Neoadjuvant immunochemotherapy (nICT) has emerged as a promising neoadjuvant strategy for esophageal squamous cell carcinoma (ESCC). Identification of the factors affecting the responsiveness to nICT could help further improve treatment efficacy. Here, we performed single-cell analysis on 14 ESCC patients undergoing nICT and revealed tumor microenvironment (TME) features associated with differential treatment responses. Nonnegative matrix factorization (NMF) identified five coordinated cellular programs with distinct response associations. Specifically, the NMF3 program mainly comprising immunosuppressive cell subsets was enriched in the minimal or no pathological tumor regression (TRS3) group, in which regulatory T cells (Tregs) and dendritic cells (DCs) exhibited close correlation. In addition, elevated expression of mitochondrial transcription factor A (TFAM) in DCs was associated with increased Treg infiltration in the TRS3 group. A myeloid-specific Tfam knockout mouse model showed that TFAM deficiency reversed the immunosuppressive TME, inhibited tumor growth, and enhanced response to anti-PD-1 therapy in ESCC. Mechanistically, TFAM deficiency in DCs activated the STING-TBK1-IRF3 pathway, thereby promoting DC maturation to enhance anti-tumor immunity. Overall, this study characterized the TME in residual ESCC after nICT and revealed an association between elevated TFAM expression in DCs and poor responsiveness to nICT. These findings indicate the critical role of TFAM deficiency in DCs in activating anti-tumor immunity, highlighting the potential of targeting TFAM to improve the efficacy of immunotherapy and optimize therapeutic strategies.
Linyan Chen, Tang Feng, Jianfeng Zhou et al.· Cancer Research· 1 citation
Background Infections are major immediate causes of death in patients with Alzheimer’s disease, trends across infection subtypes remain poorly characterized. We examined temporal trends, demographic geographic disparities, COVID-19-era patterns, projected infection-associated mortality in United States, 1999–2024. Methods Using CDC Multiple Cause of Death database, infection-associated AD deaths were classified into six subtypes. AAMRs and temporal trends were estimated using joinpoint regression. Kitagawa decomposition assessed demographic age-specific contributions to sex disparities, Bayesian Structural Time Series models projected burden through 2034. Results Among 2,342,153 AD-related deaths, 308,045 (13.2%) were infection-associated. Overall infection-associated AAMR declined by 57.6% (AAPC −3.72% per year), diverging from rising AD mortality. Respiratory infections showed the steepest decline (AAMR −68.3%) with improvements across all regions and urbanization strata. By contrast, genitourinary infections were the only subtype with rising burden—absolute deaths increased 75.1%, rural AAMR rose 73.1% over 1999–2020, and central trend-continuation projections suggest a possible further increase, particularly over the near-term horizon, although uncertainty becomes substantial in the longer term. Kitagawa decomposition showed that the female excess in genitourinary mortality was attributable to higher age-specific female rates rather than to population age structure—uniquely among the subtypes examined (cumulative risk effect +11,337; 47.4% of the female excess; cumulative female deaths exceeding male by 170%); the increase in this risk component over time was directionally consistent but of model-dependent statistical significance. Mortality was overwhelmingly concentrated in the oldest age stratum ( ≥ 85-year rate 2,516-fold that of < 65 years). During the COVID-19 era, overall infection-associated AD mortality fell below pre-pandemic projections, with genitourinary infections showing the smallest cumulative deficit of any subtype. Hispanic individuals had the highest AAMR by 2024, while Non-Hispanic Black individuals maintained elevated septicemia mortality throughout. Conclusion Although infection-associated AD mortality declined substantially, a growing genitourinary infection burden widened across sex, rural, and racial strata, with trend-continuation projections suggesting a possible further increase, particularly over the near-term horizon. These findings, combined with external clinical evidence on infection prevention, suggest that targeted measures—including CAUTI prevention, sex-specific bladder health programs, and rural infection prevention investment—merit priority attention as baby boomers enter peak AD risk.
Xuemeng Miao, Ying-Zhi Zhang, Chengtian Gao et al.· Frontiers in Aging Neuroscie...· 0 citations
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