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Human herpesvirus (HHV)-6 and HHV-7 have been detected in central nervous system and glioma tissue, while their exact role in glioma remains uncertain. Omics profiles and clinical information were downloaded from public databases, including The Cancer Genome Atlas cohort for training set and the Chinese Glioma Genome Atlas cohorts for validation sets. Differentially expressed genes between HHV-6 and HHV-7 infected or noninfected glioma patients were screened for establishing the HHV-6 and HHV-7 infection (HI) model through Lasso regression analysis. Bioinformatics methods were used to analyze the correlation between HI scores and prognosis, metastasis in glioma patients. Predictable efficacy of HI in temozolomide-resistance and HI-related genetic signatures were also explored. The HI model was constructed as: Risk score = (0.014709*DIRAS3) + (0.029787*TEX26) + (0.223492*FBXO39) + (0.074951*MYBL1) + (0.060202*HILS1). The five gene signature showed good performance in predicting survival time for glioma patients, while higher HI score is correlated with malignant features. Moreover, DNA mismatch repair genes were augmented in glioma patients with higher HI score as well as nonresponse to temozolomide treatment, which was in parallel with the transcriptomic result of temozolomide-resistant glioma cell. Targeting the five gene signature is beneficial for prognosis of glioma patients, especially in glioma patients underwent temozolomide treatment.

Polypoid giant cancer cells (PGCCs) represent a unique subgroup of stem-like cells, acting as a critical factor in promoting the recurrence of various solid tumors. The effect of PGCCs on the tumor malignancy of glioma and its immune microenvironment remains unclear.Bioinformatic analysis was performed to investigate the relationship between M2 tumor-associated macrophages (TAMs) infiltration and survival of glioblastoma (GBM) patients. The spatial location of M2 TAMs in GBM was also investigated using the Ivy Glioblastoma Atlas Project (Ivy GAP) database. PGCCs were quantified in glioma of different grades. CoClThe magnitude of M2 TAMs infiltration is significantly correlated with poor survival in GBM patients. M2 TAMs were enriched in the perinecrotic zone (PNZ) of GBM and positively correlated with hypoxic levels. Increased PGCCs were detected in glioma specimens of higher grades. CoClPGCCs promote malignancy and immune-suppressive microenvironment in GBM. PGCCs or their progeny cells may be a potential therapeutic target for GBM.

We aimed to validate the accuracy and clinical value of a novel semisupervised learning framework for gross tumor volume (GTV) delineation in nasopharyngeal carcinoma.Two hundred fifty-eight patients with magnetic resonance imaging data sets were divided into training (n = 180), validation (n = 20), and testing (n = 58) cohorts. Ground truth contours of nasopharynx GTV (GTVnx) and node GTV (GTVnd) were manually delineated by 2 experienced radiation oncologists. Twenty percent (n = 36) labeled and 80% (n = 144) unlabeled images were used to train the model, producing model-generated contours for patients from the testing cohort. Nine experienced experts were invited to revise model-generated GTV in 20 randomly selected patients from the testing cohort. Six junior oncologists were asked to delineate GTV in 12 randomly selected patients from the testing cohort without and with the assistance of the model, and revision degrees were compared under these 2 modes. The Dice similarity coefficient (DSC) was used to quantify the accuracy of the model.The model-generated contours showed a high accuracy compared with ground truth contours, with an average DSC score of 0.83 and 0.80 for GTVnx and GTVnd, respectively. There was no significant difference in DSC score between T1-2 and T3-4 patients (0.81 vs 0.83; P = .223), or between N1-2 and N3 patients (0.80 vs 0.79; P = .807). The mean revision degree was lower than 10% in 19 (95%) patients for GTVnx and in 16 (80%) patients for GTVnd. With assistance of the model, the mean revision degree for GTVnx and GTVnd by junior oncologists was reduced from 25.63% to 7.75% and from 21.38% to 14.44%, respectively. Meanwhile, the delineating efficiency was improved by over 60%.The proposed semisupervised learning-based model showed a high accuracy for delineating GTV of nasopharyngeal carcinoma. It was clinically applicable and could assist junior oncologists to improve GTV contouring accuracy and save contouring time.

