Potential role and therapeutic implications of glutathione peroxidase 4 in the treatment of Alzheimer's disease.

Alzheimer's disease is an age-related neurodegenerative disorder with a complex and incompletely understood pathogenesis. Despite extensive research, a cure for Alzheimer's disease has not yet been found. Oxidative stress mediates excessive oxidative responses, and its involvement in Alzheimer's disease pathogenesis as a primary or secondary pathological event is widely accepted. As a member of the selenium-containing antioxidant enzyme family, glutathione peroxidase 4 reduces esterified phospholipid hydroperoxides to maintain cellular redox homeostasis. With the discovery of ferroptosis, the central role of glutathione peroxidase 4 in anti-lipid peroxidation in several diseases, including Alzheimer's disease, has received widespread attention. Increasing evidence suggests that glutathione peroxidase 4 expression is inhibited in the Alzheimer's disease brain, resulting in oxidative stress, inflammation, ferroptosis, and apoptosis, which are closely associated with pathological damage in Alzheimer's disease. Several therapeutic approaches, such as small molecule drugs, natural plant products, and non-pharmacological treatments, ameliorate pathological damage and cognitive function in Alzheimer's disease by promoting glutathione peroxidase 4 expression and enhancing glutathione peroxidase 4 activity. Therefore, glutathione peroxidase 4 upregulation may be a promising strategy for the treatment of Alzheimer's disease. This review provides an overview of the gene structure, biological functions, and regulatory mechanisms of glutathione peroxidase 4, a discussion on the important role of glutathione peroxidase 4 in pathological events closely related to Alzheimer's disease, and a summary of the advances in small-molecule drugs, natural plant products, and non-pharmacological therapies targeting glutathione peroxidase 4 for the treatment of Alzheimer's disease. Most prior studies on this subject used animal models, and relevant clinical studies are lacking. Future clinical trials are required to validate the therapeutic effects of strategies targeting glutathione peroxidase 4 in the treatment of Alzheimer's disease.

A study of the impact of traffic investment on traffic fatalities in China, 2004-2020.

PURPOSE: Road traffic injuries (RTIs) have been one of the most serious public health problems in China. The purpose of this study was to investigate the extent to which traffic investment affects traffic fatalities in China as well as regional differences. METHODS: The study analyzed the correlation between traffic investment and traffic fatalities, incorporating additional factors such as economic conditions, road infrastructure, population density, and lighting. The selected variables included the number of traffic fatalities, traffic investment, urban per capita road area, urban road length, road mileage, urban road lighting, population size, and per capita gross domestic product. Relevant data between 2004 and 2020 were collected for an analysis using a fixed effect regression model. A p < 0.05 is considered statistically significant. To reduce the heterogeneity caused by regional differences, the provinces were divided into 6 groups according to administrative districts, and the clustering standard error analysis was carried out. RESULTS: Overall, there has been a significant improvement in road safety in China from 2004 to 2020, but some regions show an increase in traffic fatalities. The model reveals that traffic investment is significantly and positively correlated with the number of traffic fatalities. Holding all other factors constant, each 10,000 yuan increase in transport investment was associated with an average increase of 0.22 road traffic fatalities. In the analysis of regional differences, there was a significant positive correlation between traffic investment and traffic fatalities in the Northwest region and an increase of 10,000 yuan leads to an increase of 0.47. There was a significant negative correlation between road mileage, urban road lighting system, and population and traffic fatalities. For example, holding other factors constant, a 10,000 km reduction in road length would increase the number of traffic deaths by 45.56. The model results of urban per capita road area, urban road length, per capita gross domestic product, and the explained variables showed that p > 0.100, which was not statistically significant. CONCLUSIONS: Therefore, traffic investments are essential for governments to develop measures to enhance road safety and reduce the risk of road fatalities. Adjusting traffic road investment and other covariates is conducive to improving traffic safety and reducing the risk of road fatalities. The road safety situation in different regions of China varies greatly. Local governments should consider the actual conditions to provide better road safety configuration policies.

Clinical Efficacy and Prognostic Effects of High-quality Nursing Combined With Albumin in Treating Brainstem Hemorrhage.

