KDM6A-SND1 interaction maintains genomic stability by protecting the nascent DNA and contributes to cancer chemoresistance.

Genomic instability is one of the hallmarks of cancer. While loss of histone demethylase KDM6A increases the risk of tumorigenesis, its specific role in maintaining genomic stability remains poorly understood. Here, we propose a mechanism in which KDM6A maintains genomic stability independently on its demethylase activity. This occurs through its interaction with SND1, resulting in the establishment of a protective chromatin state that prevents replication fork collapse by recruiting of RPA and Ku70 to nascent DNA strand. Notably, KDM6A-SND1 interaction is up-regulated by KDM6A SUMOylation, while KDM6AK90A mutation almost abolish the interaction. Loss of KDM6A or SND1 leads to increased enrichment of H3K9ac and H4K8ac but attenuates the enrichment of Ku70 and H3K4me3 at nascent DNA strand. This subsequently results in enhanced cellular sensitivity to genotoxins and genomic instability. Consistent with these findings, knockdown of KDM6A and SND1 in esophageal squamous cell carcinoma (ESCC) cells increases genotoxin sensitivity. Intriguingly, KDM6A H101D & P110S, N1156T and D1216N mutations identified in ESCC patients promote genotoxin resistance via increased SND1 association. Our finding provides novel insights into the pivotal role of KDM6A-SND1 in genomic stability and chemoresistance, implying that targeting KDM6A and/or its interaction with SND1 may be a promising strategy to overcome the chemoresistance.

CAFs-derived exosomes promote the development of cervical cancer by regulating miR-18a-5p-TMEM170B signaling axis.

Mounting studies have showed that tumor microenvironment (TME) is crucial for cervical cancer (CC), and cancer-related fibroblasts (CAFs) play a major role in it. Recently, exosomal miRNAs secreted by CAFs have been found to be potential targets for cancer diagnosis and therapy. In this paper, we aimed to investigate the function of CAFs-mediated exosome miR-18a-5p (CAFs-exo-miR-18a-5p) in CC. First, in combination with bioinformatic data analysis of the GEO database (GSE86100) and RT-qPCR of CC clinical tissue samples and cell lines, miR-18a-5p was discovered to be markedly up-regulated in CC. Next, CAFs-secreted exosomes were isolated and it was found that miR-18a-5p expression was dramatically promoted in CC cell lines when treated with CAFs-exos. The CAFs-exo-miR-18a-5p was then elucidated to stimulate the proliferation and migration and inhibit the apoptosis of CC cells. In order to clarify the underlying mechanism, we further screened the target genes of miR-18a-5p. TMEM170B was selected by bioinformatic data analysis of online databases combined with RT-qPCR of CC clinical tissues and cells. Luciferase reporter gene analysis combined with molecular biology experiments further elucidated that miR-18a-5p suppressed TMEM170B expression in CC. Finally, both cell and animal experiments demonstrated that TMEM170B over-expression attenuated the oncogenic effect of CAFs-exo-miR-18a-5p. In conclusion, our study indicates that CAFs-mediated exosome miR-18a-5p promotes the initiation and development of CC by suppressing TMEM170B signaling axis, which provides a possible direction for the diagnosis and therapy of CC.

Editing of ORF138 restores fertility of Ogura cytoplasmic male sterile broccoli via mitoTALENs.

Cytoplasmic male sterility (CMS), encoded by the mitochondrial open reading frames (ORFs), has long been used to economically produce crop hybrids. However, the utilization of CMS also hinders the exploitation of sterility and fertility variation in the absence of a restorer line, which in turn narrows the genetic background and reduces biodiversity. Here, we used a mitochondrial targeted transcription activator-like effector nuclease (mitoTALENs) to knock out ORF138 from the Ogura CMS broccoli hybrid. The knockout was confirmed by the amplification and re-sequencing read mapping to the mitochondrial genome. As a result, knockout of ORF138 restored the fertility of the CMS hybrid, and simultaneously manifested a cold-sensitive male sterility. ORF138 depletion is stably inherited to the next generation, allowing for direct use in the breeding process. In addition, we proposed a highly reliable and cost-effective toolkit to accelerate the life cycle of fertile lines from CMS-derived broccoli hybrids. By applying the k-mean clustering and interaction network analysis, we identified the central gene networks involved in the fertility restoration and cold-sensitive male sterility. Our study enables mitochondrial genome editing via mitoTALENs in Brassicaceae vegetable crops and provides evidence that the sex production machinery and its temperature-responsive ability are regulated by the mitochondria.

