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BackgroundOral cancers can be preceded by clinically evident oral potentially malignant disorders (OPMDs). The current study evaluated the rate and the time of malignant transformation in the various OPMDs in a cohort of patients from southern Taiwan. Parameters possibly indicative for malignant transformation of OPMDs, such as epidemiological and etiological factors, and clinical and histopathological features were also described.MethodsWe followed-up 5071 patients with OPMDs—epithelial dysplasia with oral submucous fibrosis, epithelial dysplasia with hyperkeratosis/epithelial hyperplasia, hyperkeratosis/epithelial hyperplasia, oral submucous fibrosis, lichen planus, and verrucous hyperplasia—between 2001 and 2010 for malignant transformation.ResultsTwo hundred nineteen of these 5071 OPMD patients (202 men, 17 women; mean age: 51.25 years; range: 30–81 years) developed oral cancers (179 squamous cell carcinomas; 40 verrucous carcinomas) in the same sites as the initial lesions at least 6 months after their initial biopsies. The overall transformation rate was 4.32% (mean duration of transformation: 33.56 months; range: 6–67 months). Additionally, the mean time of malignant transformation was significantly shorter for lesions with than without epithelial dysplasia. The risk of malignant transformation was 1.89 times higher for epithelially dysplastic than non-dysplastic lesions. The anatomical site of OPMD and the presence of epithelial dysplasia were significantly associated with malignant transformation. The hazard rate ratio was 1.87 times larger for tongue lesions than for buccal lesions.ConclusionPatients with OPMDs require long-term follow up.

These results imply that fish consumption was associated with a reduced risk of all-cause mortality.

A cell-in-cell process refers to the invasion of one living cell into another homotypic or heterotypic cell. Different from non-apoptotic death processes of internalized cells termed entosis or cannibalism, we previously reported an apoptotic cell-in-cell death occurring during heterotypic cell-in-cell formation. In this study, we further demonstrated that the apoptotic cell-in-cell death occurred only in internalized immune killer cells expressing granzyme B (GzmB). Vacuole wrapping around the internalized cells inside the target cells was the common hallmark during the early stage of all cell-in-cell processes, which resulted in the accumulation of reactive oxygen species and subsequent mitochondrial injury of encapsulated killer or non-cytotoxic immune cells. However, internalized killer cells mediated rapid bubbling of the vacuoles with the subsequent degranulation of GzmB inside the vacuole of the target cells and underwent the reuptake of GzmB by killer cells themselves. The confinement of GzmB inside the vacuole surpassed the lysosome-mediated cell death occurring in heterotypic or homotypic entosis processes, resulting in a GzmB-triggered caspase-dependent apoptotic cell-in-cell death of internalized killer cells. On the contrary, internalized killer cells from GzmB-deficient mice underwent a typical non-apoptotic entotic cell-in-cell death similar to that of non-cytotoxic immune cells or tumor cells. Our results thus demonstrated the critical involvement of immune cells with cytotoxic property in apoptotic cell-in-cell death, which we termed as emperitosis taken from emperipolesis and apoptosis. Whereas entosis or cannibalism may serve as a feed-on mechanism to exacerbate and nourish tumor cells, emperitosis of immune killer cells inside tumor cells may serve as an in-cell danger sensation model to prevent the killing of target cells from inside, implying a unique mechanism for tumor cells to escape from immune surveillance.

AML1-ETO fusion gene is generated from chromosomal translocation t(8;21) mainly in acute myeloid leukemia M2 subtype (AML-M2). Its spliced variant transcript, AML1-ETO9a, rapidly induces leukemia in murine model. To evaluate its clinical significance, AML1-ETO9a expression was assessed in 118 patients with t(8;21) AML-M2, using qualitative and nested quantitative reverse transcriptase (RT)-PCR methods. These cases were accordingly divided into the AML1-ETO9a-H group (n ¼ 86, positive for qualitative RT-PCR, with higher level of AML1-ETO9a by quantitative RT-PCR) and the AML1-ETO9a-L group (n ¼ 32, negative for qualitative RT-PCR, with lower but still detectable level of AML1-ETO9a by quantitative RT-PCR). C-KIT expression was significantly increased in the AML1-ETO9a-H group, as compared with the AML1-ETO9a-L group. Of the 36 patients harboring C-KIT mutations, 32 patients overexpressed AML1-ETO9a (P ¼ 0.0209). Clinically, AML1-ETO9a-H patients exhibited significantly elevated white blood cells count, less bone marrow aberrant myelocytes, increased CD56 but decreased CD19 expression (P ¼ 0.0451, P ¼ 0.0479, P ¼ 0.0149 and P ¼ 0.0298, respectively). Moreover, AML1-ETO9a overexpression was related to short event-free and overall survival time (P ¼ 0.0072 and P ¼ 0.0076, respectively). Taken together, these data suggest that AML1-ETO9a is correlated with C-KIT overexpression/mutations and indicates poor disease outcome in t(8;21) AML-M2.

