Outcomes of Salvage Surgery Versus Non-Salvage Surgery for Initially Unresectable Hepatocellular Carcinoma After Conversion Therapy with Transcatheter Arterial Chemoembolization Combined with Lenvatinib Plus Anti-PD-1 Antibody: A Multicenter Retrospective Study.

BACKGROUND: Combination treatment with transcatheter arterial chemoembolization (TACE), lenvatinib, and anti-programmed death-1 (anti-PD-1) antibodies (triple therapy) has a high rate of tumor response and converted resection for initially unresectable hepatocellular carcinoma (uHCC) patients. This study aimed to assess the outcomes of salvage surgery in uHCC patients after conversion therapy with triple therapy. METHODS: uHCC patients who met the criteria for hepatectomy after receiving triple therapy as first-line treatment were eligible for inclusion in this study. The overall survival (OS) and progression-free survival (PFS) rates in patients who received salvage surgery (SR group) and those who did not (non-SR group) were compared. RESULTS: Of the 144 patients assessed, 91 patients underwent salvage surgery and 53 did not. The OS rates in the SR group were significantly better than those in the non-SR group. The 1- and 2-year OS rates in the SR group were 92.0% and 79.9%, respectively, whereas those in the non-SR group were 85.5% and 39.6 %, respectively (p = 0.007); however, there was no significant difference in the PFS rates. Upon further stratification, OS and PFS were significantly better in the SR group than in the non-SR group in patients who were assessed as partial responses (PR), while there was no significant difference in patients who were assessed as complete response (CR). CONCLUSIONS: Salvage surgery is recommended and is associated with a favorable prognosis for uHCC patients who were assessed as PR after conversion therapy, however it may not be necessary for uHCC if CR was achieved.

Antinociceptive iridoid glycosides from the aerial parts of Paederia foetida.

Two previously undescribed iridoid glycosides, 6'-O-trans-feruloyl-(4S,6R)-3,4-dihydro-3ß-ethoxypaederoside (1) and 6'-O-trans-caffeoyl-(4S,6R)-3,4-dihydro-2'-O-3α-paederoside (2), were isolated from the 90% EtOH extract of the air dried aerial parts of Paederia Foetida. Structural elucidation of all the compounds was performed by spectral methods such as 1D and 2D (1H-1H COSY, HMQC, and HMBC) NMR spectroscopy. The two isolated iridoid glycosides were tested in vivo for their antinociceptive properties. As a result, 2 showed potent antinociceptive effect and its ID50 value (53.4 µmol/kg) was 2-fold less than those of the positive control drugs aspirin and acetaminophen.

Antimicrobial limonoids from the seeds of Cipadessa cinerascensa.

Phytochemical investigation on the 90% EtOH extract of the seeds of Cipadessa cinerascensa led to the isolation of three new limonoids, cinerascenoids A-C (1-3). Structural elucidation of all the compounds were performed by spectral methods such as 1 D and 2 D (1H-1H COSY, HMQC, and HMBC) NMR spectroscopy. All the limonoids were in vitro evaluated for their antimicrobial activities against six pathogenic microorganisms. Limonoids 1 and 2 exhibited some activities against three Gram negative bacteria with MIC values less than 60 µg/ml.

[The distribution of Mas-related G protein-coupled receptor A in cerebrospinal fluid-contacting nucleus of normal rats and its up-regulation in neuropathic pain].

This study was aimed to observe the distribution of Mas-related G protein-coupled receptor A (MrgA) in cerebrospinal fluid (CSF)-contacting nucleus of normal rats and its expression in neuropathic pain, and to provide morphological evidence for CSF-contacting nucleus to participate in neuropathic pain. The model of neuropathic pain with chronic constriction injury (CCI) of the sciatic nerve was made in Sprague-Dawley rats. The thermal withdrawal latency (TWL) and mechanical withdrawal threshold (MWT) were measured. The expressions of MrgA in the CSF-contacting nucleus were examined by double labeling with immunofluorescent staining. The results showed that on the 5th, 7th, 10th and 14th days, the values of MWT and TWL in CCI group were all lower than those in sham group (P < 0.05). MrgA was found to be distributed in CSF-contacting nucleus of normal rats; and the expression was markedly up-regulated in rats at the peak of neuropathic pain. Our data suggest that CSF-contacting nucleus may participate in neuropathic pain through the MrgA-mediated signaling pathway.

