A miRNA-7704/IL2RB/AKT feedback loop regulates tumorigenesis and chemoresistance in ovarian cancer.

Ovarian cancer is one of the most common gynecological tumors worldwide. Despite the availability of multiple treatments for ovarian cancer, its resistance to chemotherapy remains a significant challenge. miRNAs play crucial roles in the initiation and progression of cancer by affecting processes such as differentiation, proliferation, and chemoresistance. According to microarray and qPCR analyses, miR-7704 is significantly downregulated in cisplatin-resistant cells compared to parental cells. In this study, we found that miR-7704 inhibited the proliferation and promoted cisplatin sensitivity of ovarian cancer cells in vitro and in vivo. Moreover, ectopic expression of miR-7704 had the same effect as IL2RB knockdown. Further mechanistic studies revealed that miR-7704 played an inhibitory role by regulating IL2RB expression to inactivate the AKT signaling pathway. Furthermore, IL2RB reversed the miR-7704 mediated resistance to cisplatin in ovarian cancer. Based on these findings, miR-7704 and IL2RB show the potential as novel therapeutic targets for ovarian cancer.

Promoting proliferation and tumorigenesis of breast cancer: KCND2's significance as a prognostic factor.

In recent years, the potassium voltage-gated channel subfamily D (KCND) channels, particularly KCND2 (also known as Kv4.2), have been suggested to play a role in a variety of cancers, but their role in breast cancer has not yet been revealed. We analyzed RNA sequencing data from The Cancer Genome Atlas database and the Genotype-Tissue Expression database to investigate the differential expression of KCND2 in breast cancer and normal breast tissue. In addition, we leveraged GO and KEGG analysis techniques to gain a better understanding of the potential functional enrichment of 500 genes related to KCND2. Our findings were validated using collected tissue samples and clinical data from hospitals showed that KCND2 is a crucial independent factor in the prognosis of breast cancer patients. The higher the expression of KCND2, the shorter the survival time of breast cancer patients. Colony formation assay confirmed that KCND2 promotes the proliferation of breast cancer cells, whereas transwell assay and wound healing assay verified that KCND2 promoted breast cancer invasion and migration. In addition, 5-Ethynyl-2'-deoxyuridine (EdU) and flow cytometry revealed that KCND2 affected the cycle changes of breast cancer cells and contributed to the G1/S phase transition of breast cancer cells. Overall, our study demonstrates that KCND2 holds a promising potential as a significant target for breast cancer diagnosis and therapy.

Safety, tolerability, pharmacokinetics and immunogenicity of an antibody-drug conjugate (SHR-A1201) in patients with HER2-positive advanced breast cancer: an open, phase I dose-escalation study.

SHR-A1201 is an antibody-drug conjugate (ADC) that combines trastuzumab with DM1 (a chemotherapeutic agent) using a chemical connector. This phase I study investigated the safety, tolerability and pharmacokinetics of SHR-A1201 in patients with human epidermal growth factor receptor 2-positive advanced breast cancer. This phase I study enrolled patients in a traditional 3 + 3 dose-escalation design to receive a single dose of SHR-A1201 (1.2 mg/kg, 2.4 mg/kg, 3.6 mg/kg or 4.8 mg/kg). The observation period of dose-limiting toxicity (DLT) was 21 days. A total of 12 patients were enrolled and received SHR-A1201. Most treatment-emergent adverse events (TEAEs) were grade 1 or 2 in severity, with elevated aspartate aminotransferase (75%), thrombocytopenia (75%), and nausea (66.7%) being reported most frequently. The common grade 3 TEAEs were thrombocytopenia and decreased lymphocyte count, and there were no grade 4 or above TEAEs. There were no serious adverse events or drug-related deaths. One DLT occurred in one patient treated with SHR-A1201 4.8 mg/kg (asymptomatic grade 3 increased γ-glutamyltransferase). The maximum tolerated dose of SHR-A1201 was not lower than that of T-DM1 (3.6 mg/kg). A total of 8.3% (1/12) of patients had ADA-positive reactions 504 h after administration, but no differences were observed in the type, incidence, or severity of TEAEs between patients with and without ADA. SHR-A1201 exhibited the pharmacokinetics characteristics of typical ADCs. An encouraging antitumor effect was observed in the 4.8 mg/kg dose group. SHR-A1201 was well tolerated and safe in patients with advanced HER2-positive breast cancer. The pharmacokinetics parameters showed a linear trend, and the immunogenicity results met the clinical expectations.

