BACKGROUND: The purpose of this study was to evaluate the safety and efficacy of subsequent radiotherapy (RT) following first-line treatment with durvalumab plus chemotherapy in patients with extensive-stage small cell lung cancer (ES-SCLC). METHODS: A total of 122 patients with ES-SCLC from three hospitals during July 2019 to December 2021 were retrospectively analyzed. Inverse probability of treatment weighting (IPTW) analysis was performed to address potential confounding factors. The primary focus of our evaluation was to assess the impact of RT on progression-free survival (PFS) and overall survival (OS). RESULTS: After IPTW analysis, 49 patients received durvalumab plus platinum-etoposide (EP) chemotherapy followed by RT (Durva + EP + RT) and 72 patients received immunochemotherapy (Durva + EP). The median OS was 17.2 months vs . 12.3 months (hazard ratio [HR]: 0.38, 95% confidence interval [CI]: 0.17-0.85, P = 0.020), and the median PFS was 8.9 months vs . 5.9 months (HR: 0.56, 95% CI: 0.32-0.97, P = 0.030) in Durva + EP + RT and Durva + EP groups, respectively. Thoracic radiation therapy (TRT) resulted in longer OS (17.2 months vs . 14.7 months) and PFS (9.1 months vs . 7.2 months) compared to RT directed to other metastatic sites. Among patients with oligo-metastasis, RT also showed significant benefits, with a median OS of 17.4 months vs . 13.7 months and median PFS of 9.8 months vs . 5.9 months compared to no RT. Continuous durvalumab treatment beyond progression (TBP) prolonged OS compared to patients without TBP, in both the Durva + EP + RT (NA vs . 15.8 months, HR: 0.48, 95% CI: 0.14-1.63, P = 0.238) and Durva + EP groups (12.3 months vs . 4.3 months, HR: 0.29, 95% CI: 0.10-0.81, P = 0.018). Grade 3 or 4 adverse events occurred in 13 (26.5%) and 13 (18.1%) patients, respectively, in the two groups; pneumonitis was mostly low-grade. CONCLUSION Addition of RT after first-line immunochemotherapy significantly improved survival outcomes with manageable toxicity in ES-SCLC.
Humans ; Small Cell Lung Carcinoma/therapy* ; Retrospective Studies ; Male ; Female ; Middle Aged ; Lung Neoplasms/therapy* ; Aged ; Antibodies, Monoclonal/therapeutic use* ; Adult ; Immunotherapy/methods* ; Aged, 80 and over

Homo- or heterodimeric compounds that affect dimeric protein function through interaction between monomeric moieties and protein subunits can serve as valuable sources of potent and selective drug candidates. Here, we screened an in-house dimeric natural product collection, and panepocyclinol A (PecA) emerged as a selective and potent STAT3 inhibitor with profound anti-tumor efficacy. Through cross-linking C712/C718 residues in separate STAT3 monomers with two distinct Michael receptors, PecA inhibits STAT3 DNA binding affinity and transcription activity. Molecular dynamics simulation reveals the key conformation changes of STAT3 dimers upon the di-covalent binding with PecA that abolishes its DNA interactions. Furthermore, PecA exhibits high efficacy against anaplastic large T cell lymphoma in vitro and in vivo, especially those with constitutively activated STAT3 or STAT3^Y640F. In summary, our study describes a distinct and effective di-covalent modification for the dimeric compound PecA to disrupt STAT3 function.

