An alginate-based edible coating containing lactic acid bacteria extends the shelf life of fresh strawberry (Fragaria × ananassa Duch.).

Edible coatings, formulated with sodium alginate and various strains of lactic acid bacteria, were evaluated for their effectiveness in extending the shelf life and mitigating microbial risks associated with strawberries. This study specifically employed strains of Lacticaseibacillus paracasei, Lacticaseibacillus rhamnosus, and Lacticaseibacillus plantarum as antimicrobial agents. Through physicochemical property analysis, the alginate-based antimicrobial coating proved most effective in reducing the strawberry weight loss rate, decay index, and ascorbic acid degradation. Over time, all treatments exhibited increased fungal growth. However, strawberries treated with alginate and lactic acid bacteria recorded lower final colony formation counts-6.82 log CFU/g for SA + LPC, 6.04 log CFU/g for SA + LGG, and 6.26 log CFU/g for SA + LP-compared to 8.73 log CFU/g in the control group. In terms of bacterial resistance under gastrointestinal conditions, L. paracasei demonstrated the highest survival rate post-simulated gastric fluid exposure, while L. plantarum showed the greatest resilience post-simulated intestinal fluid exposure. These findings underscore the efficacy of alginate-based antimicrobial coatings in not only enhancing the storage quality of strawberries but also ensuring microbial safety and potential benefits for gut health.

Age-Related Differences in Vancomycin-Associated Nephrotoxicity and Efficacy in Methicillin-Resistant Staphylococcus aureus Infection: A Comparative Study between Elderly and Adult Patients.

Elderly patients (age ≥ 65 years) are susceptible to methicillin-resistant Staphylococcus aureus (MRSA) infections, with potential for more adverse treatment outcomes or complications compared to younger adults (18-64 years). This study compared vancomycin-associated nephrotoxicity and efficacy in elderly and adult patients and investigated the correlation between vancomycin pharmacokinetic/pharmacodynamic (PK/PD) indices and clinical outcomes. A prospective study was conducted in 10 hospitals in Shanghai from October 2012 to November 2019. A total of 164 patients with MRSA infections were enrolled, including 83 elderly and 81 adult patients. Vancomycin therapeutic drug monitoring (TDM) was performed in all patients, indicating significantly higher vancomycin trough concentrations (Ctrough), 24-h area under the curve (AUC24) values, and AUC24/minimum inhibitory concentration (AUC24/MIC) values in elderly patients compared to adult patients. The incidence of vancomycin-associated nephrotoxicity was nearly three times higher in elderly patients (18.1% vs. 6.2%, p = 0.020), despite similar clinical and microbiological efficacy. Of particular importance, a Ctrough > 20 mg/L was found as an independent factor of nephrotoxicity in elderly patients. Further analysis of patients with an estimated glomerular filtration rate (eGFR) > 60 mL/min/1.73 m2 also revealed that elderly patients had significantly higher vancomycin-related PK/PD indices and more nephrotoxicity than adult patients. In conclusion, elderly patients receiving vancomycin therapy face a higher risk of nephrotoxicity, which requires close vancomycin TDM, especially when the Ctrough exceeds 20 mg/L.

Pharmacokinetics and safety of EVER206, a novel polymyxin antimicrobial, in healthy Chinese subjects.

EVER206 (also known as SPR206) is a novel polymyxin analog that has shown in vitro potency and in vivo efficacy against multidrug-resistant (MDR) Gram-negative pathogens. This randomized, double-blinded, placebo-controlled, Phase I study evaluated the safety, tolerability, and pharmacokinetics of EVER206 in healthy Chinese subjects. After single administration of 50-300 mg EVER206, the Cmax ranged from 3.94 to 25.82 mg/L, and the AUC0-inf ranged from 12.42 to 101.67 h·mg/L. The plasma exposure displayed a linear relationship with the dose administered. After administration of 75 and 100 mg of EVER206 every 8 hours (q8 hour), a steady state was achieved on Day 2. The accumulation ratios of Cmax and AUC from Day 1 to Day 7 were in the range of 1.12 to 1.3. The elimination half-lives ranged from 2.86 to 4.32 hours in the single-ascending-dose (SAD) study and 4.71 to 6.18 hours in the multiple-ascending-dose (MAD) study. The urinary excretion of unchanged EVER206 increased with the dose, with the mean cumulative fraction ranging from 23.70% to 47.10%. EVER206 was safe and well-tolerated in Chinese healthy subjects. No severe treatment emerging adverse events (TEAEs), serious adverse events, or TEAEs leading to discontinuation were reported. The results of the present study demonstrated a similar safety profile of EVER206 with data reported in an earlier study on SPR206-101. The exposure of EVER206 in Chinese healthy subjects was higher than that in Australian healthy subjects. These results could enable further clinical development of EVER206 in Chinese patients with severe MDR Gram-negative pathogen infections.CLINICAL TRIALSThis study was registered at the Chinese Clinical Trial Registry under identifier ChiCTR2200056692.

