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OBJECTIVE: This study aimed to clarify the mechanism by which Krüppel-like factor 12 (KLF12) affects progesterone sensitivity in endometrial cancer (EC) through the progesterone receptor PGR signaling pathway. METHODS: The relationship of KLF12 with PGR in EC patients was examined by immunohistochemistry, and the expression of KLF12 and PGR in EC cell lines was detected by real-time PCR and western blotting. Cell proliferation assay, plate clone formation, cell apoptosis assay, and cell cycle analysis were conducted to determine the impact of KLF12 intervention on progesterone therapy. CUT&Tag analysis and the dual-luciferase reporter experiment were used to determine the underlying regulatory effect of KLF12 on the PGR DNA sequence. A subcutaneous xenograft nude mouse model was established to validate the in vivo effect of KLF12 on progesterone sensitivity via PGR expression modulation. RESULTS: KLF12 demonstrated decreased progesterone sensitivity and a negative correlation with PGR expression in EC tissues. Progesterone sensitivity was increased by KLF12 deficiency through PGR overexpression, a result that could be significantly reversed by PGR downregulation. PGR was identified as a target gene of KLF12, which could directly bind to the PGR promotor region and inhibit its expression. CONCLUSION: This study is the first to investigate the effect of KLF12 expression on EC cell resistance to progesterone. Our results offer important mechanistic insight into the direct regulation of the PGR promoter region, demonstrating that KLF12 expression strongly suppressed the PGR signaling pathway and, as a result, reduced progesterone sensitivity in EC patients.

Gut microbiota can influence host gene expression and physiology through metabolites. Besides, the presence or absence of gut microbiome can reprogram host transcriptome and epitranscriptome as represented by N6-methyladenosine (m6A), the most abundant mammalian mRNA modification. However, which and how gut microbiota-derived metabolites reprogram host transcriptome and m6A epitranscriptome remain poorly understood. Here, investigation is conducted into how gut microbiota-derived metabolites impact host transcriptome and m6A epitranscriptome using multiple mouse models and multi-omics approaches. Various antibiotics-induced dysbiotic mice are established, followed by fecal microbiota transplantation (FMT) into germ-free mice, and the results show that bile acid metabolism is significantly altered along with the abundance change in bile acid-producing microbiota. Unbalanced gut microbiota and bile acids drastically change the host transcriptome and the m6A epitranscriptome in multiple tissues. Mechanistically, the expression of m6A writer proteins is regulated in animals treated with antibiotics and in cultured cells treated with bile acids, indicating a direct link between bile acid metabolism and m6A biology. Collectively, these results demonstrate that antibiotic-induced gut dysbiosis regulates the landscape of host transcriptome and m6A epitranscriptome via bile acid metabolism pathway. This work provides novel insights into the interplay between microbial metabolites and host gene expression.

Abstract The T315I mutation poses a significant threat to patients with chronic phase chronic myeloid leukemia (CP-CML). This study aimed to establish a nomogram to predict the risk of T315I mutation in CP-CML patients. The training cohort included 1,466 patients from 24 hematology centers, and the validation cohort included 820 patients from an additional 20 centers. Peripheral blood blast (PBB), additional chromosomal abnormality (ACA), dasatinib use, non-EMR at 3 months, and BCR::ABLIS > 1% at 6 months were identified as independent risk factors through multivariate Cox regression analysis. The performance of the nomogram was assessed via receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA). The area under the ROC curve (AUC) values at 5, 10, and 15 years were 0.874, 0.925, and 0.930 for the training cohort, and 0.864, 0.814, and 0.803 for the validation cohort, respectively. The calibration curves for both cohorts were close to the ideal diagonal, and the decision curves indicated clinical net benefit. In conclusion, we developed a nomogram to predict the 5-year, 10-year, and 15-year T315I-free survival probabilities of CP-CML patients. This tool can aid clinicians in the early prediction and timely management of high-risk CP-CML patients with the T315I mutation.

