Comparative effectiveness of first-line systemic treatments for metastatic castration-resistant prostate cancer: a systematic review and network meta-analysis.

OBJECTIVES: No head-to-head trials had been performed to estimate the relative effectiveness of poly ADP-ribose polymerase inhibitor (PARPi) and androgen receptor signaling inhibitor (ARSi) in the first-line treatment for metastatic castration-resistant prostate cancer (mCRPC). We aimed to perform a systematic review and network meta-analysis to evaluate the comparative effectiveness of various systemic treatment agents for patients with mCRPC. METHODS: A comprehensive literature search was conducted for abstracts and full-text articles from the database's inception through April 27, 2023. The study concentrated on assessing radiographic progression-free survival (rPFS) for both overall and homologous recombination repair mutation (HRRm) population, with overall survival (OS) as the secondary measure. Under the Bayesian framework, the overall effect was pooled using the fixed-effects model in base case analysis. Scenario analysis using restricted mean survival time (RMST) methods was performed to test the robustness of the results. RESULTS: Nine studies with 6,830 patients and 8 unique treatment options were included. Network meta-analysis demonstrated that talazoparib in combination with enzalutamide (TALA + ENZA; overall population, hazard ratio [HR], 0.20; 95% credible interval [CrI]: 0.16-0.26; RMST, 3.51; 95% confidence interval [CI] 2.46-4.60; HRRm population, HR, 0.15; 95% CrI: 0.09-0.23; RMST, 4.14; 95% CI 2.84-5.39) was superior to other treatments in the first-line setting in terms of rPFS. The results of Bayesian framework and RMST models showed consistent efficacy ranks. When extrapolated to overall survival benefit, within the Bayesian framework, olaparib plus abiraterone acetate and prednisone (OLAP + AAP) achieved the highest OS benefit for the overall population, which was not statistically significant when compared to TALA + ENZA. However, TALA + ENZA achieved the highest OS benefit at 3 years by applying RMST. CONCLUSIONS: We suggest that talazoparib in combination with enzalutamide is probably a preferred treatment agent for the overall population and HRRm patients with mCRPC. Given the limitations of network framework and the modeling assumptions undertaken to finalize the analyses, results should be cautiously interpreted.

ANGPTL3 accelerates atherosclerotic progression via direct regulation of M1 macrophage activation in plaque.

INTRODUCTION: The N-terminal domain of angiopoietin-like protein 3 (ANGPTL3) inhibits lipoprotein lipase activity. Its C-terminal fibrinogen-like (FBN) domain is a ligand of macrophage integrin αvß3. OBJECTIVES: ANGPTL3 might home to plaque where it directly regulates macrophage function via integrin αvß3 for atherosclerosis progression. METHODS: Ldlr-/- mice on a high-fat diet and ApoE-/- mice on a chow diet were received adeno-associated virus (AAV)-mediated Angptl3 gene transfer and followed up for 12 weeks. ApoE-/- mice were injected AAV containing FLAG-tagged Angptl3 cDNA for tracing. Atherosclerotic features were compared between Angptl3-/-ApoE-/- mice and ApoE-/- littermates. THP-1 cells were exposed to 0 or 50 µg/ml ANGPTL3 FBN domain for 24 h to evaluate Toll-like receptor (TLR)4 expression using western blot analysis and circulating cytokine and chemokine profiles by the MILLIPLEX MAP assay. Phospho-proteomic profile was established in ANGPTL3-treated macrophages. Integrin ß3 deficient THP-1 cells were obtained by sgRNAs targeting RGD sequence using Lentivirus-Cas9 system. RESULTS: Angptl3 overexpression increased atherosclerotic progression and CD68+ macrophages in plaque (p < 0.05 for all). By immunostaining, FLAG+ cells were identified in plaque of gene transferred ApoE-/- mice. Fluorescent immunostaining detected co-localisation of Angptl3 and CD68 in plaque macrophages. Phospho-proteomic analysis revealed that Angptl3 induced phosphorylation of proteins that were involved in the IL-17 signalling pathway in THP-1 cells. In vitro, ANGPTL3 treatment increased the production of interleukin (IL)-1ß and tumour necrosis factor-α in THP-1 cells (p < 0.05 for both). Exposure of ANGPTL3 to THP-1 cells induced Akt phosphorylation which was weakened in integrin ß3 deficient ones. ANGPTL3 elevated TLR4 expression via Akt phosphorylation. In response to lipopolysaccharide, nuclear factor-κB activity was 2.2-fold higher in THP-1 cells pre-treated with ANGPTL3 than in untreated cells (p < 0.05). CONCLUSIONS: Targeting ANGPTL3 could yield a dual benefit of lowering lipid levels in the blood and suppressing macrophage activation in plaque.

