GSDMD protects intestinal epithelial cells against bacterial infections through its N-terminal activity impacting intestinal immune homeostasis.

The intestinal mucosal barrier serves as a vital guardian for gut health, maintaining a delicate equilibrium between gut microbiota and host immune homeostasis. Recent studies have found the intricate roles of Gasdermin D (GSDMD), a key executioner of pyroptosis downstream of the inflammasome, within the intestine, including controlling colitis in intestinal macrophage and the regulatory function in goblet cell mucus secretion. Thus, the exact role and nature of GSDMD's regulatory function in maintaining intestinal immune homeostasis and defending against pathogens remain elucidation. Here, we uncover that GSDMD plays a key role in defending against intestinal Citrobacter rodentium infection, with high expression in intestinal epithelial and lamina propria myeloid cells. Our results show that GSDMD specifically acts in intestinal epithelial cells to fight the infection, independently of its effects on antimicrobial peptides or mucin secretion. Instead, the resistance is mediated through GSDMD's N-terminal fragments, highlighting its importance in intestinal immunity. However, the specific underlying mechanism of GSDMD N-terminal activity in protection against intestinal bacterial infections still needs further study to clarify in the future.

Access to Urgent Care Practices Improves Understanding and Management of Endemic Coccidioidomycosis: Maricopa County, Arizona, 2018-2023.

BACKGROUND: Coccidioidomycosis within endemic regions is often undiagnosed because appropriate testing is not performed. A dashboard was developed to provide information about the prevalence of coccidioidomycosis throughout the year. METHODS: Banner Urgent Care Service has many clinics within Maricopa County, Arizona, a highly endemic region for coccidioidomycosis. All clinic visits and subset analyses for patients with ICD10 codes for pneumonia (J18.*) or erythema nodosum (L52) between 2018-2024 were included. Tabulated were daily frequencies of visits, pneumonia and erythema nodosum coding, coccidioidal testing, and test results. Banner Urgent Care Services' counts of monthly coccidioidomycosis diagnoses were compared to those of confirmed coccidioidomycosis cases reported to Maricopa County Department of Public Health. RESULTS: Monthly frequencies of urgent care coccidioidomycosis diagnoses strongly correlated with public health coccidioidomycosis case counts (r=0.86). Testing frequency for coccidioidomycosis correlated with overall pneumonia frequency (r=0.52). The proportion of pneumonia due to coccidioidomycosis varied between <5% and greater than 45% within and between years. Coccidioidomycosis was a common cause of erythema nodosum (65%, 95% confidence: 45%-67%) and independent of pneumonia. Over half of Banner Urgent Care Services' coccidioidomycosis diagnoses were coded for neither pneumonia nor erythema nodosum. CONCLUSION: Data provided by the coccidioidomycosis dashboard can assist urgent care practitioners in knowing when coccidioidomycosis is prevalent in the community. Patients with exposure to endemic coccidioidomycosis who develop erythema nodosum or pneumonia should routinely be tested for coccidioidomycosis. Data from private healthcare organizations can augment surveillance of diseases important to public health.

Two-dimensional Mo1-xB2 with ordered metal vacancies obtained for advanced thermoelectric applications based on first-principles calculations.

The study and development of high thermoelectric properties is crucial for the next generation of microelectronic and wearable electronics. Derived from the recent experimental realization of layers of transition metal molybdenum and boride, we report the theoretical realization of advanced thermoelectric properties in two-dimensional (2D) transition metal boride Mo1-xB2 (x = 0, 0.05, 0.10, 0.125, 0.15)-based defect sheets. The introduction of metal vacancies results in stronger d-p exchange interactions and hybridization between the Mo-d and B-p atoms. Meanwhile, the ordered metal vacancies enabled transition metal borides (n-type Mo0.9B2) to widen the d-bandwidth and raise the d-band center, leading to a relatively high carrier mobility of 3262 cm2 V-1 s-1 and conductivity twice that of a bug-free n-type MoB2 layer, which indicates that it presents good electronic and thermal transport properties. Furthermore, investigations of the thermoelectric performance exhibit a maximum ZT of up to 3.29, which is superior to those of currently reported 2D materials. Modulation by defect engineering suggests that 2D transition metal boride sheets with ordered metal vacancies have promising applications in microelectronics, wearable electronics and thermoelectric devices.