A Network Meta-Analysis of the Systemic Therapies in Unresectable Head and Neck Squamous Cell Carcinoma.

The current standard treatment for locally advanced squamous cell carcinoma of the head and neck (LASCCHN) comprises concurrent radiotherapy (CRT) alongside platinum-based chemotherapy. However, innovative therapeutic alternatives are being evaluated in phase II/III randomized trials. This study employed a Bayesian network meta-analysis (NMA) using fixed effects to provide both direct and indirect comparisons of all existing treatment modalities for unresectable LASCCHN. METHODS: We referenced randomized controlled trials (RCTs) from January 2000 to July 2023 by extensively reviewing PubMed, EMBASE, and Web of Science databases, adhering to the Cochrane methodology. Relevant data, including summary estimates of overall survival (OS) and progression-free survival (PFS), were extracted from these selected studies and recorded in a predefined database sheet. Subsequently, we conducted a random effects network meta-analysis using a Bayesian framework. RESULTS: Based on the Surface Under the Cumulative Ranking (SUCRA) values, the league table organizes the various treatments for OS in the following order: IC + RT&MTT, MTT-CRT, IC + CRT&MTT, CRT, IC + CRT, MTT-RT, IC + MTT-RT, and RT. In a similar order, the treatments rank as follows according to the league table: IC + CRT&MTT, MTT-CRT, IC + CRT, IC + RT&MTT, CRT, IC + MTT-RT, MTT-RT, and RT. Notably, none of these treatments showed significant advantages over concurrent chemoradiotherapy. CONCLUSION: Despite concurrent chemoradiotherapy being the prevailing treatment for LASCCHN, our findings suggest the potential for improved outcomes when concurrent chemoradiotherapy is combined with targeted therapy or induction chemotherapy.

The current standard treatment for advanced head and neck cancer involves combining radiation therapy with chemotherapy. However, there are ongoing trials exploring alternative therapies. In this study, we conducted a comprehensive analysis of existing treatments using a statistical method called network meta-analysis. Our analysis included data from randomized controlled trials published between January 2000 and July 2023. We focused on overall survival and progression-free survival as key outcome measures. The results of our analysis showed that none of the alternative treatments demonstrated significant advantages over the standard concurrent chemoradiotherapy. Nevertheless, there is potential for improved outcomes when targeted therapy or induction chemotherapy is combined with concurrent chemoradiotherapy.

Two-Dimensional Hybrid Perovskite with High-Sensitivity Optical Thermometry Sensors.

Optical thermometry has gained significant attention due to its remarkable sensitivity and noninvasive, rapid response to temperature changes. However, achieving both high absolute and relative temperature sensitivity in two-dimensional perovskites presents a substantial challenge. Here, we propose a novel approach to address this issue by designing and synthesizing a new narrow-band blue light-emitting two-dimensional perovskite named (C8H12NO2)2PbBr4 using a straightforward solution-based method. Under excitation of near-ultraviolet light, (C8H12NO2)2PbBr4 shows an ultranarrow emission band with the full width at half-maximum (FWHM) of only 19 nm. Furthermore, its luminescence property can be efficiently tuned by incorporating energy transfer from host excitons to Mn2+. This energy transfer leads to dual emission, encompassing both blue and orange emissions, with an impressive energy transfer efficiency of 38.3%. Additionally, we investigated the temperature-dependent fluorescence intensity ratio between blue emission of (C8H12NO2)2PbBr4 and orange emission of Mn2+. Remarkably, (C8H12NO2)2PbBr4:Mn2+ exhibited maximum absolute sensitivity and relative sensitivity values of 0.055 K-1 and 3.207% K-1, respectively, within the temperature range of 80-360 K. This work highlights the potential of (C8H12NO2)2PbBr4:Mn2+ as a promising candidate for optical thermometry sensor application. Moreover, our findings provide valuable insights into the design of narrow-band blue light-emitting perovskites, enabling the achievement of single-component dual emission in optical thermometry sensors.

In Situ Self-Assembled 1D/3D Mixed-Dimensional Perovskite Heterostructures for Efficient White Light Emission.

