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APOBEC3 enzymes are part of the innate immune system and they are important in retroviral defense. The number of mutations in ovarian cancer increases with rising levels of APOBEC3B mRNA. We could confirm that APOBEC3B mRNA is upregulated in ovarian cancer cell lines and in ovarian cancer tissue. We evaluated APOBEC3B expression in histologically defined subtypes of ovarian cancer to identify its influence on overall survival (OS) and progression-free survival (PFS). Tissue microarrays from 219 patients with highgrade serous (HGSC), 61 with low-grade serous (LGSC), 62 with endometrioid (EC) and 55 with clear cell (CCC) ovarian carcinoma were stained using an antibody against APOBEC3B. Real-time quantitative PCR was performed to detect APOBEC3B mRNA levels in 274 cases of HGSC, in 11 cases of LGSC, in 47 cases of EC and in 29 cases of CCC. Tumor-infiltrating lymphocytes (TILs) have been evaluated in a previous project. APOBEC3B staining was cytoplasmic as well as nuclear and both were positively correlated (P

Treatment costs according to type of first-line treatment received by patients with EGFR Mutâ +â NSCLC. (DOCX 15 kb)

Figure S2. Differences in Cyclin A1 expression between molecular tumor subtypes (1, 2, 4, and 5), according to the molecular classification of EOC by Tothill et al. Data sets were retrieved from the NCBI GEO database and normalized using the invariant set method (dChip 2.0 software) [23]. C1 showed significantly higher expression and C5 showed significantly lower expression (Kruskall Wallis; p = 0.001). Mean value + 3SD is marked by the horizontal bar. (PPT 147 kb)

Figure S1. Survival plot depicting the impact of Cyclin A1 expression (Affymetrix probe set 205899_at) on progression-free survival in the patient group with suboptimal debulking and platinum-based therapy using an online-accessible tool ( www.kmplot.com/ ), database version 2015 [n = 1648]. Case selection [n = 264]: survival: PFS, split patients by median; restrictions: FIGO II, III, IV; histology: serous; debulk: suboptimal; chemotherapy: contains platinum. Log-rank p = 0.0088. (PPTX 84 kb)

Table S1. Cox regression analysis for TTP and OS. Covariates other than Cyclin A1 staining intensity and percentage of Cyclin A1-positive cells for univariate analysis were chosen based on clinical relevance as described in earlier studies [9, 41, 42]. The four covariates with the highest p-values were analyzed in a multivariate Cox regression analysis [the number of 49 (TTP) and 41 (OS) events allows a maximum of four covariates]. b i : regression coefficient, CI: confidence interval, HR: hazard ratio. (DOCX 14 kb)

To identify Cyclin A1-expressing solid cancer entities, HG U133 Plus 2.0 microarray data sets (Affymetrix, Santa Clara, CA) of healthy tissues and tumor samples from the NCBI GEO server were screened (NCBI GEO, http://www.ncbi.nlm.nih.gov/geo/ , GSE****). (DOC 20 kb)

Background: The mammalian target of rapamycin (mTOR) is an important regulator of cell proliferation and protein translation and is activated in various malignancies. Expression of mTOR cascade components in gastric neuroendocrine tumors (NETs), however, has not yet been fully explored. Aims: The goal of the present study was to assess the activation of mTOR and its upstream and downstream components in gastric NETs using immunohistochemistry and to investigate the relationship between expression and clinicopathological data. Methods: The expression of phosphorylated mTOR (p-mTOR) and its major target the eukaryotic initiation factor 4E-binding protein 1 (p4EBP1), phospho-phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (pPIK3CA), phospho-protein kinase B (pAkt), phospho-phosphatase and tensin homolog (pPTEN), and phosphotuberous sclerosis 2 (pTSC2) were examined in a series of 35 gastric NETs. Results: All samples from the 35 patients showed expression of the PI3K catalytic subunit PIK3CA and the mTOR inhibitor TSC2. The p-mTOR was expressed in 88.57%, pPTEN in 97.14%, and pAkt in 65.7% of the examined tumors. The mTOR effector p4E-BP1 was expressed in 88.57% of cases. In addition, the p-mTOR positive rate correlated with Ki-67 expression. In fact, patients with Ki-67 ≤ 2 had higher p-mTOR positive rates (p=0.032); however, no significant correlations between p-mTOR positivity and selected clinicopathological characteristics were observed. Conclusions: In conclusion, these data demonstrate high mTOR activation in gastric NETs, suggesting that mTOR pathway inhibition may be a possible therapeutic strategy for treatment of gastric NETs.

