Nanomedicine, acting as the magic bullet, is capable of combining immunotherapy with other treatments to reverse a cold tumor (immune depletion) into a hot tumor. However, how to comprehensively inhibit the immunosuppressive tumor microenvironment (TME) remains a major challenge for immunotherapy to achieve the maximum benefits. Thus, a strategy that can simultaneously increase the recruitment of tumor infiltrating lymphocytes (TILs) and comprehensively reprogram the immunosuppressive TME is still urgently needed. Herein, a thermal-sensitive nitric oxide (NO) donor S-nitrosothiols (SNO)-pendant copolymer (poly(acrylamide-co-acrylonitrile-co-vinylimidazole)-SNO copolymer, PAAV-SNO) with upper critical solution temperature (UCST) was synthesized and employed to fabricate an erythrocyte membrane-camouflaged nanobullet for codelivery of NIR II photothermal agent IR1061 and indoleamine 2,3-dioxygenase 1 (IDO-1) inhibitor 1-methyl-tryptophan (1-MT). This multifunctional nanobullet possessed long circulation in vivo, enhanced accumulation at the tumor site, and therapeutics-controlled release by NIR II laser, thereby it could avoid unspecific drug leakage while enhancing biosecurity. More importantly, the immunogenic cell death (ICD) induced by local hyperthermia from photothermal therapy (PTT) could be conducive for the increased recruitment of CD8+ cytotoxic T lymphocytes (CTLs) at the tumor site. Furthermore, through interfering in the IDO-1 activity by 1-MT and normalizing the tumor vessels by in situ generated NO, the immunosuppressive TME was comprehensively reprogrammed toward an immunostimulatory phenotype, achieving the excellent therapeutic efficacy against both primary breast cancer and metastases. Collectively, this multifunctional nanobullet described in this study developed an effective and promising strategy to comprehensively reprogram suppressive TME and treat “immune cold” tumors.
While the printed circuit board (PCB) has been widely considered as the building block of integrated electronics, the world is switching to pursue new ways of merging integrated electronic circuits with textiles to create flexible and wearable devices. Herein, as an alternative for PCB, we described a non-printed integrated-circuit textile (NIT) for biomedical and theranostic application via a weaving method. All the devices are built as fibers or interlaced nodes and woven into a deformable textile integrated circuit. Built on an electrochemical gating principle, the fiber-woven-type transistors exhibit superior bending or stretching robustness, and were woven as a textile logical computing module to distinguish different emergencies. A fiber-type sweat sensor was woven with strain and light sensors fibers for simultaneously monitoring body health and the environment. With a photo-rechargeable energy textile based on a detailed power consumption analysis, the woven circuit textile is completely self-powered and capable of both wireless biomedical monitoring and early warning. The NIT could be used as a 24/7 private AI “nurse” for routine healthcare, diabetes monitoring, or emergencies such as hypoglycemia, metabolic alkalosis, and even COVID-19 patient care, a potential future on-body AI hardware and possibly a forerunner to fabric-like computers.
Introduction: Metastasis is the primary cause of lung cancer-related death. Nevertheless, the underlying molecular mechanisms and evolutionary patterns of lung cancer metastases are still elusive.Methods: We performed whole-exome sequencing for 40 primary tumors (PTs) and 61 metastases from 47 patients with lung cancer, of which 40 patients had paired PTs and metastases. The PT-metastasis genomic divergence, metastatic drivers, timing of metastatic dissemination, and evolutionary origins were analyzed using appropriate statistical tools and mathematical models.Results: There were various degrees of genomic heterogeneity when comparing the paired primary and metastatic lesions or comparing metastases of different sites. Multiple metastasis-selected/enriched genetic alterations were found, such as MYC amplification, NKX2-1 amplification, RICTOR amplification, arm 20p gain, and arm 11p loss, and these results were were also featured in a meta-analysis cross-validated using an independent cohort from Memorial Sloan-Kettering Cancer Center database. To elucidate the metastatic seeding time, we applied a metastatic model and found 61.1% of the tumors were late dissemination, in which the metastatic seeding happened approximately 2.74 years before clinical detection. One exception was lymph
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