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There is a lack of effective clinical management of oral epithelial dysplasias to reduce their risk of malignant transformation and considerable gaps in knowledge regarding the most effective means of treating such lesions. A retrospective cohort of biopsy-confirmed oral epithelial dysplasias consecutively diagnosed in the period 1995–2014 and followed-up until 2017 was identified from pathology department files. Demographic, clinical and follow-up information was collected. Multivariate Cox proportional-hazards models were performed to evaluate sociodemographic, clinical and pathological factors associated with progression to oral squamous cell carcinoma. The study included 144 oral epithelial dysplasias, of which 42% progressed to oral cancer at the end of follow-up (21 years). Clinical aspect of the lesion was described for 77 (53.5%) of the patients. Treatment, age, grade of the lesion and diagnostic period were independent prognostic factors for progression. When considering only patients with described clinical aspect, only treatment and grade of the lesion were independently associated with cancer. The results from this non-selected retrospective cohort of oral epithelial dysplasias underscore the existing limitations of the current standard-of-care of the patients and provide novel insights on the management of these lesions with and without described clinical aspect. Well-designed, robust prospective studies, a homogenized staging system and multidisciplinary treatment guidelines are warranted. [ABSTRACT FROM AUTHOR]

Highlights: [•] COPs and POPs from natural, processed or metabolic origin can irreversible accumulate in central nervous system. [•] COPs and POPs exert in vitro cytotoxicity when used up to 1000-fold the potential reachable physiological concentration. [•] COPs and POPs are potential substrates to be metabolized by gut microbiota. [•] The SOPs’ inflammatory role provides additional reasons for safety studies after long-term consumption of PS. [Copyright &y& Elsevier]

Abstract: Human diets contain sterol oxidation products that can induce cytotoxic effects, mainly caused by cholesterol oxides. However, phytosterol oxides effects have been less extensively investigated. This study evaluates the production of inflammatory biomarkers (IL-1β, IL-8, IL-10, TNFα) and the influence of gene expression transporters and enzymes related to cholesterol absorption and metabolism (NPC1L1, ABCG5/8, HMGCoA, ACAT) produced by 7-ketosterols (stigmasterol/cholesterol) in Caco-2 cells. These effects were linked to intracellular signaling pathways by using several inhibitors. Results showed 7-ketostigmasterol to have a greater proinflammatory potential than 7-ketocholesterol. In non-pre-treated cells, only efflux transporters were down-regulated by 7-ketosterols, showing a greater influence upon ABCG5 expression. Cell-pre-incubation with bradykinin induced changes in ABCG expression levels after 7-ketostigmasterol-incubation; however, the energetic metabolism inhibition reduced NPC1L1 expression only in 7-ketocholesterol-incubated cells. In non-pre-treated cells, HMG-CoA was up-regulated by both 7-ketosterols. However, exposure to inhibitors down-regulated the expression levels, mainly in 7-ketocholesterol-incubated cells. While ACAT expression values in non-pre-treated cells were unchanged, exposure to inhibitors caused down-regulation of mRNA levels. These results suggest that internalization and excretion of 7-ketostigmasterol is probably influenced by [Ca]i, which also could mediate HMGCoA activity in POPs metabolism. However, energetic metabolism and reducing equivalents exert different influences upon the 7-ketosterol internalization. [Copyright &y& Elsevier]

Abstract: The biological implications of cholesterol oxidation products have been investigated, though research on plant sterol oxidation products is scarce and in some cases contradictory. The cytotoxicity of 7keto(k)-stigmasterol versus 7keto(k)-cholesterol at different concentrations (0–120μM) and incubation times (4–24h), in intestinal epithelial cells (Caco-2 cells) was evaluated. The 3-[4,5-dimethylthiazol-2-yl]-2,3-diphenyl tetrazolium bromide and neutral red uptake tests, mitochondrial membrane potential (ΔΨm), and relative DNA and RNA contents in the cell cycle phases were determined. Possible interaction effects between 7k-derivatives or non-oxidized stigmasterol were monitored. Endo/lysosomal activity was not impaired by either oxide. 7k-cholesterol showed a deleterious effect upon the mitochondrial compartment after 24h of exposure (120μM), as well as upon ΔΨm when incubated at all concentrations (12/24h). Only cells incubated with 7k-cholesterol (120μM) exhibited a decrease in RNA proportion in the G1 population. The presence of 7k-stigmasterol or stigmasterol with 7k-cholesterol reduced the deleterious metabolic effects upon mitochondrial functionality and integrity and the distribution of RNA contents in G1 and G2 phases. A decrease in the G1 phase proportion was detected in cells exposed to mixtures, without alterations in RNA content. The results obtained indicate the absence of 7k-stigmasterol cytotoxicity in Caco-2 cells and its capacity to reduce 7k-cholesterol toxicity. [Copyright &y& Elsevier]

