Patient-derived tumor organoids predict responses to irinotecan-based neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer.

Adding irinotecan to neoadjuvant chemoradiotherapy (nCRT) in locally advanced rectal cancer (LARC) increases the pathologic complete response (pCR) rate but brings more toxicities. Robust biomarkers to predict response to irinotecan-based nCRT are extremely necessary for selecting the right patients. Our previous study suggests that patient-derived tumor organoids (PDTOs) sensitivity to chemoradiotherapy matches patient responses. In this study, we investigated whether PDTOs sensitivity to irinotecan can predict complete response (CR) and survival. Eligible patients receiving irinotecan-based nCRT between April 5, 2017 and December 11, 2020 were enrolled in the training cohort (n = 91) for response prediction and survival analysis. Patients receiving nCRT between February 21, 2021 and September 17, 2021 were included in the validation cohort (n = 27). Predictive performances of irinotecan organoid size ratio (OSR) for CR or pCR were evaluated. The irinotecan-sensitive groups had higher response rates compared with the insensitive groups (training cohort: 71.8% vs 24.4%, P < .0001; validation cohort, 81.8% vs 18.8%, P = .002). Moreover, the irinotecan-sensitive group had higher rates of 3-year disease-free survival (DFS: 71.6% vs 55.5%, P = .034) and distant metastasis-free survival (DMFS, 77.9% vs 57.2%, P = .015) than the irinotecan-insensitive group. 5-FU and irradiation sensitivities failed to predict 3-year DFS (5-FU: 65.4% vs 61.9%, P = .643; irradiation: 84.8% vs 57.8%; P = .072). Performances of irinotecan OSR to predict CR or pCR were good in the training cohort (CR: AUC = 0.828; 95% CI = 0.723-0.932; pCR: AUC = 0.864; 95% CI = 0.759-0.961). The validation showed robust predictive ability (CR: AUC = 0.796, 95% CI = 0.5974-0.9952; pCR: AUC = 0.917, 95% CI = 0.7921-1.0000). Irinotecan sensitivity in PDTOs was a predictive and prognostic factor in LARC.

Deep-learning-based analysis of preoperative MRI predicts microvascular invasion and outcome in hepatocellular carcinoma.

BACKGROUND: Preoperative prediction of microvascular invasion (MVI) is critical for treatment strategy making in patients with hepatocellular carcinoma (HCC). We aimed to develop a deep learning (DL) model based on preoperative dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to predict the MVI status and clinical outcomes in patients with HCC. METHODS: We retrospectively included a total of 321 HCC patients with pathologically confirmed MVI status. Preoperative DCE-MRI of these patients were collected, annotated, and further analyzed by DL in this study. A predictive model for MVI integrating DL-predicted MVI status (DL-MVI) and clinical parameters was constructed with multivariate logistic regression. RESULTS: Of 321 HCC patients, 136 patients were pathologically MVI absent and 185 patients were MVI present. Recurrence-free survival (RFS) and overall survival (OS) were significantly different between the DL-predicted MVI-absent and MVI-present. Among all clinical variables, only DL-predicted MVI status and a-fetoprotein (AFP) were independently associated with MVI: DL-MVI (odds ratio [OR] = 35.738; 95% confidence interval [CI] 14.027-91.056; p < 0.001), AFP (OR = 4.634, 95% CI 2.576-8.336; p < 0.001). To predict the presence of MVI, DL-MVI combined with AFP achieved an area under the curve (AUC) of 0.824. CONCLUSIONS: Our predictive model combining DL-MVI and AFP achieved good performance for predicting MVI and clinical outcomes in patients with HCC.

