The Janus kinase/signal transducers and activators of transcription (JAK-STAT) control natural killer (NK) cells development and cytotoxic functions, however, whether long non-coding RNAs (lncRNAs) are involved in this pathway remains unknown. We found that miR155HG was elevated in activated NK cells and promoted their proliferation and effector functions in both NK92 and induced-pluripotent stem cells (iPSCs)-derived NK (iPSC-NK) cells, without reliance on its derived miR-155 and micropeptide P155. Mechanistically, miR155HG bound to miR-6756 and relieved its repression of JAK3 expression, thereby promoting the JAK-STAT pathway and enhancing NK cell proliferation and function. Further investigations disclosed that upon cytokine stimulation, STAT3 directly interacts with miR155HG promoter and induces miR155HG transcription. Collectively, we identify a miR155HG-mediated positive feedback loop of the JAK-STAT signaling. Our study will also provide a power target regarding miR155HG for improving NK cell generation and effector function in the field of NK cell adoptive transfer therapy against cancer, especially iPSC-derived NK cells.

OBJECTIVES: To investigate the mechanism mediating the regulatory effect of miR-155-5p on proliferation of human submandibular gland epithelial cells (HSGECs) in primary Sjogren's syndrome (pSS). METHODS: Dual luciferase reporter assay was used to verify the targeting relationship between miR-155-5p and the PI3K/AKT pathway. In a HSGEC model of pSS induced by simulation with TRAIL and INF-γ, the effects of miR-155-inhibitor-NC or miR-155 inhibitor on cell viability, cell cycle, apoptosis and proliferation were evaluated using CKK8 assay, flow cytometry and colony formation assay. ELISA and RT-PCR were used to detect the expressions of inflammatory cytokines and miR-155-5p mRNA in the cells; Western blotting was performed to detect the expressions of proteins in the PI3K/AKT signaling pathway. RESULTS: Dual luciferase assay showed that miR-155-5p targets the PI3K/AKT pathway via PIK3R1 mRNA. The HSGEC model of pSS showed significantly decreased cell viability, cell clone formation ability and expressions IL-10 and IL-4 and increased cell apoptosis, cell percentage in G2 phase, expressions of TNF‑α, IL-6, miR-155-5p and PIK3R1 mRNA, p-PI3K/PI3K ratio, p-Akt/AKT ratio, and PIK3R1 protein expression. Treatment of the cell models with miR-155 inhibitor significantly increased the cell viability, G1 phase cell percentage, colony formation ability, and expressions of IL-10 and IL-4 levels, and obviously reduced cell apoptosis rate, G2 phase cell percentage, expressions of TNF-α, IL-6, miR-155-5p and PIK3R1 mRNA, p-PI3K/PI3K ratio, p-AKT/AKT ratio, and PIK3R1 protein expression. CONCLUSIONS In HSGEC model of pSS, inhibition of miR-155-5p can promote cell proliferation and reduced cell apoptosis by targeting PI3K1 mRNA to negatively regulate the overexpression of PI3K/AKT signaling pathway.
Humans ; MicroRNAs/genetics* ; Cell Proliferation ; Signal Transduction ; Proto-Oncogene Proteins c-akt/metabolism* ; Sjogren's Syndrome/pathology* ; Epithelial Cells/cytology* ; Submandibular Gland/cytology* ; Phosphatidylinositol 3-Kinases/metabolism* ; Apoptosis ; Class Ia Phosphatidylinositol 3-Kinase ; Cells, Cultured

