Liquiritigenin Induces Cell Cycle Arrest and Apoptosis in Lung Squamous Cell Carcinoma.

Liquiritigenin (LQ), as a dihydroflavone monomer compound extracted from Glycyrrhiza uralensis Fisch, has been demonstrated to show anti-tumor effects in multiple human cancers, including lung adenocarcinoma. Our study aimed to explore its role in lung squamous cell carcinoma (LSCC) development and the related mechanism. The effects of LQ on SK-MES-1 and NCI-H520 cell proliferation, cell cycle, and apoptosis were investigated. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and colony formation assays revealed that LQ inhibited LSCC cell viability and proliferation in a dose- and time-dependent manner. Flow cytometry analysis demonstrated that LQ promoted G2/M cell cycle arrest, cell apoptosis, and loss of mitochondrial membrane potential. In vivo assays showed that LQ administration suppressed tumor growth in nude mice. Additionally, LQ treatment reduced the levels of phosphorylated PI3K, AKT, and mTOR levels in LSCC cells. Pretreatment with the PI3K inhibitor LY294002 antagonized the LQ-mediated effects on cell proliferation, cell cycle arrest, and apoptosis in LSCC cells. Collectively, LQ induces cell cycle arrest and apoptosis in LSCC by inactivating the PI3K/AKT/mTOR pathway.

Development of a Risk Prediction Model for Infection After Kidney Transplantation Transmitted from Bacterial Contaminated Preservation Solution.

Background: The risk of transplant recipient infection is unknown when the preservation solution culture is positive. Methods: We developed a prediction model to evaluate the infection in kidney transplant recipients within microbial contaminated preservation solution. Univariate logistic regression was utilized to identify risk factors for infection. Both stepwise selection with Akaike information criterion (AIC) was used to identify variables for multivariate logistic regression. Selected variables were incorporated in the nomograms to predict the probability of infection for kidney transplant recipients with microbial contaminated preservation solution. Results: Age, preoperative creatinine, ESKAPE, PCT, hemofiltration, and sirolimus had a strongest association with infection risk, and a nomogram was established with an AUC value of 0.72 (95% confidence interval, 0.64-0.80) and Brier index 0.20 (95% confidence interval, 0.18-0.23). Finally, we found that when the infection probability was between 20% and 80%, the model oriented antibiotic strategy should have higher net benefits than the default strategy using decision curve analysis. Conclusion: Our study developed and validated a risk prediction model for evaluating the infection of microbial contaminated preservation solutions in kidney transplant recipients and demonstrated good net benefits when the total infection probability was between 20% and 80%.

[Medium and Long-term Carbon Emission Projections and Emission Reduction Potential Analysis of the Lingang Special Area Based on the LEAP Model].

Based on the existing statistical data of the Lingang Special Area in Shanghai and considering its future socio-economic development， industrial structure， and technological development， a LEAP-Lingang model was developed to analyze the evolution trends of energy demand and carbon emissions under the baseline scenario， low-carbon scenario， and enhanced low-carbon scenario. To enhance the prediction accuracy of the model， the Logistic population growth model was used to predict future population data， and the learning curve model was used to simulate the cost evolution trend of related carbon reduction technologies. In addition， an economic evaluation model for carbon reduction technologies was developed， and the economic costs and emission reduction potential of typical carbon reduction technologies were evaluated by drawing a marginal emission reduction cost curve. The results showed that under the enhanced low-carbon scenario， the renewable energy accounted for 69% of the primary energy consumption， and the electric energy accounted for 91% of the terminal energy demand in 2060. The Lingang Special Area could achieve carbon peak by 2030， and the carbon emissions in 2060 were predicted to decrease by 94% compared to that in the baseline scenario. In terms of contribution to emission reduction， clean energy substitution， industrial structure optimization， and terminal energy efficiency improvement played a key role in reducing carbon emissions near the port. In the medium term （until 2035）， they were predicted to contribute 35.1%， 27.3%， and 16.2% of carbon emissions， respectively， and in the long term （until 2060）， they should contribute 50.6%， 8.75%， and 7.7% of carbon emissions， respectively. Regarding specific carbon reduction technologies， hydrogen power generation； water electrolysis for hydrogen； and carbon capture， utilization， and storage （CCUS） technology were of great significance for achieving net-zero emissions， but the costs of emission reduction were relatively high. The research results can provide ideas and references for the low-carbon and green development of the Lingang Special Area and related areas.