Regulation of Gut Microbiota and Microbial Metabolome of Kefir Supernatant against Fusobacterium nucleatum and DSS-Coinduced Colitis.

The aim of this study was to investigate the intervention effect of kefir supernatant (KS) on the initiation and progression of an ulcerative colitis (UC) murine model. We established an UC murine model by orally administrating with 109 CFUs of Fusobacterium nucleatum for 3 weeks and 3% dextran sulfate sodium (DSS) treatment in the third week. KS was used to intervene in this colitis model. Our results showed that KS supplementation ameliorated the symptoms, restrained the secretion of pro-inflammatory cytokines (TNF-α, IL-6, and IL-17F), promoted the release of anti-inflammatory cytokines (IL-4 and IL-10), and ameliorated oxidative stress. Furthermore, the increased number of goblet cells and upregulated expression of MUC2, occludin and claudin-1 indicated that the colon barrier was protected by KS. Additionally, KS supplementation mitigated gut microbiota dysbiosis in the UC murine model, leading to an increase in the abundance of Blautia and Akkermansia and a decrease in the level of Bacteroides. The altered gut microbiota also affected colon metabolism, with differential metabolites mainly associated with the biosynthesis of the l-arginine pathway. This study revealed that KS supplementation restored the community structure of gut microbiota, altered the biosynthesis of l-arginine, and thereby modulated the process of colonic inflammation.

Comparative efficacy of vancomycin in treating ST5 and ST764 methicillin-resistant Staphylococcus aureus infections in adult patients.

IMPORTANCE: Methicillin-resistant Staphylococcus aureus (MRSA) is a bacterium that is resistant to multiple drugs and can cause serious infections. In recent years, one of the most widespread strains of MRSA worldwide has been the clonal complex 5 (CC5) type. Sequence type 5 (ST5) and ST764 are two prevalent CC5 strains. Although ST5 and ST764 are genotypically identical, ST764 is classified as a hybrid variant of ST5 with characteristics of community-associated MRSA (CA-MRSA). In contrast to ST5, ST764 lacks the tst and sec genes but carries the staphylococcal enterotoxin B (seb) gene. Vancomycin is commonly used as the first-line treatment for MRSA infections. However, it is currently unclear whether the genetic differences between the ST5 and ST764 strains have any impact on the efficacy of vancomycin in treating MRSA infections. We conducted a prospective observational study comparing the efficacy of vancomycin against ST5-MRSA and ST764-MRSA in five hospitals in China. There were significant differences in bacteriological efficacy between the two groups, with virulence genes, such as the tst gene, being a risk factor for bacterial persistence (adjusted odds ratio, 4.509; 95% confidence interval, 1.216 to 16.724; P = 0.024). In the future, it may be necessary to consider personalized vancomycin treatment strategies based on the genetic characteristics of MRSA isolates.

Traction Machine State Recognition Method Based on DPCA Algorithm and Convolution Neural Network.

It is important to improve the identification accuracy of the operating status of elevator traction machines. The distribution difference of the time-frequency signals utilized to identify operating circumstances is modest, making it difficult to extract features from the vibration signals of traction machines under various operating conditions, leading to low recognition accuracy. A novel method for identifying the operating status of traction machines based on signal demodulation method and convolutional neural network (CNN) is proposed. The original vibration time-frequency signals are demodulated by the demodulation method based on time-frequency analysis and principal component analysis (DPCA). Firstly, the signal demodulation method based on principal component analysis is used to extract the modulation features of the experimentally measured vibration signals. Then, The CNN is used for feature vector extraction, and the training model is obtained through multiple iterations to achieve automatic recognition of the running state. The experimental results show that the proposed method can effectively extract feature parameters under different states. The diagnostic accuracy is up to 96.94%, which is about 16.61% higher than conventional methods. It provides a feasible solution for identifying the operating status of elevator traction machines.