Assessment of CYP-Mediated Drug Interactions for Enasidenib Based on a Cocktail Study in Patients with Relapse or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome.

As a selective and potent inhibitor targeting the isocitrate dehydrogenase-2 (IDH2) mutant protein, enasidenib obtained approval from the US Food and Drug Administration (FDA) in 2017 for adult patients with acute myeloid leukemia (AML) with an IDH2 mutation. In vitro investigations demonstrated that enasidenib affects various drug metabolic enzymes and transporters. This current investigation aimed to assess enasidenib on the pharmacokinetics (PKs) of CYP substrates, including dextromethorphan (CYP2D6 probe drug), flurbiprofen (CYP2C9 probe drug), midazolam (CYP3A4 probe drug), omeprazole (CYP2C19 probe drug), and pioglitazone (CYP2C8 probe drug), in patients with AML or myelodysplastic syndrome. Results showed that following the co-administration of enasidenib (100 mg, once daily) for 28 days, the PK parameters AUC(0-∞) and Cmax of dextromethorphan increased by 1.37 (90% confidence interval (CI): 0.96, 1.96) and 1.24 (90% CI: 0.94, 1.65)-fold, respectively, compared to dextromethorphan alone. For flurbiprofen, these parameters increased by 1.14 (90%CI: 1.01, 1.29) and 0.97 (90% CI 0.86, 1.08)-fold, respectively, when compared to flurbiprofen alone. Conversely, midazolam exhibited decreases to 0.57 (90% CI 0.34, 0.97) and 0.77 (90% CI 0.39, 1.53)-fold, respectively, in comparison to midazolam alone. The parameters for omeprazole increased by 1.86 (90% CI: 1.33, 2.60) and 1.47 (0.93, 2.31)-fold, respectively, compared to omeprazole alone, while those for pioglitazone decreased to 0.80 (90% CI: 0.62, 1.03) and 0.87 (90% CI: 0.65, 1.16)-fold, respectively, in comparison to pioglitazone alone. These findings provide valuable insights into dose recommendations concerning drugs acting as substrates of CYP2D6, CYP2C9, CYP3A4, CYP2C19, and CYP2C8 when administered concurrently with enasidenib.

Gender differences in all-cause and cardiovascular mortality among US adults: from NHANES 2005-2018.

Background: Gender disparities in mortality have drawn great interest, with previous studies identifying various biological, social, and behavioral factors contributing to the observed gender differences. This study aims to identify the sources of gender disparities in mortality rates and quantify the extent to which these factors mediate the gender differences in all-cause mortality. Methods: Data from the National Health and Nutrition Examination Survey (NHANES) conducted between 2005 and 2018 were analyzed. A total of 38,924 participants were included in the study. Gender information, socioeconomic status, lifestyle factors, and baseline disease status were obtained through questionnaires. Blood samples were collected to assess serological indicators. All-cause and cardiovascular mortality were considered as primary and secondary outcomes, respectively. Results: The study with an average age of 50.1 ± 17.9 years. Among the participants, 50.7% were women, and 41.8% were non-Hispanic White. The median follow-up length was 87 months [Inter-Quartile Range (IQR): 47-128]. Men showed higher rates of all-cause and cardiovascular mortality compared to women in both the general population and the population with cardiovascular disease. After adjustment for potential confounders (age, race, marital status, socioeconomic status, lifestyle level, smoking status, cardiovascular disease, hypertension, diabetes and cancer), the men: women hazard ratios (HRs) for all-cause and cardiovascular mortality were 1.58 [95% Confidence Interval (CI): 1.48-1.68] and 1.60 (95%CI:1.43-1.80) in the general population. Among individuals with cardiovascular disease, the fully adjusted HR for all-cause mortality was 1.34 (95% CI: 1.20 to 1.51), and for cardiovascular mortality, the fully adjusted HRs was 1.52 (95% CI: 1.26 to 1.83). Mediation analysis revealed that uric acid levels significantly mediated the association between gender and all-cause mortality, accounting for 17.53% (95% CI: 11.0% to 23.7%) in the general population and 27.47% (95% CI: 9.0% to 13.6%) in the population with cardiovascular disease. Conclusions: The study highlights the complex interplay of biological and social factors contributing to gender disparities in mortality. Uric acid was identified as key mediators of the gender-mortality association. These findings can inform targeted interventions aimed at reducing gender disparities in mortality and promoting better public health outcomes.