Association between early ondansetron administration and in-hospital mortality in critically ill patients: analysis of the MIMIC-IV database.

BACKGROUND: While ondansetron (OND) is widespread availability, the contribution of OND to improve patient outcomes among intensive care unit (ICU) patients has not been examined. This study aimed to illustrate the association between early OND use and in-hospital mortality in critically ill patients and investigate whether this association differed according to OND dose. METHODS: The MIMIC-IV database was employed to identify patients who had and had not received OND. Statistical approaches included multivariate logistic regression, propensity score matching (PSM), and propensity score-based inverse probability of treatment weighting (IPTW) models to ensure the robustness of our findings. RESULTS: In total, 51,342 ICU patients were included. A significant benefit in terms of in-hospital mortality was observed in the OND patients compared to the non-OND group in the early stage [odds ratio (OR) = 0.75, 95% CI 0.63-0.89, p < 0.001]. In the circulatory system group, the early OND administration was associated with improved in-hospital mortality in ICU patients (OR 0.48, 95% CI 0.34-0.66; P < 0.001). The risk of in-hospital mortality was also lower in early OND users than in non-OND users both in the medical admission group and the surgical ICU admission group, and ORs were 0.57 (95% CI 0.42-0.76; P < 0.001) and 0.79 (95% CI 0.62-0.91; P < 0.001), respectively. A positive role of daily low- and moderate-dose OND treatment in early-stage was showed on the in-hospital mortality in PSM cohort, and the ORs were 0.75 (95% CI 0.62-0.90; P < 0.001) and 0.63 (95% CI 0.43-0.91; P < 0.001), respectively. The relationship between the daily low- and moderate-dose of OND and in-hospital mortality was also significant in ICU patients with cardiovascular diseases, and ORs were 0.51(95% CI 0.36-0.73; P < 0.001), and 0.26(95% CI 0.11-0.65; P < 0.001), respectively. Daily low-to-moderate dose of OND was also associated with in-hospital mortality in ICU entire cohort. CONCLUSIONS: Early OND use is closely associated with lower in-hospital mortality in ICU patients. Daily low-to-moderate dose of OND application is protective against in-hospital mortality. This association is more evident in the circulatory system group.

Ferulic acid alleviates AFB1-induced duodenal barrier damage in rats via up-regulating tight junction proteins, down-regulating ROCK, competing CYP450 enzyme and activating GST.

Previous studies reported that Aflatoxin B1 (AFB1) causes cell damage through its metabolite aflatoxin B1-8, 9-epoxide (AFBO), which is catalyzed by CYP450 enzymes. AFBO can be detoxified by glutathione S transferase (GST). Ferulic acid (FA) is known for its antioxidant capacity and intestinal protective function. However, the mechanism of AFB1 causing duodenal injury and the role of FA in AFB1-induced intestinal damage remains unclear. In this study, rats were exposed to AFB1 and treated with FA for 30 days. The results showed that I) FA alleviated the histopathological changes of duodenum and the ultrastructural changes of tight junctions between duodenal epithelial cells induced by AFB1. II) FA reduced the content of AFB1-ALB adduct in blood. III) The low expression of tight junction proteins (Claudin-1 and ZO-1) and the high expression of ROCK1 and ROCK2 induced by AFB1 were significantly reversed by FA. IV) The high expression of CYP2A6 and CYP3A4 were significantly down-regulated by FA, and the activity of GST was promoted by FA. V) The binding affinity of FA to CYP2A6 is very similar to the binding affinity of AFB1 to CYP2A6, which meaning that there is a competitive relationship between FA and AFB1 when conjugating to CYP2A6. These results suggested that FA proved effective in alleviating AFB1-induced duodenal barrier damage via up-regulating tight junction proteins, down-regulating ROCK, competing CYP450 enzyme, and activating GST in duodenal epithelial cells of rats.