The dilemma of antibiotic susceptibility and clinical decision-making in a multi-drug-resistant Pseudomonas aeruginosa bloodstream infection.

Objective: How to choose the appropriate antibiotics and dosage has always been a difficult issue during the treatment of multi-drug-resistant bacterial infections. Our study aims to resolve this difficulty by introducing our multi-disciplinary treatment (MDT) clinical decision-making scheme based on rigorous interpretation of antibiotic susceptibility tests and precise therapeutic drug monitoring (TDM)-guided dosage adjustment. Method: The treatment course of an elderly patient who developed a multi-drug-resistant Pseudomonas aeruginosa (MDRPA) bloodstream infection from a brain abscess was presented. Results: In the treatment process, ceftazidime-avibactam (CAZ-AVI) was used empirically for treating the infection and clinical symptoms improved. However, the follow-up bacterial susceptibility test showed that the bacteria were resistant to CAZ-AVI. Considering the low fault tolerance of clinical therapy, the treatment was switched to a 1 mg/kg maintenance dose of susceptible polymyxin B, and TDM showed that the AUC24h, ss of 65.5 mgh/L had been achieved. However, clinical symptoms were not improved after 6 days of treatment. Facing the complicated situation, the cooperation of physicians, clinical pharmacologists, and microbiologists was applied, and the treatment finally succeeded with the pathogen eradicated when polymyxin B dose was increased to 1.4 mg/kg, with the AUC24h, ss of 98.6 mgh/L. Conclusion: MDT collaboration on the premise of scientific and standardized drug management is helpful for the recovery process in patients. The empirical judgment of doctors, the medication recommendations from experts in the field of TDM and pharmacokinetics/pharmacodynamics, and the drug susceptibility results provided by the clinical microbiology laboratory all provide the direction of treatment.

Safety, tolerability, pharmacokinetics, and immunogenicity of an anti-SARS-CoV-2 monoclonal antibody HFB30132A after single dose intravenous administration in healthy Chinese subjects: a phase 1, randomized, double-blind, placebo-controlled study.

Objective: The pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) still protracts worldwide. HFB30132A is an anti- SARS-CoV-2 monoclonal antibody purposely engineered for an extended half-life with neutralizing activity against majority of the virus variants identified so far. The aim of this study was to evaluate the safety, tolerability, pharmacokinetics (PK), and immunogenicity of HFB30132A in healthy Chinese subjects. Methods: A phase 1, randomized, double-blind, placebo-controlled, single ascending dose clinical trial was designed. Twenty subjects were enrolled to Cohort 1 (1,000 mg dose level, 10 subjects) or Cohort 2 (2,000 mg dose level, 10 subjects). Subjects in each cohort were assigned randomly to receive a single intravenous (IV) dose of HFB30132A or placebo at a ratio of 8:2. Safety was assessed in terms of treatment emergent adverse events (TEAEs), vital signs, physical examination, laboratory tests, and ECG findings. PK parameters were measured and calculated appropriately. Anti-drug antibody (ADA) test was performed to detect anti-HFB30132A antibodies. Results: All subjects completed the study. Overall, 13 (65%) of the 20 subjects experienced TEAEs. The most common TEAEs were laboratory abnormalities (12 subjects [60%]), gastrointestinal disorders (6 subjects [30%]), and dizziness (4 subjects [20%]). All TEAEs were Grade 1 or Grade 2 in severity based on the criteria of Common Terminology Criteria for Adverse Events (CTCAE). Serum exposure (Cmax, AUC0-t, AUC0-∞) of HFB30132A increased with ascending dose. After single dose of 1,000 mg and 2000 mg HFB30132A, the mean Cmax was 570.18 µg/mL and 898.65 µg/mL, the mean AUC0-t value was 644,749.42 h*µg/mL and 1,046,209.06 h*µg/mL, and the mean AUC0-∞ value was 806,127.47 h*µg/mL and 1,299,190.74 h*µg/mL, respectively. HFB30132A showed low clearance ranging from 1.38 to 1.59 mL/h, and a long terminal elimination half-life (t½) of 89-107 days. ADA test did not detect any anti-HFB30132A antibodies Conclusion: HFB30132A was safe and generally well-tolerated after single IV dose of 1,000 mg or 2000 mg in healthy Chinese adults. HFB30132A did not induce immunogenic response in this study. Our data support further clinical development of HFB30132A. Clinical Trial Registration: https://clinicaltrials.gov, identifier: NCT05275660.