Mixed-dimensional perovskite (MDP) heterostructures are promising optoelectronic semiconductors. Yet, the current preparation methods involve complex experimental procedures and material compatibility constraints, limiting their widespread applications. Here, we present a one-step room temperature solution-based approach to synthesize a range of 1D C4N2H14PbBr4 and 3D APbBr3 (A = Cs+, MA+, FA+) self-assembled MDP heterostructures exhibiting high-efficiency white light-emitting properties. The ultra-broadband emission results from the synergy between the self-captured blue broadband emission from 1D perovskites and the green emission of 3D perovskites, covering the entire visible-light spectrum with a full width at half-maximum exceeding 170 nm and a remarkable photoluminescence quantum yield of 26%. This work establishes a novel prototype for the preparation of highly luminescent MDP heterostructures, offering insights for future research and industrialization in the realm of white light LEDs.

HPV18 E6/E7 activates Ca2+ influx to promote the malignant progression of cervical cancer by inhibiting Ca2+ binding protein 1 expression.

Mounting studies have shown that the oncoproteins E6 and E7 encoded by the human papillomavirus (HPV) genome are essential in HPV-induced cervical cancer (CC). Ca2+ binding protein 1 (CABP1), a downstream target of HPV18-positive HeLa cells that interferes with E6/E7 expression, was identified through screening the GEO Database (GSE6926). It was confirmed to be down-regulated in CC through TCGA prediction and in vitro detection. Subsequent in vitro experiments revealed that knocking down E6/E7 inhibited cell proliferation, migration, and invasion, whereas knocking down CABP1 promoted these processes. Simultaneously knocking down CABP1 reversed these effects. Additionally, the results were validated in vivo. Previous studies have indicated that CABP1 can regulate Ca2+ channels, influencing Ca2+ influx and tumor progression. In this study, it was observed that knocking down CABP1 enhanced Ca2+ inflow, as demonstrated by flow cytometry and confocal microscopy. Knocking down E6/E7 inhibited these processes, whereas simultaneously knocking down E6/E7 and CABP1 restored the inhibitory effect of knocking down E6/E7 on Ca2+ inflow. To further elucidate that E6/E7 promotes CC progression by inhibiting CABP1 expression and activating Ca2+ influx, BAPTA/AM treatment was administered during CABP1 knockdown. It was discovered that Ca2+ chelation could reverse the effect of CABP1 knockdown on CC cells. In conclusion, our results offer a novel target for the diagnosis and treatment of HPV-induced CC.

The PpMYB75-PpDFR module reveals the difference between 'SR' and its bud variant 'RMHC' in peach red flesh.

'Red Meat Honey Crisp (RMHC)' has been widely cultivated by growers in recent years due to its early maturity, and red meat type characteristics. As a bud variant of 'Super Red (SR)' peach, red flesh is the most distinctive characteristic of 'Red Meat Honey Crisp (RMHC)'. However, the mechanism of red flesh formation in 'RMHC' remains unclear. In this study, 79 differentially produced metabolites were identified by metabolomics analysis. The anthocyanin content in 'RMHC' was significantly higher than that in 'SR' during the same period, such as cyanidin O-syringic acid and cyanidin 3-O-glucoside. Other flavonoids also increased during the formation of red flesh, including flavonols (6-hydroxykaempferol-7-O-glucoside, hyperin), flavanols (protocatechuic acid, (+)-gallocatechin), and flavonoids (chrysoeriol 5-O-hexoside, tricetin). In addition, transcriptomic analysis and RT-qPCR showed that the expression levels of the flavonoid synthesis pathway transcription factor MYB75 and some structural genes, such as PpDFR, PpCHS, PpC4H, and PpLDOX increased significantly in 'RMHC'. Subcellular localization analysis revealed that MYB75 was localized to the nucleus. Yeast single hybridization assays showed that MYB75 bound to the cis-acting element CCGTTG of the PpDFR promoter region. The MYB75-PpDFR regulatory network was identified to be a key pathway in the reddening of 'RMHC' flesh. Moreover, this is the first study to describe the cause for red meat reddening in 'RMHC' compared to 'SR' peaches using transcriptomics, metabolomics and molecular methods. Our study identified a key transcription factor involved in the regulation of the flavonoid synthetic pathway and contributes to peach breeding-related efforts as well as the identification of genes involved in color formation in other species.