A first-in-human, randomized, double-blind, single- and multiple-dose, phase I study of recombinant human thymosin ß4 in healthy Chinese volunteers.

The study evaluated the safety, tolerability, pharmacokinetics (PK) and anti-drug antibody (ADA) of the recombinant human thymosin ß4 (NL005) for single and multiple intravenous injections in healthy subjects. Seven cohorts, with 54 healthy subjects, were given a single intravenous dose of NL005 or placebo and were observed for 28 days. The cohorts received ascending doses of either 0.05, 0.25, 0.5, 2.0, 5.0, 12.5 or 25.0 µg/kg in the single-dose trial. A total of 30 healthy subjects were randomly enrolled in the multiple-dose trial, and 3 cohorts (0.5, 2.0 and 5.0 µg/kg) were administered once human thymosin ß4 daily for 10 days and observed for 28 days. The adverse events were mild to moderate in intensity. There were no dose-limiting toxicities or serious adverse events. The plasma concentration, maximum peak concentration (Cmax ) and AUC of each dose group increased with the increase in the dose. The tendency of terminal clearance in each dose group was consistent, and there was no obvious accumulation after continuous administration. Thus, the drug can be concluded to be well tolerated and safe in healthy people and suitable for use in a clinical study for the treatment of acute myocardial infarction.

Safety, Tolerability, Pharmacokinetics, and Immunogenicity of a Monoclonal Antibody (SCTA01) Targeting SARS-CoV-2 in Healthy Adults: a Randomized, Double-Blind, Placebo-Controlled, Phase I Study.

SCTA01 is a novel monoclonal antibody with promising prophylactic and therapeutic potential for COVID-19. This study aimed to evaluate the safety, tolerability, pharmacokinetics (PK) and immunogenicity of SCTA01 in healthy adults. This was a randomized, double-blind, placebo-controlled, dose escalation phase I clinical trial. Healthy adults were randomly assigned to cohort 1 (n = 5; 3:2), cohort 2 (n = 8; 6:2), cohort 3, or cohort 4 (both n = 10; 8:2) to receive SCTA01 (5, 15, 30, and 50 mg/kg, respectively) versus placebo. All participants were followed up for clinical, laboratory, PK, and immunogenicity assessments for 84 days. The primary outcomes were the dose-limiting toxicity (DLT) and maximal tolerable dose (MTD), and the secondary outcomes included PK parameters, immunogenicity, and adverse events (AE). Of the 33 participants, 18 experienced treatment-related AEs; the frequency was 52.0% (13/25) in participants receiving SCTA01 and 62.5% (5/8) in those receiving placebo. All AEs were mild. There was no serious AE or death. No DLT was reported, and the MTD of SCTA01 was not reached. SCTA01 with a dose range of 5 to 50 mg/kg had nearly linear dose-proportional increases in Cmax and AUC parameters. An antidrug antibody response was detected in four (16.0%) participants receiving SCTA01, with low titers, between the baseline and day 28, but all became negative later. In conclusion, SCTA01 up to 50 mg/kg was safe and well-tolerated in healthy participants. Its PK parameters were nearly linear dose-proportional. (This study has been registered at ClinicalTrials.gov under identifier NCT04483375.).

Nomogram for perinatal prediction of intrapartum fever: a retrospective case-control study.

