The combination of breast cancer PDO and mini-PDX platform for drug screening and individualized treatment.

The majority of advanced breast cancers exhibit strong aggressiveness, heterogeneity, and drug resistance, and currently, the lack of effective treatment strategies is one of the main challenges that cancer research must face. Therefore, developing a feasible preclinical model to explore tailored treatments for refractory breast cancer is urgently needed. We established organoid biobanks from 17 patients with breast cancer and characterized them by immunohistochemistry (IHC) and next generation sequencing (NGS). In addition, we in the first combination of patient-derived organoids (PDOs) with mini-patient-derived xenografts (Mini-PDXs) for the rapid and precise screening of drug sensitivity. We confirmed that breast cancer organoids are a high-fidelity three-dimension (3D) model in vitro that recapitulates the original tumour's histological and genetic features. In addition, for a heavily pretreated patient with advanced drug-resistant breast cancer, we combined PDO and Mini-PDX models to identify potentially effective combinations of therapeutic agents for this patient who were alpelisib + fulvestrant. In the drug sensitivity experiment of organoids, we observed changes in the PI3K/AKT/mTOR signalling axis and oestrogen receptor (ER) protein expression levels, which further verified the reliability of the screening results. Our study demonstrates that the PDO combined with mini-PDX model offers a rapid and precise drug screening platform that holds promise for personalized medicine, improving patient outcomes and addressing the urgent need for effective therapies in advanced breast cancer.

Megalin-targeted acetylcysteine polymeric prodrug ameliorates ischemia-reperfusion-induced acute kidney injury.

Acute kidney injury (AKI), a condition associated with reactive oxygen species (ROS), causes high mortality in clinics annually. Active targeted antioxidative therapy is emerging as a novel strategy for AKI treatment. In this study, we developed a polymeric prodrug that targets the highly expressed Megalin receptor on proximal tubule cells, enabling direct delivery of N-Acetylcysteine (NAC) for the treatment of ischemia reperfusion injury (IRI)-induced AKI. We conjugated NAC with low molecular weight chitosan (LMWC), a biocompatible and biodegradable polymer consisting of glucosamine and N-acetylglucosamine, to enhance its internalization by tubular epithelial cells. Moreover, we further conjugated triphenylphosphonium (TPP), a lipophilic cation with a delocalized positive charge, to low molecular weight chitosan-NAC in order to enhance the distribution of NAC in mitochondria. Our study confirmed that triphenylphosphonium-low molecular weight chitosan-NAC (TLN) exhibits remarkable therapeutic effects on IRI-AKI mice. This was evidenced by improvements in renal function, reduction in oxidative stress, mitigation of pathological progress, and decreased levels of kidney injury molecule-1. These findings suggested that the polymeric prodrug TLN holds promising potential for IRI-AKI treatment.

Continuous infusion versus bolus injection of loop diuretics for acute heart failure.

