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Background:In patients with hepatocellular carcinoma (HCC), the prognostic role of tumor-infiltrating lymphocytes (TILs) for survival is still controversial. A meta-analysis was performed to investigate the prognostic effect of TILs in HCC.Methods:We identify studies from PubMed, Embase, and the Cochrane Library to evaluate the prognostic value of TILs in patients with HCC. A meta-analysis was conducted to estimate overall survival and disease-free survival. The hazard ratio (HR) and 95% confidence interval (CI) were calculated employing fixed-effect or random-effect models depending on the heterogeneity of the included trials.Results:A total of 7905 patients from 46 observational studies were enrolled. For TILs subsets, the density of CD8+, FOXP3+, CD3+, and Granzyme B+ lymphocytes was significantly associated with improved survival (P < .05). The density of FOXP3+ TILs in intratumor (IT) was the most significant prognostic marker (pooled HR = 1.894; 95% CI = 1.659–2.164; P < .001). Patients with high infiltration of CD8+ TILs in IT (pooled HR = 0.676; 95% CI = 0.540–0.845; P = .001) or in margin of tumor (MT) (pooled HR = 0.577; 95% CI = 0.437–0.760; P < .001) had better OS. The pooled analysis revealed that high density of Granzyme B+ T-lymphocytes in IT was statistically significant associated with better OS (pooled HR = 0.621; 95% CI = 0.516–0.748; P < .001) and DFS (pooled HR = 0.678; 95% CI = 0.563–0.815; P < .001). It was interesting that high density of CD3+ in IT foreboded worse OS (pooled HR = 1.008; 95% CI = 1.000–1.015; P = .037), but better DFS (pooled HR = 0.596; 95% CI = 0.374–0.948; P = .029).Conclusion:Our findings suggested that some TIL subsets could serve as prognostic biomarkers in HCC. High-quality randomized controlled trials are needed to determine if these TILs could serve as targets for immunotherapy in HCC.

Background:In patients with hepatocellular carcinoma (HCC), the clinicopathologic and prognostic roles of tumor-infiltrating CD8+ T cells for survival are still controversial. A meta-analysis was performed to resolve this issue.Methods:We identified studies from PubMed, Embase, and the Cochrane Library to evaluate the clinicopathologic and prognostic value of tumor-infiltrating CD8+ T cells in patients with HCC. A meta-analysis was conducted to estimate clinicopathologic characteristics, overall survival (OS), and disease-free survival. The hazard ratio (HR) and 95% confidence interval (CI) were calculated employing fixed-effect or random-effect models depending on the heterogeneity of the included trials.Results:A total of 3509 patients from 21 observational studies were enrolled. The meta-analysis revealed that high levels of intratumoral CD8+ tumor-infiltrating lymphocytes (TILs) were associated with better OS (OS; HR = 0.676, P = .001) and disease-free survival (disease-free survival [DFS]; HR = 0.712, P = .002). The pooled analysis also demonstrated high density of infiltration of CD8+ TILs in margin of tumor (MT) was statistically significant associated with better OS (HR = 0.577; P <.001). Moreover, the patients with low CD8+ TILs infiltration had negative HBSAg (OR = 1.67, P = .02), large tumor size (OR = 1.74, P <.01), and later TNM stage (OR = 1.70, P <.01).Conclusions:Our findings suggested that low levels of CD8+ TILs predict large tumor size, later TNM stage and might be a promising prognostic factor of HCC especially for Asian patients. High-quality randomized controlled trials are needed to determine if CD8+ TILs could serve as targets for immunotherapy in hepatocellular carcinoma.

Because of the need to develop a vaccine to rapidly protect the civilian population in response to a bioterrorism attack with Bacillus anthracis, we designed AdsechPA, a replication-deficient human serotype 5 adenovirus encoding B. anthracis protective antigen (PA) with codons optimized for expression in mammalian cells. With a single intramuscular administration to mice of 10(9) particle units of AdsechPA, a dose that can be scaled to human use, anti-PA antibodies were evoked more rapidly and at a higher level than with a single administration of the new U.S. military recombinant PA/Alhydrogel vaccine. Importantly, AdsechPA afforded approximately 2.7-fold more protection than the recombinant PA vaccine against B. anthracis lethal toxin challenge 4 weeks after a single vaccination. Even at 11 days postvaccination, AdsechPA provided some survival benefit, whereas the rPA/Alhydrogel vaccine provided none. In the context that equivalent human doses of Ad vectors have already been demonstrated to be safe in humans, a single administration of AdsechPA may provide the means to rapidly protect the civilian population against B. anthracis in response to a bioterrorism attack.