Cancer-associated fibroblasts impact the clinical outcome and treatment response in colorectal cancer via immune system modulation: a comprehensive genome-wide analysis.

BACKGROUND: Cancer-associated fibroblasts (CAFs) in the tumour microenvironment are associated with poor prognosis and chemoresistance in multiple solid tumours. However, there is a lack of universal measures of CAFs in colorectal cancer (CRC). The aim of this study was to assess the utility of a fibroblast-related gene signature (FRGS) for predicting patient outcomes and reveal its relevant mechanism. METHODS: The GSE39582 dataset, which includes 316 CRC patients who did not receive adjuvant chemotherapy was used as a discovery cohort to identify the prognostic fibroblast-related genes (FRGs). A total of 1352 CRC patients were divided into one training cohort (GSE39582, n = 461) and two validation cohorts (TCGA, n = 338; meta-validation, n = 553) for the construction of the FRGS and the verification of its prognostic value in stage II/III CRC patients. Functional annotation and analysis were performed to explore the underlying mechanism. The ability of the FRGS to predict immunotherapy response was further tested in a clear cell renal cell carcinoma (ccRCC) cohort. RESULTS: An 11-gene signature that had prognostic value for stage II/III CRC patients in both validation cohorts was developed (TCGA cohort: HR = 1.90, 95% CI 1.16-3.12, P < 0.01; meta-validation cohort: HR = 1.95, 95% CI 1.39-2.73, P < 0.001). A high level of CAFs was correlated with worse prognosis in CRC patients who did not receive adjuvant chemotherapy (HR = 3.63, 95% CI 2.24-5.88, P < 0.001). Importantly, patients in the low-risk group were found to be benefit from chemotherapy (P < 0.01), but not in the high CAF group (P > 0.05). Similar results were found in the TCGA cohort. Integrated with clinical characteristics, the FRGS was confirmed to be an independent prognostic factor in the multivariate analysis after adjustment for tumour TNM stage (GSE39582 cohort: HR = 3.19, 95% CI 1.88-5.41, P < 0.001; TCGA cohort: HR = 5.00, 95% CI 1.58-15.85, P = 0.007; meta-validation cohort: HR = 2.99, 95% CI 1.44-6.21, P = 0.003). Furthermore, the enrichment analysis found that the antitumour immune response was suppressed and the infiltration of CD4 T cells and M1 macrophages was depressed in the high CAF group. The FRGS was also found to have value in predicting for immunotherapy response in the ccRCC cohort. CONCLUSIONS: The 11-gene FRGS had independent prognostic value for CRC patients, as well as utility in the prediction of benefit from chemotherapy. CAFs in the tumour microenvironment might have an impact on the prognosis of CRC patients via inhibiting immune response.

Protein-protein interaction analysis reveals a novel cancer stem cell related target TMEM17 in colorectal cancer.

BACKGROUND: Cancer stem cells (CSCs) are a small subpopulation of cells within tumors with stem cell property. Increased evidence suggest that CSCs could be responsible for chemoresistance and recurrence in colorectal cancer (CRC). However, a reliable therapeutic target on CSCs is still lacking. METHODS: Here we describe a two-step strategy to generate CSC targets with high selectivity for colon stem cell markers, specific proteins that are interacted with CSC markers were selected and subsequently validated in a survival analysis. TMEM17 protein was found and its biological functions in CRC cells were further examined. Finally, we utilized the Gene Set Enrichment Analysis (GSEA) to investigate the potential mechanisms of TMEM17 in CRC. RESULTS: By combining protein-protein interaction (PPI) database and high-throughput gene profiles, network analysis revealed a cluster of colon CSCs related genes. In the cluster, TMEM17 was identified as a novel CSCs related gene. The results of in-vitro functional study demonstrated that TMEM17 depletion can suppress the proliferation of CRC cells and sensitize CRC cells to chemotherapy drugs. Enrichment analysis revealed that the expression of TMEM17 is associated with the magnitude of activation of the Wnt/ß-catenin pathway. Further validation in clinical samples demonstrated that the TMEM17 expression was much higher in tumor than normal tissue and was associated with poor survival in CRC patients. CONCLUSION: Collectively, our finding unveils the critical role of TMEM17 in CRC and TMEM17 could be a potential effective therapeutic target for tumor recurrence and chemoresistance in the colorectal cancer (CRC).