BACKGROUND: Acute heart failure (AHF) is new onset of, or a sudden worsening of, chronic heart failure characterised by congestion in about 95% of cases or end-organ hypoperfusion in 5% of cases. Treatment often requires urgent escalation of diuretic therapy, mainly through hospitalisation. This Cochrane review evaluated the efficacy of intravenous loop diuretics strategies in treating AHF in individuals with New York Heart Association (NYHA) classification III or IV and fluid overload. OBJECTIVES: To assess the effects of intravenous continuous infusion versus bolus injection of loop diuretics for the initial treatment of acute heart failure in adults. SEARCH METHODS: We identified trials through systematic searches of bibliographic databases and in clinical trials registers including CENTRAL, MEDLINE, Embase, CPCI-S on the Web of Science, ClinicalTrials.gov, the World Health Organization (WHO) International Clinical Trials Registry platform (ICTRP), and the European Union Trials register. We conducted reference checking and citation searching, and contacted study authors to identify additional studies. The latest search was performed on 29 February 2024. SELECTION CRITERIA: We included randomised controlled trials (RCTs) involving adults with AHF, NYHA classification III or IV, regardless of aetiology or ejection fraction, where trials compared intravenous continuous infusion of loop diuretics with intermittent bolus injection in AHF. We excluded trials with chronic stable heart failure, cardiogenic shock, renal artery stenosis, or end-stage renal disease. Additionally, we excluded studies combining loop diuretics with hypertonic saline, inotropes, vasoactive medications, or renal replacement therapy and trials where diuretic dosing was protocol-driven to achieve a target urine output, due to confounding factors. DATA COLLECTION AND ANALYSIS: Two review authors independently screened papers for inclusion and reviewed full-texts. Outcomes included weight loss, all-cause mortality, length of hospital stay, readmission following discharge, and occurrence of acute kidney injury. We performed risk of bias assessment and meta-analysis where data permitted and assessed certainty of the evidence. MAIN RESULTS: The review included seven RCTs, spanning 32 hospitals in seven countries in North America, Europe, and Asia. Data collection ranged from eight months to six years. Following exclusion of participants in subgroups with confounding treatments and different clinical settings, 681 participants were eligible for review. These additional study characteristics, coupled with our strict inclusion and exclusion criteria, improve the applicability of the body of the evidence as they reflect real-world clinical practice. Meta-analysis was feasible for net weight loss, all-cause mortality, length of hospital stay, readmission, and acute kidney injury. Literature review and narrative analysis explored daily fluid balance; cardiovascular mortality; B-type natriuretic peptide (BNP) change; N-terminal-proBNP change; and adverse incidents such as ototoxicity, hypotension, and electrolyte imbalances. Risk of bias assessment revealed two studies with low overall risk, four with some concerns, and one with high risk. All sensitivity analyses excluded trials at high risk of bias. Only narrative analysis was conducted for 'daily fluid balance' due to diverse data presentation methods across two studies (169 participants, the evidence was very uncertain about the effect). Results of narrative analysis varied. For instance, one study reported higher daily fluid balance within the first 24 hours in the continuous infusion group compared to the bolus injection group, whereas there was no difference in fluid balance beyond this time point. Continuous intravenous infusion of loop diuretics may result in mean net weight loss of 0.86 kg more than bolus injection of loop diuretics, but the evidence is very uncertain (mean difference (MD) 0.86 kg, 95% confidence interval (CI) 0.44 to 1.28; 5 trials, 497 participants; P < 0.001, I2 = 21%; very low-certainty evidence). Importantly, sensitivity analysis excluding trials with high risk of bias showed there was insufficient evidence for a difference in bodyweight loss between groups (MD 0.70 kg, 95% CI -0.06 to 1.46; 3 trials, 378 participants; P = 0.07, I2 = 0%). There may be little to no difference in all-cause mortality between continuous infusion and bolus injection (risk ratio (RR) 1.53, 95% CI 0.81 to 2.90; 5 trials, 530 participants; P = 0.19, I2 = 4%; low-certainty evidence). Despite sensitivity analysis, the direction of the evidence remained unchanged. No trials measured cardiovascular mortality. There may be little to no difference in the length of hospital stay between continuous infusion and bolus injection of loop diuretics, but the evidence is very uncertain (MD -1.10 days, 95% CI -4.84 to 2.64; 4 trials, 211 participants; P = 0.57, I2 = 88%; very low-certainty evidence). Sensitivity analysis improved heterogeneity; however, the direction of the evidence remained unchanged. There may be little to no difference in the readmission to hospital between continuous infusion and bolus injection of loop diuretics (RR 0.85, 95% CI 0.63 to 1.16; 3 trials, 400 participants; P = 0.31, I2 = 0%; low-certainty evidence). Sensitivity analysis continued to show insufficient evidence for a difference in the readmission to hospital between groups. There may be little to no difference in the occurrence of acute kidney injury as an adverse event between continuous infusion and bolus injection of intravenous loop diuretics (RR 1.02, 95% CI 0.70 to 1.49; 3 trials, 491 participants; P = 0.92, I2 = 0%; low-certainty evidence). Sensitivity analysis continued to show that continuous infusion may make little to no difference on the occurrence of acute kidney injury as an adverse events compared to the bolus injection of intravenous loop diuretics. AUTHORS' CONCLUSIONS: Analysis of available data comparing two delivery methods of diuretics in acute heart failure found that the current data are insufficient to show superiority of one strategy intervention over the other. Our findings were based on trials meeting stringent inclusion and exclusion criteria to ensure validity. Despite previous reviews suggesting advantages of continuous infusion over bolus injections, our review found insufficient evidence to support or refute this. However, our review, which excluded trials with clinical confounders and RCTs with high risk of bias, offers the most robust conclusion to date.

Peritoneal B1 and B2 cells respond differently to LPS and IL-21 stimulation.