The combined analysis of transcriptomics and metabolomics reveals the mechanisms by which dietary quercetin regulates growth and immunity in Penaeus vannamei.

As a potent antioxidant, the flavonoid compound quercetin (QUE) has been widely used in the farming of aquatic animals. However, there are fewer reports of the beneficial effects, especially in improving immunity of Penaeus vannamei by QUE. The aim of this study was to investigate the effects of dietary QUE on growth, apoptosis, antioxidant and immunity of P. vannamei. It also explored the potential mechanisms of QUE in improving the growth and immunity of P. vannamei. P. vannamei were fed diets with QUE for 60 days. The results revealed that QUE (0.5 or 1.0 g/kg) ameliorated the growth, and the expressions of genes related to apoptosis, antioxidant, and immunity. The differentially expressed genes (DEGs) and differential metabolites (DMs) obtained through transcriptomics and metabolomics, respectively, enriched in pathways related to nutritional metabolism such as lipid metabolism, amino acid metabolism, and carbohydrate metabolism. After QUE addition, especially at 0.5 g/kg, DEGs were enriched into the functions of response to stimulus and antioxidant activity, and the pathways of HIF-1 signaling pathway, C-type lectin receptor signaling pathway, Toll-like receptor signaling pathway, and FoxO signaling pathway. In conclusion, dietary QUE can ameliorate growth, apoptosis, antioxidant and immunity of P. vannamei, the appropriate addition amount was 0.5 g/kg rather than 1.0 g/kg. Regulations of QUE on nutrient metabolism and immune-related pathways, and bioactive metabolites, were important factors for improving the aforementioned abilities in P. vannamei.

Effect of outer spherical shell opening structure on the sensitivity of double spherical shell electric field sensor.

A double spherical shell (DSS) electric field sensor based on charge sensing has characteristics of small size and simple fabrication, which are appropriate for measuring complex electric field environments, but the sensitivity is low. To improve the sensitivity of the DSS electric field sensor, we theoretically analyze the effect of the diameter of the outer spherical shell opening on the sensitivity of the sensor. The sensors with outer spherical shell apertures of 2, 4, and 6 mm are designed and manufactured, and the sensor's sensitivity, linearity, hysteresis, and repeatability are tested. The relative error of the sensor is evaluated by measuring the rotational characteristics of the sensor. The experimental results show that the sensor sensitivity increases with the increase in hole diameter, while the sensor has good linearity, hysteresis, and repeatability after opening the hole. The rotational characteristics experiments' results show that the sensors' relative errors with different apertures are 18, 23, and 31%, respectively. The DSS open-hole structure is more suitable for electric field measurements than the conventional flat plate structure.

Medical resource utilization and the associated costs of asthma in China: a 1-year retrospective study.

BACKGROUND: Despite evidence that severe and poorly controlled asthma are associated with more clinical unmet needs and intensive utilization of healthcare resources, limited data is available on severe asthma expenditure in China. The study aimed to assess Medical Resource Utilization (MRU) costs of asthma and explore the cost drivers in order to better understand the economic burden of the Chinese population suffered from asthma. METHODS: A retrospective analysis was conducted using Chinese sampled national claim database. Patients aged 6 years and above with primary diagnosis of asthma and asthma-related medical visit/hospitalization during 2015 were included. Medication was used as a proxy per the GINA and China guideline to identify asthma severity (i.e. mild, moderate, and severe). multiple linear regression model was conducted to identify MRU costs drivers. RESULTS: 7,254 patients diagnosed with asthma were included: 4,529 (62.4%), 2,200 (30.3%), and 525 (7.2%) had mild, moderate, and severe asthma, respectively. On average, each severe patient spent 6,782 Chinese Yuan (CNY) on asthma treatment and had 57.0% hospitalization rate during the year, 3.9- and 4.4-fold of the average of overall population (P < 0.001 for both). The proportion of patients experiencing exacerbation significantly higher in the severe asthma population (66.5%; P < 0.001) compared to mild (30.0%) and moderate (16.8%) groups. In subgroup with 1,660 samples had annual consecutive data, severe patients had annual cost of CNY 8,314 and 52.2% hospitalization rate. 13% of severe patients who had frequent severe exacerbation (≥ 2 events) experienced the highest annual average cost CNY 23,037, P < 0.001) whereas children aged from 6 to 14 with a lower annual cost of CNY 1,094.2, 1,660.2 and 3,020.2 for mild, moderate, and severe patients respectively. The multiple model identified degree of severity, control status, complications, age, and live region as independent drivers of MRU costs. CONCLUSIONS: Chinese asthma patients bear heavy economic burden. Severe asthma associated with higher MRU (mainly from hospitalization) and costs compared with mild to moderate asthma in China. More efforts should be devoted to the control of the disease severity and complication as the main drivers of asthma cost.