Taste traces: Capsaicin and sweeteners as anthropogenic markers in municipal wastewater.

Dietary-derived substances possess significant potential as anthropogenic markers owing to the large consumption and different intake habit. To investigate and evaluate such markers, wastewater samples from 35 wastewater treatment plants across 29 Chinese cities were collected to analyze artificial sweeteners (acesulfame and cyclamate) and natural spicy compounds (capsaicin and dihydrocapsaicin). Acesulfame (mean: 14.6 µg/L), cyclamate (mean: 24.3 µg/L), and capsaicin (mean: 101 ng/L) can be further investigated as anthropogenic markers due to their high detection frequency at high concentrations. Spatial use patterns revealed that acesulfame (5.31 g/d/1000 inhabitants (inh)) and cyclamate (8.16 g/d/1000 inh) use in northern China notably surpassed that in southern China (1.79 g/d/1000 inh and 3.23 g/d/1000 inh, p < 0.05). Conversely, chili pepper use was significantly higher (p < 0.05) in southern China (6702 g/d/1000 inh) than in northern China (2751 g/d/1000 inh), signifying a preference for sweetness in the northern regions and a predilection for spiciness in the southern regions. The total annual use of acesulfame (1842 t), cyclamate (3110 t), and chili (18.4 million tonnes) in China was estimated by this study, which was close to the national statistical production. In addition, sweetener use was negatively associated with the elderly population ratio, suggesting that the elderly population might not consume sweet foods. This study reveals the dietary sources of anthropogenic markers, highlighting the need for further research on the environmental implications of such markers.

Immunosuppressive therapy for progressive idiopathic membranous nephropathy: a cost-effectiveness analysis in China.

BACKGROUND: This study aims to evaluate the cost-effectiveness of immunosuppressive therapy for patients with progressive idiopathic membranous nephropathy (IMN) from the Chinese healthcare system perspective. METHODS: To estimate the cost-effectiveness of four regimens namely cyclophosphamide, cyclosporine, rituximab and tacrolimus-rituximab in treatment of IMN recommended by the updated Kidney Disease: Improving Global Outcomes (KDIGO) guideline 2021, a Markov model with five discrete states (active disease, remission, dialysis, kidney transplant and death) based on IMN patients aged 50 or above over a 30-years time horizon was constructed. Total costs were imputed from the Chinese healthcare system perspective, and health outcomes were converted into quality-adjusted life years (QALYs). The incremental cost-effectiveness ratio (ICER) was used to describe the results. The willingness-to-pay (WTP) threshold was set at $12,044 (China's 2021 Gross Domestic Product per capita). Sensitivity analyses were performed to test the uncertainties of the results. RESULT: Compared with cyclophosphamide, both cyclosporine (incremental cost $28,337.09, incremental QALY-1.63) and tacrolimus-rituximab (incremental cost $28,324.13, incremental QALY -0.46) were considered at strictly dominated for their negative values in QALYs, and the ICER value of rituximab was positive (incremental cost $9,162.19, incremental QALY 0.44). Since the ICER of rituximab exceeds the pre-determined threshold, cyclophosphamide was likely to be the best choice for the treatment of IMN within the acceptable threshold range. The results of the sensitivity analysis revealed that the model outcome was mostly affected by the probability of remission in rituximab. In a probabilistic sensitivity analysis, cyclophosphamide had 62.4% probability of being cost-effective compared with other regimens when the WTP was $12,044 per QALY. When WTP exceeded $18,300, rituximab was more cost-effective than cyclophosphamide. CONCLUSION: Compared with cyclosporine, rituximab and tacrolimus-rituximab, our model results indicated that cyclophosphamide represented the most cost-effective regimen for patients with progressive IMN in China.

Evidence of potential pro-haemorrhagic drug interactions between CYP3A4 inhibitors and direct oral anticoagulants: Analysis of the FAERS database.