Gross cystic disease fluid protein (GCDFP- 15) and mammaglobin are both widely used and accepted markers for epithelia of breast origin. We aimed to evaluate their relation of expression on parallel whole tissue sections in primary breast cancer by immunohistochemistry and also to correlate it with clinico-pathological parameters including patient survival. Primary breast carcinomas from 165 patients with a mean clinical follow-up of 73 months were immunostained using commercially available antibodies against GCDFP-15 and mammaglobin. An immunoreactive score (IRS) was calculated based on the cytoplasmic staining intensity and the number of cells stained. Cytoplasmic expression of GCDFP-15 and mammaglobin was observed in 73.3% and 72.1% of invasive breast carcinomas respectively. 91.8% of breast cancer cases expressed at least one of both markers. Both markers strongly correlated with each other and were significantly associated with lower tumour grading. Additionally, GCDFP-15 negativity was significantly associated with shortened disease-free survival times in univariate and multivariate analyses. We demonstrated the strong correlation of GCDFP-15 and mammaglobin with each other and showed that only very few primary breast cancers are completely negative for both markers. The significantly longer disease free survival times for patients with GCDFP-15 positive tumours clearly warrants further study.

Ovarian cancer is a very severe type of disease with poor prognosis. Treatment of ovarian cancer is challenging because of the lack of tests for early detection and effective therapeutic targets. Thus, new biomarkers are needed for both diagnostics and better understanding of the cellular processes of the disease. Small molecules, consisting of metabolites or lipids, have shown emerging potential for ovarian cancer diagnostics. Here we performed comprehensive lipidomic profiling of serum and tumor tissue samples from high-grade serous ovarian cancer patients to find lipids that were altered due to cancer and also associated with progression of the disease. Ovarian cancer patients exhibited an overall reduction of most lipid classes in their serum as compared to a control group. Despite the overall reduction, there were also specific lipids showing elevation, and especially alterations in ceramide and triacylglycerol lipid species were dependent on their fatty acyl side chain composition. Several lipids showed progressive alterations in patients with more advanced disease and poorer overall survival, and outperformed CA-125 as prognostic markers. The abundance of many serum lipids correlated with their abundance in tumor tissue samples. Furthermore, we found a negative correlation of serum lipids with 3-hydroxybutyric acid, suggesting an association between decreased lipid levels and fatty acid oxidation. In conclusion, here we present a comprehensive analysis of lipid metabolism alterations in ovarian cancer patients, with clinical implications.

Ovarian cancer is a heterogeneous disease of low prevalence, but poor survival. Early diagnosis is critical for survival, but it is often challenging because the symptoms of ovarian cancer are subtle and become apparent only during advanced stages of the disease. Therefore, the identification of robust biomarkers of early disease is a clinical priority. Metabolomic profiling is an emerging diagnostic tool enabling the detection of biomarkers reflecting alterations in tumor metabolism, a hallmark of cancer. In this study, we performed metabolomic profiling of serum and tumor tissue from 158 patients with high-grade serous ovarian cancer (HGSOC) and 100 control patients with benign or non-neoplastic lesions. We report metabolites of hydroxybutyric acid (HBA) as novel diagnostic and prognostic biomarkers associated with tumor burden and patient survival. The accumulation of HBA metabolites caused by HGSOC was also associated with reduced expression of succinic semialdehyde dehydrogenase (encoded by ALDH5A1), and with the presence of an epithelial-to-mesenchymal transition gene signature, implying a role for these metabolic alterations in cancer cell migration and invasion. In conclusion, our findings represent the first comprehensive metabolomics analysis in HGSOC and propose a new set of metabolites as biomarkers of disease with diagnostic and prognostic capabilities.