Abstract Background The association between social capital and trajectories of cognitive function (CF) is still unclear among older adults in mainland China. The present study aims to examine the association using a longitudinal cohort from the Ningxia Healthy Aging Cohort. Methods Four waves of longitudinal data were abstracted to identify the CF trajectories using the conditional latent class growth model (LCGM). CF was measured using the Chinese version of the Mini-Mental State Examination (MMSE) from 2012 to 2023. Social capital, including social cohesion, social interaction, civic participation, and spiritual capital, was assessed using a series of standard instruments at baseline. Multinomial logistic regression was used to test the association between social capital and each trajectory class. Results Three distinct CF trajectories were identified: Stable (72.5%), slow decline (25.8%), and deterioration (1.7%). High spiritual capital was associated with a decreased risk of developing a deterioration trajectory (OR = 0.36, 95% CI = 0.14–0.93), while high civic participation (OR = 0.61, 95% CI = 0.46–0.81) was associated with a decreased risk of developing a slow decline trajectory. Low CF at baseline was the first important risk factor, followed by age, civic participation, sex, monthly income, spiritual capital, and obesity. Conclusions The CF trajectories are heterogeneous among older Chinese adults. Civic participation was associated with a lower risk of a slow decline trajectory, and spiritual capital was slightly associated with a lower risk of a deterioration trajectory. These findings support the development of social-integrated interventions for vulnerable groups.

PurposeThis study compared the efficacy and acceptability of a ready-to-use intranasal dexmedetomidine spray (DS) versus traditional drops administered by syringe (DD) in pediatric patients undergoing elective surgery.Patients and MethodsEighty-six preschool children were enrolled in a prospective, randomized, controlled study. Children were randomly assigned to receive either DS or DD. For children weighing between 10.5 and 18.5 kg, a dexmedetomidine dosage of 30 μg (two sprays) was administered, while those weighing between 18.5 and 25.5 kg received 45 μg (three sprays). In the DD group, dexmedetomidine was administered at a dose of 2 μg/kg based on body weight. The primary outcome was the proportion of children achieving a Ramsay sedation scale (RSS) score of ≥3 within 30 min. Secondary outcomes included acceptance of intranasal medication, anxiety at parental separation and prior to induction, and compliance with induction.ResultsA total of 83 cases were analyzed. The proportion of children achieving an RSS score of ≥3 within 30 min was similar between the DS and DD groups (90.7% vs. 77.5%, respectively). However, the acceptance score was significantly better in the DS group (mean difference [95%]: −0.9 [−1.267 to −0.5325], P < 0.001). No significant differences were observed between the groups in terms of successful child-parent separation (88.4% vs. 85%) or satisfactory anxiolytic effect prior to induction (95.3% vs. 92.5%). Compliance with induction was comparable, with 53.5% in the DS group and 40.0% in the DD group demonstrating “optimal” compliance.ConclusionBoth intranasal spray and syringe drop methods were highly effective in providing sedation and anxiolysis, but the ready-to-use intranasal dexmedetomidine spray was more acceptable to children, offering a viable alternative to the syringe method.Clinical Trial RegistrationChiCTR.org.cn, identifier ChiCTR2400089374.

Abstract Background Clinical T4 (cT4) stage gastric cancer presents with frequent postoperative recurrence and poor prognosis. This study is to evaluate the oncological efficacy of laparoscopic radical total gastrectomy combined with postoperative prophylactic hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with cT4N + M0 gastric cancer who received neoadjuvant chemotherapy. Methods We reviewed the clinicopathological data of 174 patients with clinical T4 gastric cancer who underwent neoadjuvant chemotherapy followed by laparoscopic radical total gastrectomy between June 2017 and December 2021. Among them, 142 were included in the non-HIPEC group, and 32 in the HIPEC group. Patients in both groups were paired based on propensity score in a 2:1 ratio to assess disparities in tumor recurrence and long-term survival. Results After matching, there were no significant differences in the clinicopathological data between the two groups. The peritoneum (16.1%) and distant organs (10.9%) were the most frequent locations for recurrence. Prior to matching, the recurrence rates were similar at all sites for both groups. Compared with those in the non-HIPEC cohort, the recurrence rates at all sites, the lung, and the peritoneum were notably lower in the HIPEC cohort. Prior to matching, the 3-year overall survival and disease-free survival rates were similar between the two groups; following matching, the HIPEC group exhibited notably greater survival rates than did the non-HIPEC group. The disparities in survival rates between the groups became even more pronounced after conducting a stratified analysis among patients with stage III disease. Conclusions Neoadjuvant chemotherapy combined with prophylactic HIPEC after laparoscopic radical gastrectomy can effectively reduce the rate of peritoneal metastasis in patients with cT4N + M0 advanced gastric cancer and significantly improve the prognosis of such patients, which is of great clinical value.

