detection of Coccidioides posadasii in a patient with meningitis using metagenomic next-generation sequencing: a case report.

BACKGROUND: Coccidioidomycosis is a systemic infection caused by dimorphic fungi Coccidioides spp. endemic to Southwestern United States and Central and South America. A history of residence and travel in these areas is essential for the diagnostic of coccidioidomycosis, which has highly variable symptoms ranging from asymptomatic to severe, disseminated infection, and even death. Immunocompromised patients of coccidioidomycosis experience a high risk of dissemination, chronic infection, and mortality. Meningitis is one of the most deleterious coccidioidomycosis and can cause various life-threatening complications. CASE PRESENTATION: Here we report a case of Coccidioides posadasii meningitis in a 49-year-old female who returned to China after one and a half years residence in Los Angeles, USA. The repeated routine cultures using CSF for bacteria or fungi were all negative. To hunt for an infectious etiology, the state-of-the-art technology metagenomic next-generation sequencing (mNGS) was then utilized, suggesting Coccidioides posadasii. Organizational pathological examination and polymerase-chain-reaction (PCR) results subsequently confirmed the mNGS detection. CONCLUSION: To our knowledge, cases for coccidioidal meningitis have been rarely reported in China. While global travelling may spread this disease across continents and make the diagnosis more difficult. mNGS can detect almost all known pathogens with high sensitivity and specificity, especially for uncommon pathogen, such as Coccidioides posadasii in China.

Hepatitis B core antibody and liver stiffness measurements predict HBeAg seroconversion in HBeAg-positive chronic hepatitis B patients with minimally elevated alanine aminotransferase (ALT) levels.

Alanine aminotransferase (ALT) levels between 1 and 2 times the upper limit of normal (ULN) are common in patients with chronic hepatitis B (CHB) infection. There are few clinical studies focused on this group of patients because of the poorer treatment outcomes compared to those with more than 2 × ULN ALT level. However, treatments are necessary to reduce liver damage for patients with minimally elevated ALT levels. And biomarkers are needed in predicting the treatment response. In this study, a total of 106 patients with CHB were enrolled and treated with entecavir, telbivudine or tenofovir disoproxil fumarate. Liver stiffness was measured by transient elastography, and quantitative levels of hepatitis B core antibody (HBcAb) were detected by ELISA. At week 96, 31 (29.25%) patients achieved hepatitis B e antigen (HBeAg) seroconversion. Notably, baseline HBcAb levels and liver stiffness measurements (LSM) were higher in patients who achieved HBeAg seroconversion. The multivariate analysis showed that the baseline HBcAb levels and LSM were independent predictors for HBeAg seroconversion. The area under receiver operating characteristic curve of baseline HBcAb, LSM and the combination of them for HBeAg seroconversion was 0.714, 0.720 and 0.717, respectively. In addition, we discovered that the patients with baseline HBcAb levels ≥ 4.15 log10 IU/mL and LSM ≥ 9.85 kPa had higher rates of HBeAg seroconversion. Therefore, the measurement of HBcAb and liver stiffness might be good approaches for the optimization of antiviral therapy for HBeAg-positive CHB patients with minimally elevated ALT levels.

Investigating genetic characteristics of hepatitis B virus-associated and -non-associated hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is a primary liver malignancy that mainly occurs in patients with chronic liver disease and cirrhosis. Risk factors for HCC include hepatitis B virus (HBV) infection. However, the specific role of HBV infection in HCC development is not yet completely understood. In order to reveal the effects of HBV on HCC, we compare the genes of HCC patients infected with HBV with those who are not infected. METHODS: We encoded the genes of these two types of HCC in databases using enrichment scores of Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway terms. A random forest algorithm was employed in order to distinguish these two types in the classifier, and a series of feature selection approaches was used in order to select their optimal features. Novel HBV-associated and -non-associated HCC genes were predicted, respectively, based on their optimal features in the classifier. A shortest-path algorithm was also employed in order to find all of the shortest-paths genes connecting the known related genes. RESULTS: A total of 54 different features between HBV-associated and -non-associated HCC genes were identified. In total, 1236 and 881 novel related genes were predicted for HBV-associated and -non-associated HCC, respectively. By integrating the predicted genes and shortest path genes in their gene interaction network, we identified 679 common genes involved in the two types of HCC. CONCLUSION: We identified the significantly different genetic features between two types of HCC. We also predicted related genes for the two types based on their specific features. Finally, we determined the common genes and features that were involved in both of these two types of HCC.

Duck HBV DNA copy numbers in isolated hepatocyte nuclei vary dramatically and decline during entecavir therapy.

