Hepatocellular carcinoma (HCC) is well known for poor prognosis and short survival because of high recurrence rate even after curative surgery. Today there is no available biomarker or biochemical test to indicate HCC recurrence, and this study aims to identify protein markers that can discriminate postoperative patients with early recurrence (ER), i.e. disease relapsed within the first year. In this study, 103 hepatitis B-related HCC patients were recruited, and 68 of them were used for ER-related biomarker discovery study. Proteomic expression patterns of matched tumor and adjacent non-tumor tissues from these patients plus 16 normal liver tissues were delineated by the two-dimensional gel electrophoresis differential profiling method. Significant protein spots were evaluated by hierarchical clustering analysis. SSP4612 that yielded the highest receiver operating characteristic (ROC) curve value for the ER subgroup of HCC was subsequently identified by tandem mass spectrometry, and the corresponding expression patterns were further confirmed by quantitative PCR, Western blot, and immunohistochemistry. Correlation analysis with clinicopathological data was also examined. Proteomic profiling analysis revealed overexpression of mortalin (gene HSPA9) in HCC when compared with the non-tumor and normal liver tissues (area under the curve (AUC) ‫؍‬ 0.821). Furthermore, elevated mortalin level was also detected in the ER subgroup of HCC versus the recurrence-free state (where no cancer recurs for >1 year) (AUC ‫؍‬ 0.833, sensitivity ‫؍‬ 90.9%, specificity ‫؍‬ 71.4%). Metastatic HCC cell lines also exhibited higher levels of mortalin and HSPA9 mRNA. Patients diagnosed with advanced tumor stages and neoplastic metastasis are usually untreatable and very often survive briefly. Liver cancer is one of the prevalent and lethal malignancies and represents a tumor type of highly invasive and aggressive behavior with ability to adapt to new environment. Because of its asymptomatic features during malignant progression, liver cancer is often diagnosed at very late stage when conventional and effective treatment options become unavailable (1).Hepatocellular carcinoma (HCC) 1 is the most common liver malignancy, accounting for the third most common cause of cancer-related deaths worldwide, especially in parts of Asia and Africa with estimated Ͼ680,000 new cases and half million of deaths annually (2, 3). Recent epidemiological studies have also projected an alarming increase of HCC in both Japan and the United States. The only curative treatments for HCC are surgical resection or liver transplantation (4, 5). To date, conventional chemotherapeutic regimen is ineffective against HCC with a response rate between 5-10%, and no single drug or "cocktail" could prolong the patient's survival. Even though after curative surgery, the long-term prognosis of HCC still remains poor, that is largely attributable to the high tumor recurrence rate (about 56% within the first year after surgery) (6).The current paradigm of HCC development is in...

Background Although TP53 co-mutation with KRAS/ATM/EGFR/STK11 have been proved to have predictive value for response to immune checkpoint inhibitors (ICIs), not all TP53 mutations are equal in this context. As the main part of TP53 mutant types, Missense and Nonsense alternations in TP53 as independent factors to predict the response to ICIs within Lung Adenocarcinoma (LUAD) patients have not yet been reported. Methods An integrated analysis based on multiple-dimensional data types including genomic, transcriptomic, proteomic and clinical data from published lung adenocarcinoma data and local database of LUAD taking immune checkpoint inhibitors. Gene set enrichment analysis (GSEA) was used to determine potentially relevant gene expression signatures between specific subgroups. Single-sample GSEA (GSVA) is conducted to calculate the score for enrichment of a set of genes regulating DNA damage repair (DDR) pathway. Findings The TP53-missense-mutation group showed increased PD-L1 (CD274) level and enriched IFN-γ signatures compared with the TP53-wild-type subgroup, but no differences were noted in patients with nonsense-mutant vs wild-type p53. Furthermore, a group of suppressor Immune cells like M2 Macrophage and Neutrophils are found enriched in nonsense group. On the other-side, both TP53 missense and nonsense mutations are associated with elevated TMB and neoantigen levels and contribute equally to DNA damage repair deficiency. The distribution regarding to multi-dimensional factors determining the efficacy of ICIs finally transformed into diverse clinical benefits for LUAD. TP53 missense but not -nonsense Mutants are associated with better clinical benefits taking antiPD-1/1L. However, all such TP53 subgroups responds well to nivolumab (antiPD-L1) plus ipilimumab (antiCTLA-4) therapy. Interpretation Our study demonstrated that not all TP53 mutations are equal in predicting efficacy in patients with LUAD treated with ICIs. Multi-center data showed that TP53 missense and nonsense mutations were significantly different in terms of associations with PD-L1 expression, IFN-γ signatures and TME composition. Special attention should be paid to potential TP53 mutation heterogeneity when evaluating TP53 status as biomarker for ICIs. Funding The study was supported by Key Lab System Project of Guangdong Science and Technology Department – Guangdong Provincial Key Lab of Translational Medicine in Lung Cancer (Grant No. 2017B030314120, to Yi-Long WU)