Context: Brainstem hemorrhage is a disease with a high mortality rate and a poor prognosis. Its onset is urgent and critical, and patients need personalized, high-quality nursing. Also, albumin can have significant benefits in treating brainstem hemorrhage. Objective: The study intended to explore the clinical efficacy of and improved prognoses from high-quality nursing combined with albumin in treating patients with brainstem hemorrhage. Design: The research team conducted a prospective randomized controlled trial. Setting: The study took place at Heibei Fengfeng General Hospital of the North China Medical and Health Group in Hebei, China. Participants: Participants were 102 patients with brainstem hemorrhages who received treatment at the hospital between November 2020 and October 2022. Interventions: The research team randomly divided participants into two groups, each with 51 participants: (1) the intervention group, who received high-quality nursing combined with 20% human albumin, and (2) the control group, who received conventional nursing combined with 20% human albumin. Outcome Measures: The research team examined participants': (1) mortality rate; (2) scores on the Glasgow Coma Scale (GCS) and Glasgow Outcome Scale (GOS); (3) quality of life (QoL) scores, using the 36-Item Short Form Survey (SF-36); (4) scores on the Self-Rating Anxiety Scale (SAS); (5) health-behavior scores, using the Health-Behavior Scale, and (6) nursing satisfaction. Results: Postintervention compared with the control group, the intervention group's: (1) total mortality rate was significantly lower (P = .017), (2) GCS and GOS scores were significantly higher (both P < .001), (3) QoL scores for all subdimensions were significantly higher (all P < .001), (4) SAS scores for all subdimensions were significantly lower (all P < .001), (5) health-behavior scores for all subdimensions were significantly higher (P < .001), and (6) nursing satisfaction was significantly higher (P = .015). Conclusions: High-quality nursing interventions combined with albumin for brainstem-hemorrhage patients can effectively increase treatment efficacy, ensure patients' QoL, and facilitate recovery. Thus, high-quality nursing combined with albumin for brainstem-hemorrhage patients is of great significance in clinical practice.

Blood-brain barrier and blood-brain tumor barrier penetrating peptide-drug conjugate as targeted therapy for the treatment of lung cancer brain metastasis.

Lung cancer is the leading cause of cancer deaths worldwide. Brain metastasis of lung cancer, which counts for nearly 50% of late-stage lung cancer patients, is a sign of a really poor prognosis. However, the presence of blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB) limits the penetration of drugs from the blood into the brain and thus restricts their accumulation in brain tumors. Systematic delivery of drugs into brain and brain tumor lesion using BBB and BBTB penetrating vehicles represents a promising strategy to overcome the BBB and BBTB limitations. Hence, we validated one of our previously identified BBB/BBTB penetrating peptide and its drug conjugate form for the treatment of lung cancer brain metastasis. With in vitro experiment, we first validated that the receptor LRP1, which mediated the peptide penetration of the BBB, was expressed on lung cancer cells and thus can be targeted by the peptide to overcome BBTB. With this delivery peptide, we constructed peptide-paclitaxel conjugate (the PDC) and in vitro validation showed that the PDC can across the BBB and efficiently kill lung cancer cells. We therefore constructed mouse lung cancer brain metastasis xenograft. In vivo anti-tumor validations showed that the PDC efficiently inhibited the proliferation of the brain resident lung cancer cells and significantly expanded the survival of the mouse xenograft, with no visible damages to the organs. Overall, our study provided potential therapeutic drugs for the treatment of lung cancer brain metastasis that may be clinically effective in the near future.

Efficacy and safety of teriparatide vs. bisphosphonates and denosumab vs. bisphosphonates in osteoporosis not previously treated with bisphosphonates: a systematic review and meta-analysis of randomized controlled trials.

The study found that in osteoporosis patients who had not previously received bisphosphonate treatment and were in a treatment cycle of over 12 months, both teriparatide and denosumab significantly increased bone mineral density compared to bisphosphonates. Additionally, teriparatide was also shown to significantly decrease the risk of fractures. OBJECTIVE: The systematic review and meta-analysis aimed to assess and compare the safety and efficacy of teriparatide vs. bisphosphonates and denosumab vs. bisphosphonates in patients with osteoporosis who had not previously received bisphosphonates. METHODS: We conducted a search of published literature from inception to May 31, 2023, including databases such as PubMed, Embase, Cochrane Library, CNKI, SinoMed, VIP, and WanFang. The study only included head-to-head randomized controlled trials (RCTs) that compared teriparatide and denosumab with bisphosphonates to treat patients with osteoporosis. Fixed-effect model and random-effect model were used due to clinical heterogeneity. Meta-analysis was performed via Stata 17.0. RESULTS: A total of 6680 patients were enrolled across 23 eligible trials. The results of the meta-analysis showed that teriparatide was superior to bisphosphonates in decreasing the risk of fracture (risk ratio (RR) = 0.61, 95% confidence interval (CI) (0.51, 0.74), P < 0.001). Denosumab showed no benefit compared to bisphosphonates in reducing the risk of fracture in treating osteoporosis (RR 0.99, 95% CI (0.62, 1.57), P = 0.96). Compared with bisphosphonates, teriparatide and denosumab could significantly improve femoral neck, total hip, and lumbar spine bone mineral density (BMD) (P < 0.05). Furthermore, teriparatide and denosumab did not increase the incidence of adverse events (teriparatide vs. bisphosphonates, RR 0.92, 95% CI (0.79, 1.08), P = 0.32; denosumab vs. bisphosphonates, RR 0.98, 95% CI (0.95, 1.02), P = 0.37). CONCLUSIONS: Teriparatide is superior to bisphosphonates in decreasing the risk of fracture in patients with osteoporosis. In addition, teriparatide and denosumab were more efficacious than bisphosphonates in increasing the percentage change in BMD at the femoral neck, total hip, and lumbar spine.