OBJECTIVE: To explore the risk factors for intrapartum fever and to develop a nomogram to predict the incidence of intrapartum fever. METHODS: The general demographic characteristics and perinatal factors of 696 parturients who underwent vaginal birth at the Affiliated Hospital of Xuzhou Medical University from May 2019 to April 2020 were retrospectively analysed. Data was collected from May 2019 to October 2019 on 487 pregnant women who formed a training cohort. A multivariate logistic regression model was used to identify the independent risk factors associated with intrapartum fever during vaginal birth, and a nomogram was developed to predict the occurrence. To verify the nomogram, data was collected from January 2020 to April in 2020 from 209 pregnant women who formed a validation cohort. RESULTS: The incidence of intrapartum fever in the training cohort was found in 72 of the 487 parturients (14.8%), and the incidence of intrapartum fever in the validation cohort was 31 of the 209 parturients (14.8%). Multivariate logistic regression analysis showed that the following factors were significantly related to intrapartum fever: primiparas (odds ratio [OR] 2.43; 95% confidence interval [CI] 1.15-5.15), epidural labour analgesia (OR 2.89; 95% CI 1.23-6.82), premature rupture of membranes (OR 2.37; 95% CI 1.13-4.95), second stage of labour ≥ 120 min (OR 4.36; 95% CI 1.42-13.41), amniotic fluid pollution degree III (OR 10.39; 95% CI 3.30-32.73), and foetal weight ≥ 4000 g (OR 7.49; 95% CI 2.12-26.54). Based on clinical experience and previous studies, the duration of epidural labour analgesia also appeared to be a meaningful factor for intrapartum fever; therefore, these seven variables were used to develop a nomogram to predict intrapartum fever in parturients. The nomogram achieved a good area under the ROC curve of 0.86 and 0.81 in the training and in the validation cohorts, respectively. Additionally, the nomogram had a well-fitted calibration curve, which also showed excellent diagnostic performance. CONCLUSION: We constructed a model to predict the occurrence of fever during childbirth and developed an accessible nomogram to help doctors assess the risk of fever during childbirth. Such assessment may be helpful in implementing reasonable treatment measures. TRIAL REGISTRATION: Clinical Trial Registration: ( www.chictr.org.cn ChiCTR2000035593 ).

Pharmacokinetic bioequivalence and safety assessment of two metformin hydrochloride tablet formulations using a phase I, randomized, open, two-period, two cross-over, single-dose, fed study in healthy Chinese adult subjects.

OBJECTIVES: To assess the bioequivalence and safety of generic metformin hydrochloride (test preparation) and glucophage (reference preparation) in healthy Chinese subjects. MATERIALS AND METHODS: A bioequivalence and safety assessment of two formulations of metformin (850 mg) using a randomized, open, two-period, two cross-over, single-dose, fed trial in 36 healthy Chinese adult subjects was performed at our center from March 22, 2018, to April 9, 2018. Bioequivalence was determined as two-sided 90% confidence intervals (CI) of the test-to-reference ratio of area under the curve (AUC) and peak concentration (Cmax) for each constituent within 80.00 - 125.00%. SAS 9.4 software was employed for the statistical analysis. RESULTS: One subject was excluded from the trial. The 90% CIs (95.36 - 101.43% for AUC0→t, 95.65 - 101.66% for AUC0→∞; 94.43 - 101.74% for Cmax) of test/reference preparation for these pharmacokinetic parameters were within the range of 80.00 - 125.00%. No severe adverse events were observed during this trial. The two preparations were safe and well-tolerated. CONCLUSION: It was concluded that generic metformin was bioequivalent and as safe as glucophage under fed conditions in healthy Chinese subjects.

Development and validation of an ultrasensitive LC-MS/MS method for the quantification of cetagliptin in human plasma and its application in a microdose clinical trial.

This study established and validated an LC-MS/MS method for the ultrasensitive determination of cetagliptin in human plasma. Sample pretreatment was achieved by liquid-liquid extraction with ethyl acetate, and chromatographic separation was performed on an XB-C18 analytical column (50 × 2.1 mm, 5 µm) with gradient elution (0.1% formic acid in acetonitrile and 0.1% formic acid) at a flow rate of 1.0 mL/min. For mass spectrometric detection, multiple reaction monitoring was used, and the ion transitions monitored were m/z 421.2-86.0 for cetagliptin and m/z 424.2-88.0 for cetagliptin-d3. Method validation was performed according to the U.S. Food and Drug Administration Bioanalytical Method Validation Guidance, for which the calibration curve was linear in the range of 50.0-2000 pg/mL. All of the other results, such as selectivity, lower limit of quantitation, precision, accuracy, matrix effect, recovery, and stability, met the acceptance criteria. The validated method was successfully applied in a microdose clinical trial to systematically investigate the pharmacokinetic profile of cetagliptin in healthy subjects. Both rapid absorption and prolonged duration demonstrate the potential value of cetagliptin for diabetes treatment.