Gender differences in attitudes towards psychological help-seeking among chinese medical students: a comparative analysis.

BACKGROUND: Medical students are known to be at a greater risk of psychological disorders compared to the general population. However, their rate of help-seeking behavior is low. The purpose of this study was to explore the influencing factors of attitudes towards psychological help-seeking among Chinese medical students and to examine its gender differences. METHODS: A total of 3,453 medical students from three medical colleges in Hainan Province, China, completed anonymous questionnaires that included socio-demographic attributes, the Family APGAR Index, the General Health Questionnaire (GHQ-20), and the Attitudes Towards Seeking Professional Psychological Help Short Form (ATSPPH-SF). Associations between predictor variables and attitudes towards help-seeking were explored using multivariate linear regression, and regression models with interaction terms were employed to test gender difference. RESULTS: The mean score on ATSPPH-SF Scale was 15.04 ± 3.45, with males scoring significantly lower than females (14.34 vs. 15.64, P < 0.0001). For both male and female groups, psych knowledge, mental health status, family function and help-seeking utility perception significantly influenced attitudes toward psychological help-seeking. Furthermore, having more than once psycho-help experiences was positively correlated with women's attitudes. Significant interactions were found between gender and mental health status. CONCLUSION: Attitude towards seeking psychological help was relatively negative among Chinese medical students. The implementation of interventions should take into account the at-risk population, especially the males and individuals with poor mental health.

Composite water value: A way forward to balance the development and protection of transboundary lakes.

Transboundary lakes are shared by multiple administrative regions. The key to balance the development and protection of transboundary lakes is to properly measure the value of water resources. Most of previous studies on the measurement of lake water resources value have not fully considered the ecosystem service function. This paper proposes a new concept "composite water value" to measure the value of transboundary lakes by integrating the external runoff value and the internal runoff value of water resources. The study constructs a composite water value measurement system for transboundary lakes, further analyzes its influencing factors,and applies the system to the case of Nansi Lake, a representative transboundary lake in eastern China. The results show that: (1) The composite water value of lakes is influenced by various factors, including industrial structure, water withdrawal, and water use methods, which impact the external runoff water value; meanwhile, the composite water quality and fluctuations in lake level are closely associated with the internal runoff water value. From 2008 to 2021, the average annual composite water value of Nansi Lake was 39.628 billion yuan, exhibiting a "rising-falling-fluctuating rising" trend due to pollution control policies, reduced precipitation, and enhanced water-saving technologies successively. (2) From a long-term perspective, it is necessary to focus on the internal runoff water use value of lakes. The internal runoff water value of Nansi Lake has been over 75% of the composite water value, and flood storage and water conservation are important manifestations of its ecosystem service value. (3) The external runoff water value of lake is closely related to the internal runoff water value, and relevant departments need to consider the balance between the water withdrawal of multiple cities along the lake and the retained water volume of the lake to achieve the maximum benefit of composite water value.

Influence of ferroptosis indicators on the stability of atherosclerotic plaque.

Ferroptosis is a new form of cell death that is unique and closely related to iron concentration, and reactive oxygen species (ROS) production. We investigated the indicators of ferroptosis between vulnerable plaque and stable plaque in atherosclerotic. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were used to detect the expression of the ferroptosis-related genes and proteins and extracellular matrix stability-related genes and proteins (FN, CoL-1). Superoxide dismutase (SOD) activities, glutathione peroxidase (GSH) and malondialdehyde (MDA) were detected by ELISA. The commercially available kit was used to detect Fe2+ concentration in tissue. DCFH-DA fluorescent probe was used to detect the ROS levels. H&E stain, Masson trichrome stain, and Oil Red O stain were used to detect pathological states in vulnerable plaque and stable plaque. Tissue localization and positive rate of GPX4, SLC7A11, COX-2, FN, and COL-1 were evaluated by immunohistochemistry. The results showed a significant increase in the expression of COX2 and a significant decrease in the expression of GPX4 and SLC7A11 in genes related to ferroptosis in vulnerable plaque compared with stable plaque. Pathologic results showed vulnerable plaque with higher levels of inflammatory cell infiltration, more diffuse collagen fibers, and larger particles of lipid droplets. Concentrations of the antioxidant metabolites SOD and GSH were significantly reduced and concentrations of the oxidative metabolites MDA and Fe2+ were significantly increased in vulnerable plaque compared with stable plaque. The expression of FN and CoL-1 was significantly reduced in genes related to extracellular matrix stability in vulnerable plaque. Taken together, these findings indicate that the degree of ferroptosis in vulnerable plaque is higher than that in stable plaque, suggesting that changes in indicators of ferroptosis may affect carotid atherosclerotic plaque stability, target spot in the ferroptosis signaling pathway may provide further theoretical basis for the clinical treatment of carotid atherosclerosis.