A synthetic biogas stream was effectively reformed in the presence of dimethyl sulphide (used as a model sulphur-containing molecule) by a multi-metallic catalyst main composed by Ni and Ce, with Sn and Rh as promoters, supported over high surface alumina. Prior to reaction, a thermodynamic equilibrium calculation indicated that dimethyl sulphide decomposes to H 2 S and CO 2 at the reaction temperature inside the reactor. This sulphur, that strongly attaches to Ni catalyst causing deactivation, was overcome during 35 h by the studied catalyst when a moderate content was fed, 15 ppm (30 ppm of dimethyl sulphide DMS). The obtained H 2 /CO was close to 2/1 and methane conversion almost reached 60%. On the other hand, in the case of a higher concentration present at the reaction atmosphere, 50 ppm of sulphur (90 ppm of DMS), it was observed a continuous decay in activity. The analysis of the used catalysts by TEM, XRD, Raman and TGA indicated that sulphur promoted the formation of graphitic carbon, mostly nanotubes, removing the isolated nickel particles of the alumina surface, whilst a long time on stream favoured the sintering of the active phase, indicating a combination of different deactivation effects. In fact, the case of feeding 50 ppm of sulphur, different deactivation mechanisms were observed: sintering, coke deposition, fouling and leaching, whilst in the case of moderate concentration the catalyst was capable of tolerating the sulphur presence. • A multi-metallic catalyst effectively conducted biogas reforming in sulphur presence. • The sulphur inclusion induced a graphitic carbon deposition during the reaction. • The Ni clusters were deactivated during the reaction whilst the Ni–Ce remained active. [ABSTRACT FROM AUTHOR]

Anti-programmed cell death protein 1 (PD-1) agents have become the standard of care for platinum-refractory recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) and are currently being evaluated in various disease settings. However, despite the gain in overall survival seen in some of the clinical trials, the majority of patients display primary resistance and do not benefit from these agents. Taking into consideration the potentially severe immune-related toxicities and their high cost, the search for predictive biomarkers of response is crucial. Besides Programmed death ligand-1 (PD-L1) expression, other biomarkers such as immune infiltration, tumor mutational burden or immune-gene expression profiling have been explored, but none of them has been validated in this disease. Among these, the microbiota has recently garnered tremendous interest since it has proven to influence the efficacy of PD-1 blockade in some tumor types. With the accumulating evidence on the effect of the microbiota in HNSCC tumorigenesis and progression, the study of its potential role as a predictive immune biomarker is warranted. This review examines the available evidence on emerging immune predictive biomarkers of response to anti-PD-1/PD-L1 therapy in HNSCC, introducing the microbiota and its potential use as a predictive immune biomarker in this disease. [ABSTRACT FROM AUTHOR]

Objectives: HPV16-positive oropharyngeal cancer (OPC) patients experience better outcomes compared to HPV16-negative patients. Currently, strategies for treatment de-escalation are based on HPV status, smoking history and disease stage. However, the appropriate cut-point for smoking and the role of other non-clinical factors in OPC survival remains uncertain.Materials and Methods: We examined factors associated with OPC outcome in 321 patients recruited in a large European multi-center study. Seropositivity for HPV16 E6 was used as a marker of HPV16 positive cancer. Hazard ratios (HR) and confidence intervals (CI) were estimated using Cox proportional models adjusted for potential confounders.Results: Overall 5-year survival following OPC diagnosis was 50%. HPV16-positive OPC cases were at significantly lower risk of death (aHR = 0.51, 95% CI: 0.32-0.80). A significant effect on OPC survival was apparent for female sex (aHR 0.50: 95% CI: 0.29-0.85) and being underweight at diagnosis (aHR: 2.41, 95% CI: 1.38-4.21). A 10 pack year smoking history was not associated with overall survival. Higher stage at diagnosis appeared as the only factor significantly associated with OPC recurrence (aHR: 4.88, 95% CI: 2.12-11.21).Conclusion: This study confirms that HPV16 status is an independent prognostic factor for OPC survival while female sex lowers risk of death and being underweight at diagnosis increases the risk of death. Smoking was not an independent predictor of OPC survival. [ABSTRACT FROM AUTHOR]