Accurate timing of myelination is crucial for the proper functioning of the central nervous system. Here, we identified a de novo heterozygous mutation in TMEM63A (c.1894G>A; p. Ala632Thr) in a 7-year-old boy exhibiting hypomyelination. A Ca²⁺ influx assay suggested that this is a loss-of-function mutation. To explore how TMEM63A deficiency causes hypomyelination, we generated Tmem63a knockout mice. Genetic deletion of TMEM63A resulted in hypomyelination at postnatal day 14 (P14) arising from impaired differentiation of oligodendrocyte precursor cells (OPCs). Notably, the myelin dysplasia was transient, returning to normal levels by P28. Primary cultures of Tmem63a^-/- OPCs presented delayed differentiation. Lentivirus-based expression of TMEM63A but not TMEM63A_A632T rescued the differentiation of Tmem63a^-/- OPCs in vitro and myelination in Tmem63a^-/- mice. These data thus support the conclusion that the mutation in TMEM63A is the pathogenesis of the hypomyelination in the patient. Our study further demonstrated that TMEM63A-mediated Ca²⁺ influx plays critical roles in the early development of myelin and oligodendrocyte differentiation.
Animals ; Cell Differentiation/physiology* ; Oligodendroglia/metabolism* ; Mice, Knockout ; Mice ; Male ; Myelin Sheath/metabolism* ; Humans ; Child ; Cells, Cultured ; Oligodendrocyte Precursor Cells/metabolism*

Guidelines for Digital Ancient Books of TCM Indexing(T/CIATCM 119-2024)is based on the theoretical knowledge,disciplinary methods,and practical applications of TCM classical cataloging.Taking digital ancient books of TCM as the object,it systematically reveals the content of TCM knowledge,which is an essential indexing processing standard for building an intelligent retrieval system for TCM ancient books,and can provide support for the deep development and innovative utilization of TCM knowledge.It can not only promote the co-construction and sharing of ancient book resources in the TCM industry,but also promote the standardization construction and application of TCM information.This standard specifies the principles,methods,and examples of free indexing of digital ancient books of TCM based on their original content.It is applicable to the indexing and processing of digital ancient books of TCM for TCM professional libraries and related institutions,and to the data processing and construction of various types of TCM ancient book databases.

Over the past four decades，China’s response to HIV/AIDS has undergone a profound transformation—from an initial state of nearly absence to a comprehensive，robust，and highly coordinated system. The implementation of the “Four Frees and One Care” policy，the widespread adoption of antiretroviral therapy，and the integration of the “test-and-treat” strategy have collectively shifted HIV/AIDS from a fatal condition to a manageable chronic disease，significantly improving both the quality of life and life expectancy of affected individuals. This article systematically reviews three critical stages in the development of HIV/AIDS prevention and control in China，with particular emphasis on the positive impact of medical advances. It further summarizes key progress in testing capacity，drug accessibility，and service delivery，while highlighting the challenges and directions that lie ahead. This review aims to provide scientific evidence to support the ultimate goal of ending the HIV/AIDS epidemic.

Objective To construct a mammography image classification assistant system suitable for Chinese population,and explore the potential of artificial intelligence technology to assist early screening of breast cancer in China.Methods Curated breast imaging subset of digital database for screening mammography(CBIS-DDSM),Mammographic image analysis society database(MIAS)and other international open datasets were used to conduct model training respectively in order to reproduce the mainstream in-depth learning methods in the current literature.The model was also tested on the Chinese breast mammography database(CBMD)provided by Huajiao Technology Co.,Ltd,and the performance was compared.Aiming at the problem that the Chinese population data are not ideal in the performance test of the open dataset training model,an optimization strategy based on the sliding window adjustment mechanism was implemented in combination with the characteristics of Chinese population data.Then a two-stage migration learning method was designed to improve the overall performance of the model,and then development of our system was carried out.Results With the sliding window adjustment mechanism and the CBMD training model after two-stage transfer learning,the accuracy of our developed system was improved from 0.50 of the open datasets to 0.80,precision from 0.54 to 0.82,sensitivity from 0.52 to 0.80,F1 value from 0.52 to 0.80,and AUC value from 0.51 to 0.89 based on the Chinese population dataset as the test set.Conclusion Through the introduction of sliding window adjustment mechanism and two-stage migration learning strategy,the performance of the breast molybdenum target image classification model has been significantly improved in the Chinese population dataset,and our system primarily achieves the purpose of assisting the classification of breast molybdenum target images for the Chinese population.