Analysis of the detection rate and clinical characteristics of early gastric cancer by painless gastroscopy and ordinary gastroscopy.

OBJECTIVE: To investigate the difference of early gastric cancer (EGC) detection rate and endoscopic characteristics between painless and ordinary electronic gastroscopy, and summarize the clinical data of gastric cancer (GC) patients. METHODS: Clinical data of 72,000 patients who underwent gastroscopy in the First People Hospital of Huzhou (Zhejiang, China) from January 2016 to December 2021 were retrospectively analyzed. The patients were divided into painless gastroscopy group (observation group, 36,000 cases) and ordinary gastroscopy group (control group, 36,000 cases) according to the examination methods. The detection rate of EGC between the 2 groups and the endoscopic characteristics of EGC lesions between the 2 groups were compared, and the clinical data of GC were summarized. RESULTS: Painless gastroscopy is safer than ordinary gastroscopy. The detection rate of GC and EGC in the observation group was significantly higher than that in the control group (P < .05); the difference between the 2 groups in the detection rate of advanced GC was not statistically significant. The average length of EGC lesions in the observation group was significantly shorter than that in the control group (P < .05). The proportion of EGC with lesion length <2.0 cm in the observation group was significantly higher than that in the control group (P < .05). The proportion of EGC lesions with type II morphology, normal or pallor mucosal color, and no rupture in mucosa in the control group were significantly lower than that in the observation group, respectively (P < .05). The proportion of EGC distributed in the cardia, fundus and corpus was higher in the observation group than in the control group (P < .05). The incidence of helicobacter pylori (HP) infection, precancerous diseases, first-degree relatives of GC patients, and risk factors in patients with GC was significantly higher than that in non-GC patients (P < .05), multivariate logistic regression analysis showed that these were independent influencing factors for the occurrence of GC. CONCLUSION: Painless gastroscopy can effectively improve the screening and diagnostic efficiency of EGC, especially for EGC lesions that are not easy to expose the site, small in size, superficial, without obvious mucosal color change or without mucosal breakage. Therefore, the value of painless gastroscopy in EGC screening is worth further promotion and research.

A Horizontal and Longitudinal Study on the Changes of Aging Thyroid Function in Elderly Male Population.

OBJECTIVES: There are few follow-up studies on thyroid function in the same group for many years. Therefore, the purpose of this study was to retrospectively analyze the changes of thyroid function in a group of people for 8 years and to explore the changes of thyroid function in elderly men with normal thyroid function with age. METHODS: Reviewing the records of elderly men who underwent physical examination in the Beijing Hospital physical examination center from 2013 to 2020, 354 subjects were included in the study. According to age, they are divided into 4 groups. The differences in thyrotropin (TSH), anti-triiodothyronine (rT3), free triiodothyronine (FT3), and free thyroid hormone (FT4) among different age groups in initial time (2013) were compared. Longitudinal comparison of changes of thyroid function in the same age group for 8 years was compared too. RESULTS: At the initial time, age was negatively correlated with FT3 (r = 0.349, p < 0.001), positively correlated with rT3 and TSH (r = 0.182, p < 0.001, r = 0.212, p < 0.001), but not correlated with FT4. The results of eight years of analysis show that, for TSH, during the whole follow-up period, the TSH of the >80 years group was higher than that of the <60 years and 60-69 years groups, and the difference was statistically significant. The 70-79 age group was higher than the <60 years group at different time points, except for the age group <60 years. The other three groups showed an increasing trend with age, especially in the group of ≥80 years. For FT3, in 2013, the age ≥80 years group was significantly lower than that of the 70-79 years, 60-69 years, and <60 years old groups (p < 0.05). The analysis results at different time points in each age group showed a downward trend and then an upward trend. For FT4, there was no significant difference in FT4 among different age groups in 2013. Still, during the follow-up period, the age group ≥80 was lower than other age groups in 2019 and lower than the <60 years groups in 2014, 2015, 2019, and 2020, and the difference was statistically significant. The change rule of FT4 with the increase of age was not clear. For rT3, during the whole follow-up period, the rT3 of the >80 years group was higher than that of the <60 years and 60-69 years groups, and the difference was statistically significant. The analysis results at different time points in each age group showed a trend of rising first, then falling, and finally rising. After 2017, the rT3 of the 70-79 years and ≥80 years groups increased with age. CONCLUSIONS: The thyroid function index of elderly men changes with age. In transverse analysis, the value of TSH is the highest, and FT3 is the lowest in the group ≥80 years old. There are differences between the changes in the longitudinal analysis and the results of the horizontal analysis. Therefore, the law of thyroid function changing with age in different individuals is not the same as that of the same individual with age, which should be paid more attention in medical research and clinical diagnosis and treatment.