Background and aims The mechanism by which tumor cells resist metabolic stress remains unclear, but many oncogenes are known to regulate this process. Accordingly, metabolic stress is closely associated with tumor metastasis. In this study, gene chip technology showed that Ras homolog family member F, filopodia associated (RHOF), a member of the Rho guanosine triphosphatase family, is an oncogene that is significantly related to hepatocellular carcinoma (HCC) metastasis; however, it has rarely been reported in tumors. Our aim was to determine the clinicopathological significance and role of RHOF in HCC progression and investigate the associated mechanisms. Approach and results The results showed that compared to expression in adjacent noncancerous tissues, RHOF was frequently up-regulated in HCC tumor samples and elevated under conditions of glucose deprivation. RHOF expression was associated with tumor-node-metastasis stage, T grade, metastasis status, recurrence, and survival in HCC. RHOF also affected cell morphology and promoted migration, invasion, and epithelial-mesenchymal transition (EMT) of HCC cell lines. Analysis of the underlying mechanism showed that RHOF promoted the Warburg effect by up-regulating the expression and function of several glycolytic enzymes in HCC cells. This metabolic shift enhanced HCC cell migration and invasion. Specifically, RHOF exerted a tumor-promoting effect by directly interacting with AMP-activated protein kinase (AMPK) and increasing the phosphorylation of AMPK. This subsequently affected RAB3D mRNA stability and led to elevated RAB3D expression, thereby amplifying the Warburg effect and malignant biological behaviors of HCC cells. Conclusions RHOF helps tumor cells resist metabolic stress through modulating the Warburg effect and plays a critical role in promoting HCC cell migration, invasion, and EMT, highlighting its important role in remodeling the metastatic microenvironment and regulating tumor metastasis. RHOF shows potential as a therapeutic target and prognostic biomarker for HCC.

Summary Background The predictive value of systemic inflammatory markers has been explored in various types of cancer. In the present study, we aimed to investigate the association between pretreatment neutrophil/lymphocyte ratio (NLR) and tumor metastasis in pancreatic cancer, and the values of NLR as a prognostic factor of overall survival. Methods Clinical and laboratory data from 256 consecutive pancreatic cancer patients were analyzed retrospectively. The NLR was recorded before treatment and analyzed along with clinicopathological characteristics and overall survival of pancreatic cancer patients. Results Multivariate analysis revealed that pretreatment NLR (HR: 2.393; 95% CI: 1.326–4.320; P = 0.004) was an independent risk factor for distant metastasis. Furthermore, COX regression analysis showed that in addition to pretreatment NLR (HR: 1.871; 95% CI: 1.413–2.477; P Conclusion Pretreatment NLR values were significantly associated with distant metastasis in pancreatic cancer patients. Higher NLR values were detected in metastatic disease and may be an independent prognostic factor of overall survival in pancreatic cancer patients.

Recent studies have demonstrated the prognostic value of the C-reactive protein/albumin (CRP/Alb) ratio in cancer. However, the role of the CRP/Alb ratio in advanced pancreatic cancer (PC) has not been examined. A retrospective study of 233 patients with advanced PC was conducted. We investigated the relationship between the CRP/Alb ratio, clinicopathological variables, and overall survival (OS). The optimal cutoff point of the CRP/Alb ratio was 0.54. A higher CRP/Alb ratio was significantly associated with an elevated neutrophil-lymphocyte ratio (NLR) (P

Background Trastuzumab, a humanized antibody targeting HER2, exhibits remarkable therapeutic efficacy against HER2-positive gastric cancer. However, recurrent therapeutic resistance presents revolutionary claims. Warburg effect and AKT signaling pathway was involved in the resistance to trastuzumab. Our previous studies have demonstrated that overexpression of metastasis associated with the colon cancer 1 (MACC1) predicted poor prognosis of GC and promoted tumor cells proliferation and invasion. In this study, we found that MACC1 was significantly upregulated in trastuzumab-resistant cell lines. Besides, downregulation of MACC1 reversed this resistance. Methods The effect of trastuzumab and glycolysis inhibitor combination on cell viability, apoptosis, and cell metabolism was investigated in vitro using established trastuzumab-resistant GC cell lines. We assessed the impact of trastuzumab combined with oxamate on tumor growth and metabolism in an established xenograft model of HER2-positive GC cell lines. Results Here, we found that MACC1 was significantly upregulated in trastuzumab-resistant cell lines. Besides, downregulation of MACC1 in trastuzumab-resistant cells reversed this resistance. Overexpression of MACC1-induced trastuzumab resistance, enhanced the Warburg effect, and activated the PI3K/AKT signaling pathway, while downregulation of MACC1 presented the opposite effects. Moreover, when the PI3K/AKT signaling pathway was inhibited, the effects of MACC1 on resistance and glycolysis were diminished. Our findings indicated that MACC1 promoted the Warburg effect mainly through the PI3K/AKT signaling pathway, which further enhanced GC cells trastuzumab resistance. Conclusions Our results indicate that co-targeting of HER2 and the Warburg effect reversed trastuzumab resistance in vitro and in vivo, suggesting that the combination might overcome trastuzumab resistance in MACC1-overexpressed, HER2-positive GC patients. Electronic supplementary material The online version of this article (doi:10.1186/s13045-016-0302-1) contains supplementary material, which is available to authorized users.