Causal association between blood metabolites and vertigo: A Mendelian randomization study.

Metabolic disorders have been identified as an important factor causing nervous system diseases. However, due to the interference of confounding factors, the causal relationship between them has not been clearly elucidated, so it is necessary to study the causal relationship between them. To explore the causal relationship between blood metabolites and vertigo by Mendelian randomization. To assess causality, the inverse variance weighting method was employed as the primary analytical approach, complemented by additional sensitivity analyses. Metabolic pathway enrichment analysis and genetic correlation analysis were employed to further assess the metabolites. All statistical analyses were conducted using the R software. The study employed metabolite Genome Wide Association Study and vertigo diseases summary data sets to examine the causal relationship between 486 blood metabolites and 3 types of vertigo. A total of 55 potential metabolites associated with the 3 types of vertigo were identified, with 22, 16, and 13 candidate metabolites showing relatively reliable MR Evidence for Vestibular Dysfunction, Peripheral Vertigo, and Central Vertigo, respectively. Enrichment analysis was conducted to investigate the biological significance of these candidate metabolites, resulting in the identification of 7 key metabolic pathways across the 3 diseases, the metabolic pathway known as "Valine, leucine, and isoleucine biosynthesis" was found to be associated with all 3 types of vertigo, suggesting its potential influence on the vestibular system. Genetic correlation analysis revealed a genetic correlation between X-10510 and dodecanedioate with Vestibular Dysfunction. This study offers novel perspectives on the causal impact of blood metabolites on vertigo through the integration of genomics and metabolomics. Identifying metabolites that contribute to vertigo could serve as potential biomarkers and contribute to a better understanding of the underlying biological mechanisms associated with vertigo.

Involvement of BRD4 in alcoholic liver injury: Autophagy modulation via regulation of the SIRT1/Beclin1 axis.

Alcoholic liver disease (ALD) caused by chronic alcohol abuse involves complex processes from steatosis to fibrosis, cirrhosis, and hepatocellular carcinoma, posing a global health issue. Bromodomain protein 4 (BRD4) typically serves as a "reader" modulating the functions of transcription factors involved in various biological processes and disease progression. However, the specific mechanisms underlying alcoholic liver injury remain unclear. Here, we detected aberrant BRD4 expression in the alcohol-induced ALD mouse model of chronic and binge ethanol feeding developed by the National Institute on Alcohol Abuse and Alcoholism (NIAAA model), consistent with the in vitro results in Aml-12 mouse hepatocytes. Blocking and inhibiting BRD4 restored the impaired autophagic flux and lysosomal functions in alcohol-treated Aml-12 cells, whereas BRD4 overexpression reduced the expression levels of autophagy marker and lysosomal genes. Furthermore, mouse BRD4 knockdown, mediated by a short hairpin RNA carried by the adeno-associated virus serotype 8, significantly attenuated the alcohol-induced hepatocyte damage, including lipid deposition and inflammatory cell infiltration. Mechanistically, BRD4 overexpression in alcoholic liver injury inhibited the expression of sirtuin (SIRT)-1 in Aml-12 cells. Chromatin immunoprecipitation and dual-luciferase reporter assays revealed that BRD4 functions as a transcription factor and suppressor, actively binding to the SIRT1 promoter region and inhibiting its transcription. SIRT1 activated autophagy, which was suppressed in alcoholic liver injury via Beclin1 deacetylation. In conclusion, our study revealed that BRD4 negatively regulated the SIRT1/Beclin1 axis and that its deficiency alleviated alcohol-induced liver injury in mice, thus providing a new strategy for ALD treatment.

Hierarchical Porous Bi2Te3@C for Wide-Temperature-Range Aqueous Zn-Based Batteries with Air-Recharging Capability.