Paenibacillus oceani sp. nov., isolated from surface seawater.

A Gram-stain-positive and motile bacterial strain, designated IB182363T, was isolated from surface seawater of the South China Sea. Cells grew at pH 5.0-9.5 (optimum, pH 7.0-8.0), 20-40 °C (optimum, 30 °C) and with 1-8 % (w/v) NaCl (optimum, 2-4 %). On the basis of 16S rRNA gene sequence analysis, strain IB182363T was affiliated to the genus Paenibacillus and the closest phylogenetically related species was Paenibacillus ginsengarvi DSM18677T with 96.9 % sequence similarity. The values of whole genome average nucleotide identity analysis and digital DNA-DNA hybridization between the isolate and the closely related type strains were less than 86.3 and 25.6 %, respectively. Chemotaxonomic analysis revealed that strain IB182363T possessed meso-diaminopimelic acid in the cell-wall peptidoglycan and contained menaquinone MK-7 as the predominant isoprenoid quinone. The major cellular fatty acids were anteiso-C15 : 0, C16 : 0 and iso-C16 : 0. The polar lipids comprised phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol, one unidentified glycolipid, two unidentified aminolipids, two unidentified phospholipids and four unidentified aminophospholipids. The genomic DNA G+C content was 54.5 mol%. On the basis of the above results, strain IB182363T represents a novel species of the genus Paenibacillus, for which we propose the name Paenibacillus oceani sp. nov. with the type strain IB182363T (=MCCC 1K04630T=JCM 34214T).

Anti-Inflammatory Effects of Mytilus coruscus Polysaccharide on RAW264.7 Cells and DSS-Induced Colitis in Mice.

Considerable literature has been published on polysaccharides, which play a critical role in regulating the pathogenesis of inflammation and immunity. In this essay, the anti-inflammatory effect of Mytilus coruscus polysaccharide (MP) on lipopolysaccharide-stimulated RAW264.7 cells and a dextran sulfate sodium (DSS)-induced ulcerative colitis model in mice was investigated. The results showed that MP effectively promoted the proliferation of RAW264.7 cells, ameliorated the excessive production of inflammatory cytokines (TNF-α, IL-6, and IL-10), and inhibited the activation of the NF-κB signaling pathway. For DSS-induced colitis in mice, MP can improve the clinical symptoms of colitis, inhibit the weight loss of mice, reduce the disease activity index, and have a positive effect on the shortening of the colon caused by DSS, meliorating intestinal barrier integrity and lowering inflammatory cytokines in serum. Moreover, MP makes a notable contribution to the richness and diversity of the intestinal microbial community, and also regulates the structural composition of the intestinal flora. Specifically, mice treated with MP showed a repaired Firmicutes/Bacteroidetes ratio and an increased abundance of some probiotics like Anaerotruncus, Lactobacillus, Desulfovibrio, Alistipe, Odoribacter, and Enterorhabdus in colon. These data suggest that the MP could be a promising dietary candidate for enhancing immunity and protecting against ulcerative colitis.

Hypoxic tumor microenvironment activates GLI2 via HIF-1α and TGF-ß2 to promote chemoresistance in colorectal cancer.

Colorectal cancer patients often relapse after chemotherapy, owing to the survival of stem or progenitor cells referred to as cancer stem cells (CSCs). Although tumor stromal factors are known to contribute to chemoresistance, it remains not fully understood how CSCs in the hypoxic tumor microenvironment escape the chemotherapy. Here, we report that hypoxia-inducible factor (HIF-1α) and cancer-associated fibroblasts (CAFs)-secreted TGF-ß2 converge to activate the expression of hedgehog transcription factor GLI2 in CSCs, resulting in increased stemness/dedifferentiation and intrinsic resistance to chemotherapy. Genetic or small-molecule inhibitor-based ablation of HIF-1α/TGF-ß2-mediated GLI2 signaling effectively reversed the chemoresistance caused by the tumor microenvironment. Importantly, high expression levels of HIF-1α/TGF-ß2/GLI2 correlated robustly with the patient relapse following chemotherapy, highlighting a potential biomarker and therapeutic target for chemoresistance in colorectal cancer. Our study thus uncovers a molecular mechanism by which hypoxic colorectal tumor microenvironment promotes cancer cell stemness and resistance to chemotherapy and suggests a potentially targeted treatment approach to mitigating chemoresistance.