MNS1 promotes hepatocarcinogenesis and metastasis via activating PI3K/AKT by translocating ß-catenin and predicts poor prognosis.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is a fatal disease characterized by vast molecular heterogeneity. Although major advances in tumour genetics has led to the identification of new biomarkers, the prognosis of patients with HCC remains dismal. METHODS: Quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and western blot (WB) were used to evaluate meiosis-specific nuclear structural 1 (MNS1) expression in HCC cells. Immunohistochemistry staining was used to evaluate MNS1 expression in HCC tissues. Clinical significance of MNS1 was evaluated by Cox regression analysis. Transwell assays were conducted to assess cells migration ability. Cell counting kit-8 and colony formation assays were performed to detect cells proliferation ability. NOD/SCID/γc(null) (NOG) mice model was adopted to investigate functions of MNS1 in vivo. RESULTS: The expression of MNS1, which is elevated in most HCC tissues, correlated with poor survival in HCC patients. Functional experiments revealed the oncogenic role of MNS1, which promotes HCC growth and metastasis through AKT-dependent modulation of ß-catenin. ß-Catenin expression was crucial for MNS1's oncogenic effects. MNS1 indirectly translocated ß-catenin from the cytoplasm to the nucleus via the MNS1-GSK3ß axis. CONCLUSIONS: MNS1 promotes HCC growth and metastasis via activating PI3K/AKT signalling and may serve as an important prognostic biomarker as well as potential novel therapeutic target for HCC.

ROR-α-1 inhibits the proliferation, invasion, and migration of hepatocellular carcinoma MHCC97H via downregulation of chemokine CXCL5.

Hepatocarcinogenesis is a complicated process that is affected by a variety of microenvironmental factors, such as secretory chemokines and cell-extracellular matrix (ECM). Retinoic acid receptor-related orphan receptor (ROR)-α has been shown to attenuate tumor invasiveness by inducing suppressive cell microenvironment, and its low expression was associated with a worse prognosis in HCC patients. In the present study, we attempted to investigate the role and mechanism of the dominant transcript of ROR-α, ROR-α-1, in HCC development and progression. Among the four transcripts (ROR-α-1/-2/-3/-4), overexpression of ROR-α-1 dramatically suppressed the capacity of MHCC97H cells to proliferate, migrate and invade. We analyzed the differentially expressed genes in ROR-α-1-overexpressed and non-overexpressed MHCC97H cells, performed Gene Ontology (GO) enrichment analysis on these differentially-expressed genes, and found out that factors involved in the tumor microenvironment and ECM are related to the anti-tumor effects of ROR-α-1. Among these factors, chemokine CXCL5 was significantly downregulated by ROR-α-1 overexpression. Overexpression of ROR-α-1 remarkably inhibited the capacity of HCC cells to proliferate, migrate, invade, and downregulated the protein levels of ß-catenin, c-Myc, Cyclin D1, and N-cadherin, suggesting the tumor-suppressive role of ROR-α-1 in MHCC97H cells. Moreover, overexpression of CXCL5 dramatically attenuated the suppressive effects of cell proliferation, migration and invasion induced by ROR-α-1 overexpression in MHCC97H, suggesting that ROR-α-1 exerts its anti-tumor effects via downregulating CXCL5. In conclusion, we demonstrate the tumor-suppressive role of ROR-α-1 in MHCC97H cells and that ROR-α-1 might play a tumor-suppressive role via regulation of chemokine CXCL5.

Integrating multiple-level molecular data to infer the distinctions between glioblastoma and lower-grade glioma.

Glioblastomas (GBMs) and lower-grade gliomas (LGGs) are the most common malignant brain tumors. Despite extensive studies that have suggested that there are differences between the two in terms of clinical profile and treatment, their distinctions on a molecular level had not been systematically analyzed. Here, we investigated the distinctions between GBM and LGG based on multidimensional data, including somatic mutations, somatic copy number variants (SCNVs), gene expression, lncRNA expression and DNA methylation levels. We found that GBM patients had a higher mutation frequency and SCNVs than LGG patients. Differential mRNAs and lncRNAs between GBM and LGG were identified and a differential mRNA-lncRNA network was constructed and analyzed. We also discovered some differential DNA methylation sites could distinguish between GBM and LGG samples. Finally, we identified some key GBM- and LGG-specific genes featuring multiple-level molecular alterations. These specific genes participate in diverse functions; moreover, GBM-specific genes are enriched in the glioma pathway. Overall, our studies explored the distinctions between GMB and LGG using a comprehensive genomics approach that may provide novel insights into studying the mechanism and treatment of brain tumors.