Safety and pharmacokinetics of IBI112, an IL-23 monoclonal antibody, in Chinese healthy volunteers: a first-in-human phase 1 study.

BACKGROUND: Interleukin (IL) 23p19 monoclonal antibodies were efficacious and safe in the treatment of psoriasis. A first-in-human (FIH) study was conducted to evaluate the safety, tolerability, pharmacokinetics (PK) and immunogenicity of IBI112, a novel IL-23p19 monoclonal antibody. METHODS: In this FIH, randomized, double-blind, placebo-controlled, single-ascending-dose study, a subcutaneous (SC, 5-600 mg) or intravenous (IV, 100 and 600 mg) or placebo was administered to eligible healthy subjects. Safety was assessed by physical examinations, vital signs, laboratory tests, and electrocardiograms. Furthermore, non-compartment analysis and population PK modeling were conducted to characterize PK, and model-based simulation was applied to justify dose selection for psoriasis patients. RESULTS: A total of 46 subjects were enrolled, with 35 receiving IBI112 and 11 receiving placebo. No serious adverse events (SAEs) and no clinically significant adverse events were identified. After a single SC of IBI112, the median Tmax was 4-10.5 days, and the half-life (t1/2) ranged from 21.8 to 35.8 days. IBI112 exposures (Cmax and AUCinf) approached dose proportionality across 5-300 mg range. CONCLUSION: IBI112 was well tolerated and safe at SC or IV dose up to 600 mg and showed a linear PK characteristics at SC dose from 5 to 300 mg. CLINICAL TRIAL REGISTRATION: ClinicalTrial.gov NCT04511624.

Diagnostic value of human fecal SDC2 gene in colorectal cancer.

OBJECTIVE: To explore the clinical value of human fecal Syndecan-2 (SDC2) gene methylation in colorectal cancer screening. METHODS: There were 30 patients with colorectal cancer receiving treatment in Zhangjiakou First Hospital from January 2019 to December 2019 collected as the tumor group. There were 30 healthy people determined by a physical examination in 2019 collected as the normal group. The methylation level of fecal SDC2 gene and the level of serum tumor markers including carcinoembryonic antigen (CEA) and Carbohydrate antigen 19-9 (CA19-9) were analyzed. The diagnostic effects of fecal SDC2 methylation and serum tumor markers on colorectal cancer were compared. The area under curve (AUC) of different methods for colorectal cancer diagnosis were evaluated based on the receiver operating characteristic (ROC) curve. RESULTS: There was no distinction between the tumor group and the normal group in clinical basic data, including gender, age, and body mass index (P > 0.05), revealing the comparability between the two groups. The level of fecal SDC2 methylation in the tumor group was lower than that in the normal group (P < 0.05). CEA and CA19-9 in the tumor group were higher than those in the normal group (P < 0.05). Among the 30 colorectal cancers, 28 (93.33%) were positive for SDC2 gene methylation, 18 (60%) were positive for serum CEA, and 19 (63.33%) were positive for serum CA19-9. This indicated that the true positive rate of SDC2 gene methylation was higher than that of serum tumor markers (P < 0.05). The AUC of fecal SDC2 gene methylation was 0.981. These were higher than that of serum tumor markers (P < 0.05). CONCLUSIONS: Fecal SDC2 gene detection has a high sensitivity and specificity for colorectal cancer. It has a very ideal detection effect in detecting colorectal cancer patients in the population.

Diversin upregulates the proliferative ability of colorectal cancer by inducing cell cycle proteins.

Colorectal cancer (CRC) is a common gastrointestinal tumour with increasing incidence worldwide. However, the underlying molecular mechanism of CRC proliferation is not completely clear. Diversin，as an ankyrin repeat-containing protein, is upregulated in various solid tumours and accelerates cancer progression by promoting cell proliferation and increasing S phase fraction of cells. In this study, 71 CRC samples and corresponding adjacent tissue samples were included. The expression of diversin in tissues was verified via immunohistochemical analysis. The MTS assay and flow cytometry (FCM) was used to measure cell proliferation and cell cycle. Results of immunohistochemical analysis revealed that diversin was highly expressed in human CRC tissues and was significantly associated with tumour differentiation, clinical stage and lymph node metastasis. The analysis based on the CRC data from The Cancer Genome Atlas (TCGA) database showed that a high expression of diversin correlated with the poor prognosis of CRC. Results of the MTS assay indicated that the overexpression of diversin promoted the proliferation of CRC cells, while its downregulation had an inhibitory effect on CRC cell proliferation. FCM analysises presented that diversin increased the flux of the CRC cell cycle from G1 to S and regulated cycle-related proteins, namely, P21, P27, cyclin E, CDK2, cyclin D and CDK4. The results suggest that diversin contributes to CRC proliferation that involves the distribution of the cell cycle. In CRC tissues, the expression of diversin has closely related to the prognosis. The higher the expression levels of diversin, the worse the prognosis. In vitro, diversin could increase the proliferative ability of CRC cells through the G1-S checkpoint and JNK signalling pathway, confirming that diversin contributes to CRC development.