Objective To identify core targets of hepatocellular carcinoma (HCC) by using bioinformatics and specific algorithms, explore their relationships with immune cells, and investigate the causal relationships between immune cells and HCC through Mendelian randomization. Methods Relevant genes associated with the development of HCC were screened using the GEO and TCGA databases. Immune infiltration analysis was conducted using GSVA and CIBERSORT algorithms. A bidirectional Mendelian randomization analysis was then performed to explore the causal relationships between immune cells and HCC. Results A total of 284 HCC-related genes were identified, with 120 genes recognized within the protein interaction network. Immune infiltration analysis revealed significant correlations between key genes and immune cells. Mendelian randomization results indicated that HLA DR on CD33⁺ HLA DR⁺ CD14dim (OR=1.097, 95%CI: 1.002–1.201, P=0.045, P_Bonferroni=0.091) and CD8 on CD28⁺ CD45RA⁺ CD8⁺ T cell (OR=1.123, 95%CI: 1.027–1.228, P=0.011, P_Bonferroni=0.022) were the risk factors for HCC. Conversely, HLA DR⁺⁺ monocyte absolute count was identified as a protective factor for HCC (OR=0.812, 95%CI: 0.702–0.938, P=0.005, P_Bonferroni=0.139). Conclusion The occurrence and development of liver cancer may be related to CDK1, CCNB1, and CDC20, showing a high degree of correlation with Th2 cells, T helper cells, Th17 cells, and DCs. Mendelian randomization shows that HLA DR on CD33⁺HLA DR⁺ CD14dim and CD8 on CD28⁺CD45RA⁺CD8⁺T cells are associated with an increased risk of HCC. The risk of hepatocellular carcinoma is associated with a decrease in the level of HLA DR⁺⁺monocyte absolute count.

Porcine reproductive and respiratory syndrome virus(PRRSV)mainly causes sow abor-tion,stillbirth,mummified fetus and respiratory symptoms in piglets.Since first reported in China in 1996,the virus complexity has increased significantly in more than 20 years of genetic evolution,bringing huge economic losses to the pig industry.In recent years,with the emergence of various PRRSV recombinant virus strains,preventing and controlling this epidemic became increasingly difficult.The purpose of this article is to comprehensively review the genome structure and func-tion of PRRSV,RNA virus recombination mechanism,main types of recombination,and the epi-demic status and recombination for the dominant epidemic PRRSV strains,in order to provide clues for in-depth research on gene recombination of PRRSV,thus providing the theoretical sup-port for formulating scientific prevention and control strategies.

Hepatocellular carcinoma(HCC),which is essentially primary liver cancer,is closely related to CD8+T cell immune infiltration and immune suppression.We constructed a CD8+T cells related risk score model to pre-dict the prognosis of HCC patients and provided therapeutic guidance based on the risk score.Using integrated bulk RNA sequencing(RNA-seq)and single-cell RNA sequencing(scRNA-seq)datasets,we identified stable CD8+T cell signatures.Based on these signatures,a 3-gene risk score model,comprised of KLRB1,RGS2,and TN-FRSF1B was constructed.The risk score model was well validated through an independent external validation co-hort.We divided patients into high-risk and low-risk groups according to the risk score and compared the differ-ences in immune microenvironment between these two groups.Compared with low-risk patients,high-risk patients have higher M2-type macrophage content(P＜0.0001)and lower CD8+T cells infiltration(P＜0.0001).High-risk patients predict worse response to immunotherapy treatment than low-risk patients(P＜0.01).Drug sensitivity a-nalysis shows that PI3K-β inhibitor AZD6482 and TGFβRII inhibitor SB505124 may be suitable therapies for high-risk patients,while the IGF-1R inhibitor BMS-754807 or the novel pyrimidine-based anti-tumor metabolic drug Gemcitabine could be potential therapeutic choices for low-risk patients.Moreover,expression of these 3-gene mod-el was verified by immunohistochemistry.In summary,the establishment and validation of a CD8+T cell-derived risk model can more accurately predict the prognosis of HCC patients and guide the construction of personalized treatment plans.