Ferulic acid prevents aflatoxin B1-induced liver injury in rats via inhibiting cytochrome P450 enzyme, activating Nrf2/GST pathway and regulating mitochondrial pathway.

Aflatoxin B1 (AFB1) causes oxidative stress and hepatocyte apoptosis through its epoxidized metabolite AFBO, which is catalyzed by CYP450 enzymes. Ferulic acid (FA) is a phenolic acid commonly found in plants and is known for its antioxidant capacity. However, the role of FA in AFB1-induced liver injury is still elusive. In this study, rats were exposed to AFB1 and simultaneously treated with FA for 30 days. The results showed that I) FA alleviated the histopathological changes induced by AFB1, inhibited the elevation of serological indexes induced by AFB1, and reduced the production of AFBO in liver. II) AFB1-induced increase in CYP450 expression was significantly reduced by FA. The molecular docking results of FA and CYP2A6 showed high fitness score and interaction. III) FA obviously inhibited the production of MDA, and significantly activated the Nrf2/GST pathway and antioxidant enzymes (SOD and GST). IV) AFB1-induced hepatocyte apoptosis, the high expression of p53, bax, cyt-c, caspase-9, caspase-3, and the low expression of bcl-2 were all restored by FA. It has been suggested from these results that FA proved effective against AFB1-induced liver damage in rats via inhibiting CYP450 enzyme, promoting antioxidant pathway Nrf2/GST, activating antioxidant enzymes (SOD and GST), and regulating the mitochondrial pathway.

Incidence of postoperative sore throat after using a new technique of insertion of a second generation Laryngeal Mask Airway: A randomised controlled trial.

BACKGROUND: Sore throat is a common complication after Laryngeal Mask Airway Supreme (SLMA) insertion. OBJECTIVE: The aim of this study was to determine whether a new SLMA insertion technique (not removing the pilot tube blocker before insertion) lowers the incidence of sore throat in the postanaesthesia care unit (PACU). DESIGN: A prospective, single-centre, parallel randomised controlled trial. SETTING: Operating room and PACU at a hospital in China from June to September 2019. PATIENTS: Four hundred and eight patients aged 18 to 65 years with American Society of Anaesthesiologists physical status class I or II who were scheduled for elective surgery requiring anaesthesia and SLMA insertion. INTERVENTIONS: Leaving the blocker at the end of the pilot tube in situ (this blocker keeps the valve open and the balloon remains partially inflated but will deflate with pressure) or removing the blocker and actively deflating the cuff before SLMA insertion. MAIN OUTCOME MEASURES: The primary outcome was the incidence of postoperative sore throat in the PACU. The secondary outcomes included sore throat severity (Prince Henry Hospital Pain Score), first-attempt success rate, ease of insertion, time to successful SLMA insertion, oropharyngeal leak pressure, grade of view on fibreoptic bronchoscopy (indicating the accuracy of SLMA positioning) and adverse events. RESULTS: The incidence of sore throat was 33/204 (16.2%) in the nonremoval group, and 65/204 (31.9%) in the removal group (P < 0.001). The first-attempt success rate was 174/204 (85.3%) in the nonremoval group and 150/204 (73.76%) in the removal group (P = 0.003; relative risk 1.160, 95% CI 1.049 to 1.282). The Kaplan--Meier curves showed that the insertion time in the nonremoval group was shorter (log-rank P = 0.01). CONCLUSION: The new insertion technique, leaving the blocker attached to the end of the pilot balloon, resulted in a reduced incidence and severity of postoperative sore throat in the PACU, and an improved first-attempt success rate and the accuracy of SLMA positioning. TRIAL REGISTRATION: Chinese Clinical Trial Registry identifier: ChiCTR1900023022.

A Sensitive and Simple Enzyme-Linked Immunosorbent Assay Using Polymer as Carrier.