AIMS: There is no consensus on the haemorrhagic risk associated with potential interactions between commonly used CYP3A4 inhibitors and direct oral anticoagulants (DOACs). METHODS: Macrolide antibiotics and azole antimycotics were investigated in this study. Data from Food and Drug Administration Adverse Event Reporting System were retrieved from July 2010 to September 2021. Haemorrhagic signals were expressed by reporting odds ratios (RORs) and 95% confidence intervals (CIs) based on the interaction/noninteraction methodology as (a/c) / (b/d) and considered significant when the lower limit of 95% CI was >1 and the case number of interaction group was ≥3. Subgroup analyses and logistic regression were conducted by adjusting associated factors in haemorrhagic events. RESULTS: From the third quarter of 2010 to the first quarter of 2021, we retrieved 382 853 distinct cases of adverse events associated with DOACs, in which 1128 cases of bleeding were associated with coadministration of CYP3A4 inhibitors and DOACs. The haemorrhagic signal was significant for apixaban when coadministered with clarithromycin (ROR 1.60, 95% CI 1.16-2.20) and posaconazole (ROR 2.69, 95% CI 1.37-5.28). For dabigatran, coadministration with azithromycin (ROR 4.06, 95% CI 2.77-5.95), fluconazole (ROR 2.26, 95% CI 1.52-3.37), itraconazole (ROR 7.52, 95% CI 1.51-37.46) and ketoconazole (ROR 2.06, 95% CI 1.25-3.41) was associated with significantly higher risks of haemorrhages. At the same time, addition of itraconazole to rivaroxaban also indicated significant haemorrhagic signal (ROR 3.58, 95% CI 1.30-9.85). CONCLUSIONS: Macrolide antibiotics and azole antimycotics have potential but different effects on the bleeding risk of DOACs. Close attention is needed when using these drugs together. Such precautions have already been included in some drug labels.

Pharmacokinetics and Dosing Regimens of Direct Oral Anticoagulants in Morbidly Obese Patients: An Updated Literature Review.

Data on the impact of morbid obesity (body mass index [BMI] ≥ 40 kg/m2) on the pharmacokinetics (PK), pharmacodynamics (PD) of direct oral anticoagulants (DOACs) are relatively limited, making it difficult to design optimal dosing regimens in morbidly obese patients.To review literature on PK/PD profile, efficacy, and safety of DOACs in venous thromboembolism (VTE) and nonvalvular atrial fibrillation (AF) patients with morbid obesity and make recommendations regarding optimal dosing regimens in these patient populations.A detailed literature search was conducted (from inception to June 22, 2022) for relevant articles involving PK/PD and clinical data on DOACs use in morbidly obese patients with VTE or AF, or healthy volunteers.A total of 28 studies were identified. DOAC-specific PK variations and clinical outcomes have been observed. Obesity may have a modest effect on PK/PD of dabigatran, apixaban, or rivaroxaban. Dabigatran was effective in AF patients with morbid obesity but might increase the risk of gastrointestinal bleeding. Standard dosing of apixaban or rivaroxaban is effective and safe for VTE and AF patients with morbid obesity. Trough edoxaban concentration and anti-Xa activity were similar in different BMI groups (18.5 to >40 kg/m2), and standard dosing of edoxaban may be effective and safe for AF patients.Current evidence suggests dabigatran should be used with caution in patients with AF as it might increase the risk of gastrointestinal bleeding; Standard dosing of apixaban or rivaroxaban can be used in VTE or AF patients; Standard dosing of edoxaban may be considered in AF patients.

Hepatic failure associated with immune checkpoint inhibitors: An analysis of the Food and Drug Administration Adverse Event Reporting System database.