To investigate the correlation between cyclin-dependent kinase inhibitor p27kip1 and trastuzumab-resistance in gastric cancer. We selected HER2-overexpressed human gastric cancer cell line NCI-N87 to establish trastuzumab-resistant NCI-N87/TR cell line by stepwise exposure to different doses of trastuzumab. The 50% inhibitory concentration (IC(50)) of trastuzumab and resistance index (RI) were calculated or analyzed by MTT assay. The expression levels of cdk2 and p27kip1 were detected by Western blot. After the treatment with cdk2 inhibitor (Purvalanol A), the expression levels of relevant proteins in NCI-N87/TR cells were detected by Western blot, and the sensitivity to trastuzumab was analyzed by MTT assay. Compared with NCI-N87 cells, the expression of cdk2 was significantly increased in NCI-N87/TR cells (P0.001), while the expression of p27kip1 showed a significant decrease (P0.001). Restoration of the p27kip1 protein expression by cdk2 inhibitor (Purvalanol A) increased the sensitivity of NCI-N87/TR to trastuzumab. Down-regulation of p27kip1 might be a mechanism for triggering trastuzumab resistance to gastric cancer cell line NCI-N87.目的：探讨细胞周期蛋白依赖性激酶抑制蛋白p27kip1与胃癌曲妥珠单抗耐药的相关性。方法：以Her-2高表达的人胃癌细胞株NCI-N87为研究对象，采用逐步增加剂量法诱导建立曲妥珠单抗耐药细胞NCI-N87/TR；MTT法检测曲妥珠单抗对细胞的半数抑制浓度(50% inhibitory concentration，IC50)，计算耐药指数(resistant index，RI)，Western 印迹法检测细胞cdk2和p27kipl的蛋白表达；通过cdk2抑制剂Purvalanol A刺激NCI-N87/TR，再以Western 印迹法检测相关蛋白表达的变化，MTT法检测耐药细胞对曲妥珠单抗敏感性的改变。结果：与NCI-N87比较，NCI-N87/TR细胞cdk2蛋白表达水平显著升高(P0.001)，p27kipl蛋白水平显著下降(P0.001)；通过Purvalanol A恢复NCI-N87/TR的p27kip1蛋白水平后，NCI-N87/TR对曲妥珠单抗的敏感性显著增强(P0.001)。结论：p27kip1蛋白水平的下调可能是导致胃癌细胞对曲妥珠单抗耐药的机制之一。.

Tables S1 to S4. Table S1: IC50 of different GC cell lines. Table S2: IC50 and RI (resistance index) of MKN45 cells after treatment with trastuzumab at different inducing concentrations. Table S3: Fa and CI for trastuzumab and glucolysis inhibitor combinations on inhibition of cell viability. Table S4: Fa and CI for trastuzumab and glucolysis inhibitor combinations on inhibition of glucose uptake. (DOCX 45Â kb)

Trastuzumab has been successfully employed for the treatment of Her-2-positive gastric cancer. However, there are problems with both primary and secondary resistance to trastuzumab. In this study, we employed the human gastric carcinoma cell line NCI-N87 with high Her-2 expression to create trastuzumab-resistant NCI-N87/TR cells by stepwise exposure to increasing doses of trastuzumab. Western blotting and Real-time PCR were conducted to detect protein and gene levels. Compared with NCI-N87 cells, the expression of P-IGF-1R and P-AKT proteins was significantly increased in NCI-N87/TR cells (both P = 0.000), while PTEN gene and protein expression showed a significant decrease (both P = 0.000). In addition, mutations of the PTEN gene were detected at exons 5, 7 and 8. The sensitivity of NCI-N87/TR cells to trastuzumab was increased by transfection with the PTEN gene, or by incubation with a PI3K inhibitor (LY294002) or an IGF-IR inhibitor (AG1024), as well as siRNA targeting PI3K p110 or IGF-1R. Taken together, our findings showed that activation of the PI3K-AKT signaling pathway was one of the major mechanisms leading to resistance of NCI-N87/TR gastric cancer cells to trastuzumab, which was probably associated with PTEN gene down-regulation and mutation, as well as with over-activity of the IGF-1R signaling pathway.

e22079 Background: Trastuzumab has been successfully employed for the treatment of HER-2-positive breast cancer and gastric cancer, and satisfactory therapeutic results have been achieved. However,...