It is generally accepted that PIWI proteins are predominately expressed in the germline but absent in somatic tissues. Their best-characterized role is to suppress transposon expression, which ensures genomic stability in the germline. However, increasing evidence has suggested that PIWI proteins are linked to the hallmarks of cancer defined by Weinberg and Hanahan, such as cell proliferation, anti-apoptosis, genomic instability, invasion and metastasis. This provides new possibilities for anticancer therapies through the targeting of PIWI proteins, which may have fewer side effects due to their potential classification as a CTA (cancer/testis antigen). Furthermore, PIWI has been proposed to act as a diagnostic and prognostic marker for many types of cancer, and even to differentiate early-and late-stage cancers. We herein summarize the latest progress in this exciting field, hoping to encourage new investigations of PIWIs in cancer biology that will help to develop new therapeutics for clinical application.

Background: Recently, the incidence of proximal early gastric cancer (EGC) has been rising rapidly. Prevalent surgical methods are proximal gastrectomy (PG) and total gastrectomy (TG); however, which method is superior remains controversial. We conducted a systematic review and meta-analysis of original articles to compare the short- and long-term clinical outcomes of PG with TG for proximal EGC. Methods: Databases, including PubMed, Embase, Web of Science, and Cochrane Library were searched up to October 2018. The Newcastle-Ottawa scale was utilized to conduct quality assessments, and publication bias was evaluated using Egger test. STATA version 14.0 was used to perform the meta-analysis. Results: A total of 2036 patients with proximal EGC in 18 studies were included in the meta-analysis. The results showed that PG was potentially superior to TG regarding operation time, intraoperative blood loss volume, and long-term nutritional status. Overall survival between the PG and TG groups was not significantly different. PG was associated with a high incidence of 2 kinds of postoperative complications: anastomotic stenosis and reflux esophagitis. However, the incidence of these complications associated with esophagojejunostomy with double-tract reconstruction (DTR) was comparable with that of TG. Conclusions: PG has several advantages over TG for the treatment of proximal EGC, including surgical outcomes and long-term nutritional status. However, anastomotic stenosis and reflux esophagitis frequently occurred in patients undergoing PG. Esophagojejunostomy with DTR could offer a solution to reducing the incidence of these complications.

Hepatocellular carcinoma (HCC) is a common malignancy found worldwide and is associated with a high incidence of metastasis and vascular invasion. Elucidating the molecular mechanisms that underlie HCC tumorigenesis and progression is necessary for the development of novel therapeutics. By analyzing the Cancer Genome Atlas Network (TCGA) dataset, we identified Thrombospondin 4 (THBS4) is significantly overexpressed in HCC samples and is correlated with prognosis. Overexpression of THBS4 was also highly correlated with vascular invasion of advanced HCC. While THBS4 is often overexpressed in HCC it has also been shown to inhibit tumor growth by mediating cell-to-cell and cell-to-matrix interactions. Here, we identified that knockdown of THBS4 inhibits migration and invasion of HCC cells and inhibits HCC induced angiogenesis. MiRNAs are crucial regulators of multiple cellular processes, and aberrant expression of miRNAs has been observed to effect cancer development and progression. We further found that miR-142 is an upstream regulator of THBS4 in HCC cells. Moreover, miR-142 was significantly down-regulated in HCC tissue samples and correlated with overexpression of THBS4. Overexpression of miR-142 inhibited invasion and angiogenesis of HCC cells and re-expression of THBS4 overcame these effects of miR-142 expression. Stable over-expression of miR-142 significantly inhibited tumour growth in a xenograft tumour model through inhibiting THBS4 expression and tumor angiogenesis. In conclusion, our findings indicate that loss of miR-142 results in the over-expression of THBS4, which enhances HCC migration and vascular invasion. Thus, targeting THBS4 or miR-142 may provide a promising therapeutic strategy for treatment of advanced HCC.

Macrophages are essential inflammatory cells which regulate the features of immune reactions within tumors. Many studies have reported their regulatory roles in immunity through cytokines and cell signaling. However, relatively few studies have focused on their metabolic features and mechanisms. We aimed to determine the signaling pathway regulating cell metabolism and the mechanism related to the regulation of human tumor‐associated macrophages (TAMs) in gastric cancer (GC). Tumor‐infiltrated macrophages were isolated from human GC tissues using magnetic beads, gene transcription was determined by real‐time PCR, protein expression was monitored using western blots, metabolites were determined using HPLC, and transcriptional regulation was analyzed by the luciferase‐based reporter gene system. A significant decrease in microRNA (miR)‐30c and an increase in regulated in development and DNA damage responses 1 (REDD1) were detected in human GC TAMs, the transcription of miR‐30c was negatively correlated with REDD1. MicroRNA‐30c expression was suppressed by hypoxia‐inducible factor‐1α activation and related to decreased mTOR activity as well as glycolysis in human GC TAMs. Hypoxia‐regulated miR‐30c downregulated REDD‐1 expression by targeting its 3′UTR. Overexpression of miR‐30c or restored mTOR activity in macrophages with miR‐30cLow expression promoted M1 macrophage differentiation and function in TAMs. Therefore, hypoxia in the human GC microenvironment suppressed the expression of miR‐30c, and decreased mTOR activity as well as glycolysis in GC TAMs, thus inhibiting M1 differentiation and function. These results provide a novel metabolic strategy for tumor microenvironment‐based therapy.