Integrative Analyses of Tumor and Peripheral Biomarkers in the Treatment of Advanced Renal Cell Carcinoma.

The phase III JAVELIN Renal 101 trial demonstrated prolonged progression-free survival (PFS) in patients (N = 886) with advanced renal cell carcinoma treated with first-line avelumab + axitinib (A+Ax) versus sunitinib. We report novel findings from integrated analyses of longitudinal blood samples and baseline tumor tissue. PFS was associated with elevated lymphocyte levels in the sunitinib arm and an abundance of innate immune subsets in the A+Ax arm. Treatment with A+Ax led to greater T-cell repertoire modulation and less change in T-cell numbers versus sunitinib. In the A+Ax arm, patients with tumors harboring mutations in ≥2 of 10 previously identified PFS-associated genes (double mutants) had distinct circulating and tumor-infiltrating immunologic profiles versus those with wild-type or single-mutant tumors, suggesting a role for non-T-cell-mediated and non-natural killer cell-mediated mechanisms in double-mutant tumors. We provide evidence for different immunomodulatory mechanisms based on treatment (A+Ax vs. sunitinib) and tumor molecular subtypes. SIGNIFICANCE: Our findings provide novel insights into the different immunomodulatory mechanisms governing responses in patients treated with avelumab (PD-L1 inhibitor) + axitinib or sunitinib (both VEGF inhibitors), highlighting the contribution of tumor biology to the complexity of the roles and interactions of infiltrating immune cells in response to these treatment regimens. This article is featured in Selected Articles from This Issue, p. 384.

The 50% and 95% effective dose of remimazolam tosilate for anaesthesia induction in sleep disorders patients undergoing laparoscopic cholecystectomy: an up-and-down sequential allocation trial.

PURPOSE: Previous reports argue that preoperative sleep conditions of patients can influence the dosage of general anaesthesia drugs. Therefore, we aimed to investigate the dose-effect relationship of preoperative sleep disorders on the induction of general anaesthesia with remimazolam tosilate and calculate the Median effective (ED50) and 95% effective (ED95) dosages. METHODS: Included in our study were 56 patients who underwent laparoscopic cholecystectomy at our hospital. A separate group of 27 patients with sleep disorders (SD group) and 29 patients without sleep disorders (NSD group) using the Pittsburgh Sleep Quality Index (PSQI) were also included. According to the Dixon 'up-and-down' design, patients received remimazolam at preselected concentrations starting at 0.2 mg/kg. After the administration of remimazolam, loss of consciousness was observed. By observing whether consciousness disappeared within a minute, we adjusted the dose of remimazolam by 0.1 mg/kg (up and down) in the following patient. The Median effective dose (ED50), 95% effective dose (ED95), and 95% confidence interval (CI) of remimazolam for effective sedation were calculated. RESULTS: The ED50 of remimazolam was 0.226 mg/kg (95%CI 0.221-0.232 mg/kg) in the SD group and 0.191 mg/kg (95%CI, 0.183-0.199 mg/kg) in the NSD group. The ED95 of remimazolam was 0.237 mg/kg (95%CI 0.231-0.262 mg/kg) in the SD group and 0.209 mg/kg (95%CI 0.200-0.254 mg/kg) in the NSD group. CONCLUSIONS: In the SD group, the ED50 and ED95 of remimazolam during anaesthesia induction were 0.226 and 0.237 mg/kg, respectively. The induction dose of remimazolam in the SD group was significantly higher than that in the NSD group.

Bio-Inspired Trace Hydroxyl-Rich Electrolyte Additives for High-Rate and Stable Zn-Ion Batteries at Low Temperatures.

High-rate and stable Zn-ion batteries working at low temperatures are highly desirable for practical applications, but are challenged by sluggish kinetics and severe corrosion. Herein, inspired by frost-resistant plants, we report trace hydroxyl-rich electrolyte additives that implement a dual remodeling effect for high-performance low-temperature Zn-ion batteries. The additive with high Zn absorbability not only remodels Zn2+ primary solvent shell by alternating H2 O molecules, but also forms a shielding layer thus remodeling the Zn surface, which effectively enhances fast Zn2+ de-solvation reaction kinetics and prohibits Zn anode corrosion. Taking trace α-D-glucose (αDG) as a demonstration, the electrolyte obtains a low freezing point of -55.3 °C, and the Zn//Zn cell can stably cycle for 2000 h at 5 mA cm-2 under -25 °C, with a high cumulative capacity of 5000 mAh cm-2 . A full battery that stably operates for 10000 cycles at -50 °C is also demonstrated.

