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Despite the great success of immunotherapy in a small subset of cancer patients, most colorectal cancer (CRC) patients do not respond to programmed cell death receptor 1 (PD‐1) blockade immunotherapy. There is an urgent medical need to elucidate how cancer cells evade immune response and to develop novel means to boost the efficacy of immune checkpoint inhibitors. In this study, alcohol induces ligand programmed cell death receptor 1 (PD‐L1) expression of CRC cells in vitro and in vivo. Alcohol exposure is shown to induce aldehyde dehydrogenase 2 (ALDH2) expression that is a crucial enzyme involved in alcohol metabolism, and low level of lymphocytes infiltration in the murine CRC model and patients. Intriguingly, ALDH2 and PD‐L1 protein expression are positively correlated in tumor tissues from the CRC patients. Mechanistically, ALDH2 stabilizes PD‐L1 protein expression by physically interacting with the intracellular segment of PD‐L1 and inhibiting its proteasome‐dependent degradation mediated by an E3 ubiquitin ligase Speckle Type POZ Protein (SPOP). Importantly, inhibition of ALDH2 reduces PD‐L1 protein in CRC cells and promotes tumor‐infiltrating T cells (TILs) infiltration, presumably leading to the significant potentiation of anti‐PD‐1 antibody efficacy in a mouse CT26 CRC model. The findings highlight a crucial role played by ALDH2 to facilitate alcohol‐mediated tumor escape from immunity surveillance and promote tumor progression., Aldehyde dehydrogenase 2 (ALDH2) promotes alcohol‐mediated immune escape through stabilizing ligand programmed cell death receptor 1 (PD‐L1) protein expression by interacting with the intracellular segment of PD‐L1, thereby inhibiting its ubiquitination mediated by Speckle Type POZ Protein (SPOP). Silencing of ALDH2 significantly sensitizes tumors to PD‐1 blockade therapy.

Background: The current study aimed to establish a novel nomogram to predict the overall survival of individual Chinese patients with gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). Furthermore, this study sought to externally validate this nomogram using the Surveillance, Epidemiology, and End Results (SEER) database. Methods: The records of 1183 patients with GEP-NENs treated at five high-capacity institutions in China between 2005 and 2015 were retrospectively analysed. In addition, 10 236 GEP-NEN cases from the SEER database were included as an external validation set. Results: A multivariate analysis using Cox proportional hazards (PHs) regression was performed, and a nomogram was constructed. Discrimination, calibration, and external validation were performed using the SEER data set. The multivariate Cox model indicated that age, tumour size, differentiation, lymph node metastases, and distant metastases were independent covariates associated with survival. With respect to the training set, the nomogram exhibited better discrimination power than TNM classification (Harrell’s concordance index (C-index): 0.837 vs 0.784, P=0.006). Discrimination was also excellent and superior to that of TNM classification for the SEER-based validation set (C-index: 0.808 vs 0.717, P

Objective To explore the feasibility and safety of using tissue-type plasminogen activator (t-PA) to prevent graft restenosis after coronary artery bypass grafting (CABG). Methods In this prospective observational study, 37 patients underwent CABG between June 2009 and May 2013. These patients were grouped according to the anti-coagulation strategy after surgery: t-PA (n = 12) and conventional treatments (n = 25). In the t-PA group, the patients received acetylsalicylic acid (ASA) and clopidogrel plus intravenous infusion of t-PA (0.25 mg/kg/day) starting at 24 h after surgery and that lasted for 3 days. In the conventional group, the patients received only ASA and clopidogrel. 64-row spiral computed tomographic coronary angiography was performed at 1 week, 1, and 3 months after surgery to evaluate the patency of the graft vessel. Results The mean stenosis severity of the saphenous vein grafts was lower in the t-PA group compared with the conventional group at 3 months after surgery (p 0.05). The patency rate of the grafts was not significantly different between the two groups at 1 week, 1, and 3 months after surgery (p > 0.05). Conclusion Early application of t-PA after CABG was feasible and safe, and might help prevent early restenosis of SV grafts. Additional clinical randomized trials are necessary to address this issue.