Air-rechargeable batteries integrating energy harvesting, conversion, and storage provide the most portable and popular approach to self-charging power systems. However, air-rechargeable batteries are currently mostly aqueous Zn-based battery systems in which it has remained a significant challenge to solve the low discharge capacities and poor cycling stability of chemical self-charging due to continuous insertion/extraction of large-size hydrated Zn2+. Herein, efficient Bi2Te3@C cathodes with an active carbon paper substrate are developed. Further ex situ characterization analysis confirms the energy storage mechanism regarding the coexistence of H+/Zn2+ coinsertion and conversion reaction in the aqueous Zn||Bi2Te3@C battery. Benefiting from the fast dynamics process attributed to the unique mechanism, a reliable energy supply is provided even in an extended temperature range from -10 to 45 °C. More importantly, Bi2Te3@C cathodes boost the superior and repeatable air-rechargeability. A discharge capacity of up to 264.20 mA h g-1 at 0.30 A g-1 is manifested after self-charging for 11.00 h. In addition, two quasi-solid-state battery devices are connected in series to continuously power a timer. After the device is discharged and then air self-charged for just a few seconds, an LED is lit.

Long-term outcomes in rapamycin on renal allograft function: a 30-year follow-up from a single-center experience.

OBJECTIVES: To evaluate long-term renal graft prognosis and the role of rapamycin from a single-center in China over a 30-year follow-up. METHODS: This study enrolled a total of 654 patients who underwent kidney transplantation between 1989 and 2020. The basic characteristics of the included patients were collected. Graft survival was described and compared using Kaplan-Meier curves (K-M curves). Both continuous and categorical variables were included in a multivariate Cox proportional-hazards model. Patients were divided into rapamycin-based quadruple immunosuppression regimen group (rapa group, n = 41) and conventional tacrolimus-based triple immunosuppression regimen group (control group, n = 218). The indication biopsy results of the two groups were further reviewed to compare the incidence of rejection, acute rejection, and banff score. RESULTS: The overall 5, 10, 15, 20-year graft survival rate of our center is 87.5%, 62.4%, 46.4% and 20.9%, respectively. The median survival time after surgery is 14 years. Multiple Cox regression analysis identified BMI (p = 0.035), dialysis type (p < 0.001), immunosuppressants (p < 0.01), urine albumen (p < 0.001), globulin (p = 0.041), and blood glucose (p = 0.002) as risk factors. The 20-year, 10-year and 5-year AUC is 0.78, 0.75 and 0.75. The combination of FK506 and rapamycin was further suggested by the model to effectively improve the graft prognosis (p < 0.01, HR = 0.763). The K-M curve showed that the long-term survival rate of renal grafts in the rapa group was significantly better than that in the conventional group (p < 0.001). In addition, indication biopsy records revealed a lower possibility of immune rejection in the rapa group than that in the conventional group (p < 0.001). Banff score indicated that rapa group had less vascular inflammation in the transplanted kidney. CONCLUSIONS: In this study, a 30-year follow-up was performed in a single center, and a total graft 20-year survival rate of 20.9% was reported. The prognostic model and subgroup analysis suggested that FK506 combined with rapamycin could effectively improve the prognosis of renal transplantation, which could be explained by reduced acute rejection and less vascular inflammation.

Rational Design of an Artificial Metalloenzyme by Constructing a Metal-Binding Site Close to the Heme Cofactor in Myoglobin.

In this study, we constructed a metal-binding site close to the heme cofactor in myoglobin (Mb) by covalently attaching a nonnative metal-binding ligand of bipyridine to Cys46 through the F46C mutation in the heme distal site. The X-ray structure of the designed enzyme, termed F46C-mBpy Mb, was solved in the Cu(II)-bound form, which revealed the formation of a heterodinuclear center of Cu-His-H2O-heme. Cu(II)-F46C-mBpy Mb exhibits not only nitrite reductase reactivity but also cascade reaction activity involving both hydrolysis and oxidation. Furthermore, F46C-mBpy Mb displays Mn-peroxidase activity by the oxidation of Mn2+ to Mn3+ using H2O2 as an oxidant. This study shows that the construction of a nonnative metal-binding site close to the heme cofactor is a convenient approach to creating an artificial metalloenzyme with a heterodinuclear center that confers multiple functions.

Improved ECG-gated cardiac cine imaging with variable initial value based tiny golden-angle radial trajectory.