Liquid Metal-Based Stable and Stretchable Zn-Ion Battery for Electronic Textiles.

Electronic textiles harmoniously interact with the human body and the surrounding environment, offering tremendous interest in smart wearable electronics. However, their wide application faces challenges due to the lack of stable and stretchable power electrodes/devices with multifunctional design. Herein, an intrinsically stretchable liquid metal-based fibrous anode for a stable Zn-ion battery (ZIB) is reported. Benefiting from the liquid feature and superior deformability of the liquid metal, optimized Zn ion concentration distribution and Zn (002) deposition behavior are observed, which result in dendrite-free performance even under stretching. With a strain of 50%, the ZIB maintains a high capacity of 139.8 mAh cm-3 (corresponding to 83.0% of the initial value) after 300 cycles, outperforming bare Zn fiber-based ZIB. The fibrous ZIB seamlessly integrates with the sensor, Joule heater, and wirelessly charging device, which provides a stable power supply for human signal monitoring and personal thermal management, holding promise for the application of wearable multifunctional electronic textiles.

Sphere-Confined Reversible Zn Deposition for Stable Alkaline Aqueous Batteries.

The practical applications of alkaline zinc-based batteries are challenged by poor rechargeability with an insufficient zinc utilization ratio. Herein, a sphere-confined reversible zinc deposition behavior from a free-standing Zn anode is reported, which is composed of bi-continuous ZnO-protected interconnected and hollowed Zn microspheres by the Kirkendall effect. The cross-linked Zn network with in situ formed outer ZnO shell and inner hollow space not only inhibits side reactions but also ensures long-range conductivity and accommodates shape change, which induces preferential reversible zinc dissolution-deposition process in the inner space and maintains structural integrity even under high zinc utilization ratio. As a result, the Zn electrode can be stably cycled for 390 h at a high current density of 20 mA cm-2 (60% depth of discharge), outperforming previously reported alkaline Zn anodes. A stable zinc-nickel oxide hydroxide battery with a high cumulative capacity of 8532 mAh cm-2 at 60% depth of discharge is also demonstrated.

A Point-of-Care Testing Device Utilizing Graphene-Enhanced Fiber Optic SPR Sensor for Real-Time Detection of Infectious Pathogens.

Timely detection of highly infectious pathogens is essential for preventing and controlling public health risks. However, most traditional testing instruments require multiple tedious steps and ultimately testing in hospitals and third-party laboratories. The sample transfer process significantly prolongs the time to obtain test results. To tackle this aspect, a portable fiber optic surface plasmon resonance (FO-SPR) device was developed for the real-time detection of infectious pathogens. The portable device innovatively integrated a compact FO-SPR sensing component, a signal acquisition and processing system, and an embedded power supply unit. A gold-plated fiber is used as the FO-SPR sensing probe. Compared with traditional SPR sensing systems, the device is smaller size, lighter weight, and higher convenience. To enhance the detection capacity of pathogens, a monolayer graphene was coated on the sensing region of the FO-SPR sensing probe. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was used to evaluate the performance of the portable device. The device can accurately detect the SARS-CoV-2 spike S1 protein in phosphate-buffered saline (PBS) and artificial saliva within just 20 min, and the device successfully detected cultured SARS-CoV-2 virus. Furthermore, the FO-SPR probe has long-term stability, remaining stable for up to 8 days. It could distinguish between the SARS-CoV-2 spike protein and the MERS-CoV spike protein. Hence, this FO-SPR device provides reliable, rapid, and portable access to test results. It provides a promising point-of-care testing (POCT) tool for on-site screening of infectious pathogens.

Application of statistical machine learning in biomarker selection.