Peritoneal B cells can be divided into B1 cells (CD11b+CD19+) and B2 cells (CD11b-CD19+) based on CD11b expression. B1 cells play a crucial role in the innate immune response by producing natural antibodies and cytokines. B2 cells share similar traits with B1 cells, influenced by the peritoneal environment. However, the response of both B1 and B2 cells to the same stimuli in the peritoneum remains uncertain. We isolated peritoneal B1 and B2 cells from mice and assessed differences in Interleukin-10(IL-10) secretion, apoptosis, and surface molecule expression following exposure to LPS and Interleukin-21(IL-21). Our findings indicate that B1 cells are potent IL-10 producers, possessing surface molecules with an IgMhiCD43+CD21low profile, and exhibit a propensity for apoptosis in vitro. Conversely, B2 cells exhibit lower IL-10 production and surface markers characterized as IgMlowCD43-CD21hi, indicative of some resistance to apoptosis. LPS stimulates MAPK phosphorylation in B1 and B2 cells, causing IL-10 production. Furthermore, LPS inhibits peritoneal B2 cell apoptosis by enhancing Bcl-xL expression. Conversely, IL-21 has no impact on IL-10 production in these cells. Nevertheless, impeding STAT3 phosphorylation permits IL-21 to increase IL-10 production in peritoneal B cells. Moreover, IL-21 significantly raises apoptosis levels in these cells, a process independent of STAT3 phosphorylation and possibly linked to reduced Bcl-xL expression. This study elucidates the distinct functional and response profiles of B1 and B2 cells in the peritoneum to stimuli like LPS and IL-21, highlighting their differential roles in immunological responses and B cell diversity.

Early evaluation of circulating tumor DNA as marker of therapeutic efficacy and prognosis in breast cancer patients during primary systemic therapy.

BACKGROUND: We assessed the potential role of serial circulating tumor DNA (ctDNA) as a biomarker to monitor treatment response to primary systemic therapy (PST) in breast cancer and evaluated the predictive value of ctDNA to further identify patients with residual disease. METHODS: We prospectively enrolled 208 plasma samples collected at three time points (before PST, after 2 cycles of treatment, before surgery) of 72 patients with stage Ⅱ-III breast cancer. Somatic mutations in plasma samples were identified using a customized 128-gene capture panel with next-generation sequencing. The correlation between early change in ctDNA levels and treatment response or long-term clinical outcomes was assessed. RESULTS: 37 of 72 (51.4%) patients harbored detectable ctDNA alterations at baseline. Patients with complete response showed a larger decrease in ctDNA levels during PST. The median relative change of variant allele fraction (VAF) was -97.4%, -46.7%, and +21.1% for patients who subsequently had a complete response (n = 11), partial response (n = 11), and no response (n = 15) (p = 0.0012), respectively. In addition, the relative change of VAF between the pretreatment and first on-treatment blood draw exhibited the optimal predictive value to tumor response after PST (area under the curve, AUC = 0.7448, p = 0.02). More importantly, early change of ctDNA levels during treatment have significant prognostic value for patients with BC, there was a significant correlation between early decrease of VAF and longer recurrence-free survival compared to those with an VAF increase (HR = 12.54; 95% CI, 2.084 to 75.42, p = 0.0063). CONCLUSION: Early changes of ctDNA are strongly correlated with therapeutic efficacy to PST and clinical outcomes in BC patients. The integration of preoperative ctDNA evaluation could help improving the perioperative management for BC patients receiving PST.

Nesprin-2 is a novel scaffold protein for telethonin and FHL-2 in the cardiomyocyte sarcomere.