Transarterial chemoembolization prior to liver transplantation for patients with hepatocellular carcinoma: A meta-analysis.

BACKGROUND AND AIM: A debate exists over whether using preoperative transarterial chemoembolization for patients with hepatocellular carcinoma before liver transplantation. Numerous studies have been investigating on this, but there is still no unanimous conclusion about the effect of preoperative transarterial chemoembolization. We conducted the meta-analysis of all available studies to systematically evaluate the influence of preoperative transarterial chemoembolization on liver transplant. METHODS: A systematic search was performed by two authors (Si TF. and Guan RY.) through PubMed, Embase, Cochrane, and Science Citation Index Expanded, combined with Manual Retrieval and Cited Reference Search. The searching cut-off date was 2016/07/31, and all the data obtained were statistically analyzed using Review Manager version 5.1 software (Copenhagen, The Nordic Cochrane Center, The Cochrane Collaboration, 2011) recommended by Cochrane Collaboration. RESULTS: The study showed that there was no difference between the experimental group and the control group on perioperative mortality (RR = 1.10, 95% confidence interval (CI) = [0.49-2.48], P = 0.82) or biliary complications (RR = 0.96, 95%CI = [0.66-1.39], P = 0.83). Preoperative transarterial chemoembolization had no obvious effect on improving overall survival (HR = 1.05, 95%CI = [0.65-1.72], P = 0. 83) but would result in a higher rate of vascular complications (RR = 2.01, 95%CI = [1.23-3.27], P = 0.005) and a reduction of disease free survival (HR = 1.66, 95%CI = [1.02-2.70], P = 0.04). Subgroup analysis also revealed that patients from transarterial chemoembolization group in Asia had a much lower overall survival rate (HR = 2.65, 95%CI = [1.49-4.71], P = 0.0009) compared with the control group. CONCLUSIONS: Considering the possible adverse impacts on liver transplantation and the variation in sensitivity to transarterial chemoembolization, clinicians should be more cautious when considering transarterial chemoembolization as the bridging therapy for patients in the waiting list.

Preoperative transarterial chemoembolization for resectable hepatocellular carcinoma in Asia area: a meta-analysis of random controlled trials.

OBJECTIVE: We aimed to systematically evaluate the influence of preoperative transarterial chemoembolization (TACE) for resectable hepatocellular carcinoma (HCC) on long-term prognosis and perioperative safety. MATERIALS AND METHODS: Databases including PubMed, Embase, Cochrane, Wanfang, CNKI, VIP data were searched, combined with Manual Retrieval and Cited Reference Search to collect the published randomized controlled trial (RCT) about the influence of pre-TACE for curative resection of HCC. The searching cutoff date was 2016/02/25, all the data obtained were statistically analyzed using RevMan5.2 software recommended by Cochrane Collaboration. RESULTS: A total of 5 RCT including 430 (pre-TACE group: 212, surgery alone group: 218) patients were included. The results of meta-analysis showed that: there was no difference between the 2 groups on overall survival (OS) rate [HR 1.25, 95%CI (0.92-1.68)], disease free survival (DFS) rate [HR 0.95 (0.76-1.19)], perioperative mortality rate [OR 0.70 (0.22-2.30)], or blood loss [SMD 0.07 (-0.14-0.29)], whereas the subgroup analysis revealed that pre-TACE would result in longer operation time [SMD 0.31 (0.06-0.57)], higher postoperative morbidity rate [OR 1.90 (1.02-3.53)] and combined resection rate of perihepatic organs [OR 5.46 (2.73-11.78)] in subgroup with mean tumor diameter >5cm. CONCLUSIONS: According to our study, pre-TACE treatment cannot improve the long-term prognosis of resectable HCC. With the growth of the tumor diameter, especially when it is over 5cm, it might add difficulties to surgery and affect the perioperative safety.