BACKGROUND: Hepatic failure induced by immune checkpoint inhibitors (ICIs) has been reported in only a few case series and case reports. OBJECTIVE: We aimed to explore the association between ICIs and hepatic failure and characterize the clinical features of ICI-associated hepatic failure in the pharmacovigilance database. METHODS: Data from the first quarter (Q1) of 2015 to the fourth quarter (Q4) of 2021 in the US Food and Drug Administration Adverse Event Reporting System (FAERS) database were retrieved for disproportionality and Bayesian analysis. Reporting odds ratios (ROR) and information component (IC) were used to evaluate correlations between ICIs and hepatic failure. RESULTS: Hepatic failure occurred in 0.19% (18,454/9,647,655) of all cases in the FAERS database, of which 654 cases were associated with ICIs. The overall median time from ICIs initiation to hepatic failure onset was 38 days, 72.3% of the adverse events occurred within the first 3 months, and 68.65% of the cases died after developing hepatic failure. In general, a strong signal was shown between ICIs and hepatic failure (ROR025  = 2.70, IC025  = 1.39). For the three categories of ICIs, programmed cell death 1 ligand 1 inhibitors (ROR025  = 3.09, IC025  = 1.57) had a higher risk signal than programmed cell death protein 1 inhibitors and cytotoxic T lymphocyte-associated protein 4 inhibitors. For monotherapy, atezolizumab showed the strongest risk signal (ROR025  = 4.07, IC025  = 1.90). The combination of nivolumab and ipilimumab showed stronger signals of hepatic failure compared with nivolumab or ipilimumab alone (nivolumab + ipilimumab vs. ipilimumab: ROR025  = 1.40, IC025  = 0.16; nivolumab + ipilimumab vs. nivolumab: ROR025  = 1.24, IC025  = 0.34). Considering the concomitant agents used with ICIs, the majority of these regimens showed stronger signals than ICI monotherapy, such as acetaminophen (ICIs + acetaminophen vs. ICIs: ROR025  = 1.06, IC025  = 0.32). CONCLUSIONS: ICIs had possible strong signals associated with hepatic failure, and most cases of hepatic failure occurred within the first 3 months and had poor outcomes, which should attract clinical attention.

Safety, efficacy and prognosis of anticoagulant therapy for portal vein thrombosis in cirrhosis: a retrospective cohort study.

BACKGROUND: The role of anticoagulants in the treatment of cirrhotic PVT remains controversial. This study aimed to analyze the safety and efficacy of anticoagulant therapy in patients with cirrhotic portal vein thrombosis (PVT) and its impact on prognosis. METHODS: A retrospective cohort study was conducted for PVT patients with liver cirrhosis in our hospital. The primary outcome of the study was the PVT recanalization rate. Other outcomes included bleeding rate, liver function, and mortality. Cox and Logistic regression were used to explore the risk factors of outcomes. RESULTS: This study included 77 patients that 27 patients in the anticoagulant group and 50 in the non-anticoagulant group. Anticoagulant therapy was associated with higher rate of PVT recanalization (44.4% vs 20.0%, log-rank P = 0.016) and lower rate of PVT progression (7.4% vs 30.0%, log-rank P = 0.026), and without increasing the rate of total bleeding (14.8% vs 24%, P = 0.343), major bleeding (3.7% vs 6%, P = 0.665) and variceal bleeding (3.7% vs 16%, P = 0.109). The safety and efficacy of different anticoagulants were similar. The Child-Pugh grade of the anticoagulant therapy group was better than that of the non-anticoagulant therapy group (P = 0.030). There was no significant difference in the 2-year survival rate of the two groups. CONCLUSION: Anticoagulants could increase the PVT recanalization rate and reduce the PVT progression rate without increasing the rate of bleeding. Anticoagulants may be beneficial to improving the liver function of patients with cirrhotic PVT. There was no significant difference in the safety and efficacy of different anticoagulants in the treatment of cirrhotic PVT.

Allograft rejection following immune checkpoint inhibitors in solid organ transplant recipients: A safety analysis from a literature review and a pharmacovigilance system.

AIM: This study aimed to systematically characterize transplant rejection after immune checkpoint inhibitors (ICIs) initiation in solid organ transplant recipients (SOTRs). METHODS: Data were extracted from the US FDA Adverse Event Reporting System (FAERS) database and case reports in the literature. Disproportionality analysis including information component and reported odds ratio (ROR) was performed to access potential risk signals. RESULTS: A total of 168 patients with transplant rejection after ICIs usage were identified in the FAERS database, and 89 cases were identified in the literature review. ICIs were significantly associated with transplant rejection (ROR025 : 2.2). A strong risk signal was found for combination therapy with pembrolizumab and ipilimumab compared to monotherapy. CONCLUSION: Immune checkpoint inhibitors were significantly associated with transplant rejection in SOTRs.

Effect of Carbapenem-Resistant Klebsiella pneumoniae Infection on the Clinical Outcomes of Kidney Transplant Recipients.