High-risk human papillomavirus (HPV) is now recognised as the principal cause of the increasing incidence rates of oropharyngeal squamous cell carcinoma (OPSCC) in some parts of the world. The primary risk factor for developing HPV-related OPSCC is oral HPV-infection and the majority of oral HPV-infections are acquired by oral sex. Progression into an OPSCC includes persistent infection with evasion of immune response in the microenvironment, the activation of viral early genes (E6, E7) in basal epithelial cells, the deregulation of cell cycle and the accumulation of chromosomal instability. Patients affected by HPVrelated OPSCC tend to be younger and have better outcomes. This observation has lead current research to evaluate treatment de-escalation options to reduce long-term associated morbidity. Moreover, a different molecular profile for HPV-related OPSCC has been described, opening new options for targeted therapy and immunotherapy approaches. This paper comprehensively reviews our accumulated knowledge regarding the role of HPV in OPSCC spanning from infection to cancer development, including its clinical diagnosis, management and preventive strategies. [ABSTRACT FROM AUTHOR]

Abstract: Background: Certain human papillomaviruses (HPVs) are the causative agents of cervical carcinomas in humans. The identification of the link between infection and cancer has resulted in the successful establishment of clinical strategies such as screening or vaccination programs, aiming to prevent this pathology. More than 150 different HPVs have been described and classified and the large majority of them are not related to cancer. The genus Alphapapillomavirus encompasses many PVs, some of which are identified in humans as oncogenic, according to the epidemiological connection between infection and cervical cancer. Variants of some of these “high-risk” HPVs may have an increased involvement in cervical cancer, although definitive data are still wanting. The aim of the present work was to analyze the presence of HPV33, HPV45 and HPV58 variants in cases of cervical cancer. Methods: Samples from cervical lesions in the context of different cervical cancer surveys were analyzed for presence of HPV DNA. Samples positive for HPV33, HPV45 or HPV58 DNA were selected and the E6/E7 genes were amplified and sequenced. The phylogenetic relationships of these sequences were inferred using an evolutionary placement algorithm and accordingly classified at the variant level. Results: All viral E6/E7 sequences were successfully placed in the classification schemes of the corresponding viruses. For HPV33 (n =23), 45 (n =61) or 58 (n =29), the distribution of variants found in cases of cervical cancer is not a random sample of the corresponding diversity. In all three HPVs, the respective A variants were more prevalent in the viral DNA-positive cases of cervical cancer analyzed. This is the first study trying to discern the phylogenetic connection between variants of the oncogenic HPV33, 45 and 58, and squamous cell carcinoma of the cervix. [Copyright &y& Elsevier]

Introduction Human papillomavirus (HPV) infection is a risk factor for various cancer types, including head and neck squamous cell carcinoma (HNSCC). HPV-positive HNSCC show better survival compared to HPV-negative HNSCC despite their frequent early metastatic spread to cervical lymph nodes. Patients initially presenting only with a cervical lymph node metastasis (CLNM) during work-up are frequently diagnosed with HNSCC. In a few CLNM cases no primary tumor is detected. Aggressive multimodal treatment of these cancers of unknown primary site (CUP) often leads to substantial side effects and loss of quality of life. Recent studies provide evidence that the HPV status may have a prognostic value in CUP and may serve as a predictor for oropharyngeal localization of the primary tumor. Material and methods In a multinational retrospective study (Heidelberg, Barcelona, Treviso) we want to determine the prevalence of HPV-driven SCC in CLNM with unknown or identified primary tumor. Presence of 51 mucosal HPV types will be analyzed in fresh-frozen and/or formalin-fixed paraffin-embedded tissue from lymph node metastases and, if available, the corresponding primary tumor. To identify truly HPV-driven cases additional markers including viral load, E6*I oncogene mRNA and expression levels of the cellular proteins p16INK4a, p53 and pRb will be determined. In addition, if fresh-frozen tissue and serum are available viral transformation-associated RNA patterns and anti-HPV antibodies, respectively, will be analyzed. Results Results of ongoing HPV status analyses will be presented. Conclusion These data will be correlated with clinical parameters to assess, whether active HPV involvement is associated with a better prognosis and may help to direct the search for the primary tumor towards the oropharynx. Furthermore, we want to study pairs of HPV-driven oropharyngeal tumors and the corresponding cervical lymph node metastases by comparing the HPV status and integration patterns. The study is open for participation of additional clinical collaborators. [ABSTRACT FROM AUTHOR]