BACKGROUND: Pulmonary arterial hypertension (PAH) presents a significant health burden in Asia and remains a critical challenge. This study aims to delineate the PAH burden in Asia from 1990 to 2021. METHODS: Using the latest data from the Global Burden of Disease 2021, we evaluated and analyzed the distributions and patterns of PAH disease burden among various age groups, sexes, regions, and countries in Asia. Additionally, we examined the associations between PAH disease burden and key health system indicators, including the socio-demographic index (SDI) and the universal health coverage (UHC) index. RESULTS: In 2021, there were 25,989 new PAH cases, 103,382 existing cases, 13,909 PAH-associated deaths, and 385,755 DALYs attributed to PAH in Asia, which accounted for approximately 60% of global PAH cases. The age-standardized rates (ASRs) for prevalence and deaths were 2.05 (95% uncertainty interval [UI]: 1.66-2.52) per 100,000 population and 0.31 (95% UI: 0.23-0.38) per 100,000 population, respectively. From 1990 to 2021, Asia reported the lowest ASRs for PAH prevalence but the highest ASRs for deaths compared to other continents. While the ASRs for prevalence increased slightly, ASRs for mortality and DALYs decreased over time. This increasing burden of PAH was primarily driven by population growth and aging. The burden was especially pronounced among individuals aged ≥60 years and <9 years, who collectively accounted for the majority of deaths and DALYs. Moreover, higher SDI and UHC levels were linked to reduced incidence, but higher prevalence rates. CONCLUSIONS Although progress has been made in reducing PAH-related mortality and DALYs, the disease continues to impose a substantial burden in Asia, particularly among older adults and young children. Region-specific health policies should focus on improving early diagnosis, expanding access to treatment, and effectively addressing the growing PAH burden in the region.
Humans ; Global Burden of Disease ; Male ; Female ; Middle Aged ; Adult ; Asia/epidemiology* ; Prevalence ; Aged ; Pulmonary Arterial Hypertension/mortality* ; Adolescent ; Young Adult ; Child ; Child, Preschool ; Infant ; Hypertension, Pulmonary/epidemiology*

BACKGROUND: Cervical squamous cell carcinoma (CESC), the most common subtype of cervical cancer, is primarily caused by the high-risk human papillomavirus (HPV) infection and genetic susceptibility. Single-cell RNA sequencing (scRNA-seq) has been widely used in CESC research to uncover the diversity of cell types and states within tumor tissues, enabling a detailed study of the tumor microenvironment (TME). This technology allows precise mapping of HPV infection in cervical tissues, providing valuable insights into the initiation and progression of HPV-mediated malignant transformation. METHODS: We performed the scRNA-seq to characterize gene expression in tumor tissues and paired adjacent para-cancerous tissues from four patients with early-stage CESC using the 10× Genomics platform. The HPV infection and its subtypes were identified using the scRNA data and viral sequence mapping, and trajectory analyses were performed using HPV+ or HPV- cells. Interactions between different types of keratinized cells and their interactions with other cell types were identified, and pathways and specificity markers were screened for proliferating keratinized cells. The Cancer Genome Atlas (TCGA) dataset was used to verify the prognostic correlation between tumor-specific PI3+S100A7+ keratinocyte infiltration and CESC, and the localization relationship between PI3+S100A7+ keratinocytes and macrophages was verified by immunofluorescence staining. RESULTS: Various types of keratinocytes and fibroblasts were the two cell types with the most significant differences in percentage between the tumor tissue samples and paired adjacent non-cancerous tissue samples in the early stages of CESC. We found that PI3+S100A7+ keratinocytes were associated with early HPV-positive CESC, and PI3+S100A7+ keratinocytes were more abundant in tumors than in adjacent normal tissues in the TCGA-CESC dataset. Analysis of clinical information revealed that the infiltration of PI3+S100A7+ keratinocytes was notably higher in tumors with poor prognosis than in those with good prognosis. Additionally, multiplex immunofluorescence analysis showed a specific increase in PI3+S100A7+ expression within tumor tissues, with PI3+S100A7+ keratinocytes and CD163+ macrophages being spatially very close to each other. In the analysis of cell-cell interactions, macrophages exhibited strong crosstalk with PI3+S100A7+ proliferating keratinocytes in HPV-positive CESC tumors, mediated by tumor necrosis factor (TNF), CCL2, CXCL8, and IL10, highlighting the dynamic and tumor-specific enhancement of macrophage-keratinocyte interactions, which are associated with poor prognosis and immune modulation. Using CIBERSORTx, we discovered that patients with high infiltration of both PI3+S100A7+ proliferating keratinocytes and macrophages had the shortest overall survival. In the analysis of cell-cell interactions, PI3+S100A7+ proliferating keratinocytes and macrophages were found to be involved in highly active pathways that promote differentiation and structure formation, including cytokine receptor interactions, the Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway, and TNF signaling pathway regulation. Further subtyping of fibroblast populations identified four subtypes. The C1 group, characterized by its predominance in tumor tissues, is a subtype enriched with cancer-associated fibroblasts (CAFs), whereas the C3 group is primarily enriched in adjacent non-cancerous tissues and consists of undifferentiated cells. Moreover, the distinct molecular and cellular differences between HPV16- and HPV66-associated tumors were demonstrated, emphasizing the unique tumor-promoting mechanisms and microenvironmental influences driven by each HPV subtype. CONCLUSIONS We discovered a heterogeneous population of keratinocytes between tumor and adjacent non-cancerous tissues caused by HPV infection and identified macrophages and specific CAFs that play a crucial role during the early stage in promoting the inflammatory response and remodeling the cancer-promoting TME. Our findings provide new insights into the transcriptional landscape of early-stage CESC to understand the mechanism of HPV-mediated malignant transformation in cervical cancer.
Humans ; Female ; Papillomavirus Infections/genetics* ; Uterine Cervical Neoplasms/genetics* ; Carcinoma, Squamous Cell/pathology* ; Keratinocytes/metabolism* ; Single-Cell Analysis/methods* ; Tumor Microenvironment/genetics*