Nesprins comprise a family of multi-isomeric scaffolding proteins, forming the linker of nucleoskeleton-and-cytoskeleton complex with lamin A/C, emerin and SUN1/2 at the nuclear envelope. Mutations in nesprin-1/-2 are associated with Emery-Dreifuss muscular dystrophy (EDMD) with conduction defects and dilated cardiomyopathy (DCM). We have previously observed sarcomeric staining of nesprin-1/-2 in cardiac and skeletal muscle, but nesprin function in this compartment remains unknown. In this study, we show that specific nesprin-2 isoforms are highly expressed in cardiac muscle and localize to the Z-disc and I band of the sarcomere. Expression of GFP-tagged nesprin-2 giant spectrin repeats 52 to 53, localized to the sarcomere of neonatal rat cardiomyocytes. Yeast two-hybrid screening of a cardiac muscle cDNA library identified telethonin and four-and-half LIM domain (FHL)-2 as potential nesprin-2 binding partners. GST pull-down and immunoprecipitation confirmed the individual interactions between nesprin-2/telethonin and nesprin-2/FHL-2, and showed that nesprin-2 and telethonin binding was dependent on telethonin phosphorylation status. Importantly, the interactions between these binding partners were impaired by mutations in nesprin-2, telethonin, and FHL-2 identified in EDMD with DCM and hypertrophic cardiomyopathy patients. These data suggest that nesprin-2 is a novel sarcomeric scaffold protein that may potentially participate in the maintenance and/or regulation of sarcomeric organization and function.

Near-infrared II theranostic agents for the diagnosis and treatment of Alzheimer's disease.

BACKGROUND: Near-infrared II theranostic agents have gained great momentum in the research field of AD owing to the appealing advantages. Recently, an array of activatable NIR-II fluorescence probes has been developed to specifically monitor pathological targets of AD. Furthermore, various NIR-II-mediated nanomaterials with desirable photothermal and photodynamic properties have demonstrated favorable outcomes in the management of AD. METHODS: We summerized amounts of references and focused on small-molecule probes, nanomaterials, photothermal therapy, and photodynamic therapy based on NIR-II fluorescent imaging for the diagnosis and treatment in AD. In addition, design strategies for NIR-II-triggered theranostics targeting AD are presented, and some prospects are also addressed. RESULTS: NIR-II theranostic agents including small molecular probes and nanoparticles have received the increasing attention for biomedical applications. Meanwhile, most of the theranostic agents exhibited the promising results in animal studies. To our surprise, the multifunctional nanoplatforms also show a great potential in the diagnosis and treatment of AD. CONCLUSIONS: Although NIR-II theranostic agents showed the great potential in diagnosis and treatment of AD, there are still many challenges: 1) Faborable NIR-II fluorohpores are still lacking; 2) Biocompatibility, bioseurity and dosage of NIR-II theranostic agents should be further revealed; 3) New equipment and software associated with NIR-II imaging system should be explored.

Anisotropic Hardening and Plastic Evolution Characterization on the Pressure-Coupled Drucker Yield Function of ZK61M Magnesium Alloy.

This paper studies the plastic behavior of the ZK61M magnesium alloy through a combination method of experiments and theoretical models. Based on a dog-bone specimen under different loading directions, mechanical tests under uniaxial tension were carried out, and the hardening behavior was characterized by the Swift-Voce hardening law. The von Mises yield function and the pressure-coupled Drucker yield function were used to predict the load-displacement curves of the ZK61M magnesium alloy under various conditions, respectively, where the material parameters were calibrated by using inverse engineering. The experimental results show that the hardening behavior of the ZK61M magnesium alloy has obvious anisotropy, but the effect of the stress state is more important on the strain hardening behavior of the alloy. Compared with the von Mises yield function, the pressure-coupled Drucker yield function is more accurate when characterizing the plastic behavior and strain hardening in different stress states of shear, uniaxial tension, and plane strain tension for the ZK61M alloy.

Natural products for the treatment of chemotherapy-related cognitive impairment and prospects of nose-to-brain drug delivery.

Chemotherapy-related cognitive deficits (CRCI) as one of the common adverse drug reactions during chemotherapy that manifest as memory, attention, and executive function impairments. However, there are still no effective pharmacological therapies for the treatment of CRCI. Natural compounds have always inspired drug development and numerous natural products have shown potential therapeutic effects on CRCI. Nevertheless, improving the brain targeting of natural compounds in the treatment of CRCI is still a problem to be overcome at present and in the future. Accumulated evidence shows that nose-to-brain drug delivery may be an excellent carrier for natural compounds. Therefore, we reviewed natural products with potential anti-CRCI, focusing on the signaling pathway of these drugs' anti-CRCI effects, as well as the possibility and prospect of treating CRCI with natural compounds based on nose-to-brain drug delivery in the future. In conclusion, this review provides new insights to further explore natural products in the treatment of CRCI.

A UV-Vis spectroscopic detection method for cobalt ions in zinc sulfate solution based on discrete wavelet transform and extreme gradient boosting.