BACKGROUND: Breath-held electrocardiogram-gated cardiac cine imaging (ECG-CINE), as the gold standard for assessing cardiac function in magnetic resonance imaging (MRI), is prone to motion artifacts. Conventional golden-angle (CGA) sampling has emerged as a promising technique for mitigating motion effects in real-time cardiac cine imaging. However, in ECG-CINE, the irregular re-binning of radial k-space profiles based on CGA can exacerbate k-space non-uniformity, resulting in severe streaking artifacts. The recently introduced segmented golden-angle ratio (SGA) scheme aims to solve this problem; nevertheless, it sacrifices the desired motion insensitivity. PURPOSE: The study aims to develop a more efficient k-space sampling scheme for ECG-CINE that guarantees both improved motion insensitivity and optimized k-space coverage. METHOD: Theoretically, to enhance motion insensitivity, it is essential that the single-frame radial k-space profiles acquired within each heartbeat (HB) span as close to a full 360-degree range as possible. Meanwhile, to ensure uniform data coverage, the sequentially acquired k-space profiles need to be evenly distributed both within each HB and across multiple HBs. In this study, we propose a Variable Initial value-based tiny Golden-Angle radial trajectory (VIGA) to achieve these two goals. Specifically, VIGA is a two-step approach: First, the tiny golden-angle ratio is applied to the k-space profiles within each HB to maintain motion insensitivity and k-space uniformity as in CGA. Second, a golden ratio of the golden angle used within each HB is applied to the initial k-space profiles across adjacent HBs to optimize coverage further. We validated the proposed VIGA method through numerical simulations, phantom experiments, and prospective and retrospective in vivo cardiac cine experiments. RESULTS: Numerical simulations revealed that the k-space uniformity of CGA is highly dependent on the number of spokes per HB, whereas VIGA and SGA maintained nearly optimal k-space coverage regardless of this parameter. Both phantom and prospective studies demonstrated that VIGA outperforms CGA when the number of spokes per HB is suboptimal, and surpasses SGA in conditions with residual respiratory motion. The standard deviation of gradient scores indicates statistical significance between CGA and VIGA under free-breathing conditions (p = 0.039) and between SGA and VIGA under all conditions tested (Free-breathing, 200 spokes/HB: p = 0.028; Breath-holding, 200 spokes/HB: p = 0.008; Free-breathing, 200 spokes/HB: p = 0.013; Breath-holding, 200 spokes/HB: p = 0.011). Retrospective results demonstrated that doctor ratings for SGA were lower than those for VIGA, and the ratings for systole images using VIGA were significantly higher than those using CGA (2.55 ± 0.45 vs. 3.29 ± 0.52; p = 0.04). CONCLUSION: A novel and efficient k-space sampling scheme, named VIGA, was proposed to improve k-space uniformity and motion insensitivity. VIGA facilitates robust image quality in both prospective and retrospective cardiac cine imaging, demonstrating its potential as a clinically viable alternative to CGA and SGA.

tRF-Leu reverse breast cancer cells chemoresistance by regulation of BIRC5.

OBJECTIVE: Accumulating studies reported the crucial roles of tRFs in tumorigenesis. However, their further mechanisms and clinical values remains unclear. This study aimed at the further investigation of tRF-Leu in breast cancer chemotherapy resistance. METHODS: The high-throughput sequencing was performed and identified the downregulation of tRF-Leu in MCF7/ADR cells. The function of tRF-Leu in breast cancer cells and breast cancer chemotherapy resistance was investigated in vitro and in vivo, including colony formation assay, CCK-8 assay, transwell assay and apoptosis assay. The binding site of tRF-Leu on BIRC5 was verified by dual-luciferase assay. RESULTS: tRF-Leu was downregulated in MCF7/ADR cells. Overexpression of tRF-Leu inhibited the migration of breast cancer cells. Furthermore, tRF-Leu could reverse the resistance of MCF7/ADR cells to Adriamycin both in vitro and in vivo. BIRC5 was a target of tRF-Leu, which might be involved in the chemotherapy resistance regulation. CONCLUSION: We demonstrated that tRF-Leu could inhibit the chemotherapy resistance of breast cancer by targeting BIRC5. These findings might identify new biomarkers of breast cancer therapy and bring new strategies to reverse chemotherapy resistance.

Modified dorsal recumbent position versus lithotomy position for flexible ureteroscopic lithotomy: a multicenter prospective randomized controlled clinical trial.