In the recent JAVELIN Bladder 100 phase 3 trial, avelumab plus best supportive care significantly prolonged overall survival relative to best supportive care alone as first-line maintenance therapy following first-line platinum-based chemotherapy in patients with advanced urothelial cancer (aUC). Discovering biomarkers using genomic profiling to understand potential patient heterogeneity is essential to help improve patient care with precision medicine. For the JAVELIN Bladder 100 trial, it is unclear which variable selection methods can most reliably identify biomarkers to inform patient care because the dataset is characterized by high collinearity and low signal. The aim of this paper was to evaluate available selection methods and their ability to discover prognostic and predictive biomarkers in patients with aUC receiving first-line maintenance therapy. A simulation study evaluated the performance of popular variable selection approaches for high-dimensional data, including penalized regression models, random survival forests, and Bayesian variable selection methods. For Bayesian variable selection methods, a modified Bayesian Information Criterion (BIC) thresholding rule was proposed in addition to the traditional BIC thresholding rule. These methods were applied to the JAVELIN Bladder 100 dataset to investigate potential biomarkers associated with survival benefit. Results from the simulations demonstrated the strengths and limitations of the different methods. The variable selection methods demonstrated low false discovery rates under different conditions. However, their performance declined in the presence of high collinearity. Using the JAVELIN Bladder 100 data, we identified some potentially significant biomarkers across multiple models. Several lasso-related methods were able to identify potentially biologically meaningful variables in the trial. Some variable selection methods (such as stochastic search variable selection and random survival forest) may not be well suited to this type of data due to the presence of extreme collinearity and low signal. Future research should explore novel variable selection methods that may be more suitable for identifying prognostic and predictive biomarkers in this population.Trial registration: ClinicalTrials.gov Identifier: NCT02603432.

RBM25 regulates hypoxic cardiomyocyte apoptosis through CHOP-associated endoplasmic reticulum stress.

Ischemic heart failure (HF) is one of the leading causes of global morbidity and mortality; blocking the apoptotic cascade could help improve adverse outcomes of it. RNA-binding motif protein 25 (RBM25) is an RNA-binding protein related to apoptosis; however, its role remains unknown in ischemic HF. The main purpose of this study is to explore the mechanism of RBM25 in ischemic HF. Establishing an ischemic HF model and oxygen-glucose deprivation (OGD) model. ELISA was performed to evaluate the BNP level in the ischemic HF model. Echocardiography and histological analysis were performed to assess cardiac function and infarct size. Proteins were quantitatively and locationally analyzed by western blotting and immunofluorescence. The morphological changes of endoplasmic reticulum (ER) were observed with ER-tracker. Cardiac function and myocardial injury were observed in ischemic HF rats. RBM25 was elevated in cardiomyocytes of hypoxia injury hearts and localized in nucleus both in vitro and in vivo. In addition, cell apoptosis was significantly increased when overexpressed RBM25. Moreover, ER stress stimulated upregulation of RBM25 and promoted cell apoptosis through the CHOP related pathway. Finally, inhibiting the expression of RBM25 could ameliorate the apoptosis and improve cardiac function through blocking the activation of CHOP signaling pathway. RBM25 is significantly upregulated in ischemic HF rat heart and OGD model, which leads to apoptosis by modulating the ER stress through CHOP pathway. Knockdown of RBM25 could reverse apoptosis-mediated cardiac dysfunction. RBM25 may be a promising target for the treatment of ischemic HF.

Association between life's essential 8 and biological ageing among US adults.

BACKGROUND: Biological ageing is tightly linked to cardiovascular disease (CVD). We aimed to investigate the relationship between Life's Essential 8 (LE8), a currently updated measure of cardiovascular health (CVH), and biological ageing. METHODS: This cross-sectional study selected adults ≥ 20 years of age from the 2005-2010 National Health and Nutrition Examination Survey. LE8 scores (range 0-100) were obtained from measurements based on American Heart Association definitions, divided into health behavior and health factor scores. Biological ageing was assessed by different methods including phenotypic age, phenotypic age acceleration (PhenoAgeAccel), biological age and biological age acceleration (BioAgeAccel). Correlations were analyzed by weighted linear regression and restricted cubic spline models. RESULTS: Of the 11,729 participants included, the mean age was 47.41 ± 0.36 years and 5983 (51.01%) were female. The mean phenotypic and biological ages were 42.96 ± 0.41 and 46.75 ± 0.39 years, respectively, and the mean LE8 score was 67.71 ± 0.35. After adjusting for potential confounders, higher LE8 scores were associated with lower phenotypic age, biological age, PhenoAgeAccel, and BioAgeAccel, with nonlinear dose-response relationships. Negative associations were also found between health behavior and health factor scores and biological ageing, and were stronger for health factors. In health factor-specific analyses, the ß negativity was greater for blood glucose and blood pressure. The inverse correlations of LE8 scores with phenotypic age and biological age in the stratified analyses remained solid across strata. CONCLUSIONS: LE8 and its subscale scores were strongly negatively related to biological ageing. Encouraging optimal CVH levels may be advantageous in preventing and slowing down ageing.