A Phase I Study to Evaluate the Safety and Pharmacokinetics of SHR0302 Base Ointment in Healthy Adult Volunteers.

INTRODUCTION: SHR0302 is a highly selective JAK1 inhibitor. This study aimed to investigate the safety, tolerability, and pharmacokinetics of single and multiple-dose topical skin application of SHR0302 base ointment in healthy adult subjects. METHODS: This phase I clinical trial (registration number: CTR20192188) consisted of two parts. Part 1 was a single-dose ascending study with four dose levels in 32 healthy Australian adults (8 subjects in each dose group). All Australian subjects were randomized 3:1 to a single-dose topical skin application of SHR0302 base ointment or placebo. The dose escalated from 1% SHR0302 base ointment on 3% of body surface area (BSA) to 2% SHR0302 base ointment on 20% of BSA. Part 2 combined single and multiple-dose ascension studies with two dose levels in 20 healthy Chinese adults (10 subjects in each dose group). All Chinese subjects were randomized 4:1 to a combination of single and multiple doses for consecutive 10 days of topical application of 1% SHR0302 base ointment on 20% BSA or 2% SHR0302 base ointment on 20% BSA. The safety and pharmacokinetics of the SHR0302 base ointment were evaluated. RESULTS: The incidence of treatment-emergent adverse events (TEAEs) in both parts was comparable between the SHR0302 base ointment group and the vehicle group (part 1: 33.3% vs. 37.5%; part 2: 56.3% vs. 75.0%). All TEAEs were transient, recovered, and equally well-tolerated in the two racial groups. The overall absorption of the SHR0302 base ointment was slow after topical application, with Tmax>10 h. After a single dose of the SHR0302 base ointment, drug exposure in healthy Australian and Chinese subjects increased nonlinearly with the increase in the administration area and drug content. Drug exposure increased in a less-than-dose-proportional manner within the dose range tested. Due to differences in the clinical practice of topical application, the Tmax of the drug in Australian subjects was earlier than in Chinese subjects, but the overall extent of absorption seemed comparable in Australian and Chinese subjects (with comparable AUC0-t). CONCLUSION: The SHR0302 base ointment (either single or multiple doses) was well tolerated and safe, with no racial disparity. KEY MESSAGE: The SHR0302 base ointment (either single or multiples doses) was well tolerated and safe.

The interaction of ABA and ROS in plant growth and stress resistances.

The plant hormone ABA (abscisic acid) plays an extremely important role in plant growth and adaptive stress, including but are not limited to seed germination, stomatal closure, pathogen infection, drought and cold stresses. Reactive oxygen species (ROS) are response molecules widely produced by plant cells under biotic and abiotic stress conditions. The production of apoplast ROS is induced and regulated by ABA, and participates in the ABA signaling pathway and its regulated plant immune system. In this review, we summarize ABA and ROS in apoplast ROS production, plant response to biotic and abiotic stresses, plant growth regulation, ABA signal transduction, and the regulatory relationship between ABA and other plant hormones. In addition, we also discuss the effects of protein post-translational modifications on ABA and ROS related factors.

Sequence Type 5 (ST5) as a Possible Predictor of Bacterial Persistence in Adult Patients with Methicillin-Resistant Staphylococcus aureus Pneumonia Treated with Vancomycin.