Zinc is a crucial strategic metal resource. The concentration of cobalt ions in zinc refining solution significantly impacts the efficiency of zinc electrolysis production. The traditional method of detecting cobalt ions in zinc solution is time-consuming, labor-intensive and ineffective. However, optical detection offers the advantage of high efficiency and low cost, making it a potential replacement for the traditional method. In this study, the spectral curve of cobalt ions in zinc solution is detected by ultraviolet-visible (UV-Vis) spectrophotometry. Additionally, we propose a model for the concentration-absorbance relationship of cobalt ions in zinc solution based on discrete wavelet transform and extreme gradient boosting (DWT-XGBoost) algorithms. First, the spectral curve's information region is denoised by using Savitzky-Golay (S-G) smoothing. Then, the denoised spectra is utilized to extract features through discrete wavelet transform and principal component analysis. These features are used as inputs to the XGBoost model to establish prediction models for low and high cobalt ions in zinc solution. Bayesian optimization is implemented to adjust the model's hyperparameters, including learning rate, feature sampling ratio, to enhance the prediction performance. Finally, applying the model to zinc solution samples from a zinc smelter and compared with other state-of-the-art algorithms, the DWT-XGBoost algorithm exhibits the lowest RMSE, MAE and MAPE, with values of 0.034 mg/L, 0.025 mg/L, 6.983 % for low cobalt and with values of 0.231 mg/L, 0.067 mg/L and 0.472 % for high cobalt. The experimental results demonstrate that the DWT-XGBoost model exhibits significantly superior prediction performance.

Sertraline Promotes Health and Longevity in Caenorhabditis elegans.

INTRODUCTION: While several antidepressants have been identified as potential geroprotectors, the effect and mechanism of sertraline on healthspan remain to be elucidated. Here, we explored the role of sertraline in the lifespan and healthspan of Caenorhabditis elegans. METHODS: The optimal effect concentration of sertraline was first screened in wild-type N2 worms under heat stress conditions. Then, we examined the effects of sertraline on lifespan, reproduction, lipofuscin accumulation, mobility, and stress resistance. Finally, the expression of serotonin signaling and aging-related genes was investigated to explore the underlying mechanism, and the lifespan assays were performed in ser-7 RNAi strain, daf-2, daf-16, and aak-2 mutants. RESULTS: Sertraline extended the lifespan in C. elegans with concomitant extension of healthspan as indicated by increasing mobility and reducing fertility and lipofuscin accumulation, as well as enhanced resistance to different abiotic stresses. Mechanistically, ser-7 orchestrated sertraline-induced longevity via the regulation of insulin and AMPK pathways, and sertraline-induced lifespan extension in nematodes was abolished in ser-7 RNAi strain, daf-2, daf-16, and aak-2 mutants. CONCLUSION: Sertraline promotes health and longevity in C. elegans through ser-7-insulin/AMPK pathways.

Fluoxetine Promotes Longevity via Reactive Oxygen Species in Caenorhabditis elegans.

Although several antidepressants have been identified as potential geroprotectors, the effect and mechanism of fluoxetine, a representative selective serotonin reuptake inhibitor, on longevity have not been fully elucidated. Here, we found that fluoxetine promoted longevity in Caenorhabditis elegans with a concomitant extension of a healthy life span as indicated by increasing mobility, reducing fertility and lipofuscin accumulation, and enhanced resistance to different abiotic stresses. Fluoxetine increased the level of reactive oxygen species (ROS), and antioxidant N-acetylcysteine abolished ROS elevation and the pro-longevity effect of fluoxetine. Additionally, fluoxetine extended life span through the daf-2-sod-3 pathway in daf-16-dependent and -independent manners, and fluoxetine-induced life-span extension was abolished in C. elegans sod-3, daf-2, and daf-16 mutants. In conclusion, these findings suggest that fluoxetine can promote health and longevity in C. elegans via the interaction of ROS and insulin signaling.

Interleukin-4 and Interleukin-17 are associated with coronary artery disease.