Understanding the Excited-State Relaxation Mechanisms of Xanthophyll Lutein by Multi-configurational Electronic Structure Calculations.

The contradictory behaviors in light harvesting and non-photochemical quenching make xanthophyll lutein the most attractive functional molecule in photosynthesis. Despite several theoretical simulations on the spectral properties and excited-state dynamics, the atomic-level photophysical mechanisms need to be further studied and established, especially for an accurate description of geometric and electronic structures of conical intersections for the lowest several electronic states of lutein. In the present work, semiempirical OM2/MRCI and multi-configurational restricted active space self-consistent field methods were performed to optimize the minima and conical intersections in and between the 1Ag-, 2Ag-, 1Bu+, and 1Bu- states. Meanwhile, the relative energies were refined by MS-CASPT2(10,8)/6-31G*, which can reproduce correct electronic state properties as those in the spectroscopic experiments. Based on the above calculation results, we proposed a possible excited-state relaxation mechanism for lutein from its initially populated 1Bu+ state. Once excited to the optically bright 1Bu+ state, the system will propagate along the key reaction coordinate, i.e., the stretching vibration of the conjugated carbon chain. During this period of time, the 1Bu- state will participate in and forms a resonance state between the 1Bu- and 1Bu+ states. Later, the system will rapidly hop to the 2Ag- state via the 1Bu+/2Ag- conical intersection. Finally, the lutein molecule will survive in the 2Ag- state for a relatively long time before it internally converts to the ground state directly or via a twisted S1/S0 conical intersection. Notably, though the photophysical picture may be very different in solvents and proteins, the current theoretical study proposed a promising calculation protocol and also provided many valuable mechanistic insights for lutein and similar carotenoids.

Delayed intubation associated with in-hospital mortality in patients with COVID-19 respiratory failure who fail heated and humified high flow nasal canula.

BACKGROUND: Advanced respiratory support modalities such as non-invasive positive pressure ventilation (NiPPV) and heated and humidified high flow nasal canula (HFNC) served as useful alternatives to invasive mechanical ventilatory support for acute respiratory failure (ARF) during the peak of the SARS-CoV-2/COVID-19 pandemic. Unlike NiPPV, HFNC is a newer modality and its role in the treatment of patients with severe ARF is not yet clearly defined. Furthermore, the characteristics of responders versus non-responders to HFNC have not been determined. Although recent evidence indicates that many patients with ARF treated with HFNC survive without needing intubation, those who fail and are subsequently intubated have worse outcomes. Given that prolonged use of HFNC in patients with ARF might exacerbate patient self-inflicted lung injury, we hypothesized that among those patients with ARF due to COVID-19 pneumonia, prolonged HFNC beyond 24 h before intubation would be associated with increased in-hospital mortality. METHODS: This was a retrospective, multicenter, observational cohort study of 2720 patients treated for ARF secondary to SARS-CoV-2/COVID-19 pneumonia and initially managed with HFNC within the Banner Health system during the period from March 1st, 2020, to July 31st, 2021. In the subgroup of patients for went from HFNC to IMV, we assessed the effect of the duration of HFNC prior to intubation on mortality. RESULTS: 1392 (51%) were successfully treated with HFNC alone and 1328 (49%) failed HFNC and were intubated (HFNC to IMV). When adjusted for the covariates, HFNC duration less than 24 h prior to intubation was significantly associated with reduced mortality. CONCLUSIONS: Among patients with ARF due to COVID-19 pneumonia who fail HFNC, delay of intubation beyond 24 h is associated with increased mortality.

[Nursery Services for Children Under 3 in Sichuan Province].