Purpose Early-stage hepatocellular carcinoma (E-HCC) is being diagnosed increasingly, and in one half of diagnosed patients, recurrence will develop. Thus, it is urgent to identify recurrence-related markers. We investigated the effectiveness of CpG methylation in predicting recurrence for patients with E-HCCs. Patients and Methods In total, 576 patients with E-HCC from four independent centers were sorted by three phases. In the discovery phase, 66 tumor samples were analyzed using the Illumina Methylation 450k Beadchip. Two algorithms, Least Absolute Shrinkage and Selector Operation and Support Vector Machine-Recursive Feature Elimination, were used to select significant CpGs. In the training phase, penalized Cox regression was used to further narrow CpGs into 140 samples. In the validation phase, candidate CpGs were validated using an internal cohort (n = 141) and two external cohorts (n = 191 and n =104). Results After combining the 46 CpGs selected by the Least Absolute Shrinkage and Selector Operation and the Support Vector Machine-Recursive Feature Elimination algorithms, three CpGs corresponding to SCAN domain containing 3, Src homology 3-domain growth factor receptor-bound 2-like interacting protein 1, and peptidase inhibitor 3 were highlighted as candidate predictors in the training phase. On the basis of the three CpGs, a methylation signature for E-HCC (MSEH) was developed to classify patients into high- and low-risk recurrence groups in the training cohort ( P < .001). The performance of MSEH was validated in the internal cohort ( P < .001) and in the two external cohorts ( P < .001; P = .002). Furthermore, a nomogram comprising MSEH, tumor differentiation, cirrhosis, hepatitis B virus surface antigen, and antivirus therapy was generated to predict the 5-year recurrence-free survival in the training cohort, and it performed well in the three validation cohorts (concordance index: 0.725, 0.697, and 0.693, respectively). Conclusion MSEH, a three-CpG–based signature, is useful in predicting recurrence for patients with E-HCC.

Hepatocellular carcinoma (HCC) is the one of most common and deadly cancers, and is also highly resistant to conventional chemotherapy treatments. Mitochondrial phosphoglycerate mutase/protein phosphatase (PGAM5) regulates mitochondrial homeostasis and cell death, however, little is known about its roles in cancer. The aim of this study was to explore the clinical significance and potential biological functions of PGAM5 in hepatocellular carcinoma. For the first time, our results show that PGAM5 is significantly upregulated in HCC compared with corresponding adjacent noncancerous hepatic tissues and high PGAM5 expression is an independent predictor of reduced survival times in both univariate and multivariate analyses. Additionally, in vivo and in vitro studies showed that depleting PGAM5 expression inhibited tumor growth and increased the 5-fluorouracil sensitivity of HCC cells. Conversely, restoring PGAM5 expression in PGAM5-knockdown cells dramatically enhanced HCC cell resistance to 5-fluorouracil. Importantly, we demonstrated that the mechanism of 5-fluorouracil resistance conferred to HCC cells by PGAM5 was via inhibiting BAX- and cytochrome C-mediated apoptotic signaling by interacting and stabilizing Bcl-xL. Consistently, in the same cohorts of HCC patient tissues, Bcl-xL expression was positively correlated with PGAM5, and together predicted poor prognoses. In Conclusion, Our data highlight the molecular etiology and clinical significance of PGAM5 in HCC. Targeting the novel signaling pathway mediated by PGAM5/Bcl-xL may represent a new therapeutic strategy to improve the survival outcomes of HCC patients.