OBJECTIVE To systematically evaluate the efficacy and safety of cadonilimab in patients with malignant solid tumors. METHODS The related literature was comprehensively searched from PubMed， Embase， Cochrane Library， Web of Science， CNKI， Wanfang， VIP， and CBM databases， and the search time ranged from the establishment date to August 2025. Literature screening was strictly adhered to predefined inclusion and exclusion criteria， the quality of randomized controlled trials and single-arm studies were evaluated using the Cochrane risk of bias assessment tool and the MINORS scale， respectively. Meta- analysis was conducted using RevMan and Stata software. RESULTS A total of 23 studies （2 randomized controlled trials， 21 single-arm studies） with 2 539 patients were included. Pooled analysis of RCTs showed that the objective response rate （ORR） was significantly higher in the trial group than in the control group （RR＝1.24， 95%CI：1.08-1.42； P＝0.002）， but the risk of any-grade immune-related adverse events （irAEs） was also significantly increased （RR＝5.36， 95%CI：3.88-7.42； P＜0.000 01）. Pooled analysis of single-arm studies showed that the ORR of cadonilimab was 39.8% （95%CI：31.0%-49.7%）， and the median progression free survival was 6.39 months （95%CI：4.11-8.67）. Subgroup analysis indicated that the ORR for patients with cervical cancer and gastric or gastroesophageal junction adenocarcinoma were 54.5% （95%CI：40.8%-67.6%） and 54.1% （95%CI： 45.1%-62.7%）， respectively. In terms of safety， the incidences of grade ≥3 treatment-related adverse events and irAEs were 41.0% （95%CI： 31.0%-51.0%） and 9.9% （95%CI： 7.4%-13.8%）， respectively. CONCLUSIONS Cadonilimab demonstrates significant efficacy advantages in multiple solid tumors， with manageable safety， holding particularly important clinical value in cervical cancer and gastric or gastroesophageal junction adenocarcinoma.

Objective:Based on the benchmarking theory,to elaborate the key issues,paradigm innovations and realization paths of modernized performance management in China's public hospitals,and to provide policy recommendations for the government and hospitals.Methods:Literature/document collection,expert consultation and prototyping were used as methodological support.Results:Hospital performance management lacks management standards,multivariate dynamic indicator systems and realization tools;the digital governance model of"digital technology+management system"has not been established;and horizontal and vertical comparisons among geographic regions,hospitals,departments,and disease types based on standards have not been realized.Innovative paradigms include the establishment of a standard paradigm based on the smallest functional units such as disease types,indexes,bed days,operators,doctors,etc.;the construction of a dynamic index library,the mining of different combinations of indexes and their internal relationships,and the establishment of an evaluation paradigm;the establishment of a longitudinal evaluation of disease types,the evaluation of"specialties,hospitals,and industries",and the positioning of internal functions of hospitals,resource efficiency and the application of healthcare quality evaluation.It creates a multivariate,multidimensional,dynamic evaluation method and visualized evaluation tool and realization path based on big data.Conclusion:It is needed to emancipate the mind to further enhance the cognitive level of digital governance,innovate the paradigm to accelerate the construction of modernized performance management system in public hospitals,and build a platform to promote the application of modernized performance management system in public hospitals.

Objective:Based on the benchmarking theory,to elaborate the key issues,paradigm innovations and realization paths of modernized performance management in China's public hospitals,and to provide policy recommendations for the government and hospitals.Methods:Literature/document collection,expert consultation and prototyping were used as methodological support.Results:Hospital performance management lacks management standards,multivariate dynamic indicator systems and realization tools;the digital governance model of"digital technology+management system"has not been established;and horizontal and vertical comparisons among geographic regions,hospitals,departments,and disease types based on standards have not been realized.Innovative paradigms include the establishment of a standard paradigm based on the smallest functional units such as disease types,indexes,bed days,operators,doctors,etc.;the construction of a dynamic index library,the mining of different combinations of indexes and their internal relationships,and the establishment of an evaluation paradigm;the establishment of a longitudinal evaluation of disease types,the evaluation of"specialties,hospitals,and industries",and the positioning of internal functions of hospitals,resource efficiency and the application of healthcare quality evaluation.It creates a multivariate,multidimensional,dynamic evaluation method and visualized evaluation tool and realization path based on big data.Conclusion:It is needed to emancipate the mind to further enhance the cognitive level of digital governance,innovate the paradigm to accelerate the construction of modernized performance management system in public hospitals,and build a platform to promote the application of modernized performance management system in public hospitals.