INTRODUCTION: The present study aimed to examine the correlation between serum cytokine levels and the incidence of coronary artery disease (CAD), a leading cause of mortality globally, which is known to have a strong association with inflammatory factors. The study further sought to determine the predictors of CAD to distinguish patients with coronary artery lesions from those suspected of having CAD. METHODS AND RESULTS: In this study, 487 patients who underwent coronary angiography as a result of suspected CAD but without acute myocardial infarction (AMI) were recruited. The serum levels of the cytokines interleukin (IL)-1ß, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-17, tumor necrosis factor-α, interferon (IFN)-α, and IFN-γ were measured using a multiplexed particle-based flow cytometric assay technique. The results of the study revealed that the levels of IL-4, IL-12p70, IL-17, IFN-α, and IFN-γ in the CAD group were significantly lower compared to those in the non-CAD group. Multivariate logistic regression analysis indicated that two serum cytokines (IL-4 and IL-17), one protective factor (high-density lipoprotein cholesterol [HDL-C]), and three risk factors (sex, smoking, and diabetes) were independently predictive of CAD. The receiver operating characteristic curve analysis showed that the combined use of these predictors in a multivariate model demonstrated good predictive performance for CAD, as evidenced by an area under the curve value of 0.826. CONCLUSION: The results of the study indicated that serum IL-4 and IL-17 levels serve as independent predictors of CAD. The risk prediction model established in the research, which integrates these serum cytokines (IL-4 and IL-17) with relevant clinical risk factors (gender, smoking, and diabetes) and the protective factor HDL-C, holds the potential to differentiate patients with CAD from those suspected of having CAD but without AMI.

TET2 is recruited by CREB to promote Cebpb, Cebpa, and Pparg transcription by facilitating hydroxymethylation during adipocyte differentiation.

Ten-eleven translocation proteins (TETs) are dioxygenases that convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), an important epigenetic mark that regulates gene expression during development and differentiation. Here, we found that the TET2 expression was positively associated with adipogenesis. Further, in vitro and in vivo experiments showed that TET2 deficiency blocked adipogenesis by inhibiting the expression of the key transcription factors CCAAT/enhancer-binding protein beta (C/EBPß), C/EBPα and peroxisome proliferator-activated receptor gamma (PPARγ). In addition, TET2 promoted 5hmC on the CpG islands (CGIs) of Cebpb, Cebpa and Pparg at the initial time point of their transcription, which requires the cAMP-responsive element-binding protein (CREB). At last, specific knockout of Tet2 in preadipocytes enabled mice to resist obesity and attenuated the obesity-associated insulin resistance. Together, TET2 is recruited by CREB to promote the expression of Cebpb, Cebpa and Pparg via 5hmC during adipogenesis and may be a potential therapeutic target for obesity and insulin resistance.

Ursodeoxycholic acid alleviates sepsis-induced lung injury by blocking PANoptosis via STING pathway.

Acute lung injury (ALI), a progressive lung disease mostly caused by sepsis, is characterized by uncontrolled inflammatory responses, increased oxidative stress, pulmonary barrier dysfunction, and pulmonary edema. Ursodeoxycholic acid (UDCA) is a natural bile acid with various pharmacological properties and is extensively utilized in clinical settings for the management of hepatobiliary ailments. Nonetheless, the potential protective effects and mechanism of UDCA on sepsis-induced lung injuries remain unknown. In this study, we reported that UDCA effectively inhibited pulmonary edema, inflammatory cell infiltration, pro-inflammatory cytokines production, and oxidative stress. Furthermore, UDCA treatment significantly alleviated the damage of pulmonary barrier and enhanced alveolar fluid clearance. Importantly, UDCA treatment potently suppressed PANoptosis-like cell death which is demonstrated by the block of apoptosis, pyroptosis, and necroptosis. Mechanistically, UDCA treatment prominently inhibited STING pathway. And the consequential loss of STING substantially impaired the beneficial effects of UDCA treatment on the inflammatory response, pulmonary barrier, and PANoptosis. These results indicate that STING plays a pivotal role in the UDCA treatment against sepsis-induced lung injury. Collectively, our findings show that UDCA treatment can ameliorate sepsis-induced lung injury and verified a previously unrecognized mechanism by which UDCA alleviated sepsis-induced lung injury through blocking PANoptosis-like cell death via STING pathway.

Efficacy of breast reconstruction for N2-3M0 stage female breast cancer on breast cancer-specific survival: A population-based propensity score analysis.

