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Oral cancer (OC) is one of the most recurrent cancers in the head and neck squamous cancer (SCCHN) category. Recently, the genome-wide association studies (GWAS) have gained growing interest in the scientific community. GWAS have identified several pathways involved in the interactions among general risk factors and genomic variants affecting SCCHN. This systematic overview aims to critically evaluate the latest data reported within the scientific literature. The aim was to investigate the impact of genetic aspects on SCCHN onset and prognosis, involving other clinical and systemic co-factors. PubMed, Google Scholar, and Cancer Genetics Web databases have been systematically investigated for original articles published in the last two years, reporting studies on the main queries addressed in this work. This review also comparatively describes the impact of environmental and pathological co-factors in different types of cancers, clarifying and updating the role of genetic factors in SCCHN onset and development. The main outcomes reported may be helpful to drive clinicians towards their clinical evaluations for the most appropriate therapeutic approach in SCCHN. [ABSTRACT FROM AUTHOR]

Oral cancer (OC) is one of the most recurrent cancers in the head and neck squamous cancer (SCCHN) category. Recently, the genome-wide association studies (GWAS) have gained growing interest in the scientific community. GWAS have identified several pathways involved in the interactions among general risk factors and genomic variants affecting SCCHN. This systematic overview aims to critically evaluate the latest data reported within the scientific literature. The aim was to investigate the impact of genetic aspects on SCCHN onset and prognosis, involving other clinical and systemic co-factors. PubMed, Google Scholar, and Cancer Genetics Web databases have been systematically investigated for original articles published in the last two years, reporting studies on the main queries addressed in this work. This review also comparatively describes the impact of environmental and pathological co-factors in different types of cancers, clarifying and updating the role of genetic factors in SCCHN onset and development. The main outcomes reported may be helpful to drive clinicians towards their clinical evaluations for the most appropriate therapeutic approach in SCCHN. [ABSTRACT FROM AUTHOR]

Abstract: Aims: To investigate whether sulfatides modulate indoleamine 2,3-dioxygenase (IDO)1, a fine-tuned enzymatic mechanism for controlling immune responses, gene expression/function in antigen presenting cells (APC). The relationship between structure and activity (SAR) of newly synthesized sulfatide isoforms (C16:0, C18:0, C22:0, C24:1) was also evaluated. Main methods: CD1d-transfected THP-1 human cells were used as APC and treated with increasing concentrations (0.01–10μΜ) of each compound for an appropriate period of time. The gene expression and the enzymatic activity of IDO1 were examined using reverse transcription-polymerase chain reaction (RT-PCR) and high performance liquid chromatography (HPLC). Compound-untreated cells were taken as negative, while 1000U/ml interferon (IFN)-γ-treated cells as positive controls. Key findings: Not all sulfatides induced the same effect: the basal IDO1 expression was significantly reduced (−48±3% at 0.01μΜ) by C16:0 sulfatide, while it was increased by C18:0 or C24:1 sulfatide (+87±7% and +50±5% at 1μΜ, respectively) over negative controls; C22:0 sulfatide resulted ineffective at all concentrations tested. These effects functionally correlated with changes in IDO1 activity: l-kynurenine contents in the culture media were significantly reduced by C16:0 sulfatide (−29±4% at 0.01μM), while it was increased by C18:0 or C24:1 sulfatide (+61±8% and +48±4% at 1μM, respectively) over negative controls. C22:0 sulfatide resulted ineffective at all concentration tested. Significance: The overall data demonstrate that specific sulfatide isoforms differently modulate IDO1 in APC. The sulfatide-induced effects are structurally dependent on the length/saturation of their fatty acid chain. [Copyright &y& Elsevier]

Background: Multiple myeloma (MM) is a hematologic malignancy characterized by high genomic instability, and telomere dysfunction is an important cause of acquired genomic alterations. Telomeric repeat-containing RNA (TERRA) transcripts are long non-coding RNAs involved in telomere stability through the interaction with shelterin complex. Dysregulation of TERRAs has been reported across several cancer types. We recently identified a small molecule, hit 17, which stabilizes the secondary structure of TERRA. In this study, we investigated in vitro and in vivo anti-MM activities of hit 17. Methods: Anti-proliferative activity of hit 17 was evaluated in different MM cell lines by cell proliferation assay, and the apoptotic process was analyzed by flow cytometry. Gene and protein expressions were detected by RT-qPCR and western blotting, respectively. Microarray analysis was used to analyze the transcriptome profile. The effect of hit 17 on telomeric structure was evaluated by chromatin immunoprecipitation. Further evaluation in vivo was proceeded upon NCI-H929 and AMO-1 xenograft models. Results: TERRA G4 stabilization induced in vitro dissociation of telomeric repeat‐binding factor 2 (TRF2) from telomeres leading to the activation of ATM-dependent DNA damage response, cell cycle arrest, proliferation block, and apoptotic death in MM cell lines. In addition, up-regulation of TERRA transcription was observed upon DNA damage and TRF2 loss. Transcriptome analysis followed by gene set enrichment analysis (GSEA) confirmed the involvement of the above-mentioned processes and other pathways such as E2F, MYC, oxidative phosphorylation, and DNA repair genes as early events following hit 17-induced TERRA stabilization. Moreover, hit 17 exerted anti-tumor activity against MM xenograft models. Conclusion: Our findings provide evidence that targeting TERRA by hit 17 could represent a promising strategy for a novel therapeutic approach to MM. [ABSTRACT FROM AUTHOR]