Background: Carbapenem-resistant Klebsiella pneumoniae (CRKP) infection has proven to be difficult to control and typically presents with devastating effects. Methods: This retrospective study was conducted on the renal recipients at our institution between January 2021 to January 2022. Clinical data was collected to identify factors associated with CRKP infection and clinical outcomes. Results: There were 104 cases out of 186 total renal recipients who presented with at least one infection within 3 months after KT, and 14 cases developed unfavorable clinical outcomes. We identified 16 confirmed CRKP infected cases with the incidence of 8.60%. Possible donor derived infection (DDI) (OR = 6.743; 95% CI: 1.477-30.786; P = 0.014) were independent risk factors for the occurrence of CRKP infection of renal recipients in our analysis, CRKP infection (OR = 20.723; 95% CI: 3.448-124.547; P = 0.001) and pneumonia (OR = 28.458; 95% CI: 1.956-413.984 P = 0.014) were independent risk factors for the occurrence of unfavorable clinical outcomes following KT, and the occurrence of unfavorable clinical outcomes following KT were significantly associated with CRKP infection (r = 0.535; P < 0.001) and antibiotic regimen containing ceftazidime/avibactam (CZA) (r = -0.655; P = 0.006). The use of CZA was significantly different in the comparison of antibiotic regimens between the CRKP infected renal recipients with unfavorable outcomes and CRKP infected patients with favorable outcomes. Conclusion: It is possible that DDI can lead to CRKP infection, and CRKP infection and pneumonia were closely correlated with poor prognosis. The use of CZA may play a role in avoiding the unfavorable outcomes of CRKP infected recipients.

Central nervous system adverse events of ceftazidime/avibactam: A retrospective study using Food and Drug Administration Adverse Event Reporting System.

WHAT IS KNOWN AND OBJECTIVE: Many antibiotics are well known for being associated with adverse events (AEs) of central nervous system, ceftazidime/avibactam (CAZ/AVI) is a novel ß-lactam/ß-lactamase inhibitor combinations. In this commentary, we analyzed reports of nervous system disorders associated with CAZ/AVI, meropenem, imipenem, ceftazidime, ceftriaxone, and cefepime in the Food and Drug Administration (FDA) Adverse Event Reporting System database from January 2015 to March 2022. COMMENT: The reporting odds ratios (RORs) method was used to detect the safety signals. Up to 15.62% of CAZ/AVI AEs exhibit nervous system disorders associated with CAZ/AVI. A nervous system disorder signal was detected for CAZ/AVI compared with meropenem, ceftazidime, and ceftriaxone. Compared with meropenem, imipenem, ceftazidime, and ceftriaxone, encephalopathy, myoclonus, reported with CAZ/AVI exhibited significant RORs. WHAT IS NEW AND CONCLUSION: This study found that CAZ/AVI showed a relatively stronger sign nervous system disorder than meropenem, ceftazidime, and ceftriaxone in the real world. The poor clinical outcome of these events should attract clinical attention, especially for patients with older than 65 years old and long treatment courses.

Evogliptin for the treatment option for type 2 diabetes: an update of the literature.

INTRODUCTION: Dipeptidyl peptidase-4 (DPP-4) inhibitors have been the most widely used for type 2 diabetes (T2D) available worldwide since 2006. DPP-4 inhibitors exert their effects by inhibiting dipeptidyl peptidase-4 to increase the concentration of endogenous incretin hormones (incretin hormone analogues and incretin potentiators) and promote insulin secretion, thereby acting as a glucose regulator. Evogliptin is a new member of the DPP-4 inhibitor family with high selectivity and low risk of hypoglycemia, and extensive clinical data has been accumulated in its treatment of T2D since its introduction in October 2015. AREAS COVERED: This review summarized the recently reported studies associated with the pharmacokinetics, pharmacodynamics, safety and tolerability, and clinical application of evogliptin for managing T2D. We searched the MEDLINE and PubMed databases with the titles 'evogliptin' to identify all the information. The abstracts and posters of the annual meetings of ADA and EASD and clinicalTrials.gov. have been searched up to now. EXPERT COMMENTARY: Evogliptin is a potent, orally effective, and highly selective DPP-4 inhibitor that is not only indicated for the treatment of T2D but may also be beneficial to arterial inflammation and atherosclerosis, with good safety and tolerance.

Transcriptomic analysis and discovery of genes involving in enhanced immune protection of Pacific abalone (Haliotis discus hannai) in response to the re-infection of Vibrio parahaemolyticus.

