Immunotherapy might be an effective treatment in extrahepatic cholangiocarcinoma (eCCA), a tumor with extremely limited therapeutic options. Our study is to characterize the programmed death ligand-1 (PD-L1) protein expression and cancer microenvironment profiles in surgically resected eCCA samples. PD-L1 positivity was observed on tumor cells (32.3%) as well as on tumor-associated macrophages (74.2%). PD-L1 expression by eCCA correlated significantly with immune parameters such as intra-tumoral CD3+ tumor infiltrating lymphocytes (TILs) density (P = 0.002), intra-tumoral CD8+ TILs density (P < 0.001), and the expression pattern of human leukocyte antigen (HLA) class I (P < 0.001). Immunofluorescence showed that PD-L1 positive tumor cells were adjacent to PD-1 positive cells and the stroma covered with interferon-γ. Correlation with clinicopathological parameters and survival analyses revealed that PD-L1 positivity in eCCA was related to the absence of venous invasion (P = 0.030), improved overall survival (P = 0.020) and progressionfree survival (P = 0.011). HLA class I molecules defect, which is an important mechanism of immune evasion, was frequently observed in eCCA (50.0%) and was associated with a decreased number of intra-tumoral CD8+ TIL density (P = 0.028). Additionally, the presence of unusually high numbers of tumor-associated macrophages (TAMs) subsets M2 in most of eCCA (74.2%) was noted. Our study indicated that PD-L1 expression in association with intra-tumoral TILs infiltration and HLA class I expression in 32.3% of the eCCA reflects an active immune microenvironment potentially responsive to PD-1/PD-L1 inhibitors. In addition, the combination of macrophage-targeting agents may provide therapeutic synergy for future immunotherapy.
A 4-year-old girl with pituitary dysplasia for 2 years presented to our hospital after swallowing a coin 3 hours earlier. An abdominal X-ray revealed the coin in her stomach, along with an unexpected string of beaded, high-density images in the right upper abdomen ([Fig. 1]). Her parents disclosed that the girl had played with magnetic beads a month prior and might have ingested them then, but she had no symptoms of abdominal pain, vomiting, or fever. Under intravenous anesthesia, the girl underwent gastroscopy.
The mechanisms of soil preferential flow occurrence and development are influenced by topographic and geomorphological factors. However, the complex distribution patterns of soil preferential flow paths on different slopes remain unclear. Therefore, taking the subtropical evergreen broad-leaved forest area of Simian Mountain as the study area, this study conducted a quantitative analysis of the spatial distribution characteristics and spatial association of soil preferential flow at different slope positions (slope shoulder (SS), mid-slope (SM) and slope foot (SF)) using field staining tracer tests and spatial point pattern analysis. Results showed that the maximum infiltration depth, the depth of matrix flow, average dye coverage, preferential flow fraction and length index of the SM plot were all greater than those of the SS and SF plots. The number of preferential flow paths in different slope positions decreases with soil depth, with most preferential flow paths measuring 2.5–5.0 mm in each soil layer. The total number of preferential flow paths in SM plot was approximately twice that of the SS and SF plots, and the preferential flow paths in SM plot, regardless of pore size, were all in an aggregated distribution. These findings indicated that differences in soil physical properties and vegetation coverage at different slope positions lead to variations in the spatial distribution and association of soil preferential flow paths. Accordingly, strategies must be modified for the distribution, storage and utilisation of soil water resources. This study provides a theoretical basis for the effective management and protection of water resources in the Simian Mountain area and a scientific basis for exploring the mechanisms of the occurrence and development of the water cycle in forested watersheds.
6-Gingerol (6-G) is the main bioactive component in Ginger (Zingiber officinale Roscoe). The aim of this study was to explore the contribution of macrophage polarization in 6-G-associated anti-cancer effects. In a urethane-induced lung carcinogenic model, lung carcinogenesis was positively correlated with macrophage (F4/80+) infiltration in lung interstitial in the control group. Furthermore, higher numbers of arginase+/F4/80+ M2 cells than iNOS+/F4/80+ M1 cells were observed in interstitial macrophages. Moreover, macrophage depletion by liposome-encapsulated clodronate (LEC) could significantly prevent lung carcinogenesis, whereas pexidartinib promoted lung carcinogenesis. After 6-G treatment, lung carcinogenesis was ameliorated with increased M1 macrophages and decreased M2 macrophages in the lung interstitial. ELISA showed that the levels of IFN-γ and IL-12 increased and the levels of IL-10 and TGF-β1 decreased in the alveolar cavity compared to those in the control group. Unexpectedly, the carcinogenesis-preventing efficacy of 6-G was promoted in LEC-treated mice, but completely aborted in pexidartinib-treated mice. In the in vitro experiment, 6-G reset the IL-4-induced arginase+ M2 cells toward iNOS+ M1 cells and exhibited reduced levels of arginase 1 and ROS and elevated levels of L-arginine and NO. LEC and nor-NOHA selectively suppressed M2 macrophages but had a negligible effect on M1 macrophages, whereas pexidartinib decreased both M2 and M1 macrophages. The iNOS+ macrophage-promoting efficacy of 6-G was increased by LEC, but was completely eliminated by pretreatment with pexidartinib or nor-NOHA. M2 macrophage-resetting efficacy of 6-G was confirmed in a Lewis lung cancer allograft model. This study indicated a reprogramming effect of 6-G as an arginase inhibitor on tumor supporting macrophages.