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Long non-coding RNAs (lncRNAs) have been known to partake in the development and the immune escape of hepatocellular carcinoma (HCC). The initial microarray analysis of GSE115018 expression profile revealed differentially expressed lncRNA fetal-lethal non-coding developmental regulatory RNA (FENDRR) in HCC. Therefore, this study’s main purpose was to explore the mechanism of tumor suppressor lncRNA FENDRR in regulating the immune escape of HCC cells. Notably, it was further validated through this study that lncRNA FENDRR competitively bound to microRNA-423-5p (miR-423-5p), and miR-423-5p specifically targeted growth arrest and DNA-damage-inducible beta protein (GADD45B). The effects that lncRNA FENDRR and miR-423-5p have on the cell proliferation and apoptosis, the immune capacity of regulatory T cells (Tregs), and the tumorigenicity of HCC cells were examined through overexpressing or the knocking down of lncRNA FENDRR and miR-423-5p both in vitro and in vivo . Subsequently, lncRNA FENDRR and GADD45B were revealed to have poor expressions in HCC. Meanwhile, miR-423-5p was highly expressed in HCC. Importantly, overexpressed lncRNA FENDRR and downregulated miR-423-5p diminished cell proliferation and tumorigenicity, and promoted apoptosis in HCC cells, thus regulating the immune escape of HCC mediated by Tregs. Taken conjointly, lncRNA FENDRR inhibited the Treg-mediated immune escape of HCC cells by upregulating GADD45B by sponging miR-423-5p.

Advanced pancreatic cancer has remained challenging to treat effectively. This study aimed to investigate the clinical effects and safety of immunotherapy with dendritic cells and cytokine-induced killer cells (DC-CIK) administered with the chemotherapy (CT) S-1 in this malignancy. Consecutive patients ( = 47) with advanced pancreatic cancer were treated with either DC-CIK + S-1, DC-CIK alone, S-1 alone, or best supportive care. DC-CIK plus S-1 produced significantly longer median OS and PFS (212 and 136 days) compared with DC-CIK (128 and 85 days), CT (141 and 92 days), or supportive care only (52 and 43 days; < 0.001). After adjusting for competing risk factors, DC-CIK combined with S-1 and receipt of 2 or more cycles of DC-CIK treatment remained independent predictors of disease-free and overall survival ( < 0.05). Phenotypic analysis of PBMCs demonstrated that the CD3, CD3/CD4, and CD8/CD28 T-cell subsets were elevated ( < 0.05), while the CD3/CD8, CD3/CD16/CD56 and CD4/CD25 cell subsets were significantly decreased after DC-CIK cell therapy ( < 0.05). There were no grade 3 or 4 toxicities. In addition, the mutational frequency in cell-free tumor DNA (cfDNA) declined in 4 of 14 patients who received DC-CIK, and was associated with a more favorable survival. Treatment of advanced pancreatic cancer with combined DC-CIK infusions and S-1 was safe, resulted in favorable PFS and OS, and modulated the peripheral blood immune repertoire. .