Vancomycin remains the mainstay of treatment for methicillin-resistant Staphylococcus aureus (MRSA) pneumonia. This study assessed risk factors for vancomycin failure in 63 patients with MRSA pneumonia through detailed clinical, microbiological, pharmacokinetic/pharmacodynamic, and genetic analyses of prospective multicenter studies conducted from February 2012 to July 2018. Therapeutic drug monitoring was performed during vancomycin treatment, and the 24-h area under the curve (AUC0-24) was calculated. All baseline strains were collected for MIC determination, heterogeneous vancomycin-intermediate S. aureus (hVISA) screening, and biofilm determination. Whole-genome sequencing was performed on the isolates to analyze their molecular typing and virulence and adhesion genes. Clinical signs and symptoms improved in 44 patients (44/63, 69.8%), with vancomycin daily dose (P = 0.045), peak concentration (P = 0.020), and sdrC (P = 0.047) being significant factors. Isolates were eradicated in 51 patients (51/63, 81.0%), with vancomycin daily dose (P = 0.009), cardiovascular disease (P = 0.043), sequence type 5 (ST5; P = 0.017), tst (P = 0.050), and sec gene (P = 0.044) associated with bacteriological failure. Although the AUC0-24/MIC was higher in the groups with bacterial eradication, the difference was not statistically significant (P = 0.108). Multivariate analysis showed that no variables were associated with clinical efficacy; ST5 was a risk factor for bacterial persistence (adjusted odds ratio, 4.449; 95% confidence interval, 1.103 to 17.943; P = 0.036). ST5 strains had higher frequencies of the hVISA phenotype, biofilm expression, and presence of some adhesion and virulence genes such as fnbB, tst, and sec than non-ST5 strains. Our study suggests that ST5 is a possible predictor of bacterial persistence in MRSA pneumonia treated with vancomycin. IMPORTANCE Few studies have simultaneously examined the influence of clinical characteristics of patients with pneumonia, the vancomycin pharmacokinetic/pharmacodynamic (PK/PD) index, and the phenotypic and genetic characteristics of methicillin-resistant Staphylococcus aureus (MRSA) strains. We assessed risk factors for vancomycin failure in patients with MRSA pneumonia by analyzing these influences in a prospective multicenter study. Sequence type 5 (ST5) was a possible predictor of bacterial persistence in adult patients with MRSA pneumonia (adjusted odds ratio, 4.449). We found that this may be related to ST5 strains having higher levels of vancomycin heterogeneous resistance, biofilms, and the presence of adhesion and virulence genes such as fnbB, tst, and sec.

Elevated Serum Tenascin-C Predicts Mortality in Critically Ill Patients With Multiple Organ Dysfunction.

Background: Multiple organ dysfunction is a complex and lethal clinical feature with heterogeneous causes and is usually characterized by tissue injury of multiple organs. Tenascin-C (TNC) is a matricellular protein that is rarely expressed in most of the adult tissues, but re-induced following injury. This study aimed to evaluate serum TNC in predicting mortality in critically ill patients with multiple organ dysfunction. Methods: Adult critically ill patients with at least two organs dysfunction and an increase of Sequential Organ Failure Assess (SOFA) score ≥ 2 points within 7 days were prospectively enrolled into two independent cohorts. The emergency (derivation) cohort was a consecutive series and the patients were from Emergency Department. The inpatient (validation) cohort was a convenience series and the patients were from medical wards. Their serum samples at the first 24 h after enrollment were collected and subjected to TNC measurement using ELISA. The association between serum TNC level and 28-day all-cause mortality was investigated, and then the predictive value of serum TNC was analyzed. Results: A total of 110 patients with a median age of 64 years (53, 73) were enrolled in the emergency cohort. Compared to the survivors, serum TNC in the non-survivors was significantly higher (467.7 vs. 197.5 ng/ml, p < 0.001). Multivariate logistic regression analysis revealed that the association between serum TNC and 28-day mortality was independent of sepsis or critical illness scores such as SOFA, Acute Physiology and Chronic Health Evaluation (APACHE II), and Simplified Acute Physiology Score (SAPS II), respectively (p < 0.001 for each). The area under receiver operating characteristic curve of serum TNC for predicting mortality was 0.803 (0.717-0.888) (p < 0.001), similar with SOFA 0.808 (0.725-0.891), APACHE II 0.762 (0.667-0.857), and SAPS II 0.779 (0.685-0.872). The optimal cut-off value of serum TNC was 298.2 ng/ml. Kaplan-Meier analysis showed that the survival of patients with serum TNC ≥ 300 ng/ml was significantly worse than that of patients with serum TNC < 300 ng/ml. This result was validated in the inpatient cohort. The sensitivity and specificity of serum TNC ≥ 300 ng/ml for predicting mortality were 74.3 and 74.7% in the emergency cohort, and 63.0 and 70.1% in the inpatient cohort, respectively. Conclusion: Serum TNC was associated with mortality in critically ill patients with multiple organ dysfunction, and would be used as a prognostic tool for predicting mortality in this population.

