Pancreatic cancer-derived exosomes induce apoptosis of T lymphocytes through the p38 MAPK-mediated endoplasmic reticulum stress.

Pancreatic cancer is the fourth most lethal malignancy and is characterized by poor immunogenicity. Pancreatic cancer cells have various strategies to suppress host immune response, evade immune defenses, and facilitate tumor growth and development. As a mode of long-range intercellular communication, cancer-derived exosomes contribute to impairment of the immune system. However, the mechanisms that induce changes in the activities of signal transduction pathways in immune cells, which are influenced by tumor-derived exosomes, are poorly understood. We (1) treated peripheral T lymphocytes with pancreatic cancer-derived exosomes, tagged CD63 with tdTomato, to trace exosome transfer from pancreatic cancer cells to T lymphocytes; (2) carried out a cytotoxicity assay of exosome-treated T lymphocytes using the Real Time Cellular Analysis system; (3) performed RNA sequencing and gene set enrichment analysis to explore the pivotal signaling pathway that mediates apoptosis in exosome-treated T lymphocytes; and (4) demonstrated the role of p38 mitogen-activated protein kinase (MAPK) and endoplasmic reticulum (ER) stress in exosome-induced T-lymphocyte apoptosis. In conclusion, these results indicate that pancreatic cancer cells secrete exosomes, which are taken up by T lymphocytes to activate p38 MAPK, and then induce ER stress-mediated apoptosis, ultimately causing immunosuppression.

Volatile organic compound emissions from straw-amended agricultural soils and their relations to bacterial communities: A laboratory study.

A laboratory study was conducted to investigate volatile organic compound (VOC) emissions from agricultural soil amended with wheat straw and their associations with bacterial communities for a period of 66days under non-flooded and flooded conditions. The results indicated that ethene, propene, ethanol, i-propanol, 2-butanol, acetaldehyde, acetone, 2-butanone, 2-pentanone and acetophenone were the 10 most abundant VOCs, making up over 90% of the total VOCs released under the two water conditions. The mean emission of total VOCs from the amended soils under the non-flooded condition (5924ng C/(kg·hr)) was significantly higher than that under the flooded condition (2211ng C/(kg·hr)). One "peak emission window" appeared at days 0-44 or 4-44, and over 95% of the VOC emissions occurred during the first month under the two water conditions. Bacterial community analysis using denaturing gradient gel electrophoresis (DGGE) showed that a relative increase of Actinobacteria, Bacteroidetes, Firmicutes and γ-Proteobacteria but a relative decrease of Acidobacteria with time were observed after straw amendments under the two water conditions. Cluster analysis revealed that the soil bacterial communities changed greatly with incubation time, which was in line with the variation of the VOC emissions over the experimental period. Most of the above top 10 VOCs correlated positively with the predominant bacterial species of Bacteroidetes, Firmicutes and Verrucomicrobia but correlated negatively with the dominant bacterial species of Actinobacteria under the two water conditions. These results suggested that bacterial communities might play an important role in VOC emissions from straw-amended agricultural soils.

Hsa_circ_002178 Promotes the Growth and Migration of Breast Cancer Cells and Maintains Cancer Stem-like Cell Properties Through Regulating miR-1258/KDM7A Axis.

Breast cancer (BrCa) is the most common malignancy in women. Accumulating evidence demonstrated that abnormal circRNA expression is associated with the occurrence and progression of tumors. We analyzed the GSE101123 data and found that the expression of hsa_circ_002178 (circ_002178) was significantly increased in BrCa tissues. However, the role and possible underlying mechanisms of circ_002178 in BrCa still remain unrevealed. In this investigation, the expression levels of circ_002178 in cancer tissues or BrCa cells were significantly upregulated compared with those in paracancer tissues or normal cells. High expression of circ_002178 was correlated with the low survival rate, clinical tumor size, lymph node metastasis, and tumor, nodes, and metastases grade. After microsphere culture, the expression of circ_002178 in SUM149PT and MDA-MB-231 cells was significantly increased. Further investigation exhibited that overexpression of circ_002178 contributed to the formation of microspheres, the elevated protein levels of stemness marker, and the increased activity of ALDH1 in SUM149PT cells. Besides, the overexpression of circ_002178 also significantly promoted the growth, invasion, and migration of BrCa cells. Correspondingly, the knockdown of circ_002178 showed the opposite result in MDA-MB-231 cells. Hsa_circ_002178 was further proved to downregulate the level of miR-1258 and reduce the inhibitory effect of miR-1258 on KDM7A, thus regulating the stem-like characteristics of BrCa cells and promoting the growth and migration of BrCa cells. Taken together, targeting the circ_002178/miR-1258/KDM7A axis may be a prospective strategy for the diagnosis and therapies of BrCa in the future.

Prognostic value of programmed cell death protein 1 expression on CD8+ T lymphocytes in pancreatic cancer.

Pancreatic cancer is one of the most aggressive malignancies and has a highly immunosuppressive tumour microenvironment. Immune checkpoint blockade has led to remarkable and durable objective responses in a number of malignancies and antibody-based strategies targeting programmed cell death protein 1 (PD-1) are showing promise where traditional modalities of surgery, radiotherapy, and chemotherapy have failed. In this study, we examined the clinical value of PD-1 protein expression by CD8+ peripheral T lymphocytes or tumour-infiltrating T lymphocytes (TILs) in pancreatic ductal adenocarcinoma (PDAC). Expression of PD-1 protein on CD8+ TILs correlated with overall survival and clinicopathological characteristics such as clinical stage, N classification, and M classification. Similar findings were observed for the expression of PD-1 protein on peripheral CD8+ T cells, whereas its expression on peripheral CD4+ T cells showed no significance. Comparison of the levels of PD-1 protein expressed by peripheral CD8+ T cells before and 4 weeks after surgery indicated that preoperative and postoperative status of peripheral PD-1 expression was unchanged. Our findings showed that PD-1 protein expressed by peripheral or tumour-infiltrated CD8+ T cells was a promising biomarker for diagnosis and prognosis in PDAC and might help guide future immunotherapies.