No abstract

A high prevalence of hr and lr HPV infections was detected in the OSCC patients included in the study. Moreover, hr HPV positivity was correlated with a decreased 5-year disease-free survival rate compared with HPV- and lr HPV+.

Cancer cells generally rely on aerobic glycolysis as a major source of energy. Methylglyoxal (MG), a dicarbonyl compound that is produced as a side product during glycolysis, is highly reactive and induces the formation of advanced glycation end-products that are implicated in several pathologies including cancer. All mammalian cells have an enzymatic defense against MG composed by glyoxalases GLO1 and GLO2 that converts MG to d-lactate. Colorectal cancer (CRC) is one of the most frequently occurring cancers with high morbidity and mortality. In this study, we used immunohistochemistry to examine the level of MG protein adducts, in a series of 102 CRC human tumors divided into four clinical stages. We consistently detected a high level of MG adducts and low GLO1 activity in high stage tumors compared to low stage ones suggesting a pro-tumor role for dicarbonyl stress. Accordingly, GLO1 depletion in CRC cells promoted tumor growth in vivo that was efficiently reversed using carnosine, a potent MG scavenger. Our study represents the first demonstration that MG adducts accumulation is a consistent feature of high stage CRC tumors. Our data point to MG production and detoxification levels as an important molecular link between exacerbated glycolytic activity and CRC progression.

BackgroundDespite recent advances in colorectal cancer (CRC) diagnosis and population screening programs, the identification of patients with preneoplastic lesions or with early CRC stages remains challenging and is important for reducing CRC incidence and increasing patient’s survival. MethodsWe analysed 76 colorectal tissue samples originated from early CRC stages, normal or inflamed mucosa by label-free proteomics. The characterisation of three selected biomarker candidates was performed by immunohistochemistry on an independent set of precancerous and cancerous lesions harbouring increasing CRC stages.ResultsOut of 5258 proteins identified, we obtained 561 proteins with a significant differential distribution among groups of patients and controls. KNG1, OLFM4 and Sec24C distributions were validated in tissues and showed different expression levels especially in the two early CRC stages compared to normal and preneoplastic tissues.ConclusionWe highlighted three proteins that require further investigations to better characterise their role in early CRC carcinogenesis and their potential as early CRC markers.Electronic supplementary materialThe online version of this article (doi:10.1186/s12014-017-9143-3) contains supplementary material, which is available to authorized users.

Histopathological assessment of ductal carcinoma in situ (DCIS), a non-obligate precursor of invasive breast cancer, is characterized by considerable inter-observer variability. Previously, post hoc dichotomization of multi-categorical variables was used to determine the 'ideal' cut-offs for dichotomous assessment. The present international multi-center study evaluated inter-observer variability among 39 pathologists who performed upfront dichotomous evaluation of 149 consecutive DCIS.All pathologists independently assessed nuclear atypia, necrosis, solid DCIS architecture, calcifications, stromal architecture and lobular cancerization in one digital slide per lesion. Stromal inflammation was assessed semi-quantitatively. Tumor-infiltrating lymphocytes (TILs) were quantified as percentages and dichotomously assessed with a cut-off at 50%. Krippendorff's alpha (KA), Cohen's kappa and intraclass correlation coefficient were calculated for the appropriate variables.Lobular cancerization (KA = 0,396), nuclear atypia (KA = 0,422) and stromal architecture (KA = 0,450) showed the highest inter-observer variability. Stromal inflammation (KA = 0,564), dichotomously assessed TILs (KA = 0,520) and comedonecrosis (KA = 0,539) showed slightly lower inter-observer disagreement. Solid DCIS architecture (KA = 0,602) and calcifications (KA = 0,676) presented with the lowest inter-observer variability. Semi-quantitative assessment of stromal inflammation resulted in a slightly higher inter-observer concordance than upfront dichotomous TILs assessment (KA = 0,564 versus KA = 0,520). High stromal inflammation corresponded best with dichotomously assessed TILs when the cut-off was set at 10% (kappa = 0,881). Nevertheless, a post hoc TILs cut-off set at 20% resulted in the highest inter-observer agreement (KA = 0,669).Despite upfront dichotomous evaluation, the inter-observer variability remains considerable and is at most acceptable, although it varies among the different histopathological features. Future studies should investigate its impact on DCIS prognostication. Forthcoming machine learning algorithms may be useful to tackle this substantial diagnostic challenge.