Comparative Analysis of Gut Microbiota between Wild and Captive Golden Snub-Nosed Monkeys.

Environmental shifts and dietary habits could directly affect the gut microbiota of animals. In this study, we investigated the gut microbiota of golden snub-nosed monkeys under two different conditions: captive and wild. Our study adopted a non-invasive sampling method, using full-length 16S rRNA Pacbio SMAT sequencing technology to compare the gut microbiota of wild and captive golden snub-nosed monkeys. The results showed that the captive populations had higher alpha diversity than the wild populations, and there were also significant differences in beta diversity. The linear discriminant analysis effect size (LEfSe) analysis showed 39 distinctly different taxonomic units. At the phylum level, the most dominant bacteria under captive and wild conditions were Bacteroidetes and Firmicutes. This study revealed that the different fiber intake between wild and captive populations might be the main reason for the difference in the gut microbiota. We found that captive golden snub-nosed monkeys had less beneficial bacteria and more potentially pathogenic bacteria than wild ones. Functional predictions showed that the most significant functional pathway at the second level between the captive and wild monkeys was carbohydrate metabolism. Therefore, our results indicate that diet changes caused by captivity could be the main reason impacting the gut microbiota of captive golden snub-nosed monkeys. We further highlight the potential impact of diet changes on the health of captive golden snub-nosed monkeys and offer some suggestions for the feeding of captive golden snub-nosed monkeys.

Autochthonous bioaugmentation accelerates phenanthrene degradation in acclimated soil.

Bioaugmentation helps to obtain a microbiome capable of remediating polycyclic aromatic hydrocarbons (PAHs). In this study, acclimation of microorganisms to soil supplemented with phenanthrene (PHE) led to enrichment with PAH-degraders, including those in Actinobacteriota and in the genera Streptomyces, Rhodococcus, Nocardioides, Sphingomonas, and Mycobacterium. Aqueous (28 °C, pH 6.5) and soil cultures inoculated with PHE-acclimated soil showed a high PHE (ca. 50 mg L-1) degradation efficiency. The PHE degradation kinetics in aqueous and soil incubations fitted to the Gompertz equation and the first-order kinetic equation, respectively. Indigenous microorganisms adapted to PHE in their environment, and this increased their capacity to degrade PHE. The effect of co-contaminants and pathway intermediates on PHE degradation showed that the degradation of PHE improved in the presence of diesel while being hindered by lubricant oil, catechol, salicylic and phthalic acid. Our findings provide theoretical and practical support for bioremediationof PAHs in the environment.

Recent Insights into Neutrophil Extracellular Traps in Cardiovascular Diseases.

Neutrophils are primary effector cells of the innate immune system. Emerging evidence has consistently shown that activated neutrophils produce and release neutrophil extracellular traps (NETs) that play roles in immunity and non-infectious diseases. NETs are composed of DNA and proteins and serve as a structural platform for pathogen sequestration and degradation. In contrast to their protective role during pathogenic infection, NETs are pathologically involved in cardiovascular disease (CVD). In this review, we introduce the formation, release, and clearance of NETs and the regulatory mechanisms of NETs formation, followed by an overview of the clinical evidence for the involvement of NETs in CVD. Because atherosclerosis is a fundamental part of the pathogenesis of CVD, we chose to focus on the mechanisms by which NETs promote endothelial cell damage and collaborate with macrophages and platelets to accelerate plaque progression and thrombosis. Finally, we present options for clinical intervention to inhibit NETs production and release in the treatment of CVD. In conclusion, this review integrates the latest findings and provides new insights into NETs, which represent a novel biomarker and therapeutic target in clinical practice.