Purpose: Erlotinib is a targeted agent commonly used in advanced non-small cell lung cancer (aNSCLC). However, drug-related skin toxicity often may affect the quality of life of cancer patients and lead to treatment discontinuation. Genetic polymorphisms in drug transporters and metabolizing enzymes play a major role in the interindividual variability in terms of efficacy and toxicity of erlotinib treatment. The aim of our study was to identify genetic determinants in adsorption, distribution, metabolism, and excretion genes influencing skin rash (SR) by the novel drug-metabolizing enzyme and transporter (DMET) microarray Affymetrix platform in aNSCLC patients.Methods: In a retrospective study, 34 erlotinib-treated aNSCLC patients were genotyped by DMET Plus chip: 23 patients experienced SR (cases), while 11 patients did not (controls). Peripheral blood DNA was genotyped. Genotype association was analyzed by Fisher's exact test, and the toxicity-associated gene sets underwent Ingenuity Pathway Analysis (IPA).Results: Seven SNPs in six genes (CYP27B1, MAT1A1, CHST1, CYP4B1, ADH6, and SLC22A1) were associated with the occurrence of SR or with a protective effect. Specifically, the rs8176345 in CYP27B1 gene was significantly correlated with SR (p = 0.0003, OR 55.55, 95% CI 2.7036-1141.1707). The IPA on SR-related genes highlighted the role of a variety of canonical pathways including 1,25-dihydroxyvitamin D3 biosynthesis, S-adenosyl-L-methionine biosynthesis, and methionine degradation I (to homocysteine) in SR development.Conclusion: Although exploratory, this study indicates rs8176345 in CYP27B1 gene as significantly correlated with erlotinib-induced SR in aNSCLC patients probably through a mechanism mediated by vitamin D3 and inflammation at skin level. [ABSTRACT FROM AUTHOR]

Background & Aim: The miR-221/222 cluster is upregulated in malignant plasma cells from multiple myeloma (MM) patients harboring the t(4;14) translocation. We previously reported that silencing of miR-221/222 by an antisense oligonucleotide induces anti-MM activity and upregulates canonical miR-221/222 targets. The in vivo anti-tumor activity occurred when miR-221/222 inhibitors were delivered directly into MM xenografts. The aim of the present study was to evaluate the anti-MM activity of a novel phosphorothioate modified backbone 13-mer locked nucleic acid (LNA)-Inhibitor-miR-221 (LNA-i-miR-221) specifically designed for systemic delivery. Methods: In vitro anti-MM activity of LNA-i-miR-221 was evaluated by cell proliferation and BrdU uptake assays. In vivo studies were performed with non-obese diabetic/severe combined immunodeficient (NOD.SCID) mice bearing t(4;14) MM xenografts, which were intraperitoneally or intravenously treated with naked LNA-i-miR-221. RNA extracts from retrieved tumors were analyzed for miR-221 levels and modulation of canonical targets expression. H&E staining and immunohistochemistry were performed on retrieved tumors and mouse vital organs. Results: In vitro, LNA-i-miR-221 exerted strong antagonistic activity against miR-221 and induced upregulation of the endogenous target p27Kip1. It had a marked anti-proliferative effect on t(4;14)-translocated MM cells but not on MM cells not carrying the translocation and not overexpressing miR-221. In vivo, systemic treatment with LNA-i-miR-221 triggered significant anti-tumor activity against t(4;14) MM xenografts; it also induced miR-221 downregulation, upregulated p27Kip1 and reduced Ki-67. No behavioral changes or organ-related toxicity were observed in mice as a consequence of treatments. Conclusions: LNA-i-miR-221 is a highly stable, effective agent against t(4;14) MM cells, and is suitable for systemic use. These data provide the rationale for the clinical development of LNA-i-miR-221 for the treatment of MM. [ABSTRACT FROM AUTHOR]