Hepatocellular carcinoma (HCC) is one of the most lethal malignancies, in which the NF-κB pathway plays an important role and is constitutively activated. Better understanding of the molecular pathogenesis of HCC and the NF-κB pathway are needed to improve patient outcomes. Herein, we identified an unappreciated protein involved in NF-κB-induced activation, Golgi phosphoprotein 3 (GOLPH3). The mRNA and protein expression levels of GOLPH3 were frequently up-regulated in HCC and GOLPH3 expression correlated closely with clinical stage and survival in both the testing and validation cohorts. Ectopic over-expression of GOLPH3 in PLC/PRF/5 (PLC) and Huh7 HCC cells protected against cisplatin-induced apoptosis, promoted angiogenesis and proliferation and increased the aggressiveness of HCC cells in vitro and in vivo, whereas inhibition of GOLPH3 led to decreased aggressiveness. Through analysis of two published HCC patient profiles, GOLPH3 expression significantly correlated with NF-κB signalling. Furthermore, we demonstrated that GOLPH3 promoted K63-linked polyubiquitination of tumour necrosis factor receptor-associated factor 2 (TRAF2), receptor interacting protein (RIP) and NF-κB essential modulator (NEMO) and substantially sustained the activation of NF-κB in HCC cells. Taken together, our findings provided evidence that GOLPH3 is a prognostic and/or potential therapeutic biomarker for HCC patients and plays an important role in activation of the NF-κB pathway during HCC progression.

Cytoplasmic polyadenylation element-binding protein 4 (CPEB4), a zinc-finger-containing sequence-specific RNA-binding protein, has been associated with tumor proliferation, invasion, and migration. Expression of CPEB4 and its prognostic significance in human colorectal cancer (CRC) have not been studied. The aim of the present study was to investigate expression of CPEB4 and its prognostic significance in CRC. Expression of CPEB4 in CRC tissues from two independent cohorts was examined by immunohistochemistry. Prognostic significance was analyzed using receiver operating characteristic curve analysis, Kaplan-Meier curves, and Cox regression analysis. High expression of CPEB4 was observed in 14.8 % of CRCs in the training cohort and 12.2 % of CRCs in the validation cohort. High expression of CPEB4 was significantly correlated with the pM classification, TNM stage, and poorer overall survival in both cohorts. Through multivariate Cox regression analysis, high expression of CPEB4 was found to be an independent prognostic biomarker for overall survival in CRC patients. High expression of CPEB4 may be an independent and useful biomarker for predicting the poor survival of patients with CRC.

Tumor-associated epigenetic alterations including DNA methylation and histone modifications are important determinants in the initiation and progression of hepatocellular cancer (HCC) and represent promising biomarkers and therapeutic targets. Locus-specific trimethylation of histone H3 lysine 4 (H3K4me) is a well-known modification linked to the enhanced transcriptional expression of many genes activated in HCC. Our aim was to assess the cellular expression pattern of H3K4me3 in HCC and its association with clinicopathologic variables and outcome. Expression of H3K4me3 and the histone methyltransferase (HMT) SET and MYND domain-containing protein 3 (SMYD3) was studied by Western blotting and immunohistochemistry in cell lines and tumor tissue microarray from a well-characterized series of HCC patients (n = 168). The optimal cut-point of H3K4me3 expression for prognosis was determined by the X-tile program. The prognostic significance was evaluated using Kaplan-Meier survival estimates and log-rank tests. Tumor tissue microarray from another independent HCC patients cohort (n = 147) was used for validation studies. Expression of H3K4me3 and SMYD3 were enhanced in HCC cell lines. In tumor specimens, enhanced expression of H3K4me3 was correlated with reduced overall survival (P < .0001), especially in early-stage HCC patients (TNM I/II). Furthermore, both univariate and multivariate analyses revealed that H3K4me3 level was a significant and independent predictor of poor survival (hazard ratio, 3.592; 95% confidence interval, 2.302-5.605). In addition, H3K4m3 expression was positively correlated with SMYD3 expression in both testing and validation cohorts (P < .0001). In conclusion, H3K4me3 level defines unrecognized subsets of HCC patients with distinct epigenetic phenotype and clinical outcome and can thus be a novel predictor for poor prognosis of HCC patients, especially at TNM I/II stage.