In this study, a new and sensitive enzyme-linked immunosorbent assay (ELISA) was developed by introducing a polymer as a reaction carrier. The results suggest that the newly developed ELISA method is more convenient than the existing paper-based ELISA method and applicable to a wider range of environments. In addition, the sensitivity of the new method is much higher than that of the existing paper-based ELISA method and even higher than that of the traditional ELISA method.

The efficacy and safety of intrathecal dexmedetomidine for parturients undergoing cesarean section: a double-blind randomized controlled trial.

BACKGROUND: The efficacy and safety of spinal anesthesia by intrathecal dexmedetomidine (DEX) for parturients undergoing cesarean section are still lack of evidence. This aim of our study was to evaluate the efficacy and safety of intrathecal DEX for parturients undergoing cesarean section to provide more data evidence for intrathecal applications. METHODS: Three hundred parturients undergoing cesarean section under spinal anesthesia were randomly assigned into three groups: group B: 9.0 mg (1.2 ml) of 0.75% bupivacaine with saline (1 ml); group FB: 9.0 mg (1.2 ml) of 0.75% bupivacaine with 20 µg of fentanyl (1 ml); group DB: 9.0 mg (1.2 ml) of 0.75% bupivacaine with 5 µg of DEX (1 ml). Intraoperative block characteristics, parturients' postoperative quality of recovery, maternal and neonatal outcomes and the plasma concentration of DEX were measured. All parturients were followed up for 30 days to determine whether nerve injury occurred. RESULTS: Compared with group B, the duration of sensory block in group FB and group DB were significantly prolonged (108.4 min [95% Confidence Interval (CI) = 104.6-112.3] in group B, and 122.0 min [95% CI = 116.8-127.3] in group FB, 148.2 min [95% CI = 145.3-151.1] in group DB). The overall score of quality recovery in group DB (71.6 [95% CI = 71.0-72.2]) was significantly higher than that in group FB (61.5 [95% CI = 60.8-62.2]) and group B (61.7 [95% CI = 61.0-62.4]). There was no statistically significant difference among the three groups for PH, PaO2, and PaCO2 of newborn. The plasma concentration of DEX in umbilical artery and umbilical vein was low and cannot be detected. The 30-days follow-up of parturients did not show any new onset of back, buttock or leg pain or paresthesia. CONCLUSIONS: DEX is a potential local anesthetic adjuvant that the intrathecal combination of 5 µg DEX can safely exhibit a facilitatory block effect and improve parturients' recovery quality. TRIAL REGISTRATION: Chinese Clinical Trial Registry (Registration number # ChiCTR1900022019 ; Date of Registration on March 20th, 2019).

Development of a Gold Nanoparticle-Functionalized Surface Plasmon Resonance Assay for the Sensitive Detection of Monoclonal Antibodies and Its Application in Pharmacokinetics.

As a prominent human therapeutic, therapeutic monoclonal antibodies (mAbs) have attracted increasing attention in the past decade due to their high-targeting specificity, low toxicity, and prolonged efficacy. Systematic pharmacokinetic analysis of mAbs not only largely facilitates the understanding of their biologic functions but also promotes the development of therapeutic drug discovery, early clinical trial implementation, and therapeutic monitoring. However, the extremely complex nature of biomatrices and the especially low dosages of mAbs make their detection in biomatrices and further pharmacokinetic analysis highly challenging. Therefore, a method capable of reliably, quickly, and sensitively quantifying mAbs in biomatrices is urgently needed. In this work, we developed and evaluated an gold nanoparticle-functionalized surface plasmon resonance assay for cetuximab (C225) detection and pharmacokinetic analysis in rhesus monkeys. Combining its advantages of label-free pretreatment and amplified signal response, the lower limit of quantitation of C225 in monkey serum was reduced to 0.0125 µg/ml, and the linear range had an order of magnitude comparable to that of an ELISA-based method. Furthermore, the pharmacokinetics of C225 in rhesus monkeys was studied after intravenous infusions of single doses at 7.5, 24, and 75 mg/kg. The concentration of C225 in monkey serum was detectable after dosing for 720 hours. We believe that this new strategy will be applicable as a general protocol for mAb quantification, pharmacokinetic characteristic determination, and toxicokinetic analysis during drug development.