Marine sponge-derived manoalide has a potent anti-inflammatory effect, but its potential application as an anti-cancer drug has not yet been extensively investigated. The purpose of this study is to evaluate the antiproliferative effects of manoalide on oral cancer cells. MTS assay at 24 h showed that manoalide inhibited the proliferation of six types of oral cancer cell lines (SCC9, HSC3, OC2, OECM-1, Ca9-22, and CAL 27) but did not affect the proliferation of normal oral cell line (human gingival fibroblasts (HGF-1)). Manoalide also inhibits the ATP production from 3D sphere formation of Ca9-22 and CAL 27 cells. Mechanically, manoalide induces subG1 accumulation in oral cancer cells. Manoalide also induces more annexin V expression in oral cancer Ca9-22 and CAL 27 cells than that of HGF-1 cells. Manoalide induces activation of caspase 3 (Cas 3), which is a hallmark of apoptosis in oral cancer cells, Ca9-22 and CAL 27. Inhibitors of Cas 8 and Cas 9 suppress manoalide-induced Cas 3 activation. Manoalide induces higher reactive oxygen species (ROS) productions in Ca9-22 and CAL 27 cells than in HGF-1 cells. This oxidative stress induction by manoalide is further supported by mitochondrial superoxide (MitoSOX) production and mitochondrial membrane potential (MitoMP) destruction in oral cancer cells. Subsequently, manoalide-induced oxidative stress leads to DNA damages, such as γH2AX and 8-oxo-2’-deoxyguanosine (8-oxodG), in oral cancer cells. Effects, such as enhanced antiproliferation, apoptosis, oxidative stress, and DNA damage, in manoalide-treated oral cancer cells were suppressed by inhibitors of oxidative stress or apoptosis, or both, such as N-acetylcysteine (NAC) and Z-VAD-FMK (Z-VAD). Moreover, mitochondria-targeted superoxide inhibitor MitoTEMPO suppresses manoalide-induced MitoSOX generation and γH2AX/8-oxodG DNA damages. This study validates the preferential antiproliferation effect of manoalide and explores the oxidative stress-dependent mechanisms in anti-oral cancer treatment.

Background Glutamine is the primary fuel for the gastrointestinal epithelium and maintains the mucosal structure. Oncologists frequently encounter oral mucositis, which can cause unplanned breaks in radiotherapy (RT). Objectives The aim of this study was to explore the association between oral glutamine and acute toxicities in patients with head and neck cancer undergoing RT. Methods This was a parallel, double-blind, randomized, placebo-controlled Phase III trial conducted in a university hospital. A central randomization center used computer-generated tables to allocate interventions to 71 patients with stages I–IV head and neck cancers. The patients, care providers, and investigators were blinded to the group assignment. Eligible patients received either oral glutamine (5 g glutamine and 10 g maltodextrin) or placebo (15 g maltodextrin) 3 times daily from 7 d before RT to 14 d after RT. The primary and secondary endpoints were radiation-induced oral mucositis and neck dermatitis, respectively. These were documented in agreement with the National Cancer Institute Common Terminology Criteria for Adverse Events version 3. Results The study included 64 patients (placebo n = 33; glutamine n = 31) who completed RT for the completers’ analysis. Based on multivariate analysis, glutamine had no significant effect on the severity of oral mucositis (OR: 0.3; 95% CI: 0.05, 1.67; P = 0.169). Only the change in body mass index (BMI) was significant in both multivariate completers (OR: 0.41; 95% CI: 0.20, 0.84; P = 0.015) and per-protocol analysis (OR: 0.40; 95% CI: 0.20, 0.83; P = 0.014). No difference was found in the incidence and severity of neck dermatitis between the two arms. Conclusions The decrease in BMI was strongly related to the severity of oral mucositis in the head and neck cancer patients under RT, but not to the use of glutamine. This trial was registered at clinicaltrials.gov as NCT03015077.

Plane-strain elastic-plastic crack-tip fields at a constant J and various elastic T-stress levels were obtained in a modified boundary layer (MBL) formulation similar to that of Betegón and Hancock but with a slightly different power law hardening stress-strain law. The analyses were based upon small geometry change formulation and deformation theory plasticity. To verify the two-parameter characterization of elastic-plastic crack-tip fields, three-dimensional (3-D) elastic-plastic finite element (FE) analyses were performed on plates with deep (a/t = 0.60) and shallow (a/t = 0.15) semielliptical surface cracks under both remote tension and bending. Here t is the plate thickness and a is the maximum penetration of the crack through the plate thickness. In topological planes perpendicular to the semielliptical crack fronts, the crack-opening stress fields, normalized by the local J, were compared with the plane-strain MBL predictions based upon the local J and T. In all four cases studied, better than 94% agreement between the 3-D FE solutions and the plane-strain solutions was obtained for loads up to general yielding. This remarkable agreement held throughout all crack-front locations where the stress fields could be resolved accurately. Given the vastly different distributions of J, T, and crack-opening stress profiles along the collective set of respective crack fronts, the elastic T-stress appears to be a tractable, predictive parameter in quantifying elastic-plastic crack-front stress constraint.