BackgroundThis study examined the interhemispheric integration function pattern in patients with iridocyclitis utilizing the voxel-mirrored homotopic connectivity (VMHC) technique. Additionally, we investigated the ability of VMHC results to distinguish patients with iridocyclitis from healthy controls (HCs), which may contribute to the development of objective biomarkers for early diagnosis and intervention in clinical set.MethodsTwenty-six patients with iridocyclitis and twenty-six matched HCs, in terms of sex, age, and education level, underwent resting-state functional magnetic resonance imaging (fMRI) examinations. The study employed the voxel-mirrored homotopic connectivity (VMHC) technique to evaluate interhemispheric integration functional connectivity indices at a voxel-wise level. The diagnostic efficacy of VMHC was evaluated using a support vector machine (SVM) classifier, with classifier performance assessed through permutation test analysis. Furthermore, correlation analyses was conducted to investigate the associations between mean VMHC values in various brain regions and clinical features.ResultsPatients with iridocyclitis exhibited significantly reduced VMHC signal values in the bilateral inferior temporal gyrus, calcarine, middle temporal gyrus, and precuneus compared to HCs (voxel-level P < 0.01, Gaussian Random Field correction; cluster-level P < 0.05). Furthermore, the extracted resting-state zVMHC features effectively classified patients with iridocyclitis and HCs, achieving an area under the receiver operating characteristic curve (AUC) of 0.74 and an overall accuracy of 0.673 (P < 0.001, non-parametric permutation test).ConclusionOur findings reveal disrupted interhemispheric functional organization in patients with iridocyclitis, offering insight into the pathophysiological mechanisms associated with vision loss and cognitive dysfunction in this patient population. This study also highlights the potential of machine learning in ophthalmology and the importance of establishing objective biomarkers to address diagnostic heterogeneity.

Cancer is a serious public health problem in humans, and prevention and control strategies are still necessary. Therefore, the development of new therapeutic drugs is urgently needed. Targeting programmed cell death, particularly via the induction of cancer cell apoptosis, is one of the cancer treatment approaches employed. Recently, an increasing number of studies have shown that compounds from natural plants can target programmed cell death and kill cancer cells, laying the groundwork for use in future anticancer treatments. In this review, we focus on the latest research progress on the role and mechanism of natural plant active ingredients in different forms of programmed cell death, such as apoptosis, autophagy, necroptosis, ferroptosis, and pyroptosis, to provide a strong theoretical basis for the clinical development of antitumor drugs.

Currently, the application of robotics technology in sports training and competitions is rapidly increasing. Traditional methods mainly rely on image or video data, neglecting the effective utilization of textual information. To address this issue, we propose: TL-CStrans Net: A vision robot for table tennis player action recognition driven via CS-Transformer. This is a multimodal approach that combines CS-Transformer, CLIP, and transfer learning techniques to effectively integrate visual and textual information. Firstly, we employ the CS-Transformer model as the neural computing backbone. By utilizing the CS-Transformer, we can effectively process visual information extracted from table tennis game scenes, enabling accurate stroke recognition. Then, we introduce the CLIP model, which combines computer vision and natural language processing. CLIP allows us to jointly learn representations of images and text, thereby aligning the visual and textual modalities. Finally, to reduce training and computational requirements, we leverage pre-trained CS-Transformer and CLIP models through transfer learning, which have already acquired knowledge from relevant domains, and apply them to table tennis stroke recognition tasks. Experimental results demonstrate the outstanding performance of TL-CStrans Net in table tennis stroke recognition. Our research is of significant importance in promoting the application of multimodal robotics technology in the field of sports and bridging the gap between neural computing, computer vision, and neuroscience.