Background: The lithotomy position (LP) may pose limitations and discomfort for elderly patients and those with a history of lower limb surgery, potentially leading to an increased risk of complications. And the LP is the conventional position during flexible ureteroscopic lithotomy for the treatment of ureteral calculi. However, it has some disadvantages, such as peripheral nerve injury and deep venous thrombosis in the lower limbs, etc. Therefore, we performed a new approach, which is named as modified dorsal recumbent position (MDRP). Currently, there is a lack of systematic analysis and standardization regarding the surgical positioning for flexible ureteroscopic lithotripsy. The objective of the study was to assess whether there were any disparities in the overall duration of the procedure when comparing the MDRP with the LP. The investigation of the optimal position for flexible ureteroscopic lithotomy is essential for enhancing patient safety and comfort. Methods: This is a prospective, multicenter, randomized clinical trial. A total of 144 patients with renal or ureteral calculi from April 2021 to June 2022 were enrolled. Eligible patients were randomized to the MDRP group (n=72) or LP group (n=72). The patient's demographics, the placement of the surgical position (time of position placement, time of disinfection and towel laying, time of position return, degree of medical fatigue) and the operation safety (time of operation, time of ureteroscope from bladder neck to ureteral orifice, heart rate, blood pressure) of two groups were compared and analyzed. Results: Between the two groups, the body positioning time (93.8±31.6 vs. 134.8±40.1 s, P=0.02), operation time (71.8±36.7 vs. 77.7±48.6 min, P=0.04), the time from the bladder neck to the ureteral orifice of the flexible ureteroscope spent by the doctors (3.4±4.7 vs. 10.3±14.7 s, P<0.001) and incidence rate of patient's lower limb soreness (19.4% vs. 49.7%, P=0.01) in the MDRP group were significantly shorter than those in the LP group. However, there was no significant difference in the stone removal rate (87.6% vs. 85.4%, P=0.09) or postoperative hospitalization days (4.3±1.4 vs. 4.1±1.6 d, P=0.08) between the two groups. Conclusions: This trial showed that the MDRP could not only effectively shorten the operation time, shorten the time from the bladder neck to the ureteral orifice of the ureteroscopic lithotripsy, but also place the patient's body in a functional position, stabilize the blood pressure during the operation, improve the comfort of the patient. Trial Registration: Chinese Clinical Trial Registry (No. ChiCTR2100053416).

Predicting soil ecological criteria of 17 metal(loid)s in China based on quantitative ion character-activity relationship - Species sensitivity distribution (QICAR-SSD) coupled model.

Soil pollution caused by metal(loid)s is increasingly serious and poses unexpected risks to terrestrial organisms. Establishing soil quality standards is essential for assessing ecological risks of metal(loid)s and protecting soil ecosystems. However, the limited availability of metal(loid) ecotoxicological data has hampered the development of soil quality standards due to financial and practical constraints on toxicity testing. This study collected 77 normalization equations and 58 cross-species extrapolation equations to calculate the normalized EC10 (the added concentration causing a 10 % inhibition effect) of metal(loid)s under a representative scenario. A set of quantitative ion character-activity relationship (QICAR) models were then constructed using normalized EC10 and nine critical ionic characters (AR, AR/AW, BP, MP, Z/r2, Z/r, Xm, σp, and |Log(KOH)|). Subsequently, these QICAR models were employed to predict ecotoxicological EC10 of 17 metal(loid)s to 12 soil species and coupled with species sensitivity distribution (SSD) to determine Predicted No Effect Concentration (PNEC). The results demonstrated the coupled QICAR-SSD model could effectively derive terrestrial PNEC for data-poor metal(loid)s, with errors between the predicted PNEC and reported soil standards (excluding soil background levels) from different countries mostly <0.3 orders of magnitude. Finally, soil ecological criteria (SEC) for 17 metal(loid)s were calculated using an added risk approach based on PNEC and national soil background concentration. Overall, the coupled model proposed here can provide a valuable supplement to the development of soil quality standards for numerous metal(loid)s in soil components.

Synchronous reinforcement azo dyes decolorization and anaerobic granular sludge stability by Fe, N co-modified biochar: Enhancement based on extracellular electron transfer.

Anaerobic digestion (AD) treatment of azo dyes wastewater often suffers from low decolorization efficiency and poor stability of anaerobic granular sludge (AnGS). In this study, iron and nitrogen co-modified biochar (FNC) was synthesized based on the secondary calcination method, and the feasibility of this material for enhanced AD treatment of azo dye wastewater and its mechanism were investigated. FNC not only formed richer conducting functional groups, but also generated Fe2+/Fe3+ redox pairs. The decolorization efficiency of Congo red and AD properties (e.g., methane production) were enhanced by FNC. After adding FNC, the content of extracellular polymeric substances (EPS) and the ratio of proteins remained stable under the impact of Congo red, which greatly protected the internal microbial community. This was mainly contributed to the excellent electrochemical properties of FNC, which strengthened the microbial extracellular electron transfer and realized the coupled mechanism of action: On the one hand, an electron transfer bridge between decolorizing bacteria and dyes was constructed to achieve rapid decolorization of azo dyes and mitigate the impact on methanogenic bacteria; On the other hand, the stability of AnGS was enhanced based on enhanced extracellular polymeric substances secretion, microbial community and direct interspecies electron transfer (DIET) process. This study provides a new idea for enhanced AD treatment of azo dyes wastewater.

