Background:Autophagy is a programmed cell survival mechanism that has a key role in both physiologic and pathologic conditions. The relationship between autophagy and cancer is complex because autophagy can act as either a tumour suppressor or as a tumour promoter. The role of autophagy in oral squamous cell carcinoma (OSCC) is controversial. Several studies have claimed that either a high or low expression of autophagy-related proteins was associated with poor prognosis of OSCCs. The aims of the study were to compare autophagy in OSCCs, verrucous hyperplasias, and normal oral mucosas, and to inspect the prognostic role of autophagy in OSCCs.Methods:We used the autophagosome marker, LC3B, and autophagy flux marker, p62/SQSTM1 (p62), by using immunohistochemistry, and examined p62 mRNA by RNA in situ hybridization, to evaluate autophagy in 195 OSCCs, 47 verrucous hyperplasias, and 37 normal oral mucosas. The prognostic roles of LC3B and p62 protein expressions in OSCCs were investigated.Results:We discovered that the normal oral mucosa exhibited limited LC3B punctae and weak cytoplasmic p62 staining, whereas the OSCCs exhibited a marked increase in LC3B punctae and cytoplasmic p62 expression. The expression pattern of LC3B and cytoplasmic p62 of the verrucous hyperplasias were between normal oral mucosas and OSCCs. The normal oral mucosas, verrucous hyperplasias, and OSCCs presented no differences in nuclear p62 expression and the p62 mRNA level. p62 mRNA expression was elevated in a minority of cases. High p62 mRNA expression was associated with high p62 protein expression in the cytoplasm. Increased LC3B punctae, high cytoplasmic p62, and low nuclear p62 expressions in OSCCs were associated with aggressive clinicopathologic features and unfavourable prognosis. In addition, low nuclear p62 expression was an independent prognostic factor for overall and disease-specific survival rates. Furthermore, we disclosed that high cytoplasmic p62 expression accompanied with either a low or high LC3B expression, which indicated autophagy impairment under basal or activated autophagic activity, was associated with aggressive behaviour in advanced OSCCs.Conclusions:We suggested that autophagy was altered during cancer initiation and progression. Autophagy impairment contributed to cancer progression in advanced OSCCs.

Reactive oxygen species (ROS) and endoplasmic reticulum (ER) stress are paradoxically implicated in myocardial ischemia/reperfusion (I/R) injury and cardioprotection. However, the precise interpretation for the dual roles of ROS and its relationship with the ER stress during I/R remain elusive. Here we investigated the concentration-dependent effects of hydrogen peroxide (H2O2) preconditioning (PC) and postconditioning (PoC) on the ER stress and prosurvival reperfusion injury salvage kinase (RISK) activation using an ex vivo rat myocardial I/R model. The effects of H2O2 PC and PoC showed three phases. At a low level (1 μM), H2O2 exacerbated I/R-induced left ventricular (LV) contractile dysfunction and ER stress, as indicated by enhanced phosphorylation of protein kinase-like ER kinase and expressions of glucose-regulated protein 78, X-box-binding protein 1 splicing variant, TNF receptor-associated factor 2, activating transcription factor-6 cleaved 50 kDa fragment, and caspase-12 cleavage, but the I/R-induced RISK activation including protein kinase B (PKB/Akt) and protein kinase Cɛ (PKCɛ) remained unchanged. Consistently, the postischemic LV performance in 1 μM H2O2 PC and PoC groups was improved by inhibiting ER stress with 4-phenyl butyric acid but not affected by the ER stress inducer, tunicamycin. At a moderate level (10–100 μM), H2O2 significantly improved postischemic LV performance and enhanced RISK activation, but it did no further alter the ER stress. The cardioprotection but not ER stress was abrogated with Akt or PKCɛ inhibitor wortmannin or ɛV1–2. At a high level (1 mM), H2O2 markedly aggravated the reperfusion injury and the oxidative stress but did not further enhance the RISK activation. In addition, 1 or 20 μM of H2O2 PC did not alter cardioprotective effects of ischemic PC in postischemic contractile performance and protein oxidation. Our data suggest that the differential effects of H2O2 are derived from a concentration-dependent wrestling between its detrimental stress and protective signaling.

This study aims to investigate the role of diffusion-weighted magnetic resonance imaging (DW-MRI) in ESCC patients receiving neoadjuvant concurrent chemoradiotherapy (CCRT), and the efficacy of apparent diffusion coefficient (ADC) values in predicting pathologic response to neoadjuvant CCRT. Twenty-eight locally advanced ESCC patients treated with neoadjuvant CCRT followed by radical resection were prospectively enrolled. DW-MRI was recommended to be performed within 2 weeks before and 4-6 weeks after neoadjuvant CCRT. The calculated ADCs pre- (ADC1) and post- (ADC2) neoadjuvant CCRT, the definite (ΔADC) and percentage changes (ΔADC%) were analyzed for the efficacy of predicting pathologic response to neoadjuvant CCRT. Twenty patients had been identified as responders (tumor regression grade 1-2). Among them, ADC2 (3.02 ± 0.84 vs. 2.12 ± 0.44 × 10-3 mm2/s, P = 0.001) and ΔADC (1.22 ± 0.78 vs 0.64 ± 0.26 × 10-3 mm2/s, P = 0.007) were significantly higher than those of nonresponders (tumor regression grade: 3-5). Receiver operating characteristic analysis revealed that ADC2 exhibited an overall accuracy of in 71.4% in predicting pathologic response, with a sensitivity of 60.0%, a specificity of 100%, a positive predictive value of 100%, and a negative predictive value of 50.0%, when 3.04 × 10-3 mm2/s was used as the cutoff value. ADC value could be useful in predicting pathologic response to neoadjuvant CCRT in ESCC patients. High postneoadjuvant CCRT ADC is a predictive indicator for good response.

This meta-analysis demonstrates a significant association between PD1.3A and SLE among non-Spanish European descents, while a negative association was observed in Spanish population.