Interleukin-33 Potentiates TGF-ß Signaling to Regulate Intestinal Stem Cell Regeneration After Radiation Injury.

Epithelial regeneration is critical for barrier maintenance and organ function after intestinal radiation injury. Accumulating evidence indicates that the interleukin family members play critical roles in intestinal stem-cell-mediated epithelial regeneration. However, little is known about the relationship between interleukin 33 (IL-33)/ST2 axis and intestinal regeneration after radiation injury. We demonstrate here that IL-33 expression significantly increased after radiation treatment. Deficiency of IL-33/ST2 promotes intestinal epithelial regeneration, resulting in a reduction of mortality during radiation-induced intestine injury. Using ex vivo organoid cultures, we show that recombinant IL-33 promotes intestinal stem cell differentiation. Mechanistically, the effects of IL-33 were mediated by activation of transforming growth factor-ß signaling. Our findings reveal a fundamental mechanism by which IL-33 is able to regulate the intestinal crypt regeneration after tissue damage.

Antiviral therapy improves postoperative survival of patients with HBV-related hepatocellular carcinoma.

BACKGROUND: We aimed to investigate whether improvements in the prognosis of patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) who have undergone hepatectomy are associated with reductions in the liver inflammation and fibrosis by antiviral therapy (AVT). METHODS: Patients who underwent hepatectomy and re-hepatectomy for HBV-related HCC between 2010 and 2019 were divided into two groups. Histological changes in liver were compared between initial and recurrence stages within each group. Propensity score matching (PSM) analysis was performed to compare prognostic outcomes. RESULTS: After PSM, AVT group showed a significantly better prognosis than did non-AVT group (RFS: 19.1% vs. 5.8%, P = 0.001; OS: 64.0% vs. 43.2%, P < 0.001). The improvements in G and S were independent protective factors for RFS (G: P < 0.001; S: P < 0.001) and OS (G: P = 0.013; S: P < 0.001). CONCLUSIONS: The application of AVT after initial surgery improved liver inflammation and fibrosis, further benefiting long-term outcomes of patients with HBV-related HCC.

The LINC00152/miR-205-5p/CXCL11 axis in hepatocellular carcinoma cancer-associated fibroblasts affects cancer cell phenotypes and tumor growth.