BACKGROUND: The efficacy of breast reconstruction for patients with N2-3M0 stage female breast cancer (FBC) remained unclear due to the lack of randomized clinical trials. This retrospective study aimed to explore the efficacy of breast reconstruction for patients with N2-3M0 stage FBC. METHODS: Two thousand five hundred forty-five subjects with FBC staged by N2-3M0 from 2010 to 2016 were retrieved from the Surveillance, Epidemiology, and End Results database. Generalized boosted model (GBM) and propensity score matching (PSM) analyses and multivariable Cox analyses were employed to assess the clinical prognostic effect of postmastectomy reconstruction for patients with N2-3M0 stage FBC in breast cancer-specific survival (BCSS). RESULTS: Totally, 1784 candidates underwent mastectomy alone (mastectomy group), and 761 candidates underwent postmastectomy reconstruction (PMbR group), with 418 breast-specific deaths after a median follow-up time of 57 months (ranging from 7 to 227 months). BCSS in the mastectomy group showed no statistical difference from that in the PMbR group in the PSM cohort (HR = 0.93, 95% CI: 0.70-1.25, p = 0.400) and GBM cohort (HR = 0.75, 95% CI: 0.56-1.01, p = 0.057). In the multivariate analyses, there was no difference in the effect of PMbR and mastectomy on BCSS in the original cohort (HR = 0.85, 95% CI: 0.66-1.09, p = 0.197), PSM cohort (HR = 0.86, 95% CI: 0.64-1.15, p = 0.310), and GBM cohort (HR = 0.84, 95% CI: 0.61-1.17, p = 0.298). Triple-negative breast cancer (TNBC) was a detrimental factor affecting BCSS for patients in the PMbR group. CONCLUSIONS: Our study demonstrated that PMbR is an oncologically safe surgical treatment and can be widely recommended in clinics for females with non-TNBC staged by T0-3N2-3M0.

The dynamic expression of SOX17 in germ cells from human female foetus and adult ovaries after specification.

Background: SOX17 has been identified as a critical factor in specification of human primordial germ cells, but whether SOX17 regulates development of germ cells after sex differentiation is poorly understood. Methods: We collected specimens of gonadal ridge from an embryo (n=1), and ovaries of foetuses (n=23) and adults (n=3). Germ cells were labelled with SOX17, VASA (classic germ cells marker), phosphohistone H3 (PHH3, mitosis marker) and synaptonemal complex protein 3 (SCP3, meiosis marker). Results: SOX17 was detected in both cytoplasm and nucleus of oogonia and oocytes of primordial and primary follicles from 15 to 28 gestational weeks (GW). However, it was exclusively expressed in cytoplasm of oogonia at 7 GW, and in nucleus of oocytes in secondary follicles. Co-expression rates of SOX17 in VASA+ germ cells ranged from 81.29% to 97.81% in foetuses. Co-staining rates of SOX17 and PHH3 or SCP3 were 0%-34% and 0%-57%, respectively. Interestingly, we distinguished a subpopulation of SOX17+VASA- germ cells in fetal ovaries. These cells clustered in the cortex and could be co-stained with the mitosis marker PHH3 but not the meiosis marker SCP3. Conclusions: The dynamic expression of SOX17 was detected in human female germ cells. We discovered a population of SOX17+ VASA- germ cells clustering at the cortex of ovaries. We could not find a relationship between mitosis or meiosis and SOX17 or VASA staining in germ cells. Our findings provide insight into the potential role of SOX17 involving germ cells maturation after specification, although the mechanism is unclear and needs further investigation.

Global disease burden attributed to unsafe sex in 204 countries and territories from 1990 to 2019: results from the Global Burden of Disease Study 2019.