BACKGROUND: We aimed to develop a quantitative assay to measure duck HBV (DHBV) DNA in single hepatocyte nuclei from DHBV-infected animals and to observe intranuclear DHBV DNA kinetics undergoing entecavir (ETV) therapy. METHODS: DHBV DNA in isolated nuclei was amplified by quantitative real-time PCR. Liver tissues from chronically-infected ducks with or without ETV treatment were assessed. Cell cycle phases were defined with flow cytometry in single nuclei. RESULTS: We successfully established a quantitative assay to measure intranuclear DHBV DNA in single nuclei with high specificity, sensitivity and acceptable interassay variations. The intranuclear viral DNA copy numbers varied dramatically (2-204 copies/nuclei) in 11 ducks with active viral replication. Average intranuclear DHBV DNA copies from individual animals (7.57-57.67 copies/nuclei) significantly correlated with total intranuclear (rs=0.955, P<0.001) and serum (rs=0.745, P=0.008) viral DNA levels. The median intranuclear DHBV DNA copies in virus-positive nuclei were greater in gap 0/1 than those in gap 2/mitosis and synthesis phases (P<0.001). Median intranuclear viral DNA copies in virus-positive nuclei decreased from 21 to 6 (P<0.001) under 14-19 weeks of ETV therapy. However, subsequently, further reductions were not achieved in four animals after extended 16 week treatment (6 versus 11, P=0.034). CONCLUSIONS: Intranuclear DHBV DNA levels varied significantly, which could be partially attributed to effects of cell cycle phases, and could be decreased by ETV therapy.

Experimental demonstration of OpenFlow-based control plane for elastic lightpath provisioning in Flexi-Grid optical networks.

Due to the prominent performance on networking virtualization and programmability, OpenFlow is widely regarded as a promising control plane technology in packet-switched IP networks as well as wavelength-switched optical networks. For the purpose of applying software programmable feature to future optical networks, we propose an OpenFlow-based control plane in Flexi-Grid optical networks. Experimental results demonstrate its feasibility of dynamic lightpath establishment and adjustment via extended OpenFlow protocol. Wireshark captures of the signaling procedure are printed out. Additionally, the overall latency including signaling and hardware for lightpath setup and adjustment is also reported.

[Construction of a duck hepatitis B virus YMDD mutant and identification of its resistance phenotype].

OBJECTIVE: To construct a lamivudine-resistant plasmid containing 1.2 unit genome of duck hepatitis B virus and identify its replication and drug-resistance in avian LMH hepatica cells. METHODS: The recombinant plasmid PBS-DHBV1.2 was constructed using the 1.2-genome length DHBV DNA sequence from a dimer DHBV genome with pcDNA3.1 as the template. With site-directed mutagenesis, we obtained PBS-DHBV1.2-M512V plasmids with polymerase gene mutation from PBS-DHBV1.2. Two constructed plasmids were transiently transfected into LMH cells using FuGENETM6 transfection reagent and cultured in the medium containing different concentrations of lamivudine. Southern blot hybridization was performed to detect DHBV replication intermediates. RESULTS: PCR amplification, restriction digestion and plasmid sequencing all confirmed successful construction of PBS-DHBV1.2-M512V recombinant plasmid. Southern blot analysis identified the presence of all the expected DHBV replication intermediates in LMH cells. The replication capacity of the mutant plasmid was decreased by 2.7 times compared with that of the wild plasmid. The IC(50) of lamivudine was 37.12∓8.81 ng/ml for the mutant, greater than that of the wild plasmid (10.90∓4.80 ng/ml). CONCLUSION: Compared with the wild plasmid, the mutant plasmid has a lower replication capacity and sensitivity to lamivudine in vitro.

Interaction of hepatitis C virus envelope glycoprotein E2 with the large extracellular loop of tupaia CD81.

AIM: To further analyze the interaction of tupaia CD81 with hepatitis C virus (HCV) envelope protein E2. METHODS: A tupaia CD81 large extracellular loop (CD81 LEL), which binds to HCV E2 protein, was cloned and expressed as a GST-fusion protein, and interaction of HCV E2 protein with a tupaia CD81 LEL was evaluated by enzyme-linked immunosorbent assay (EIA). RESULTS: Although tupaia and human CD81 LEL differed in 6 amino acid changes, tupaia CD81 LEL was strongly recognized by anti-CD81 antibodies against human CD81 LEL conformation-dependent epitopes. Investigating LEL CD81-E2 interactions by EIA, we demonstrated that binding of tupaia CD81 LEL GST fusion protein to recombinant HCV E2 protein was markedly reduced compared to binding of human CD81 LEL GST fusion protein to recombinant HCV E2 protein. CONCLUSION: These data suggest that the structural differences in-between the tupaia and human CD81 may alter the interaction of the large extracellular loop with HCV envelope glycoprotein E2. These findings may be important for the understanding of the mechanisms of binding and entry of HCV to PTHs.