BACKGROUND: CXCL11 has been reported to be up-regulated in hepatocellular carcinoma (HCC) tissues and cancer-associated fibroblasts (CAFs), and CAF-secreted CXCL11 has been found to promote HCC cell proliferation and migration. Knowledge on how CAFs promote HCC progression is imperative for the future design of anti-tumor drugs addressing the high rates of disease recurrence. Herein, we propose a mechanism by which LINC00152 positively regulates CXCL11 expression and, subsequently, HCC cell phenotypes and growth characteristics via miR-205-5p in CAFs. METHODS: The expression of LINC00152, miR-205-5p in HCC/non-cancerous tissues, CAFs/NFs and HCC cell lines was determined by RT-qPCR. The CXCL11 expression and secretion were determined by westernblot and ELISA. Different expressions of LINC00152, CXCL11 and miR-205-5p in CAFs were achieved by transfection with corresponding overexpression/knockdown vectors or mimics/inhibitor. The interactions among LINC00152, miR-205-5p and CXCL11 were confirmed by FISH, luciferase, AGO2 and RNA-pulldown assays. Transwell, colony formation and MTT assays were performed to assess the role of CAFs conditioned medium (CM) in HCC cell phenotype. BALB/c nude mice xenografts were used to determine the role of CAFs on HCC growth in vivo. RESULTS: We found that in vitro, CM from CAFs transfected with sh-LINC00152 dramatically suppressed HCC cell viability, colony formation and migration, and that CM from CAFs transfected with miR-205-5p inhibitor (CAF-CM (miR-205-5p inhibitor)) exerted opposite effects on HCC cell phenotypes. Exogenous overexpression of CXCL11 in CAFs or CAF-CM (miR-205-5p inhibitor) could partially attenuate the effects of LINC00152 knockdown. In contrast, CM from CAFs transfected with LINC00152 dramatically increased HCC cell viability, colony formation and migration, and CM from CAFs transfected with miR-205-5p mimics (CAF-CM (miR-205-5p mimics)) exerted opposite effects on HCC cell phenotypes. Knockdown of CXCL11 in CAFs or CAF-CM (miR-205-5p mimics) could partially attenuate the effects of LINC00152 overexpression. In vivo, LINC00152 knockdown in CAFs inhibited tumor growth in a mouse model, which could be reversed by CXCL11 overexpression in CAFs. Mechanistically, we found that LINC00152 could act as a ceRNA to counteract miR-205-5p-mediated suppression on CXCL11 by directly binding to miR-205-5p and the 3'UTR of CXCL11. CONCLUSION: Our data indicate that a LINC00152/miR-205-5p/CXCL11 axis in HCC CAFs can affect the proliferative and migrative abilities of HCC cells in vitro and HCC tumor growth in vivo.

Assay establishment and validation of a high-throughput organoid-based drug screening platform.

BACKGROUND: Organoids are three-dimensional structures that closely recapitulate tissue architecture and cellular composition, thereby holding great promise for organoid-based drug screening. Although growing in three-dimensional provides the possibility for organoids to recapitulate main features of corresponding tissues, it makes it incommodious for imaging organoids in two-dimensional and identifying surviving organoids from surrounding dead cells after organoids being treated by irradiation or chemotherapy. Therefore, significant work remains to establish high-quality controls to standardize organoid analyses and make organoid models more reproducible. METHODS: In this study, the Z-stack imaging technique was used for the imaging of three-dimensional organoids to gather all the organoids' maximum cross sections in one imaging. The combination of live cell staining fluorescent dye Calcein-AM and ImageJ assessment was used to analyze the survival of organoids treated by irradiation or chemotherapy. RESULTS: We have established a novel quantitative high-throughput imaging assay that harnesses the scalability of organoid cultures. Using this assay, we can capture organoid growth over time, measure multiple whole-well organoid readouts, and show the different responses to drug treatments. CONCLUSIONS: In summary, combining the Z-stack imaging technique and fluorescent labeling methods, we established an assay for the imaging and analysis of three-dimensional organoids. Our data demonstrated the feasibility of using organoid-based platforms for high-throughput drug screening assays.

Dissecting Intra-Tumoral Changes Following Immune Checkpoint Blockades in Intrahepatic Cholangiocarcinoma via Single-Cell Analysis.

Purpose: To dissect the tumor ecosystem following immune checkpoint blockades (ICBs) in intrahepatic cholangiocarcinoma (ICC) at a single-cell level. Methods: Single-cell RNA sequencing (scRNA-seq) data of 10 ICC patients for the ICB clinical trial were extracted from GSE125449 and systematically reanalyzed. Bulk RNA-seq data of 255 ICC patients were analyzed. Infiltration levels of SPP1+CD68+ tumor-associated macrophages (TAMs) were examined by dual immunofluorescence (IF) staining in 264 resected ICC samples. The correlation between SPP1+ TAMs and clinicopathological features as well as their prognostic significance was evaluated. Results: Among the 10 patients, five received biopsy at baseline, and others were biopsied at different timings following ICBs. Single-cell transcriptomes for 5,931 cells were obtained. A tighter cellular communication network was observed in ICB-treated ICC. We found a newly emerging VEGF signaling mediated by PGF-VEGFR1 between cancer-associated fibroblasts (CAFs) and endothelial cells in ICC following ICBs. SPP1 expression was dramatically upregulated, and SPP1+ TAM gene signatures were enriched in TAMs receiving ICB therapy. We also identified SPP1+ TAMs as an independent adverse prognostic indicator for survival in ICC. Conclusion: Our analyses provide an overview of the altered tumor ecosystem in ICC treated with ICBs and highlight the potential role of targeting CAFs and SPP1+TAMs in developing a more rational checkpoint blockade-based therapy for ICC.