Traditionally, invertebrates were thought to lack immune memory owing to a lack of acquired immune-related factors such as immunoglobulin. Nonetheless, with the in-depth consideration of invertebrate immune priming, scholars have gradually realized that the immune defenses of invertebrates are more complex than previously imagined. In the current investigation, the survival rate of Vibrio parahaemolyticus re-infected Haliotis discus hannai (VV group) was significantly different from the other groups (p < 0.05), indicating that an enhanced immune response may commence after first exposure to the same strain of V. parahaemolyticus. The transcriptome profiles of hemocytes obtained 102,052 unigenes, and 27,449 of them were annotated successfully. Venn diagram analysis showed that 2832 DEGs commonly responded to the first and second immune responses. 1734 "immune response genes" and 1460 "potential immune-enhancing genes" were also identified. A comparison of both "immune response genes" and "potential immune-enhancing genes" revealed 1019 immune-enhancing regulatory genes and 281 essential immune-enhancing genes. According to the KEGG enrichment analysis results of ERGs and EEGs, classical immune-related signaling pathways, such as NF-kappa B signaling pathway, NOD-like receptor signaling pathway, IL-17 signaling pathway, and TLR signaling pathway were significantly enriched, indicating that they were all involved in the response to V. parahaemolyticus re-infection and were likely dominant in the immune enhancement process of H. discus hannai hemocytes. The intermolecular interactions generated by Cytoscape after re-infection of V. parahaemolyticus appear more intuitively to demonstrate that hemocytes regulation was not an independent process, but rather an intricate regulatory network. H. discus hannai demonstrated enhanced immunological activity after re-infection with V. parahaemolyticus, showing immune memory in hemocytes. The current study's findings have broadened the study of immune enhancement in invertebrates and laid the framework for future research into the molecular mechanism of immune enhancement in abalones.

Coagulation dysfunction events associated with tigecycline: a real-world study from FDA adverse event reporting system (FAERS) database.

BACKGROUND: Tigecycline has broad-spectrum anti-bacterial activity and often used for critically ill patients with complicated infections. Only a few clinical studies have reported the coagulation disorder induced by tigecycline. The aim of this study was to investigate the association between tigecycline and coagulation dysfunction using the US Food and Drug Administration Adverse Event Reporting System (FAERS) database. METHOD: Data from January 2005 to December 2020 in FAERS were retrieved. We investigated the clinical characteristics of the coagulation dysfunction events and conducted disproportionality analysis by using reporting odds ratios (ROR) to compare tigecycline with the full database and other antibiotics. RESULTS: The total number of reports of coagulation dysfunction related to tigecycline as the primary suspect drug was 223. The median time to event of the coagulation dysfunction events was 10 (interquartile range [IQR] 6.75-13) days. 80.72% coagulation-related adverse events appeared within the first 14 days since the initiation of tigecycline administration. The overall ROR (95% CI) for coagulation-related adverse events was 3.55 (3.08, 4.09). The RORs (95% CI) for thrombocytopenia, hypofibrinogenaemia, coagulopathy, activated partial thromboplastin time prolonged, international normalized ratio increased, prothrombin time prolonged were 8.21 (6.34, 10.62), 705.41 (526.81, 944.54), 30.67 (21.92, 42.92), 42.98 (24.85, 74.31), 4.67 (2.51, 8.71), and 27.99 (15.01, 52.19), respectively. In analyses stratified on comparing tigecycline to vancomycin and daptomycin, significant coagulation dysfunction signals were found with the RORs (95% CI) 2.74 (2.34, 3.22) and 3.08 (2.57, 3.70). CONCLUSIONS: We found a strong signal of high frequency of reporting coagulation dysfunction in tigecycline. Health professionals should be aware of the potential coagulation disorders risk and monitor coagulation parameters during anti-bacterial therapy with tigecycline, particularly the need to monitor fibrinogen levels.

Evaluation of rivaroxaban-, apixaban- and dabigatran-associated hemorrhagic events using the FDA-Adverse event reporting system (FAERS) database.

