Removal of acetaldehyde from saliva by mucoadhesive formulations containing cysteine and chlorhexidine diacetate: a possible approach to the prevention of oral cavity alcohol-related cancer

The aim of our work has been to develop buccoadhesive formulations (tablets) containing both L-cysteine and chlorhexidine diacetate and to verify their ability to reduce oral acetaldehyde produced after alcoholic drinks consumption

Immunological and Molecular Correlates of Disease Recurrence after Liver Resection for Hepatocellular Carcinoma

The definition of the risk of hepatocellular carcinoma (HCC) recurrence after resection represents a central issue to improve the clinical management of patients. In this study we examined the prognostic relevance of infiltrating immune cell subsets in the tumor (TIL) and in nontumorous (NT) liver (LIL), and the expression of immune-related and lineage-specific mRNAs in HCC and NT liver derived from 42 patients. The phenotype of infiltrating cells was analyzed by flow cytometry, and mRNA expression in liver tissue was examined by real-time reverse transcription (RT)-PCR. The tumor immune microenvironment was enriched in inhibitory and dysfunctional cell subsets. Enrichment in CD4+ T-cells and in particular CD4 and CD8+ memory subsets within TIL was predictive of better overall survival (OS) and time to recurrence (TTR). Increased programmed death ligand 1 (PDL1) mRNA content and higher prevalence of invariant NKT (iNKT) cells were associated with shorter OS and TTR, respectively. By combined evaluation of infiltrating cell subsets along with mRNA profiling of immune and tumor related genes, we identified the intratumoral frequency of memory T-cells and iNKT-cells as well as PDL1 expression as the best predictors of clinical outcome. HCC infiltrate is characterized by the expression of molecules with negative regulatory function that may favor tumor recurrence and poor survival

Alcohol-Metabolite Acetaldehyde Affects Integrin Expression on PDLFs

It is well known the deleterious effect of alcohol on the oral health of alcoholics.We investigated the effects of the first metabolite of alcohol, the acetaldehyde, that was demonstrated to be present in a toxic quantity in the human mouth because of an enzymatic imbalance. In this investigation we examined the noxious local effect of alcohol via its first metabolite acetaldehyde on integrin expression in periodontal ligament fibroblasts (PDLFs) “in vitro”.A dose dependent acetaldehyde influence on mRNAs encoding for alpha and beta integrin subunits was detected with both the molecular and the immunocytochemical approach suggesting an altered compartmentalization process in which the integrin molecules are produced but are not appropriately transferred to the cell membrane

Buccal tablets containing cysteine and chlorhexidine for the reduction of acetaldehyde levels in the oral cavity

There is growing evidence that a large proportion of upper digestive tract tumors are ascribable to heavy alcohol drinking and tobacco consumption. The cancer-promoting action of ethanol is mediated by acetaldehyde, its first metabolite, also derived from the bacterial oxidation of alcohol by the oral microflora, classified by the International Agency for the Research on Cancer as a carcinogen. Acetaldehyde is also one of the major components of tobacco smoke. These findings suggest two different strategies to decrease the risk of alcohol-related oral cancers: the reduction of the levels of alcohol-derived acetaldehyde in saliva and the reduction of oral bacterial flora. Therefore, the aim of our study was to develop and characterize some buccal tablet formulations containing both 20 mg l-cysteine hydrochloride (able to chemically neutralize acetaldehyde) and 10 mg chlorhexidine diacetate (well-known antiseptic compound active against a large spectrum of oral microbes). One of these formulations, chosen on the basis of its favourable delivery kinetics of the active principles, was demonstrated to be able to reduce acetaldehyde concentration in an in vitro system and to lower its salivary levels in volunteers after ethanol contact. Our findings support the hypothesis that the application of buccal devices containing cysteine and chlorhexidine could reduce salivary acetaldehyde levels and thus the incidence of upper gastrointestinal cancer in drinkers and smokers

HLA and killer immunoglobulin-like receptor genes as outcome predictors of hepatitis C virus-related hepatocellular carcinoma

Purpose: We evaluated the impact of the killer immunoglobulin-like receptors (KIR) of natural killer (NK) cells and of their HLA ligands over the clinical outcome of hepatitis C virus (HCV)-related hepatocellular carcinoma after curative treatment by either surgical resection or radiofrequency thermal ablation (RTA). Experimental Design: Sixty-one consecutive patients with HCV-related hepatocellular carcinoma underwent KIR genotyping and HLA typing. A phenotypic/functional characterization of NK cells was carried out in patients with different KIR/KIR-ligand genotype. Results: Activating KIR2DS5 was associated with significantly longer time to recurrence (TTR) and overall survival (OS; P < 0.03 each). Homozygous HLA-C1 (P < 0.02) and HLA-Bw4I80 (P < 0.05) were expressed by patients with significantly better OS, whereas HLA-C2 (P < 0.02) and HLA-Bw4T80 (P < 0.01) were associated with a worse OS. Multivariate analysis identified as parameters independently related to TTR the type of treatment (surgical resection vs. RTA; P < 0.03) and HLA-C1 (P < 0.03), whereas only KIR2DS5 was an independent predictor of longer OS (P < 0.05). Compound KIR2DL2-C1 and KIR3DS1-Bw4T80 genotypes were associated with better TTR (P < 0.03) and worse OS (P = 0.02), respectively. A prevalent cytotoxic (CD56dim) NK phenotype was detected in patients with both longer TTR and OS. Cytotoxic capacity measured by upregulation of CD107a was significantly higher in subjects with HLA-C1 alone or combined with KIR2DL2/KIR2DL3. Conclusions: These results support a central role of NK cells in the immune response against hepatocellular carcinoma, providing a strong rationale for therapeutic strategies enhancing NK response and for individualized posttreatment monitoring schemes. © 2013 American Association for Cancer Research

Kaplan-Meier curves of time to recurrence (TTR) among HCC patients.

<p>Prognostic significance of the frequency of tumor (TIL) or nontumorous liver infiltrating lymphocytes (LIL) are shown in the upper part of the figure. mRNA expression in nontumourus liver of IFN-γ and EpCAM is shown in the lower part of the figure. A specific cut-off (above or below 2.5-fold reference normal liver) was applied to EpCAM mRNA. TL: total lymphocytes; low, high: lower or higher than median value. P values were determined by the log-rank test.</p

Kaplan-Meier curves of overall survival (OS) among HCC patients.

<p>Prognostic significance of the frequency of tumor infiltrating lymphocytes (TIL) are shown in the upper part of the figure. mRNA expression of PDL1 in tumor and of CD8 and IFN-γ in nontumorous liver is shown in the lower part of the figure. Low, high: lower or higher than median value. P values were determined by the log-rank test.</p