Sintilimab combined with bevacizumab in relapsed or persistent ovarian clear cell carcinoma (INOVA): a multicentre, single-arm, phase 2 trial.

BACKGROUND: Ovarian clear cell carcinoma rarely responds to second-line chemotherapy, the recommended treatment for relapsed epithelial ovarian cancer. Here, we report the activity and safety of sintilimab in combination with bevacizumab in patients with relapsed or persistent ovarian clear cell carcinoma. METHODS: In the prospective, multicentre, single-arm, phase 2 INOVA trial, patients aged 18-75 years with histologically confirmed relapsed or persistent ovarian clear cell carcinoma were enrolled from eight tertiary hospitals in China. Eligible patients had an Eastern Cooperative Oncology Group performance status score of 0-2 and previous exposure to at least one cycle of platinum-containing chemotherapy. Enrolled patients received sintilimab (200 mg) and bevacizumab (15 mg/kg) intravenously every 3 weeks until disease progression. The primary endpoint was objective response rate assessed by independent central review based on Response Evaluation Criteria in Solid Tumours version 1.1. Eligible enrolled patients who received at least one cycle of treatment and had at least one tumour response assessment following the baseline assessment per protocol were included in the activity analysis. Patients who received at least one dose of study drug were included in the safety analysis. The study is registered with ClinicalTrials.gov (NCT04735861) and is ongoing. FINDINGS: Between April 8, 2021, and July 3, 2023, 51 patients were screened and 41 patients received at least one dose of sintilimab in combination with bevacizumab. Response evaluation was completed in 37 patients. Objective responses were observed in 15 patients (objective response rate 40·5%; 95% CI 24·8-57·9), of which five (14%) were complete responses and ten (27%) were partial responses. At data cutoff (Jan 29, 2024), the median follow-up was 16·9 months (IQR 7·5-23·4). Three (7%) patients developed grade 3 treatment-related adverse events including one patient with proteinuria, one patient with myocarditis, and one patient with rash. No treatment-related adverse events of worse than grade 3 severity were recorded. Treatment-related serious adverse events occurred in two (5%) patients including one patient with immune-related myocarditis and another with hypertension and renal dysfunction. No treatment-related deaths occurred. INTERPRETATION: Sintilimab in combination with bevacizumab showed promising anti-tumour activity and manageable safety in patients with relapsed or persistent ovarian clear cell carcinoma. Larger, randomised trials are warranted to compare this low-toxicity, chemotherapy-free combinatorial regimen with standard chemotherapy. FUNDING: National Key Technology Research and Development Program of China, National Natural Science Foundation of China, Beijing Xisike Clinical Oncology Research Foundation, and Innovent Biologics. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Efficacy and safety of tocilizumab in Chinese patients with systemic juvenile idiopathic arthritis: a multicentre phase IV trial.

OBJECTIVES: Given the limited tocilizumab (TCZ) treatment data for systemic juvenile idiopathic arthritis (sJIA) in China, we evaluated the long-term efficacy and safety of TCZ in Chinese patients with sJIA. METHOD: In this multicentre, interventional Phase IV study, patients with sJIA and inadequate clinical response to non-steroidal anti-inflammatory drugs/corticosteroids received TCZ infusions every 2 weeks based on body weight (< 30 kg, 12 mg/kg; ≥ 30 kg, 8 mg/kg), over a 52-week open-label period and an 8-week safety follow-up period. The primary endpoint was the proportion of patients with a JIA American College of Rheumatology (ACR) 30 response and absence of fever at Week 12. RESULTS: Sixty-two patients were enrolled and treated (12-mg/kg group, 34; 8-mg/kg group, 28). At Week 12, 87.1% (95% confidence interval 78.8%-95.4%) of patients had JIA ACR 30 response and absence of fever; Week 52 results were similar. The proportion of JIA ACR 30/50/70/90 responders rapidly increased at Week 12, up to Week 52. High-sensitivity C-reactive protein (hsCRP) levels decreased within 4 weeks; 44/58 patients (75.9%) with elevated baseline hsCRP recovered at Week 52. Childhood Health Assessment Questionnaire pain scores, disability index scores, and mean corticosteroid dose decreased over time. Height standard deviation score changes at Week 52 indicated catch-up growth. Most adverse events (AEs) were mild (serious AE incidence, 17.7%). No deaths or macrophage activation syndrome occurred. CONCLUSION: This is the first multicentre trial to report the efficacy and safety of TCZ in Chinese patients with sJIA at 52 weeks. No new safety concerns were found.