Curcumin confers hepatoprotection against AFB1-induced toxicity via activating autophagy and ameliorating inflammation involving Nrf2/HO-1 signaling pathway.

The current study demonstrated curcumin intervention against AFB1-indeuced hepatotoxicity. The hallmarks of autophagy and inflammation were assessed by transmission electron microscopy, RT-PCR and western blot. Besides, normal cellular morphology, autophagosomes were found in control and curcumin control group. In contrast, fragmented and swollen mitochondria, irregular shaped nuclei and fat droplets were visible but autophagosomes disappear in AFB1-treated group. The mRNA and protein expression levels of autophagy-related genes indicated that AFB1 significantly inhibited autophagy and induced inflammation. In addition, Nrf2 and HO-1 mRNA and protein level was significantly (p < 0.05) reduced in AFB1-fed group. Intriguingly, dietary curcumin supplementation modulated autophagy through the activation of beclin-1, ATG5, Dynein, LC3a, LC3b-I/II and downregulation of p53 & mTOR expression level. Curcumin significantly ameliorated AFB1-induced inflammation. Moreover, curcumin treatment significantly (p < 0.05) elevated AFB1-induced decrease in Nrf2 and HO-1 mRNA and protein expression level. In summary, curcumin activated autophagy and ameliorated inflammation involving Nrf2 signaling pathway which may become a new targeted therapy to prevent AFB1-induced hepatotoxicity.

Protective role of curcumin in ameliorating AFB1-induced apoptosis via mitochondrial pathway in liver cells.

It is well documented that liver is the primary target organ of aflatoxin B1 (AFB1) and curcumin proved to be effective against AFB1-induced liver injury. In the present study, we investigated the preventive effects of curcumin against AFB1-induced apoptosis through the molecular regulation of p53, caspase-3, Bax, caspase-9, Bcl-2 and cytochrome-C associated with mitochondrial pathway. Liver antioxidant levels were measured. The hallmarks of apoptosis were analysed by methyl green-pyronin-Y staining, transmission electron microscopy, RT-PCR and western blot. Results revealed that dietary curcumin ameliorated AFB1-induced oxidative stress in a dose-dependent manner. Methyl green-pyronin-Y staining and transmission electron microscopy showed that AFB1 induced apoptosis and caused abnormal changes in liver cells morphology such as condensation of chromatin material, reduces cell volume and damaged mitochondria. Moreover, mRNA and protein expression results manifested that apoptosis associated genes showed up-regulation in AFB1 fed group. However, the supplementation of dietary curcumin (dose-dependently) alleviated the increased expression of the apoptosis associated genes at mRNA and protein level, and restored the hepatocytes normal morphology. The study provides an insight and a better understanding of the preventive mechanism of curcumin against AFB1-induced apoptosis in hepatocytes and provide scientific basis for the therapeutic uses of curcumin.

Identification of a Group of Therapeutic Targets and Prognostic Biomarker for Triple Negative Breast Cancer.

INTRODUCTION: Triple-negative breast cancer (TNBC) is a highly heterogeneous disease. Mining differentially expressed genes of TNBC is helpful to explore new therapeutic targets. This study aimed to investigate diagnostic biomarker genes in TNBC compared to normal tissue. Additionally, we explored the functions and prognostic value of these key genes as well as potential targeted drugs that could affect these genes. METHODS: Differential gene expression analysis was conducted using the R software with data from the Gene Expression Omnibus (GEO) database. Then, the identified differentially expressed genes (DEGs) were used to construct a protein-protein interaction (PPI) network using the Search Tool for the Retrieval of Interacting Genes (STRING) database and Cytoscape software. The mRNA expression levels of key genes were analyzed using the UALCAN database with data from The Cancer Genome Atlas (TCGA). Enrichment and survival analyses were performed using R software. In addition, potential compounds showing sensitivity to key genes were identified by gene set cancer analysis (GSCA). RESULTS: Compared with normal tissues, a total of 203 DEGs were upregulated in TNBC. These DEGs participated in various biological processes including nuclear division, microtubule binding, cell cycle, and the p53 signaling pathway. Through the PPI network analysis, ten key genes were identified, among which four genes showed significant correlation with poor progression-free interval (PFI) in patients with TNBC. Moreover, the four survival-related genes were found to act as sensitive therapeutic targets. CONCLUSION: The identified four key genes were considered new biomarkers for diagnosis and prognosis and also potential therapeutic targets for TNBC.