Objectives: We aimed to investigate the nature of endometrial stromal sarcoma (ESS) arising from endometriosis. Methods: The clinical data of 5 patients with ESS arising from endometriosis were reviewed retrospectively. The expression of CD117, HER2/neu, EGFR, VEGF, and PDGFR was analyzed by immunohistochemical staining. Results: The median age of the 5 patients was 45 years. The primary tumor sites were the ovary in 2, the pelvis in 2, and the cervical canal in 1 patient. Three patients had disseminated disease at diagnosis. Four patients underwent complete tumor resection. All of the 5 cases received adjuvant chemotherapy and 2 received progesterone therapy, while none were treated with radiotherapy. No recurrence occurred in the 4 cases who had complete tumor resection, and the only patient who progressed was the patient in whom the tumor was unresectable. Tumor cells in all cases exhibited positive staining for PDGFR and were negative for CD117 and HER2/neu. The expression of EGFR and VEGF was observed in 2 and 4 cases, respectively. Conclusion: ESS arising from endometriosis is rare. Complete tumor resection in ESS arising from endometriosis may reduce the recurrence rate.

Acylglycerol kinase (AGK) had been shown to contribute to cancer progression and unfavorable clinical outcomes of patients. Our study aimed to investigate the expression pattern and clinical significance of AGK in patients with early-stage cervical squamous cell cancer (CSCC). The protein and messenger RNA (mRNA) expression of AGK was analyzed in six cervical cancer cell lines and four paired early-stage CSCC specimens and normal cervical tissues (NCT), using Western blotting and real-time PCR (RT-PCR). And we investigated the AGK protein expression in paraffin-embedded specimens from 140 patients with early-stage CSCC and 30 cases of NCT by immunohistochemistry (IHC). Statistical analyses were performed to evaluate the clinicopathological significance of AGK expression. The expressions of AGK protein and mRNA were significantly up-regulated in cervical cancer cell lines and cancer tissues. IHC analyses revealed that AGK was highly expressed in 93 (66.4 %) of 140 early-stage CSCC specimens, but in none of the NCT. Moreover, AGK expression in early-stage CSCC was significantly correlated with tumor stage (P

It has been suggested that hexokinase 1 (HK1) is involved in tumorigenesis. However, the expression dynamics of HK1 and its prognostic significance in human colorectal cancer (CRC) still remain unclear. The aim of the present study was to investigate the expression of HK1 and its prognostic significance in CRC. In this study, immunohistochemical analysis was used to examine the expression dynamics of HK1 in CRC tissues from two independent cohorts. Receiver operating characteristic curve analysis, Kaplan-Meier curves, and Cox regression analysis were utilized to investigate the prognostic significance. Results showed that a high expression of HK1 was observed in 106 of 393 (27.0 %) and 69 of 229 (30.1 %) of CRC in the training cohort and validation cohort, respectively. Further correlation analyses indicated that the increased HK1 expression was strongly correlated with the pN classification and TNM stage. Both cohorts showed a close association between the overexpression of HK1 and poorer overall survival. Importantly, multivariate analysis identified HK1 expression in CRC as an independent prognostic factor. Overexpression of HK1 may act as a significant biomarker of poor prognosis for patients with CRC.