BRG1 regulates lipid metabolism in hepatocellular carcinoma through the PIK3AP1/PI3K/AKT pathway by mediating GLMP expression.

BACKGROUND: Brahma-related gene 1 (BRG1) is essential for embryogenesis and cellular metabolism. A deficiency of BRG1 in vivo decreases lipid droplets, but the molecular mechanism underlying its role in lipid metabolism associated with hepatocellular carcinoma (HCC) remains unknown. AIMS: We aimed to determine the role of BRG1 in lipid metabolism in HCC. METHODS: We assessed the differential expression of BRG1 in HCC and adjacent non-tumorous tissues using tissue microarrays. We stained lipid droplets in HCC cells with Bodipy fluorescence and Oil Red O, and verified BRG1 binding to the promoter region of glycosylated lysosomal membrane protein (GLMP) using chromatin immunoprecipitation. RESULTS: The expression of GLMP, a potential lipid metabolism regulator, was suppressed by BRG1 via transcriptional activity. Knockdown of BRG1 decreased lipid droplets, increased GLMP expression and altered the phosphoinositide-3-kinase adaptor protein 1 (PIK3AP1)/phosphatidylinositol-3 kinase (PI3K)/protein kinase B (AKT) pathway in HCC, which further GLMP knockdown partially restored. Thus, GLMP knockdown increased lipid droplets and differentially altered the PI3K/AKT pathway. CONCLUSIONS: Downregulating BRG1 decreased lipid droplet deposition in HCC cells by upregulating GLMP and altering the PI3K/AKT pathway. Both BRG1 and GLMP might serve as therapeutic targets for disorders associated with dysregulated lipid metabolism, such as NAFLD and NAFLD-associated HCC.

Patient-Derived Organoids from Colorectal Cancer with Paired Liver Metastasis Reveal Tumor Heterogeneity and Predict Response to Chemotherapy.

There is no effective method to predict chemotherapy response and postoperative prognosis of colorectal cancer liver metastasis (CRLM) patients. Patient-derived organoid (PDO) has become an important preclinical model. Herein, a living biobank with 50 CRLM organoids derived from primary tumors and paired liver metastatic lesions is successfully constructed. CRLM PDOs from the multiomics levels (histopathology, genome, transcriptome and single-cell sequencing) are comprehensively analyzed and confirmed that this organoid platform for CRLM could capture intra- and interpatient heterogeneity. The chemosensitivity data in vitro reveal the potential value of clinical application for PDOs to predict chemotherapy response (FOLFOX or FOLFIRI) and clinical prognosis of CRLM patients. Taken together, CRLM PDOs can be utilized to deliver a potential application for personalized medicine.

Cancer-associated fibroblast-derived CXCL11 modulates hepatocellular carcinoma cell migration and tumor metastasis through the circUBAP2/miR-4756/IFIT1/3 axis.