Abstract Understanding farmers’ future residential preferences and the factors affecting these choices is crucial for tackling the issues related to hollow village management and rural planning. Despite limited research on the role of the family life cycle, this study explores how the family life cycle, characteristics of the household head, livelihood strategies, and resource availability shape farmers’ future residential preferences. Data were collected from 777 households in China’s main grain-producing area. The findings reveal that 52.90% of households prefer to stay in their current rural residences. Other favored options are elderly care facilities (13.90%), living with children in the village (12.36%), and ancestral homes (11.68%). The family life cycle significantly affects these preferences (p

Abstract Background Platinum-based chemotherapy regimens are a mainstay in the management of ovarian cancer (OC), but emergence of chemoresistance poses a significant clinical challenge. The persistence of ovarian cancer stem cells (OCSCs) at the end of primary treatment contributes to disease recurrence. Here, we hypothesized that the extracellular matrix protects CSCs during chemotherapy and supports their tumorigenic functions by activating integrin-linked kinase (ILK), a key enzyme in drug resistance. Methods TCGA datasets and OC models were investigated using an integrated proteomic and gene expression analysis and examined ILK for correlations with chemoresistance pathways and clinical outcomes. Canonical Wnt pathway components, pro-survival signaling, and stemness were examined using OC models. To investigate the role of ILK in the OCSC-phenotype, a novel pharmacological inhibitor of ILK in combination with carboplatin was utilized in vitro and in vivo OC models. Results In response to increased fibronectin secretion and integrin β1 clustering, aberrant ILK activation supported the OCSC phenotype, contributing to OC spheroid proliferation and reduced response to platinum treatment. Complexes formed by ILK with the Wnt receptor frizzled 7 (Fzd7) were detected in tumors and correlated with metastatic progression. Moreover, TCGA datasets confirmed that combined expression of ILK and Fzd7 in high grade serous ovarian tumors is correlated with reduced response to chemotherapy and poor patient outcomes. Mechanistically, interaction of ILK with Fzd7 increased the response to Wnt ligands, thereby amplifying the stemness-associated Wnt/β-catenin signaling. Notably, preclinical studies showed that the novel ILK inhibitor compound 22 (cpd-22) alone disrupted ILK interaction with Fzd7 and CSC proliferation as spheroids. Furthermore, when combined with carboplatin, this disruption led to sustained AKT inhibition, apoptotic damage in OCSCs and reduced tumorigenicity in mice. Conclusions This “outside-in” signaling mechanism is potentially actionable, and combined targeting of ILK-Fzd7 may lead to new therapeutic approaches to eradicate OCSCs and improve patient outcomes.

Abstract Depression has been reported as one of the most prevalent psychiatric illnesses globally. This study aimed to obtain information on the global burden of depression and its associated spatiotemporal variation, by exploring the correlation between the global burden of depression and the social development index (SDI) and associated risk factors. Using data from the Global Burden of Disease study from 1990 to 2019, we described the prevalence and burden of disease in 204 countries across 21 regions, including sex and age differences and the relationship between the global disease burden and SDI. The age-standardized rate and estimated annual percentage change were used to assess the global burden of depression. Individuals with documented depression globally ranged from 182,183,358 in 1990 to 290,185,742 in 2019, representing an increase of 0.59%. More patients experienced major depressive disorder than dysthymia. The incidence and disability-adjusted life years of depression were the highest in the 60–64 age group and much higher in females than in males, with this trend occurring across all ages. The age-standardized incidence and adjusted life-years-disability rates varied with different SDI levels. Relevant risk factors for depression were identified. National governments must support research to improve prevention and treatment interventions.

Abstract Extreme within-lake conditions have the potential to exert detrimental effects on lakes. Here we use satellite observations to investigate how the occurrence of multiple types of extremes, notably algal blooms, lake heatwaves, and low lake levels, have varied in 2724 lakes since the 1980s. Our study, which focuses on bloom-affected lakes, suggests that 75% of studied lakes have experienced a concurrent increase in at least two of the extremes considered (27% defined as having a notable increase), with 25% experiencing an increase in frequency of all three extremes (5% had a notable increase). The greatest increases in the frequency of these extremes were found in regions that have experienced increases in agricultural fertilizer use, lake warming, and a decline in water availability. As extremes in lakes become more common, understanding their impacts must be a primary focus of future studies and they must be carefully considered in future risk assessments.