Cysteine-rich 61 (CYR61) has been proven to be an oncogene with potential predictive and prognostic implications in a variety of human cancers. However, the expression pattern of CYR61 and its role in ovarian carcinoma remains largely unknown. In this study, the mRNA and protein levels of CYR61 in normal ovaries and ovarian carcinoma tissues were evaluated using reverse transcription-polymerase chain reaction, immunohistochemistry, and Western blotting. Compared to normal ovarian tissues, the mRNA and protein levels of CYR61 were significantly higher in ovarian carcinoma tissues. Moreover, receiver operating characteristic (ROC) curve analysis, Spearman's rank correlation, Kaplan-Meier plots, and the Cox proportional hazards regression model were used to investigate the potential association of the CYR61 protein with the development of ovarian carcinoma in an ovarian carcinoma cohort. Based on ROC curve analysis, high expression of CYR61 was defined as a tumor in which more than 70 % of cells were positively stained. Based on this cutoff value, high expression of CYR61 was detected in 51.5 % of invasive carcinomas, 35.3 % of borderline tumors, 25.9 % of cystadenomas, and 20 % in the normal ovaries. In ovarian carcinomas, CYR61 overexpression was associated with advanced FIGO stage. Univariate survival analysis on the ovarian carcinoma cohorts showed that overexpression of CYR61 was associated with poor survival of ovarian cancer patients. Multivariate analysis suggested that the protein level of CYR61 was an independent and significant prognostic factor for ovarian carcinoma. Our results suggest that the CYR61 protein is an important and independent biomarker for prognostic implications of ovarian carcinoma.

Replication factor C3 (RFC3) is an oncogene that can potentially predict prognosis in a variety of human cancers. RFC3 expression in ovarian carcinoma has not yet been determined. In this study, we evaluated the messenger RNA (mRNA) and protein expression levels of RFC3 in normal ovarian and ovarian carcinoma tissues using reverse transcription-polymerase chain reaction (RT-PCR), immunohistochemistry, and Western blots (WB). Results showed that higher RFC3 mRNA and protein levels were detected in ovarian carcinoma tissues by RT-PCR and WB. High RFC3 expression was defined as positive staining in >70 % of each tumor cell. High RFC3 expression was detected in 28.1, 17.6, 11.1, and 5.0 % of invasive carcinomas, borderline tumors, cystadenomas, and in normal ovary cells, respectively. Overexpression of RFC3 was associated with later pN status (p = 0.001), pM status (p = 0.001), and advanced International Federation of Gynecology and Obstetrics (FIGO) stage (p = 0.012) in ovarian carcinomas. Univariate survival analyses showed that RFC3 overexpression was also associated with shortened patient survival (mean 7.7 months in tumors with RFC3 overexpression vs 92.9 months in tumors with normal RFC3 levels; p

The aim of this study was to evaluate the prognostic value of light chain 3 (LC3) expression in triple-negative breast cancer (TNBC) and describe the association of LC3 expression with the occurrence of metastasis. LC3 expression in tissue microarray was evaluated by immunohistochemistry in 163 patients with TNBC. The prognostic value of LC3 expression was assessed by a Cox regression model adjusted for clinical characteristics. Low LC3 expression in TNBC was observed in 56 (34.4 %) of 163 TNBC. Low LC3 expression significantly correlated with a higher risk of distant metastasis, rather than locoregional relapse. The 10-year distant metastases-free survival for LC3-negative and LC3-positive patients was 57.2 and 95.1 %, respectively (p < 0.0001). Accordingly, a significant correlation was found between LC3 expression and disease-free survival (DFS) and overall survival (OS). Multivariate analysis indicated that LC3 negative was a significant independent prognostic factor of DFS (p = 0.019), but not for OS (p = 0.545) in all patients. Our results suggested that expression of LC3 in TNBC was associated with higher distant metastases. This finding could open new avenues for the development of novel therapy strategies to TNBC.

Cyclin F, capable of forming Skp1‐Cul1‐F‐box protein ubiquitin ligase complex, is implicated in controlling centrosome duplication and preventing genome instability. Cyclin F oscillates during cell cycle with a similar pattern to cyclin A. However, its expression and significance in cancer remain obscure. In this study, we showed that cyclin F was noticeably decreased in 16 pairs of tissue samples of hepatocellular carcinoma (HCC) compared to paracarcinoma tissues, at both mRNA and protein levels. Immunohistochemical staining data revealed that in 71.8% (176/245) of HCC cases, cyclin F expression in tumor tissue was much lower than that in nontumorous tissue. Low cyclin F expression, defined by receiver operating characteristic curve analysis, was present in 69.0% of HCC patients. Low expression of cyclin F was significantly correlated with tumor size, clinical stage, serum alpha‐fetoprotein level and tumor multiplicity. Further study showed that cyclin F expression was reversely associated with tumor differentiation in HCC. Kaplan– Meier analysis indicated that low cyclin F expression was related to poor overall survival and recurrence‐free survival. The prognostic impact of cyclin F was further confirmed by stratified survival analysis. Importantly, multivariate analysis revealed that low cyclin F expression was an independent poor prognostic marker for overall survival. We conclude that cyclin F is downregulated in HCC and is a promising prognostic marker for patients suffering from this deadly disease.