Cancer-associated fibroblasts (CAFs) are commonly acquired activated extracellular matrix (ECM)-producing myofibroblasts, a phenotypes with multiple roles in hepatic fibrogenesis and carcinogenesis via crosstalk with cohabitating stromal/cancer cells. Here, we discovered a mechanism whereby CAF-derived cytokines enhance hepatocellular carcinoma (HCC) progression and metastasis by activating the circRNA-miRNA-mRNA axis in tumor cells. CAFs secreted significantly higher levels of CXCL11 than normal fibroblasts (NFs), and CXCL11 also had comparatively higher expressions in HCC tissues, particularly in metastatic tissues, than para-carcinoma tissues. Both CAF-derived and experimentally introduced CXCL11 promoted HCC cell migration. Likewise, CAFs promoted tumor migration in orthotopic models, as shown by an increased number of tumor nodules, whereas CXCL11 silencing triggered a decrease of it. CXCL11 stimulation upregulated circUBAP2 expression, which was significantly higher in HCC tissues than para-carcinoma tissues. Silencing circUBAP2 reversed the effects of CXCL11 on the expression of IL-1ß/IL-17 and HCC cell migration. Further downstream, the IFIT1 and IFIT3 levels were significantly upregulated in HCC cells upon CXCL11 stimulation, but downregulated upon circUBAP2 silencing. IFIT1 or IFIT3 silencing reduced the expression of IL-17 and IL-1ß, and attenuated the migration capability of HCC cells. Herein, circUBAP2 counteracted miR-4756-mediated inhibition on IFIT1/3 via sponging miR-4756. miR-4756 inhibition reversed the effects induced by circUBAP2 silencing on the IL-17 and IL-1ß levels and HCC cell migration. In orthotopic models, miR-4756 inhibition also reversed the effects on metastatic progression induced by silencing circUBAP2.

Glioblastoma stem cells and Wnt signaling pathway: molecular mechanisms and therapeutic targets.

Glioblastoma is the most common form of primary brain tumor. Glioblastoma stem cells play an important role in tumor formation by activation of several signaling pathways. Wnt signaling pathway is one such important pathway which helps cellular differentiation to promote tumor formation in the brain. Glioblastoma remains to be a highly destructive type of tumor despite availability of treatment strategies like surgery, chemotherapy, and radiation. Advances in the field of cancer biology have revolutionized therapy by allowing targeting of tumor-specific molecular deregulation. In this review, we discuss about the significance of glioblastoma stem cells in cancer progression through Wnt signaling pathway and highlight the clinical targets being potentially considered for therapy in glioblastoma.

Clinical significance of herpes virus entry mediator expression in hepatitis B virus-related hepatocellular carcinoma.

Herpes virus entry mediator (HVEM) is overexpressed in several malignancies, including hepatocellular carcinoma (HCC). However, to the best of our knowledge, the clinical significance of HVEM in hepatitis B virus (HBV)-related HCC remains unclear. Thus, the present study aimed to explore the clinical significance of HVEM in HBV-related HCC. In the present study, HVEM expression was evaluated in HCC cell lines and HCC frozen samples. The prognostic value of HVEM was assessed in a cohort of 221 patients with HBV-related HCC, following radical resection. B- and T-lymphocyte attenuator (BTLA) expression in subsets of CD8+ T cells was determined via flow cytometry analysis. The results demonstrated high HVEM expression in HCC cell lines, and in HCC tissues compared with paired non-cancerous liver tissues. HVEM expression was demonstrated to be significantly associated with tumor encapsulation and vascular invasion. Furthermore, tumor HVEM status was significantly associated with infiltration of regulatory T cells, but not with CD8+ T cells. Notably, high HVEM expression in HCC was determined to be an independent predictor of an unfavorable outcome of patients with HCC following radical resection. Higher BTLA expression (the receptor of HVEM) was observed in both HCC-infiltrating CD8+ effector memory (CCR7- CD45RA-) and CD45RA+ effector memory (CCR7- CD45RA+) T cells in HCC tissues and blood compared with those in paired peritumor tissues or peripheral blood. Taken together, the results of the present study suggest that HVEM may serve a critical role in HBV-related HCC, most likely by promoting tumor progression and tumor immune evasion, thus the HVEM/BLTA signaling pathway may be a potential target in tumor immunotherapy.