Tolerability, Safety, Pharmacokinetics, and Immunogenicity of a Novel SARS-CoV-2 Neutralizing Antibody, Etesevimab, in Chinese Healthy Adults: a Randomized, Double-Blind, Placebo-Controlled, First-in-Human Phase 1 Study.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to spread rapidly worldwide. This study is the first to report the tolerability, safety, pharmacokinetics (PK), and immunogenicity of a recombinant human anti-SARS-CoV-2 monoclonal antibody, etesevimab (CB6, JS016, LY3832479, or LY-CoV016), in healthy adults. This paper describes a randomized, double-blind, placebo-controlled, phase 1 study. A total of 40 participants were enrolled to receive a single intravenous dose of either etesevimab or placebo in one of four sequential ascending intravenous dose cohorts. All 40 participants completed the study. Seventeen (42.5%) participants experienced 22 treatment emergent adverse events (TEAEs) that were drug-related, and the rates of these TEAEs among different dose cohorts were numerically comparable. No difference was observed between the combined etesevimab group and the placebo group. The exposure after etesevimab infusion increased in an approximately proportional manner as the dose increased from 2.5 to 50 mg/kg. The elimination half-life (t1/2) value did not differ among different dose cohorts and was estimated to be around 4 weeks. Etesevimab was well tolerated after administration of a single dose at a range of 2.5 mg/kg to 50 mg/kg in healthy Chinese adults. The PK profiles of etesevimab in healthy volunteers showed typical monoclonal antibody distribution and elimination characteristics. (This study has been registered at ClinicalTrials.gov under identifier NCT04441918.).

Emerging roles of circular RNAs in non­small cell lung cancer (Review).

Circular RNAs (circRNAs) are a class of novel endogenous transcripts with limited protein­coding abilities. CircRNAs have been demonstrated to function as critical regulators of tumor development and distant metastasis through binding to microRNAs (miRNAs) and interacting with RNA­binding proteins, thereby regulating transcription and translation. Emerging evidence has illustrated that certain circRNAs can serve as biomarkers for diagnosis and prognosis of cancer, and/or serve as potential therapeutic targets. Expression of functional circRNAs is commonly dysregulated in cancer and this is correlated with advanced Tumor­Node­Metastasis stage, lymph node status, distant metastasis, poor differentiation and shorter overall survival of cancer patients. Recently, an increasing number of studies have shown that circRNAs are closely associated with NSCLC. Functional experiments have revealed that circRNAs are intricately associated with the pathological progression of NSCLC. The present review provides an overview of the regulatory effect of circRNAs in the development and progression of NSCLC, taking into consideration various physiological and pathological processes, such as proliferation, apoptosis, invasion and migration, and their potential value as biomarkers and therapeutic targets.

CircHIPK3 Promotes Clear Cell Renal Cell Carcinoma (ccRCC) Cells Proliferation and Metastasis via Altering of miR-508-3p/CXCL13 Signal.

INTRODUCTION: Accumulating evidence has demonstrated that circular RNAs (circRNAs) play a key role in the tumorigenesis of various types of cancers, including clear cell renal cell carcinoma (ccRCC). MATERIALS AND METHODS: Reverse transcription-quantitative polymerase chain reaction was used to detect the expression of circRNA homeodomain interacting protein kinase 3 (circHIPK3) and microRNAs (miRNAs), including miR-508-3p. The clinical measurement of circHIPK3 was evaluated by Kaplan-Meier survival analysis and receiver operating characteristic analysis. Cell Counting Kit-8 and Transwell chamber assays were performed to determine the changes in the proliferative and metastatic ability of A498 and 786-O cells. C-X-C motif chemokine ligand 13 (CXCL13) protein expression was detected by Western blot analysis. The targeted binding effect between miR-508-3p and circHIPK3 or CXCL13 was confirmed by constructed luciferase and RNA immunoprecipitation (RIP) assays, respectively. Fluorescence in situ hybridization (FISH) assay was used to measure the subcellular localization of circHIPK3 and miR-508-3p. RESULTS: It was found that circHIPK3 was markedly upregulated in ccRCC tissue and cell lines, and circHIPK3-upregulation was closely correlated with poor clinicopathological features in patients with ccRCC. It was found that both miR-508-3p and circHIPK3 were localized in the cytoplasm of ccRCC cells. The up- and downregulation of circHIPK3 positively regulated ccRCC cell proliferation and metastasis, and this regulatory effect was reversed by miR-508-3p. Through luciferase and RIP assays, it was confirmed that circHIPK3 could interacted with miR-508-3p. Furthermore, it was revealed that CXCL13, which was negatively correlated with miR-508-3p, was upregulated in ccRCC. It was also shown that CXCL13 was a downstream target of miR-508-3p. miR-508-3p suppressed ccRCC cell proliferation and metastasis by targeting CXCL13. Lastly, it was demonstrated that circHIPK3 promoted CXCL13 to facilitate ccRCC cell proliferation and metastasis by decoying miR-508-3p. CONCLUSION: In brief, the results of the present study showed that circHIPK3 promoted ccRCC cell proliferation and metastasis by altering miR-5083p/CXCL13 signaling. The present findings might provide a novel target for the molecular treatment of ccRCC.