T-2 toxin is a mycotoxin produced by the Fusarium genus of molds, often contaminating cereal-based foods, with detrimental effects on human health such as nausea, vomiting, and long-term immune suppression. Highly sensitive detection of this toxin is vital for food safety and public health. In this work, a digital aptasensor is developed for the ultrasensitive detection of T-2 toxin by combining aptamer and single-molecule array technology. Initially, T-2 toxin competed with the biotin-labeled complementary sequence probe to bind the T-2 toxin aptamer. The free biotin-labeled probe was then hybridized with a capture probe modified on the magnetic beads to form a stable double-stranded structure. After combining with streptavidin-enzyme, the structure was used for fluorescence imaging analysis via single-molecule microwell arrays. By correlating the concentration of T-2 toxin with the number of fluorescent microtiter wells, the ultra-sensitive detection of the T-2 toxin was realized. The developed digital aptasensor has demonstrated remarkable sensitivity toward T-2 toxin, with a detection range between 0.16 and 300 pM (approximately 0.075-140 pg/mL) and a detection limit of 44.5 fM (approximately 20.8 fg/mL). Additionally, 87.0%-103.1% recoveries were obtained from spiked samples in cereal-based foods. This work offers a highly effective approach to detecting trace amounts of T-2 toxin, which has the potential to be used for enhancing food safety protocols, providing a powerful tool for industries and regulatory agencies to protect public health.
Abstract: NUT (nuclear protein in testis) midline carcinoma is a rare malignant tumor arising in midline structures, such as head, neck and mediastinum. In the 2015 WHO classification of lung tumours, it was categorized in "Epithelial tumors". However, because of limited clinical data, its biological features have not been fully recognized. We report a case of NUT midline carcinoma presented as a primary lung tumor. Pneumonectomy was performed without any neoadjuvant therapy and it turned out to be a gross total resection. Even so, the prognosis is poor with a disease-free survival of 2 months and an overall survival of 6 months.
Ethnopharmacological relevance: Atractylodes macrocephala Koidz (AMK) and Paeonia lactiflora Pall (PLP), frequently used traditional Chinese medicine (TCM) in treatment of gastrointestinal disease, exerted predominate efficacies in colitis treatment. Meanwhile, AMK and PLP were normally used synergistically due to their similar and strong pharmacological effects clinically, but only certain patients will benefit from this combination.Aim of the study: To systematically explore the pharmacological effect of the combination of AMK and PLP in treating colitis, we used DSS-induced colitis model, either in alone or combined prescriptions.Materials and methods: For the in vivo animal experiment, colitis mice model was established using 2.5% DSS drinking water, AMK-PLP herb pair and corresponding single drugs were administrated daily. Weight changes, disease-activity (DAI) score, colon length and histopathology of colon were the parameters to evaluate colitis model and therapeutic effects. Bioinformatics tools were used to explore the underlying mechanism of combined use of AMK and PLP. After prediction of compounds and targets, we screened core targets of AMK and PLP, molecular docking was conducted. And targets shared by AMK-PLP herb pair and exclusively in AMK or PLP were analyzed separately.Results: Through colitis mice model, we found that when treated with single herb, the significant effects could be observed, while for combination, the strong effects from single herb were attenuate dramatically, either in colon shortening preventing effect or DAI score. As for study of network pharmacology, 16 core targets were overlapped in AMK and PLP, among these targets and 10 of key components, scopoletin from AMK, and sitogluside from PLP simultaneously targeting AKT1 at similar binding pocket, which would attribute to the attenuated effects via exhibiting competitive inhibition. Furthermore, targets exclusively belonged to AMK or PLP targeting MAPK and the toll-like receptor pathways seemed to exert opposite effects, which would alternate clue for the antagonism of AMK and PLP.Conclusions: In summary, our study indicated that AMK and PLP alone could exert strong anti-colitis effects, but that of which was significantly attenuated by their combination, and the competitive binding to AKT1 and opposite effects in MAPK and toll-like receptor pathways would the novel mechanism underlying. Our study not only provide the first evidence for understanding the combined effect of AMK and PLP, but also bring up a new strategy and suggestive thoughts for reconsideration of the rational of herbal pairs used frequently in TCM.
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