Improvement of hybrid grouper (Epinephelus fuscoguttatus ♀ × E. lanceolatus ♂) by enzyme-digested poultry by-product: Growth performance, amino acid and peptide transport capacity, and intestinal morphology.

Background: At present, fish meal (FM) resources are in short supply, and competition for food between humans and animals is becoming increasingly critical. Finding non-grain protein sources that can replace FM is the key to solving the rapid development of aquaculture. Methods: Seven trial diets were prepared with 0 g/kg (EP0), 30 g/kg (EP3), 60 g/kg (EP6), 90 g/kg (EP9), 120 g/kg (EP12), 150 g/kg (EP15), and 180 g/kg (EP18) of enzyme-digested poultry by-product meal (EPBM) by replacing of FM. A total of 630 hybrid groupers (Epinephelus fuscoguttatus ♀ × E. lanceolatus ♂) were equally portioned into 21 tanks. At 8:00 and 16:00 each day, groupers were fed until they were full for a cumulative period of 8 weeks. Results: The results showed that 30 g/kg of EPBM significantly increased the rates of weight gain and special growth (P < 0.05). Significantly higher activities of serum glutamic pyruvic transaminase, glutamic oxaloacetic transaminase, catalase, and superoxide dismutase were observed in the EP3 group (P < 0.05). The categories and numbers of the top 10 dominant bacteria in the phylum and genus levels were not significantly influenced by feed (P > 0.05). In the proximal intestine and distal intestine, there were significantly higher expressions of SNAT3, LAAT1, CAT2, and CAT1 in the EP3 group compared with the EP0 group (P < 0.05). In the EP3 group, the expressions of PepT1, LAAT1, B0, +AT, and CAT2 were significantly increased in MI than those in all other groups (except the EP0 group, P < 0.05). Conclusion: When FM was replaced by 30 g/kg of EPBM, growth performance, antioxidant capacity, and the ability to transport amino acids and peptides of hybrid grouper were significantly improved.

Flesh quality of hybrid grouper (Epinephelus fuscoguttatus ♀ × Epinephelus lanceolatus ♂) fed with hydrolyzed porcine mucosa-supplemented low fishmeal diet.

Iso-nitrogenous and iso-lipidic diets containing 0%, 3%, 6%, 9%, and 12% hydrolyzed porcine mucosa (namely, HPM0, HPM3, HPM6, HPM9, and HPM12) were prepared to evaluate their effects on the growth performance, muscle nutrition composition, texture property, and gene expression related to muscle growth of hybrid groupers (Epinephelus fuscoguttatus ♀ × Epinephelus lanceolatus ♂). Groupers were fed to apparent satiation at 08:00 and 16:00 every day for a total of 56 days. It was found that the weight gain percentage in the HPM0, HPM3, and HPM6 groups did not differ (P > 0.05). The cooking loss and drip loss of the dorsal muscle in the HPM3 group were lower than those in the HPM6 and HPM9 groups (P < 0.05). The hardness and chewiness of the dorsal muscle in the HPM3 group were higher than those in the HPM0, HPM9, and HPM12 groups (P < 0.05). The gumminess in the HPM3 group was higher than that in the HPM9 and HPM12 groups (P < 0.05). The total essential amino acid content of the dorsal muscle in the HPM12 group was higher than that in the HPM0 group (P < 0.05). The contents of total n-3 polyunsaturated fatty acid and total n-3 highly unsaturated fatty acid, as well as the ratio of n-3/n-6 polyunsaturated fatty acid in the dorsal muscle was higher in the HPM0 group than in all other groups (P < 0.05). The relative expressions of gene myogenic factor 5, myocyte enhancer factor 2c, myocyte enhancer factor 2a, myosin heavy chain, transforming growth factor-beta 1 (TGF-ß1), and follistatin (FST) were the highest in the dorsal muscle of the HPM3 group. The results indicated that the growth performance of hybrid grouper fed a diet with 6% HPM and 27% fish meal was as good as that of the HPM0 group. When fish ingested a diet containing 3% HPM, the expression of genes TGF-ß1 and FST involved in muscle growth were upregulated, and then the muscle quality related to hardness and chewiness were improved. An appropriate amount of HPM could be better used in grouper feed.