Heterologous Expression of the Cotton NBS-LRR Gene GbaNA1 Enhances Verticillium Wilt Resistance in Arabidopsis.

Verticillium wilt caused by Verticillium dahliae results in severe losses in cotton, and is economically the most destructive disease of this crop. Improving genetic resistance is the cleanest and least expensive option to manage Verticillium wilt. Previously, we identified the island cotton NBS-LRR-encoding gene GbaNA1 that confers resistance to the highly virulent V. dahliae isolate Vd991. In this study, we expressed cotton GbaNA1 in the heterologous system of Arabidopsis thaliana and investigated the defense response mediated by GbaNA1 following inoculations with V. dahliae. Heterologous expression of GbaNA1 conferred Verticillium wilt resistance in A. thaliana. Moreover, overexpression of GbaNA1 enabled recovery of the resistance phenotype of A. thaliana mutants that had lost the function of GbaNA1 ortholog gene. Investigations of the defense response in A. thaliana showed that the reactive oxygen species (ROS) production and the expression of genes associated with the ethylene signaling pathway were enhanced significantly following overexpression of GbaNA1. Intriguingly, overexpression of the GbaNA1 ortholog from Gossypium hirsutum (GhNA1) in A. thaliana did not induce the defense response of ROS production due to the premature termination of GhNA1, which lacks the encoded NB-ARC and LRR motifs. GbaNA1 therefore confers Verticillium wilt resistance in A. thaliana by the activation of ROS production and ethylene signaling. These results demonstrate the functional conservation of the NBS-LRR-encoding GbaNA1 in a heterologous system, and the mechanism of this resistance, both of which may prove valuable in incorporating GbaNA1-mediated resistance into other plant species.

The island cotton NBS-LRR gene GbaNA1 confers resistance to the non-race 1 Verticillium dahliae isolate Vd991.

Wilt caused by Verticillium dahliae significantly reduces cotton yields, as host resistance in commercially cultivated Gossypium species is lacking. Understanding the molecular basis of disease resistance in non-commercial Gossypium species could galvanize the development of Verticillium wilt resistance in cultivated species. Nucleotide-binding site leucine-rich repeat (NBS-LRR) proteins play a central role in plant defence against pathogens. In this study, we focused on the relationship between a locus enriched with eight NBS-LRR genes and Verticillium wilt resistance in G. barbadense. Independent virus-induced gene silencing of each of the eight NBS-LRR genes in G. barbadense cultivar Hai 7124 revealed that silencing of GbaNA1 alone compromised the resistance of G. barbadense to V. dahliae isolate Vd991. In cultivar Hai 7124, GbaNA1 could be induced by V. dahliae isolate Vd991 and by ethylene, jasmonic acid and salicylic acid. Nuclear protein localization of GbaNA1 was demonstrated by transient expression. Sequencing of the GbaNA1 orthologue in nine G. hirsutum accessions revealed that all carried a non-functional allele, caused by a premature peptide truncation. In addition, all 10 G. barbadense and nine G. hirsutum accessions tested carried a full-length (∼1140 amino acids) homologue of the V. dahliae race 1 resistance gene Gbve1, although some sequence polymorphisms were observed. Verticillium dahliae Vd991 is a non-race 1 isolate that lacks the Ave1 gene. Thus, the resistance imparted by GbaNA1 appears to be mediated by a mechanism distinct from recognition of the fungal effector Ave1.