Unsafe sex has become a public safety problem that endangers society, and research on deaths and disability-adjusted life years (DALYs) related to unsafe sex is valuable for global policy-making. We aimed to estimate the deaths and DALYs attributable to unsafe sex by country, gender, age group, and sociodemographic status from 1990 to 2019. We extracted data on disease burden from the Global Disease Burden 2019 (GBD 2019) database for unsafe sex, including deaths, DALYs and age-standardized rates (ASRs). Comparative analyses were performed on data about deaths, DALYs and the responding ASRs attributable to unsafe sex in different countries and regions using the Social Demographic Index (SDI). The global age-standardized mortality rate (ASMR) and age-standardized DALY rate (ASDR) attributable to unsafe sex were 11.98 (95% uncertainty intervals (UI): 10.97-13.52) per 100,000 people and 570.78 (95% UI: 510.24-658.10) per 100,000 people, respectively. Both the ASMRs and ASDRs were the highest in southern sub-Saharan Africa and lowest in Australasia and decreased with increasing SDI levels. About unsafe-sex-related disease, HIV/AIDS has the highest ASMR [8.48 (95% UI: 7.62-9.95)/100,000 people] and ASDR [447.44 (95% UI: 394.82-533.10)/100,000 people], followed by Cervical cancer [ASMR: 3.40 (95% UI: 2.90-3.81)/100,000 people and ASDR: 107.2 (95% UI: 90.52-119.43)/100,000 people] and sexually transmitted infections excluding HIV [ASMR: 0.10 (95% UI: 0.08-0.11)/100,000 people and ASDR: 16.14 (95% UI: 10.51-25.83)/100,000 people]. The death and DALY burden caused by these three diseases were more serious in the over 75 years old age group. The 40-44 age group for men and the 35-39 age group for women had the highest population of unsafe sex-related deaths and DALYs, respectively. In addition, the burden of unsafe sex in women was more serious than those in men. Unsafe sex is an important risk factor for global disease burden and a leading cause of substantial health loss. We found that the risk of ASMRs and ASDRs attributable to unsafe sex had negative correlation with SDI levels. These results demonstrate that the need for revised policies that focus on efforts to reduce overall unsafe sex worldwide.

Feasibility and safety of Post-Urgent PCI Same-DaY discharge (PUSDY Trial) in China: protocol for a multicentre randomised controlled trial.

INTRODUCTION: In the Chinese healthcare system, where there is overcrowding in hospitals, especially in tertiary care centres, adoption of same-day discharge (SDD) post-percutaneous coronary intervention (PCI) could potentially lead to significant savings of healthcare resources and costs. This study is a non-inferiority trial examining whether post-PCI SDD is feasible in China. The primary hypothesis is that patient outcomes in post-urgent PCI SDD patients are non-inferior to regular discharge patients. METHODS AND ANALYSIS: Post-Urgent PCI Same-DaY is an investigator-initiated multicentre randomised unblinded clinical non-inferiority trial, with 1:1 centralised randomisation to the SDD or usual care (UC) group. Based on sample size calculations, 1296 patients from at least three hospitals, with mild to moderate myocardial infarction, will be included, and acute coronary syndrome patients will be excluded. All patients will receive UC while patients assigned to the SDD group will be discharged on the same day or within 12 hours post-PCI. The primary outcome is major adverse cardiovascular and cerebrovascular events 30 days after discharge. The secondary outcomes are all-cause mortality, bleeding and access site complications. The outcome rates will be compared between groups with the absolute risk difference with a 95% CI. ETHICS AND DISSEMINATION: The study protocol V.2.0 has been approved on 21 January 2022 by the Ethics Committee of Beijing Anzhen Hospital, Capital Medical University (approval number: 2021 KLSD No. 23). The outcomes of this study will be disseminated through a peer-reviewed journal and presented at international conferences. TRIAL REGISTRATION NUMBER: ChiCTR 2200057065; China Clinical Trial Registration.

Integrated Optimal Control for Electrolyte Temperature With Temporal Causal Network and Reinforcement Learning.

The electrowinning process is a critical operation in nonferrous hydrometallurgy and consumes large quantities of power consumption. Current efficiency is an important process index related to power consumption, and it is vital to operate the electrolyte temperature close to the optimum point to ensure high current efficiency. However, the optimal control of electrolyte temperature faces the following challenges. First, the temporal causal relationship between process variables and current efficiency makes it difficult to estimate the current efficiency accurately and set the optimal electrolyte temperature. Second, the substantial fluctuation of influencing variables of electrolyte temperature leads to difficulty in maintaining the electrolyte temperature close to the optimum point. Third, due to the complex mechanism, building a dynamic electrowinning process model is intractable. Hence, it is a problem of index optimal control in the multivariable fluctuation scenario without process modeling. To get around this issue, an integrated optimal control method based on temporal causal network and reinforcement learning (RL) is proposed. First, the working conditions are divided and the temporal causal network is used to estimate current efficiency accurately to solve the optimal electrolyte temperature under multiple working conditions. Then, an RL controller is established under each working condition, and the optimal electrolyte temperature is placed into the controller's reward function to assist in control strategy learning. An experiment case study of the zinc electrowinning process is provided to verify the effectiveness of the proposed method and to show that it can stabilize the electrolyte temperature within the optimal range without modeling.