Status of professional mental health help-seeking intention associated factors among medical students: a cross-sectional study in China.

Aim: Low professional help-seeking intention (PHSI) hinders effective treatment of mental illness. PHSI among Chinese students is still understudied and under-recognized. This study aimed to evaluate the status of PHSI and its associated risk factors among Chinese medical students. Methods: A cross-sectional survey was conducted in Hainan province, South China, between January 1, 2021, and May 31, 2021. A total of 2182 medical students were recruited and surveyed via an anonymous structured questionnaire. Logistic regression analyses were performed to identify the factors associated with PHSI. Results: Among the 2182 medical students (mean age 21.0 years (SD = 3.70), 61.5% females), those with and without PHSI were 72.0% and 28.0%, and 16.4% with moderate to severe depression. Male students, those with a high level of depression stigma, serious family dysfunction, and heavy dependence on mobile phones were significantly less likely to seek professional mental health help, with odds ratios (ORs) of 1.5, 2.0, 2.1, and 1.7, respectively. Conclusion: A significant proportion of Chinese medical students demonstrate low PHSI, influenced by factors such as gender, depression stigma, family dysfunction, and mobile phone dependence. Future interventions aimed at increasing medical students' PHSI should prioritize reducing depression stigma, mitigating reliance on mobile phone use, and enhancing family function to address these key barriers to seeking professional mental health support.

An AlScN Piezoelectric Micromechanical Ultrasonic Transducer-Based Power-Harvesting Device for Wireless Power Transmission.

Ultrasonic wireless power transfer technology (UWPT) represents a key technology employed for energizing implantable medical devices (IMDs). In recent years, aluminum nitride (AlN) has gained significant attention due to its biocompatibility and compatibility with complementary metal-oxide-semiconductor (CMOS) technology. In the meantime, the integration of scandium-doped aluminum nitride (Al90.4%Sc9.6%N) is an effective solution to address the sensitivity limitations of AlN material for both receiving and transmission capabilities. This study focuses on developing a miniaturized UWPT receiver device based on AlScN piezoelectric micro-electromechanical transducers (PMUTs). The proposed receiver features a PMUT array of 2.8 × 2.8 mm2 comprising 13 × 13 square elements. An acoustic matching gel is applied to address acoustic impedance mismatch when operating in liquid environments. Experimental evaluations in deionized water demonstrated that the power transfer efficiency (PTE) is up to 2.33%. The back-end signal processing circuitry includes voltage-doubling rectification, energy storage, and voltage regulation conversion sections, which effectively transform the generated AC signal into a stable 3.3 V DC voltage output and successfully light a commercial LED. This research extends the scope of wireless charging applications and paves the way for further device miniaturization by integrating all system components into a single chip in future implementations.

Third birth intention of the working women with two existing children in Hainan Island, China: The impact of fertility costs and utility.

This study evaluates the impact of fertility costs and utility on the third birth intentions among working women with two children in Hainan, China. A cross-sectional survey was conducted in Hainan Island, China in 2021 using an offline survey. Among 1067 working women with two children, only 8.06 % of participants reported having a third-birth intention. After adjustment for potential confounding factors, higher economic cost (odds ratio = 1.89) and lower succession utility (odds ratio = 5.08) were significantly associated with the lack of intention to have a third child. The analysis further demonstrates that family values significantly modulate these economic and utility considerations, highlighting a strong cultural influence on fertility decisions. This finding underscores the necessity for policies that not only mitigate financial burdens but also promote family values supportive of higher fertility. Such measures are essential for creating a cultural and economic environment conducive to higher birth rates.