Diffuse large B-cell lymphoma (DLBCL) can be molecularly subtyped as either germinal center B-cell (GCB) or non-GCB. The role of rituximab(R) in these two groups remains unclear. We studied 204 patients with de novo DLBCL (107 treated with first-line CHOP; 97 treated with first-line R-CHOP), patients being stratified into GCB and non-GCB on the basis of BCL-6, CD10, and MUM1 protein expression. The relationships between clinical characteristics, survival data, and immunophenotype (IHC) were studied. The 5-year overall survival (OS) in the CHOP and R-CHOP groups was 50.4% and 66.6% (P=0.031), respectively. GCB patients had a better 5-year OS than non-GCB patients whether treated with CHOP or not (65.0% versus 40.9%;P=0.011). In contrast, there is no difference in the 5-year OS for the GCB and non-GCB with R-CHOP (76.5% versus 61.3%;P=0.141). In non-GCB subtype, additional rituximab improved survival better than CHOP (61.3% versus 40.9%;P=0.0303). These results indicated that addition of rituximab to standard chemotherapy eliminates the prognostic value of IHC-defined GCB and non-GCB phenotypes in DLBCL by improving the prognostic value of non-GCB subtype of DLBCL.

SIRT3, a mitochondrial sirtuin belonging to nicotinamide adenine nucleotide (NAD) dependent deacetylases, is implicated in metabolism, longevity and carcinogenesis. SIRT3 expression and its significance in hepatocellular carcinoma (HCC) remain largely unclear. In this study, we demonstrated that SIRT3 expression in HCC tissue was much lower than that in paracarcinoma tissue, at both mRNA and protein levels. The cutoff value for low SIRT3 expression in HCC was defined according to receiver operating characteristic curve (ROC) analysis. As disclosed by immunohistochemistry (IHC) results, low SIRT3 expression was present in 67.3% (167/248) of HCC cases. Furthermore, low expression of SIRT3 was significantly correlated to differentiation (P = 0.013), clinical stage (P = 0.005), serum AFP level (P

Background Age at diagnosis has been shown to be an independent prognostic factor of localized renal cell carcinoma (RCC) in several studies. We used contemporary statistical methods to reevaluate the effect of age on the cancer-specific survival (CSS) of localized RCC. Methods and findings 1,147 patients with localized RCC who underwent radical nephrectomy between 1993 and 2009 were identified in our four institutions. The association between age and CSS was estimated, and the potential threshold was identified by a univariate Cox model and by martingale residual analysis. Competing risks regression was used to identify the independent impact of age on CSS. The median age was 52 years (range, 19-84 years). The median follow-up was 61 months (range, 6-144 months) for survivors. A steep increasing smoothed martingale residual plot indicated an adverse prognostic effect of age on CSS. The age cut-off of 45 years was most predictive of CSS on univariate Cox analysis and martingale residual analysis (p = 0.005). Age ≤45 years was independently associated with a higher CSS rate in the multivariate Cox regression model (HR = 1.59, 95% CI = 1.05-2.40, p = 0.027) as well as in competing risks regression (HR = 3.60, 95% CI = 1.93-6.71, p = 0.001). Conclusions Increasing age was associated with a higher incidence of cancer-specific mortality of localized RCC. Age dichotomized at 45 years would maximize the predictive value of age on CSS, and independently predict the CSS of patients with localized RCC.