Hepatic stellate cells promote the progression of hepatocellular carcinoma through microRNA-1246-RORα-Wnt/ß-Catenin axis.

Hepatic stellate cells (HSCs) play vital roles in tumorigenesis and progression of hepatocellular carcinoma (HCC). However, there remains a lack of high-throughput studies on gene expression alterations in HCC cells in response to direct interactions with HSCs. In this study, we established a direct co-culture model of HSCs and HCC cells. We found that the expression of a set of miRNAs, most notably miR-1246, was triggered by HSCs. RORα was confirmed as the target gene of miR-1246. Either overexpression of miR-1246 or knockdown of RORα enhanced the proliferation, invasiveness, and metastatic capability of HCC both in vitro and in vivo, through Wnt/ß-catenin pathway activation and promotion of epithelial-mesenchymal transition (EMT). Moreover, upregulation of miR-1246 and repression of RORα were prominent features of aggressive clinical HCC. The miR-1246-RORα-Wnt/ß-catenin axis is a novel pathway through which HSCs accelerate HCC progression.

Clinical efficacy of robot-assisted versus laparoscopic liver resection: a meta analysis.

To compare the clinical efficacy and safety of robotic-assisted liver resection (RLR) and laparoscopic liver resection (LLR) by the means of meta-analytical techniques. We searched PubMed, Cochrane library, Embase and Web of Science databases, collecting randomized or non-randomized studies about robotic-assisted and laparoscopic liver resections. The searching cutoff date was 2017/6/30, all the data obtained were statistically analyzed using RevMan5.3 software recommended by Cochrane Collaboration. A total of thirteen articles, involving 938 patients were enrolled in meta-analysis. Among them, 435 cases underwent RLR, and 503 cases underwent LLR. Compared with LLR, the RLR had longer operative time [MD=65.49, 95%CI (42.00, 88.98) P＜0.00001＝more intraoperative blood loss [MD=69.88, 95%CI (27.11, 112.65) P=0.001] and a higher cost [MD=4.24, 95%CI (3.08, 5.39) P＜0.00001＝. There were no significant differences between the two groups in transfusion rate, complication rate, conversion rate, the R1 resection rate and hospital stay. In the subgroup analysis of surgery after 2010, a lower conversion rate was observed in RLR, other clinical outcomes are comparable between RLR and LLR. In the subgroup analysis of minor hepatectomy, RLR is still associated with longer operative time, but there is no difference in other outcomes. In the subgroup analysis of left hemihepatectomy or left lateral hepatectomy, RLR is associated with more blood loss. Although RLR associated with Longer operative time and more intraoperative blood loss, it displays the same safety and effectiveness as LLR for hepatectomies. And the high cost is still a major hindrance for the widely application of robotic surgery.

Inferring immune-associated signatures based on a co-expression network in Guillain-Barré syndrome.

OBJECTIVES: Guillain-Barré syndrome (GBS) is a type of acute autoimmune disease, which occurs in peripheral nerves and their roots. There is extensive evidence that suggests many immune-associated genes have essential roles in GBS. However, the associations between immune genes and GBS have not been sufficiently examined as most previous studies have only focused on individual genes rather than their entire interaction networks. MATERIALS AND METHODS: In this study, multiple levels of data including immune-associated genes, GBS-associated genes, protein-protein interaction (PPI) networks and gene expression profiles were integrated, and an immune or GBS-directed neighbour co-expressed network (IOGDNC network) and a GBS-directed neighbour co-expressed network (GDNC network) were constructed. RESULTS: Our analysis shows the immune-associated genes are strongly related to GBS-associated genes whether at the interaction level or gene expression level. Five immune-associated modules were also identified which could distinguish between GBS and normal samples. In addition, functional analysis indicated that immune-associated genes are essential in GBS. CONCLUSIONS: Overall, these results highlight a strong relationship between immune-associated genes and GBS existed and provide a potential role for immune-associated genes as novel diagnostic and therapeutic biomarkers for GBS.