Nature Medicine最新文献

Chimeric antigen receptor (CAR) T cells and bispecific T cell engagers have become integral components in the treatment of relapsed/refractory multiple myeloma. We report a 63-year-old male who received ciltacabtagene autoleucel CAR T cells and the GPRC5D × CD3 bispecific talquetamab for early relapse of his multiple myeloma. Nine months after CAR T therapy, he developed a symptomatic leukemic peripheral T cell lymphoma with cutaneous and intestinal involvement. Longitudinal single-cell RNA and T cell receptor sequencing of peripheral blood and bone marrow revealed two hyperexpanded CAR-carrying T cell clones. These expanded clones exhibited an exhausted effector-memory T cell transcriptional signature, and the neoplasm itself was sensitive to dexamethasone treatment. The immunophenotypic and transcriptional alterations of these abnormal T cells resembled those of T-large granular lymphocytic leukemia. Spatial transcriptomes of skin lesions confirmed the aberrant CAR-expressing T cells. Whole-genome sequencing revealed three distinct integration sites, within the introns of ZGPAT, KPNA4 and polycomb-associated noncoding RNAs. Before and after CAR T whole-genome analyses implicated clonal outgrowth of a TET2-mutated precursor propelled by additional subclone-specific loss of heterozygosity and other secondary mechanisms. This case highlights the evolution of a CAR-carrying peripheral T cell lymphoma following CAR T cell and bispecific T cell engager therapy, offering critical insights into the clonal evolution from a predisposed hematopoietic precursor to a mature neoplasm.

In rural China, where healthcare relies on village doctors (nonspecialized practitioners who work exclusively in their village clinics), delivering integrated atrial fibrillation (AF) management poses challenges. We developed a telemedicine-based, village doctor-led integrated care model and conducted a cluster randomized clinical trial to assess its efficacy compared to usual care. A total of 30 village clinics were randomly assigned (1:1) to the intervention or control group, with 1,039 village residents aged ≥65 years with AF (44.3% women) recruited. The primary outcome in stage 1 is adherence to integrated AF care at 12 months. In stage 2, the primary outcome is a composite of cardiovascular death, all strokes, heart failure or acute coronary syndrome hospitalization, and AF emergency visits over 36 months. Both primary outcomes were met. At 12 months, 33.1% in the telemedicine-based, village doctor-led care group and 8.7% in the usual care group met all criteria for integrated AF care (between-group difference, 24.4% (95% confidence interval (CI), 18.3–30.5%); P < 0.001). Over 34.0 months, 41.8% in the telemedicine-based, village doctor-led care group and 10.3% in the usual care group met all criteria for integrated AF care (P < 0.001). The rate of the composite cardiovascular event outcome was lower in the telemedicine-based, village doctor-led care group than in the usual care group (6.2% versus 9.6% per year; hazard ratio, 0.64 (95% CI, 0.50–0.82); P < 0.001). Our trial intervention by this telemedicine-based integrated care delivery model of AF care in rural villages demonstrates better adherence and improved clinical outcomes compared to usual care. ClinicalTrials.gov registration: NCT04622514.

Both environmental exposures and genetics are known to play important roles in shaping human aging. Here we aimed to quantify the relative contributions of environment (referred to as the exposome) and genetics to aging and premature mortality. To systematically identify environmental exposures associated with aging in the UK Biobank, we first conducted an exposome-wide analysis of all-cause mortality (n = 492,567) and then assessed the associations of these exposures with a proteomic age clock (n = 45,441), identifying 25 independent exposures associated with mortality and proteomic aging. These exposures were also associated with incident age-related multimorbidity, aging biomarkers and major disease risk factors. Compared with information on age and sex, polygenic risk scores for 22 major diseases explained less than 2 percentage points of additional mortality variation, whereas the exposome explained an additional 17 percentage points. Polygenic risk explained a greater proportion of variation (10.3–26.2%) compared with the exposome for incidence of dementias and breast, prostate and colorectal cancers, whereas the exposome explained a greater proportion of variation (5.5–49.4%) compared with polygenic risk for incidence of diseases of the lung, heart and liver. Our findings provide a comprehensive map of the contributions of environment and genetics to mortality and incidence of common age-related diseases, suggesting that the exposome shapes distinct patterns of disease and mortality risk, irrespective of polygenic disease risk.