Compound Shenma Jingfu granule alleviates cerebral ischemia via HIF-1α-mediated promotion of angiogenesis.

BACKGROUND: Shenma Jingfu Granule, a traditional Chinese medicine formula, has been used clinically for the treatment of cerebral circulation insufficiency. However, the mechanism involved in alleviating cerebral ischemia has not yet been fully elucidated. METHODS: An integrated approach involving network pharmacology and transcriptomics was utilized to clarify the potential mechanisms of SMJF Granule. Molecular docking and surface plasmon resonance (SPR) were employed to identify potential targets and ingredients of SMJF Granule. The anti-CI effect of SMJF Granule was determined on the middle cerebral artery occlusion (MCAO) model by using hematoxylin-eosin (H&E) and Nissl's staining, as well as triphenyl tetrazolium chloride (TTC) staining, and the potential targets involved in the mechanisms were validated by RT-qPCR and western blotting. RESULTS: Integrated analysis revealed the mechanism of SMJF Granule intervening in CI injury might be related to the HIF-1 signaling pathway and angiogenesis. Molecular docking and SPR assays demonstrated robust binding interactions between key compounds like salvianolic acid A and naringenin with the core target HIF-1α protein. The experiment confirmed that SMJF Granule lowered neurological scores, diminished infarct volume, and alleviated histopathological changes in vivo. The possible mechanism of SMJF Granule was due to regulating HIF-1 pathway, which contributed to up-regulating expression of VEGF and vWF in the penumbral region, showing a significant promotion of angiogenesis. CONCLUSION: SMJF Granule promoted angiogenesis through HIF-1α pathway, thereby alleviating cerebral ischemia injury. In addition, our findings provide some evidence that SMJF Granule is a candidate compound for further investigation in treating CI in the clinical.

Favorable prostate-specific antigen levels correlate with a worse prognosis in high-grade prostate cancer: a population-based analysis.

BACKGROUND: To compare the association between prostate-specific antigen (PSA) levels and prostate cancer-specific mortality (PCSM), and the effectiveness of local treatment in patients with high-grade and low-grade prostate cancer (PCa). METHODS: This retrospective cohort study enrolled patients diagnosed with clinically localized PCa (cT1-4N0M0) from January 2010 to December 2020 in the Surveillance, Epidemiology and End Results (SEER) database. Fine-Gray competing risk regression analysis was conducted to generate cumulative incidence plots and estimate the hazards ratio (HR) and 95% confidence interval (95% CI) of PCSM. Multivariable restricted cubic spline (RCS) analysis was used to examine the non-linear associations of continuous values of PSA levels with PCSM. Inverse probability of treatment weighting (IPTW) was employed to minimize imbalances in baseline characteristics between different local treatment cohorts. RESULTS: A total of 392083 eligible patients were included in the study, including 327659 low-grade (Gleason score [GS]≤7) PCa and 64424 high-grade (GS≥8) PCa. In multivariate Fine-Gray competing risk regression analysis, using PSA levels of 4.1-10.0 ng/ml as the reference, the adjusted HR among high-grade patients with PSA levels ≤2.5 ng/ml, 2.6-4.0 ng/ml, 10.1-20.0 ng/ml and >20.0 ng/ml were 1.988 (95% CI=1.677-2.358), 1.411 (95% CI=1.194-1.668), 1.472 (95% CI=1.351-1.603) and 2.506 (95% CI=2.318-2.709), respectively. Among low-grade PCa, the adjusted HR were 0.985 (95% CI=0.800-1.213), 0.727 (95% CI=0.602-0.877), 1.844 (95% CI=1.679-2.026) and 3.574 (95% CI=3.220-3.966), respectively. Multivariable-adjusted RCS analysis showed a U/J-shaped distribution relationship between PSA levels and PCSM in high-grade PCa, while there was a positive association between PSA levels and PCSM in low-grade PCa. As for local treatment effectiveness, radiation therapy (RT) provided better control of PCSM compared to radical prostatectomy (RP) and RP+RT in high-grade PCa, while RP provided better control of PCSM compared to RT and RP+RT in low-grade PCa. CONCLUSION: Low PSA level (≤2.5 ng/ml) is significantly associated with very high risk of PCSM in high-grade localized PCa but not in low-grade localized PCa. High-grade localized PCa patients benefit more from RT in terms of PCSM control, while low-grade localized PCa patients benefit more from RP. High-grade localized PCa with low PSA level may be a unique subgroup that could benefit from novel risk stratification strategies in PCa, which requires further studies to investigate the potential of developing novel therapeutic strategies, prognostic tools, and clinical management approaches.