Carbon reduction and cost control of container shipping in response to the European Union Emission Trading System.

In response to the EU ETS, we propose a cost model considering carbon emissions for container shipping, calculating fuel consumption, carbon emissions, EUA cost, and total cost of container shipping. We take a container ship operating on a route from the Far East to Northwest Europe as a case study. Environmental and economic impacts of including maritime transport activities in the EU ETS on container shipping are assessed. Results show that carbon emissions from the selected container ship using methanol are the smallest, and total cost of the selected container ship using methanol is the lowest. Among MGO, HFO, LNG, and methanol, methanol is the most environmentally and cost-effective option. Using LNG has greater environmental benefit, while using HFO has greater economic benefit. Compared to MGO, carbon reduction effects of LNG and methanol are 14.2% and 57.1%, and their cost control effects are 7.8% and 26.5%. Compared to HFO, carbon reduction effects of LNG and methanol are 11.7% and 55.8%, and the cost control effect of methanol is 9.3%. Speed reduction is effective in achieving carbon reduction and cost control of container shipping only when the sailing speed of the selected container ship is greater than 8.36 knots. Once the sailing speed is less than this threshold, speed reduction will increase carbon emissions and total cost of container shipping. This model can assess the environmental and economic impacts of including maritime transport activities in the EU ETS on container shipping and explore the measures to achieve carbon reduction and cost control of container shipping in response to the EU ETS.

Semirecumbent Positioning During Anesthesia Recovery and Postoperative Hypoxemia: A Randomized Clinical Trial.

Importance: The efficacy of a semirecumbent position (SRP) in reducing postoperative hypoxemia during anesthesia emergence is unclear despite its widespread use. Objective: To determine the differences in postoperative hypoxemia between patients in an SRP and a supine position. Design, Setting, and Participants: This randomized clinical trial was performed at a tertiary hospital in China between March 20, 2021, and May 10, 2022. Patients scheduled to undergo laparoscopic upper abdominal surgery under general anesthesia were enrolled. Study recruitment and follow-up are complete. Interventions: Patients were randomized to 1 of the following positions at the end of the operation until leaving the postanesthesia care unit: supine (group S), 15° SRP (group F), or 30° SRP (group T). Main Outcomes and Measures: The primary outcome was the incidence of postoperative hypoxemia in the postanesthesia care unit. Severe hypoxemia was also evaluated. Results: Out of 700 patients (364 men [52.0%]; mean [SD] age, 47.8 [11.3] years), 233 were randomized to group S (126 men [54.1%]; mean [SD] age, 48.2 [10.9] years), 233 to group F (122 men [52.4%]; mean [SD] age, 48.1 [10.9] years), and 234 to group T (118 women [50.4%]; mean [SD] age, 47.2 [12.1] years). Postoperative hypoxemia differed significantly among the 3 groups (group S, 109 of 233 [46.8%]; group F, 105 of 233 [45.1%]; group T, 76 of 234 [32.5%]; P = .002). This difference was statistically significant for groups T vs S (risk ratio [RR], 0.69 [95% CI, 0.55-0.87]; P = .002) and groups T vs F (RR, 0.72 [95% CI, 0.57-0.91]; P = .007), but not for groups F vs S (RR, 0.96 [95% CI, 0.79-1.17]; P = .78). Severe hypoxemia also differed among the 3 groups (group S, 61 of 233 [26.2%]; group F, 53 of 233 [22.7%]; group T, 36 of 234 [15.4%]; P = .01). This difference was statistically significant for groups T vs S (RR, 0.59 [95% CI, 0.41-0.85]; P = .005). Conclusions and Relevance: In this randomized clinical trial of SRP during anesthesia recovery in patients undergoing laparoscopic upper abdominal surgery, postoperative hypoxemia was significantly reduced in group T compared with group F or group S. Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR2100045087.