Economic Evaluation of Population-Based BRCA1 and BRCA2 Testing in Canada.

Importance: Population-based BRCA testing can identify many more BRCA carriers who will be missed by the current practice of BRCA testing based on family history (FH) and clinical criteria. These carriers can benefit from screening and prevention, potentially preventing many more breast and ovarian cancers and deaths than the current practice. Objective: To estimate the incremental lifetime health outcomes, costs, and cost-effectiveness associated with population-based BRCA testing compared with FH-based testing in Canada. Design, Setting, and Participants: For this economic evaluation, a Markov model was developed to compare the lifetime costs and outcomes of BRCA1/BRCA2 testing for all general population women aged 30 years compared with FH-based testing. BRCA carriers are offered risk-reducing salpingo-oophorectomy to reduce their ovarian cancer risk and magnetic resonance imaging (MRI) and mammography screening, medical prevention, and risk-reducing mastectomy to reduce their breast cancer risk. The analyses were conducted from both payer and societal perspectives. This study was conducted from October 1, 2022, to February 20, 2024. Main Outcomes and Measures: Outcomes of interest were ovarian cancer, breast cancer, additional heart disease deaths, and incremental cost-effectiveness ratio ICER per quality-adjusted life-year (QALY). One-way and probabilistic-sensitivity-analyses (PSA) were undertaken to explore the uncertainty. Results: In the simulated cohort of 1 000 000 women aged 30 years in Canada, the base case ICERs of population-based BRCA testing were CAD $32 276 (US $23 402.84) per QALY from the payer perspective or CAD $16 416 (US $11 903.00) per QALY from the societal perspective compared with FH-based testing, well below the established Canadian cost-effectiveness thresholds. Population testing remained cost-effective for ages 40 to 60 years but not at age 70 years. The results were robust for multiple scenarios, 1-way sensitivity, and PSA. More than 99% of simulations from payer and societal perspectives were cost-effective on PSA (5000 simulations) at the CAD $50 000 (US $36 254.25) per QALY willingness-to-pay threshold. Population-based BRCA testing could potentially prevent an additional 2555 breast cancers and 485 ovarian cancers in the Canadian population, corresponding to averting 196 breast cancer deaths and 163 ovarian cancer deaths per 1 000 000 population. Conclusions and Relevance: In this economic evaluation, population-based BRCA testing was cost-effective compared with FH-based testing in Canada from payer and societal perspectives. These findings suggest that changing the genetic testing paradigm to population-based testing could prevent thousands of breast and ovarian cancers.

CRADD and cIAP1 antagonistically regulate caspase-9-mediated apoptosis in teleost.

Caspase 9 (CASP9) is a well-known initiator caspase of intrinsic apoptosis. In humans, cIAP1 binds and induces degradation of the activated form of CASP9, but not pro-CASP9. In fish, the activity and regulation of CASP9 remain unknown. In this work, using flounder Paralichthys olivaceus as a representative species, we examined the regulatory mechanism of CASP9 in teleost. P. olivaceus CASP9 (PoCASP9) induced robust apoptosis, which was inhibited by P. olivaceus cIAP1 (PocIAP1). Unlike human cIAP1, PocIAP1 bound both pro- and active PoCASP9 and induced their degradation via the RING domain-involved proteasome pathway. In humans, the adaptor molecule CRADD cannot interact with CASP9. In contrast, P. olivaceus CRADD (PoCRADD) bound both pro- and active PoCASP9 via CARD-CARD interaction and enhanced apoptosis by promoting the cellular levels of pro- and active PoCASP9. Furthermore, PoCRADD abrogated the inhibition of PoCASP9 by PocIAP1 by preventing PocIAP1-PoCASP9 interaction. Together these results reveal a CASP9 regulation mechanism in teleost that differs from that in humans and demonstrate that teleost CASP9 is tightly and directly controlled by both negative and positive regulators that exert a regulation effect both before and after CASP9 activation. These findings advance our understanding of the regulation of CASP9-mediated apoptosis in vertebrates.