Real-World Data on the Use of Sirolimus in Asian Children with Vascular Malformations.

OBJECTIVES: The management of vascular malformations is complex and challenging. This study aimed to explore efficacy, plasma trough concentrations of sirolimus, post-withdrawal conditions, and adverse reactions of sirolimus in treating complex vascular malformations. METHODS: In our center, we analyzed vascular malformations treated with sirolimus (and corticosteroid) from August 2017 to June 2021. Meanwhile, we reviewed the medical records, the efficacy, side effects, and laboratory tests. Patients who had stopped taking sirolimus were followed up by telephone. RESULTS: A total of 25 patients with complicated vascular malformations in our center, including 7 females and 18 males aged 4 months to 15 years, were enrolled. In all, 19 patients (76.0%) responded to sirolimus, and the plasma concentration of sirolimus fluctuated between 0.97 and 27.15 ng/ml. In all, 24 patients (96.0%) were in follow-up. A total of 15 patients (62.5%) stopped taking sirolimus during follow-up, and 2 patients (13.3%) discontinued the sirolimus due to side effects. A total of 3 patients (20.0%) restarted sirolimus treatment. CONCLUSION: Starting dose of 1.5-2 mg/m2 sirolimus is effective and safe in vascular malformation treatment. The best treatment regimen and discontinuation indications needed more investigation. Most should be done about targeted therapy to improve effectiveness and reduce side effects.

Regulation mechanism of GPS2 on PGC-1α/Drp1-mediated mitochondrial dynamics in inflammation of acute lung injury.

Acute lung injury (ALI) has been a hot topic in the field of critical care research in recent years. Mitochondrial dynamics consists of mitochondrial fusion and mitochondrial fission. Dynamin-related protein 1 (Drp1), a key molecule that regulates mitochondrial fission, is important in the oxidative stress and inflammatory response to ALI. Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is a core protein that mediates mitochondrial biogenesis. G-protein pathway suppressor 2 (GPS2) acts as a transcriptional cofactor with regulatory effects on nuclear-encoded mitochondrial genes. This study aimed to investigate the mechanism of PGC-1α/Drp1-mediated mitochondrial dynamics involved in ALI and to demonstrate the protective mechanism of GPS2 in regulating mitochondrial structure and function and inflammation in ALI. The ALI model was constructed using LPS-induced wild-type mice and human pulmonary microvascular endothelial cells (HPMVECs). It was found that lung injury, oxidative stress and inflammation were exacerbated in the mice ALI model and that mitochondrial structure and function were disrupted in HPMVECs. In vitro studies revealed that LPS led to the upregulated expression of Drp1 and the downregulated expression of PGC-1α and GPS2. Mitochondrial division was reduced and respiratory function was restored in Drp1 knockdown cells, which inhibited oxidative stress and inflammatory response. In addition, the overexpression of PGC-1α and GPS2 significantly inhibited the expression of Drp1, mitochondrial function was restored, and inhibited reactive oxygen species (ROS) production and inflammatory factor release. Moreover, the overexpression of GPS2 promoted the upregulated expression of PGC-1α. This mechanism was also validated in vivo, in which the low expression of GPS2 in mice resulted in the upregulated expression of Drp1 and the downregulated expression of PGC-1α, and further exacerbated LPS-induced ALI. In the present study, we also found that LPS-induced the downregulated expression of GPS2 may be associated with its increased degradation by the proteasome. Therefore, these findings revealed that GPS2 inhibited oxidative stress and inflammation by modulating PGC-1α/Drp1-mediated mitochondrial dynamics to alleviate LPS-induced ALI, which may provide a new approach to the therapeutic orientation for LPS-induced ALI.