Background Rivaroxaban, apixaban and dabigatran are non-vitamin K antagonist oral anticoagulants (NOACs) that are widely used for treatment or prevention of venous thromboembolism and stroke in patients with atrial fibrillation. Objective To estimate and compare hemorrhagic events report of rivaroxaban, apixaban and dabigatran. Setting FDA Adverse Event Reporting System (FAERS) database. Methods The reporting odds ratio (ROR) was used to assess the signal of hemorrhagic events of different NOACs. Main outcome measure The overall hemorrhagic events and hemorrhagic events in different physiological systems. Results From January 1, 2014 to December 31, 2019, the total number of reports of hemorrhage related to rivaroxaban was 53,085, and the numbers of apixaban and dabigatran were 13,151 and 14,100 respectively. The overall ROR (95% CI) of hemorrhagic events reporting for rivaroxaban versus dabigatran and apixaban versus dabigatran were 1.58 (1.54-1.62) and 0.47 (0.46-0.48) respectively. The ROR (95% CI) for rivaroxaban versus dabigatran in gastrointestinal system, nervous system, renal and urinary system, skin and subcutaneous tissue, and eye system was 1.38 (1.34-1.42), 0.94 (0.90-0.98), 1.07 (1.01-1.13), 0.80 (0.70-0.90), and 1.38 (1.19-1.60) respectively. The RORs (95% CI) for apixaban versus dabigatran in gastrointestinal system, nervous system, renal and urinary system, skin and subcutaneous tissue, and eye system were 0.28 (0.27-0.29), 0.69 (0.66-0.73), 0.31 (0.29-0.34), 0.98 (0.86-1.12), and 1.18 (1.00-1.39), respectively. Conclusions Overall, we found a moderate signal of higher frequency of reporting hemorrhage in rivaroxban compared with dabigatran and decreased hemorrhagic event reporting in apixaban compared with dabigatran. While this potential signal has not been confirmed in clinical trials or observational studies, in clinical practice, attention should be paid to the risk of potential hemorrhage when the patients switch from apixaban to dabigatran or rivaroxban.

Regulatory effect of heat shock transcription factor-1 gene on heat shock proteins and its transcriptional regulation analysis in small abalone Haliotis diversicolor.

BACKGROUND: The effects of diverse stresses ultimately alter the structures and functions of proteins. As molecular chaperones, heat shock proteins (HSPs) are a group of highly conserved proteins that help in the refolding of misfolded proteins and the elimination of irreversibly damaged proteins. They are mediated by a family of transcription factors called heat shock factors (HSFs). The small abalone Haliotis diversicolor is a species naturally distributed along the southern coast of China. In this study, the expression of HdHSF1 was inhibited by RNAi in hemocytes in order to further elucidate the regulatory roles of HdHSF1 on heat shock responsive genes in abalone. Meanwhile, to understand the transcriptional regulation of the HdHSF1 gene, the 5'-upstream regulatory region of HdHSF1 was characterized, and the relative promoter activity was examined by dual-luciferase reporter gene assay system in HEK293T cell lines. RESULTS: After the inhibition of the H. diversicolor HSF1 gene (HdHSF1) by dsRNA (double-stranded RNA), the expression of most heat shock related-genes was down-regulated (p < 0.05). It indicated the importance of HdHSF1 in the heat shock response of H. diversicolor. Meanwhile, 5'-flanking region sequence (2633 bp) of the HdHSF1 gene was cloned; it contained a putative core promoter region, TATA box, CAAT box, CpG island, and many transcription elements. In HEK293T cells, the 5'-flanking region sequence can drive expression of the enhanced green fluorescent protein (EGFP), proving its promoter function. Exposure of cells to the high-temperature (39 °C and 42 °C) resulted in the activation of HdHSF1 promoter activity, which may explain why the expression of the HdHSF1 gene participates in heat shock response. Luciferase activity of different recombinant plasmids, which contained different truncated promoter fragments of the HdHSF1 gene in HEK293T cells, revealed the possible active regions of the promoter. To further identify the binding site of the critical transcription factor in the region, an expression vector with the site-directed mutation was constructed. After being mutated on the GATA-1 binding site, we found that the luciferase activity was significantly increased, which suggested that the GATA-1 binding site has a certain weakening effect on the activity of the HdHSF1 promoter. CONCLUSIONS: These findings suggest that GATA-1 may be one of the transcription factors of HdHSF1, and a possible signaling pathway mediated by HdHSF1 may exist in H. diversicolor to counteract the adverse effects of heat shock stress.

JAK3-selective inhibitor peficitinib for the treatment of rheumatoid arthritis.

