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Abstract Background Natural killer/T cell lymphoma (NKTCL) is an aggressive lymphoma with a poor prognosis. Chimeric antigen receptor-transduced T (CAR-T) cell therapy has become a promising immunotherapeutic strategy against haematologic malignancies. Methods In this study, four CAR-T cell lines (CD38-CAR, LMP1-CAR, CD38-LMP1 tandem CAR 1 and CD38-LMP1 tandem CAR 2) were generated. The effect of CAR-T cells against NKTCL cells was evaluated both in vitro and in vivo. Expression of T cell activation markers and cytokines produced by CAR-T cells were detected by flow cytometry. Results The four CAR-T cell lines could effectively eliminate malignant NKTCL cells. They could be activated and produce inflammatory cytokines in a target-dependent manner. In vivo tests showed that the CAR-T cells exhibited significant antitumour effects in a xenotransplanted NKTCL mouse model. Conclusions In summary, four CAR-T cell lines exhibited significant cytotoxicity against NKTCL cells both in vitro and in vivo. These results indicated the effective therapeutic promise of CD38 and LMP1 CAR-T cells in NKTCL.

Abstract Background PARP inhibitor (PARPi), as a kind of DNA damage repair inhibitor, has been shown to be effective in various solid tumors and hematologic malignancies. Natural killer/T cell lymphoma (NKTCL) is a highly aggressive malignancy, the treatment of which has long been a major challenge in the clinic. Here, we investigated the efficacy and mechanism of PARPi, and the therapeutic value of PARPi combined with cisplatin in NKTCL. Methods The cell proliferation, cell apoptosis, and cell cycle of NKTCL cells were detected respectively by CCK-8 and flow cytometry. The changes of mRNA expression and protein level were measured respectively by mRNA-sequencing, quantitative real-time PCR, western blotting, and immunofluorescence. LMO2 expression was detected by immunohistochemistry and western blotting. Targeted knockdown of LMO2 was conducted by short hairpin RNA. The tumor xenograft models were established to evaluate the efficacy of drugs in vivo. Results PARPi inhibited cell proliferation, promoted cell apoptosis, and induced S-phase cell cycle arrest in NKTCL cells. PARPi led to the accumulation of DNA damage by blocking DNA repair and DNA replication. Additionally, LMO2 deficiency reduced the sensitivity of NKTCL cells to PARPi. Finally, the combination of PARPi and cisplatin exhibited significant synergistic effects both in vitro and in vivo. Conclusions In summary, we found that PARPi exerted an anti-tumor effect via LMO2 and synergized with cisplatin in NKTCL, which provides the theoretical basis for the clinical application of PARPi.

Abstract Background Natural killer/T-cell lymphoma (NKTCL) is a rare and aggressive subtype of Non-Hodgkin’s Lymphoma. CircRNA has shown great potential to become a biomarker in plasma. In this study, we aimed to determine circRNA for its diagnostic and prognostic value and biological function in NKTCL. Method The circRNA microarray of plasma from NKTCL patients and healthy donors were conducted. The relative expressions of target circRNA were verified by qRT-PCR. We conducted function experiments in vitro and in vivo. Bioinformatics predicted the target miRNA of the target circRNA and the binding site was detected by the dual luciferase report assay. Downstream target protein was predicted and detected by western blot in vitro and immunohistochemistry in vivo. Result By analyzing the plasma circRNA microarrays in NKTCL, 6137 circRNAs were up-regulated and 6190 circRNAs were down-regulated. The relative expressions of circADARB1 were significantly higher in NKTCL patients. The knockdown of circADARB1 inhibited proliferation of NKTCL cells in vitro and in vivo. CircADARB1 could bind to miR-214-3p in the downstream and regulate the expression of p-Stat3. In nude mice tumor tissue, p-Stat3 was under-expressed in the circADARB1 knockdown group. Conclusion CircADARB1 was highly expressed in NKTCL plasma and circADARB1 was a potential biomarker to assist diagnosis and predict the response in NKTCL. CircADARB1 bound up to miR-214-3p and regulated p-Stat3.