Objective: To study the current status of nursery services for children under 3 in Sichuan Province, to analyze the problems and causes, and to provide policy recommendations for the high-quality development of nursery services in Sichuan Province for children under the age of 3. Methods: Using a combination of qualitative and quantitative methods, we analyzed the current status of nursery services in Sichuan Province and the problems encountered in the development of nursery services in Sichuan Province by collecting information on relevant government policies of Sichuan and the status quo of nursery services for children under 3 in the 21 cities/prefectures of Sichuan through policy research, interviews conducted at nursery service institutions, questionnaire surveys, and expert panel discussions. Results: The supply of nursery services, or nursery enrollment capacity, in Sichuan Province reached 3 nursery enrollment opportunities per thousand people, with the enrollment utilization rate reaching 48.2%. Among all the nursery service institutions in the province, 55.4% were concentrated in the Chengdu, Mianyang, and Meishan regions. There were 1667 pilot nursery service institutions providing government-subsidized affordable nursery services and supplying 72971 subsidized affordable enrollment opportunities, accounting for 28.7% of the total number of all nursery service institutions and 29.1% of their total enrollment. There were a total of 37995 nursery service professionals, including 28468 caregivers (including teachers), with an average of 6 employees per institution and 5 caregivers per institution. 49.6% of the nursery service institutions hired healthcare workers on a part-time basis and 11.3% of them did not have healthcare workers on their staffs. Conclusion: Nursery services for children under 3 years old have developed rapidly in Sichuan Province, but there are a number of problems, including uneven distribution of resources in different regions, inadequate supply of government-subsidized affordable nursery services, mismatch between supply and demand, insufficient utilization of services, lack of professionals, and insufficient driving force for sustainable development in the industry. We have suggested that actions be taken to improve the policy and regulatory system for nursery services, actively develop care facilites that are government-subsidized affordable services, integrated daycare service for all preschool children, and integrated medical and education facilites, provide support for home care, establish an information system for nursery services, optimize the professional training and development system, strengthen scientific research and international exchanges on nursery services, and comprehensively promote the high-quality development of nursery services and the construction of a childrearing-friendly environment in Sichuan Province.

Updates on global epidemiology, risk and prognostic factors of gastric cancer.

Gastric cancer (GC) is defined as the primary epithelial malignancy derived from the stomach, and it is a complicated and heterogeneous disease with multiple risk factors. Despite its overall declining trend of incidence and mortality in various countries over the past few decades, GC remains the fifth most common malignancy and the fourth leading cause of cancer-related death globally. Although the global burden of GC has shown a significant downward trend, it remains severe in certain areas, such as Asia. GC ranks third in incidence and mortality among all cancer types in China, and it accounts for nearly 44.0% and 48.6% of new GC cases and GC-related deaths in the world, respectively. The regional differences in GC incidence and mortality are obvious, and annual new cases and deaths are increasing rapidly in some developing regions. Therefore, early preventive and screening strategies for GC are urgently needed. The clinical efficacies of conventional treatments for GC are limited, and the developing understanding of GC pathogenesis has increased the demand for new therapeutic regimens, including immune checkpoint inhibitors, cell immunotherapy and cancer vaccines. The present review describes the epidemiology of GC worldwide, especially in China, summarizes its risk and prognostic factors, and focuses on novel immunotherapies to develop therapeutic strategies for the management of GC patients.

SH3BP1 Regulates Melanoma Progression Through Race1/Wace2 Signaling Pathway.

Background: SH3-domain binding protein-1 (SH3BP1), which specifically inactivates Rac1 and its target protein Wave2, has been shown to be an important regulator of cancer metastasis. However, the effects of SH3BP1 in melanoma progression remain unclear. The current study aimed to explore the function of SH3BP1 in melanoma and its possible molecular mechanism. Methods: TCGA database was used to analyze the expression of SH3BP1 in melanoma. Then, reverse transcription-quantitative polymerase chain reaction was performed to detect the expression of SH3BP1 in melanoma tissues and cells. Next, genes related to SH3BP1 were analyzed by LinkedOmics database, and protein interactions were analyzed by STRING database. These genes were further subjected to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis. In addition, the signaling pathway of SH3BP1 action was screened by bioinformatics analysis. Finally, the function of SH3BP1 and its mediated signaling pathway in melanoma progression were investigated in vitro and in vivo. Results: SH3BP1 was significantly upregulated in melanoma tissues and cells. The pathways regulated by SH3BP1 are closely related to the occurrence and development of tumors. And we found that overexpression of SH3BP1 promoted the proliferation, migration, and invasion of melanoma cells by increasing Rac1 activity and Wave2 protein levels in vitro. Similarly, overexpression of SH3BP1 facilitated melanoma progression by upregulating Wave2 protein expression in vivo. Conclusion: In summary, this study revealed for the first time that SH3BP1 promoted melanoma progression through Rac1/Wave2 signaling pathway, providing a new therapeutic target for melanoma.