Introduction: Rheumatoid arthritis (RA) is a chronic progressive autoimmune disease characterized by synovitis as well as symmetric and destructive arthropathy. Although several disease modified antirheumatic-drugs (DMARDs) have widely used in clinical practice, certain patients are nonresponsive to or cannot take such medications due to adverse reactions. It is evident that Janus kinase (JAK) inhibitors have the potential to provide a significant breakthrough in the treatment of RA. These potent, orally administered, JAK inhibitors simplify the treatment options for patients. Areas covered: We discuss the pharmacodynamics, pharmacokinetics, efficacy, and safety of peficitinib for the treatment of RA. Expert opinion: Peficitinib is a novel JAK3 inhibitor potently inhibiting JAK3 enzymatic activity and JAK1/3-mediated cell proliferation. Its selectivity for JAK family kinases is similar to that of tofacitinib, but slightly less potent for JAK2. It is currently being evaluated by the FDA to treat adult patients with moderately to severely active RA who show inadequate response to or are intolerant of methotrexate. It can be used either as monotherapy or combination therapy with methotrexate, or other DMARDs. However, we think that more cautious consideration and measurement for adverse events are needed, after considering the safety results of ongoing clinical studies of peficitinib.

Decreased circular RNA hsa_circ_0001649 predicts unfavorable prognosis in glioma and exerts oncogenic properties in vitro and in vivo.

Glioma is a devastating disease with increasing incidence worldwide. Circular RNAs (circRNAs) was demonstrated to be involved in a wide range of pathophysiological processes, including tumorigenesis and development. Recently, the abnormally expressed hsa_circ_0001649 was found in several malignancies. In the current study, the expression levels of hsa_circ_0001649 in glioma and its clinical significance were explored. The biological functions including cell growth, colony-forming ability and apoptosis altered by hsa_circ_0001649 were further investigated in vitro. Tumor formation assay was also carried out to elucidate the oncogenic properties of hsa_circ_0001649. The data documented a decrease of hsa_circ_0001649 expression in glioma specimens and cell lines. In addition, down-regulated hsa_circ_0001649 is linked to larger tumor size (p = 0.002) and advanced WHO grade (p = 0.023). Additionally, hsa_circ_0001649 may be an independent prognostic marker for glioma patients after surgery (p = 0.046). Moreover, up-regulated hsa_circ_0001649 inhibits glioma cell growth in vitro and in vivo. Importantly, increased expression of hsa_circ_0001649 facilitates apoptosis by regulating Bcl-2/caspase-3 pathway. Ultimately, this study suggests that hsa_circ_0001649 may be a potential glioma-related prognostic/therapeutic target.

Bilirubin neurotoxicity is associated with proteasome inhibition.

The molecular mechanism underlying bilirubin neurotoxicity remains obscure. Ubiquitin-proteasome system-mediated proteolysis is pivotal to virtually all cellular processes and cell survival. Here we report for the first time that bilirubin at a clinically relevant elevated level impairs proteasomal function via inhibiting both the 19S proteasome-associated deubiquitinases (USP14 and UCHL5) and the chymotrypsin-like (CT-like) peptidase activity of 20S proteasomes, thereby contributing to bilirubin neurotoxicity. This is supported by multiple lines of evidence. First, sera from patients with hyperbilirubinemia were able to inhibit the peptidase activity of purified 20S proteasome in vitro in a bilirubin concentration-dependent manner; meanwhile, the blood cells of these patients showed significantly increased levels of ubiquitinated proteins (Ub-prs), consistent with proteasome inhibition. Second, intracerebroventricular injection to adult rats or intraperitoneal injections to neonatal rats of bilirubin-induced neural accumulation of Ub-prs, concurrent with other neural pathology; and brain malfunction and pathology induced by neonatal exposure to hyperbilirubinemia were detectable in the rats during their adulthood. Third, in primary cultures of hippocampal neurons, bilirubin strikingly induced Ub-pr accumulation before the activation of cell death pathway becomes discernible. Finally, bilirubin in vitro directly inhibited both the deubiquitination activity of proteasome-associated USP14 and UCHL5 and the CT-like peptidase activity of purified 20S proteasomes, in a dose-dependent manner. Hence, this study has discovered that increased bilirubin at a clinically achievable level can act as a proteasome inhibitor via targeting the 19S proteasome-associated deubiquitinases (DUBs) and, perhaps to a less extent, the 20S proteasome, identifying a novel mechanism for bilirubin neurotoxicity.