Abstract Background Breast cancer is the fastest-growing cancer among females and the second leading cause of female death. At present, targeted antibodies combined with hyperthermia locally in tumor has been identified as a potential combination therapy to combat tumors. But in fact, the uniformly deep distribution of photosensitizer in tumor sites is still an urgent problem, which limited the clinical application. We reported an HER2-modified thermosensitive liposome (immunoliposome)-assisted complex by reducing gold nanocluster on the surface (GTSL-CYC-HER2) to obtain a new type of bioplasma resonance structured carrier. The HER2 decoration on the surface enhanced targeting to the breast cancer tumor site and forming irregular, dense, "petal-like" shells of gold nanoclusters. Due to the good photothermal conversion ability under near-infrared light (NIR) irradiation, the thermosensitive liposome released the antitumor Chinese traditional medicine, cyclopamine, accompanied with the degradation of gold clusters into 3–5 nm nanoparticles which can accelerate renal metabolism of the gold clusters. With the help of cyclopamine to degrade the tumor associated matrix, this size-tunable gold wrapped immunoliposome was more likely to penetrate the deeper layers of the tumor, while the presence of gold nanoparticles makes GTSL-CYC-HER2 multimodal imaging feasible. Results The prepared GTSL-CYC-HER2 had a size of 113.5 nm and displayed excellent colloidal stability, photo-thermal conversion ability and NIR-sensitive drug release. These GTSL-CYC-HER2 were taken up selectively by cancer cells in vitro and accumulated at tumour sites in vivo. As for the in vivo experiments, compared to the other groups, under near-infrared laser irradiation, the temperature of GTSL-CYC-HER2 rises rapidly to the phase transition temperature, and released the cyclopamine locally in the tumor. Then, the released cyclopamine destroyed the stroma of the tumor tissue while killing the tumor cells, which in turn increased the penetration of the liposomes in deep tumor tissues. Moreover, the GTSL-CYC-HER2 enhanced the performance of multimodal computed tomography (CT) and photothermal (PT) imaging and enabled chemo-thermal combination therapy. Conclusions This optically controlled biodegradable plasmonic resonance structures not only improves the safety of the inorganic carrier application in vivo, but also greatly improves the anti-tumor efficiency through the visibility of in vivo CT and PT imaging, as well as chemotherapy combined with hyperthermia, and provides a synergistic treatment strategy that can broaden the conventional treatment alone. Graphic Abstract

Abstract Background Conotruncal defects (CTDs) are a type of heterogeneous congenital heart diseases (CHDs), but little is known about their etiology. Increasing evidence has demonstrated that fibroblast growth factor (FGF) 8 and FGF10 may be involved in the pathogenesis of CTDs. Methods The variants of FGF8 and FGF10 in unrelated Chinese Han patients with CHDs (n = 585), and healthy controls (n = 319) were investigated. The expression and function of these patient-identified variants were detected to confirm the potential pathogenicity of the non-synonymous variants. The expression of FGF8 and FGF10 during the differentiation of human embryonic stem cells (hESCs) to cardiomyocytes and in Carnegie stage 13 human embryo was also identified. Results Two probable deleterious variants (p.C10Y, p.R184H) of FGF8 and one deletion mutant (p.23_24del) of FGF10 were identified in three patients with CTD. Immunofluorescence suggested that variants did not affect the intracellular localization, whereas ELISA showed that the p.C10Y and p.23_24del variants reduced the amount of secreted FGF8 and FGF10, respectively. Quantitative RT-PCR and western blotting showed that the expression of FGF8 and FGF10 variants was increased compared with wild-type; however, their functions were reduced. And we found that FGF8 and FGF10 were expressed in the outflow tract (OFT) during human embryonic development, and were dynamically expressed during the differentiation of hESCs into cardiomyocytes. Conclusion Our results provided evidence that damaging variants of FGF8 and FGF10 were likely contribute to the etiology of CTD. This discovery expanded the spectrum of FGF mutations and underscored the pathogenic correlation between FGF mutations and CTD.