Objective:Based on the benchmarking theory,to elaborate the key issues,paradigm innovations and realization paths of modernized performance management in China's public hospitals,and to provide policy recommendations for the government and hospitals.Methods:Literature/document collection,expert consultation and prototyping were used as methodological support.Results:Hospital performance management lacks management standards,multivariate dynamic indicator systems and realization tools;the digital governance model of"digital technology+management system"has not been established;and horizontal and vertical comparisons among geographic regions,hospitals,departments,and disease types based on standards have not been realized.Innovative paradigms include the establishment of a standard paradigm based on the smallest functional units such as disease types,indexes,bed days,operators,doctors,etc.;the construction of a dynamic index library,the mining of different combinations of indexes and their internal relationships,and the establishment of an evaluation paradigm;the establishment of a longitudinal evaluation of disease types,the evaluation of"specialties,hospitals,and industries",and the positioning of internal functions of hospitals,resource efficiency and the application of healthcare quality evaluation.It creates a multivariate,multidimensional,dynamic evaluation method and visualized evaluation tool and realization path based on big data.Conclusion:It is needed to emancipate the mind to further enhance the cognitive level of digital governance,innovate the paradigm to accelerate the construction of modernized performance management system in public hospitals,and build a platform to promote the application of modernized performance management system in public hospitals.

Objective:Based on the benchmarking theory,to elaborate the key issues,paradigm innovations and realization paths of modernized performance management in China's public hospitals,and to provide policy recommendations for the government and hospitals.Methods:Literature/document collection,expert consultation and prototyping were used as methodological support.Results:Hospital performance management lacks management standards,multivariate dynamic indicator systems and realization tools;the digital governance model of"digital technology+management system"has not been established;and horizontal and vertical comparisons among geographic regions,hospitals,departments,and disease types based on standards have not been realized.Innovative paradigms include the establishment of a standard paradigm based on the smallest functional units such as disease types,indexes,bed days,operators,doctors,etc.;the construction of a dynamic index library,the mining of different combinations of indexes and their internal relationships,and the establishment of an evaluation paradigm;the establishment of a longitudinal evaluation of disease types,the evaluation of"specialties,hospitals,and industries",and the positioning of internal functions of hospitals,resource efficiency and the application of healthcare quality evaluation.It creates a multivariate,multidimensional,dynamic evaluation method and visualized evaluation tool and realization path based on big data.Conclusion:It is needed to emancipate the mind to further enhance the cognitive level of digital governance,innovate the paradigm to accelerate the construction of modernized performance management system in public hospitals,and build a platform to promote the application of modernized performance management system in public hospitals.

Objective:Based on the benchmarking theory,to elaborate the key issues,paradigm innovations and realization paths of modernized performance management in China's public hospitals,and to provide policy recommendations for the government and hospitals.Methods:Literature/document collection,expert consultation and prototyping were used as methodological support.Results:Hospital performance management lacks management standards,multivariate dynamic indicator systems and realization tools;the digital governance model of"digital technology+management system"has not been established;and horizontal and vertical comparisons among geographic regions,hospitals,departments,and disease types based on standards have not been realized.Innovative paradigms include the establishment of a standard paradigm based on the smallest functional units such as disease types,indexes,bed days,operators,doctors,etc.;the construction of a dynamic index library,the mining of different combinations of indexes and their internal relationships,and the establishment of an evaluation paradigm;the establishment of a longitudinal evaluation of disease types,the evaluation of"specialties,hospitals,and industries",and the positioning of internal functions of hospitals,resource efficiency and the application of healthcare quality evaluation.It creates a multivariate,multidimensional,dynamic evaluation method and visualized evaluation tool and realization path based on big data.Conclusion:It is needed to emancipate the mind to further enhance the cognitive level of digital governance,innovate the paradigm to accelerate the construction of modernized performance management system in public hospitals,and build a platform to promote the application of modernized performance management system in public hospitals.