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are the severe lung damage and respiratory failure without effective therapy. However, there was a lack of understanding of the mechanism by which exosomes regulate autophagy during ALI/ARDS. Here, we found lipopolysaccharide (LPS) significantly increased inflammatory factors, administration of exosomes released by human umbilical cord mesenchymal stem cells (hucMSCs) successfully improved lung morphometry. Further studies showed that miR-377-3p in the exosomes played a pivotal role in regulating autophagy, leading to protect LPS induced ALI. Compared to exosomes released by human fetal lung fibroblast cells (HFL-1), hucMSCs-exosomes overexpressing miR-377-3p more effectively suppressed the bronchoalveolar lavage (BALF) and inflammatory factors and induced autophagy, causing recoveration of ALI. Administration of miR-377-3p expressing hucMSCs-exosomes or its target regulatory-associated protein of mTOR (RPTOR) knockdown significantly reduced ALI. In summary, miR-377-3p released by hucMSCs-exosomes ameliorated Lipopolysaccharide-induced acute lung injury by targeting RPTOR to induce autophagy in vivo and in vitro.

Background: Dysphagia may delay the functional recovery and substantially affects the quality of life after stroke, mainly if left untreated. Electrical stimulation has been reported as a treatment for pharyngeal dysphagia in recent studies, but the therapeutic effect of neuromuscular electrical stimulation (VitalStim) therapy lacks convincing supporting evidence and needs further clinical investigation. Methods: A total of 135 subjects were randomly divided into 3 groups: traditional swallowing therapy (n = 45), VitalStim therapy (n = 45), and VitalStim therapy plus traditional swallowing therapy (n = 45). The traditional swallowing therapy included basic training and direct food intake training. Electrical stimulation was applied by an occupational therapist, using a modified handheld battery-powered electrical stimulator (VitalStim Dual Channel Unit and electrodes, Chattanooga Group, Hixson, Tennessee). The surface electromyography (sEMG), standardized swallowing assessment (SSA), videofluoroscopic swallowing study (VFSS), and visual analog scale (VAS) were used to assess swallowing function before and 4 weeks after the treatment. Results: A total of 118 subjects with dysphagia completed the study, 40 in the traditional swallowing group and VitalStim therapy group and 38 in the VitalStim and traditional swallowing therapy group. There were significant differences in sEMG values and SSA and VFSS scores in each group after the treatment (P < .001). After 4-week treatment, sEMG value (917.1; standard deviation [SD], 91.2), SSA value (21.8; SD, 3.5), oral transit time (0.4; SD, 0.1), and pharyngeal transit time (0.8; SD, 0.1) were significantly improved in the VitalStim and traditional swallowing therapy group than in the other 2 groups (P < .001). Conclusions: Data suggest that VitalStim therapy coupled with traditional swallowing therapy may be beneficial for poststroke dysphagia.

High-level tissue tumor mutational burden (tTMB) or blood TMB (bTMB) are associated with better response of immunotherapy in non-small cell lung cancer (NSCLC) patients. However, the correlations of single-region tTMB, multi-region tTMB and bTMB remain to be determined. Moreover, whether intratumor heterogeneity (ITH) has impact on TMB should be clarified. We collected multi-region tumor tissues with matched blood from 32 operative NSCLC and evaluated single-region tTMB, multi-region tTMB and bTMB through a 1021-gene panel sequencing. TMB of > 9 mutations/Mb was classified as high. Besides, we used tTMB fold-change to evaluate the influence of the enrolled region number on tTMB. We found both of single-region tTMB and bTMB showed strong correlations with multi-region tTMB, while the former correlated better (Pearson r = 0.94, P = 2E-84; Pearson r = 0.47, P = 0.0067). It showed extremely high specificity (100%) but low sensitivity (43%) when using bTMB to define TMB-high patients, while most false-negative predictions were in early-stage patients. Compared to single region, we found significantly enhanced tTMB fold-change if taking multi-regions for consideration. However, it showed insignificant tTMB fold-change increase if the included regions’ number more than three. Moreover, ITH-high patients had significantly higher tTMB fold-change compared with ITH-low patients (2.32 vs. 1.02, P = 8.879e-05). The conversion rate of tTMB level (tTMB-low to tTMB-high) was numerically higher in ITH-high group than that in ITH-low group (16.67% vs. 3.84%). In summary, single-region tTMB has stronger correlation with multi-region tTMB compared with bTMB. ITH has an impact on tTMB, especially in high-level ITH patients. Electronic supplementary material The online version of this article (10.1186/s40425-019-0581-5) contains supplementary material, which is available to authorized users.