Abstract Background Microcirculatory perfusion disorder and inflammatory response are critical links in acute kidney injury (AKI). We aim to construct anti‐vascular cell adhesion molecule‐1(VCAM‐1) targeted microbubbles (TM) to monitor renal microcirculatory perfusion and inflammatory response. Methods TM carrying VCAM‐1 polypeptide was constructed by biological coupling. The binding ability of TM to human umbilical vein endothelial cells (HUVECs) was detected. Bilateral renal ischemia–reperfusion injury (IRI) models of mice were established to evaluate microcirculatory perfusion and inflammatory response using TM. Thirty‐six mice were randomly divided into six groups according to the different reperfusion time (0.5, 2, 6, 12, and 24 h) and sham‐operated group (Sham group). The correlation of TM imaging with serum and histopathological biomarkers was investigated. Results TM has advantages such as uniform distribution, regular shape, high stability, and good biosafety. TM could bind specifically to VCAM‐1 molecule expressed by tumor necrosis factor‐alpha (TNF‐α)‐treated HUVECs. In the renal IRI‐AKI model, the area under the curve (AUC) of TM significantly decreased both in the renal cortical and medullary after 2 h of reperfusion compared with the Sham group (p

Introduction: We aimed to determine whether sestamibi scan changes management of renal masses. Methods: All patients undergoing sestamibi scan for renal masses between 2008 and 2022 at a single center were retrospectively reviewed. Data were gathered on patient demographics, pre- and postoperative creatinine, sestamibi scan parameters, and cross-sectional imaging characteristics. Outcomes included whether the patient underwent renal mass biopsy or surgical resection and the final pathological diagnosis if tissue was obtained from biopsy or resection. Data regarding postbiopsy as well as postoperative complications were also collected. The odds ratio (OR) for surgery or biopsy based on sestamibi result was calculated. Results: Forty-three patients underwent sestamibi scan from 2008 to 2022, with 10 scans consistent with oncocytoma and 33 with nononcocytoma. The mean tumor size at initial presentation was 4.0 ± 1.8 cm with a median RENAL score of 7 (range: 4–11). For patients with sestamibi scans negative for oncocytoma, the OR for surgery was 12.5 (95% confidence interval [CI]: 2.1–71.2, P = 0.005), and the OR for biopsy was 0.04 (95% CI: 0.005–0.39, P = 0.005). Conversely, for patients with sestamibi scans positive for oncocytoma, the OR for surgery was 0.28 (95% CI: 0.03–2.4, P = 0.24) and the OR for biopsy was 24.0 (95% CI: 2.6–222.7, P = 0.005). Creatinine at the last follow-up was similar between patients with positive and negative sestamibi scans. No patients experienced complications from surgery or biopsy. The median follow-up was 19 months (range: 2–163). Conclusions: A sestamibi scan positive for oncocytoma led to increased use of renal mass biopsy for confirmation. Sestamibi scans that were negative for oncocytoma were more likely to result in surgical resection without biopsy.

Abstract This study assessed the global and regional burden of IS (ischemic stroke) deaths due to LPA (low physical activity) from 1990 to 2019, analyzed regional, sex, and age differences in ASMR (age-standardized mortality rate), and provided a comprehensive understanding of the impact of age, period, and cohort on low physical activity related ischemic stroke ASMR. We conducted an APC (age-period-cohort) analysis of the global and four World Bank income level regions’ IS mortality data attributed to LPA from 1990 to 2019, using the GBD2019 database, and the results showed that the global net drift of the Ischemic stroke age-standardized mortality attributable to low physical activity was − 1.085%[95% CI: − 1.168, − 1.003].The ASMR drop is most pronounced in the high-income zone, with a net drift of − 2.473% [95% CI: − 2.759, − 2.187] across the four income groups. The influence of age on mortality is increasing in the worldwide old population, while the period and cohort effects are decreasing. We also performed a Joinpoint regression analysis, which revealed that the specific time of considerable drop in ASMR of IS in the global LPA population was 2002–2007, with an APC of -2.628%. The specific period of considerable drop in ASMR in high-income regions with the highest variation was 1999–2007, with an APC = − 4.726%. The global burden of public health deaths caused by LPA is diminishing, with the most notable progress observed in high-income regions. However, in low and lower-middle income areas, the situation continues to deteriorate. Within the global elderly population, the effects of age on mortality is increasing, while the effects of period and cohort are diminishing. These trends vary across income levels, highlighting the necessity for enhanced international collaboration to formulate context-specific public health strategies aimed at enhancing cardiovascular health on a global, regional, and national scale.