BackgroundIncreased histone H3 phosphorylation is an essential regulatory mechanism for neoplastic cell transformation. We aimed to explore the role of histone H3 phosphorylation at serine10 (p-H3Ser10) in Epstein-Barr virus (EBV) latent membrane protein-1 (LMP1)-induced carcinogenesis of nasopharyngeal carcinoma (NPC).MethodsThe expression of p-H3Ser10 was detected by the immunohistochemical analysis in NPC, chronic nasopharyngitis and normal nasopharynx tissues, and its correlation with LMP1 was analyzed in NPC tissues and cell lines. Using the small interfering RNA (siRNA)-H3 and histone H3 mutant (S10A), the effect of histone H3 Ser10 motif on LMP1-induced CNE1 cell proliferation, transformation and activator protein-1 (AP-1) activation were evaluated by CCK-8, focus-forming and reporter gene assay respectively. Mitogen- and stress-activated kinase 1 (MSK1) kinase activity and phosphorylation were detected by in vitro kinase assay and western blot. Using MSK1 inhibitor H89 or siRNA-MSK1, the regulatory role of MSK1 on histone H3 phosphorylation and AP-1 activation were analyzed.ResultsImmunohistochemical analysis revealed that the expression of p-H3Ser10 was significantly higher in the poorly differentiated NPC tissues than that in chronic nasopharyngitis (p <0.05) and normal nasopharynx tissues (p <0.001). Moreover, high level of p-H3Ser10 was positively correlated with the expression of LMP1 in NPC tissues (χ2=6.700, p =0.01; C=0.350) and cell lines. The knockdown and mutant (S10A) of histone H3 suppressed LMP1-induced CNE1 cell proliferation, foci formation and AP-1 activation. In addition, LMP1 could increase MSK1 kinase activity and phosphorylation. MSK1 inhibitor H89 or knockdown of MSK1 by siRNA blocked LMP1-induced phosphorylation of histone H3 at Ser10 and AP-1 activation.ConclusionEBV-LMP1 can induce phosphorylation of histone H3 at Ser10 via MSK1. Increased phosphorylation of histone H3 at Ser10 is likely a crucial regulatory mechanism involved in LMP1-induced carcinogenesis of NPC.

Objective: First, to evaluate the sensitivity and positive predictive value (PPV) of intra-operative frozen section (FS) diagnosis in borderline ovarian tumors (BOTs), and to explore the factors affecting the diagnostic accuracy. Second, to assess the clinical outcomes of misdiagnosed BOT patients.Methods: We performed a retrospective study of all patients diagnosed as BOT through FS or paraffin section (PS) at Qilu Hospital between January 2005 and December 2015. Clinical and pathologic data were extracted. Univariate analysis was performed using standard two-sided statistical tests. We also performed a meta-analysis to further validate the findings.Results: In our retrospective study, 155 patients were included. Agreement between FS and PS diagnosis was observed in 127/155 (81.9%) patients, yielding a sensitivity of 92.7% and a PPV of 87.6%. Under-diagnosis and over-diagnosis occurred in 22 cases (14.2%) and 6 cases (3.9%), respectively. In our univariate analysis of our retrospective study, tumor size (p=0.048) and surgery approach (p=0.024) were significantly associated with misdiagnosis.The pooled analysis of 13 studies including 1,577 patients indicated that the accuracy (69.2%), sensitivity (82.5%), and PPV (81.1%) were low; also under-diagnosis (20.2%) and over-diagnosis (10.5%) were frequent. The meta-analysis results showed that mucinous histology (p < 0.0001, OR=2.03 [1.47-2.81]) and unilateral tumors (p=0.001, OR=2.39 [1.41-4.06]) were associated with the misdiagnosis of BOT. In our retrospective study, there was no statistical significance of clinical outcome such as extent of surgery (p=0.838), recurrence (p=0.586), fertility (p=0.560), death (p=0.362) between misdiagnosed and accurately diagnosed BOT patients.Conclusions: FS analysis of BOTs has low accuracy, sensitivity, and PPV. Under-diagnosis and over-diagnosis are frequent. Meta-analysis results verify that mucinous histology and unilateral tumors are associated with misdiagnosis of FS. Nevertheless, misdiagnosed patients have a good clinical outcome despite the high frequency of misdiagnosis through FS.

BackgroundIdiopathic pulmonary fibrosis (IPF) is a deadly disease characterized by excessive collagen in the extracellular matrix (ECM) of the lungs. Collagen is the primary protein component of the ECM. However, the exact mechanisms underlying the formation and deposition of collagen in the ECM under normal and pathological conditions remain unclear. Previous studies showed that lysyl hydroxylase (LH) plays a crucial role in the formation of collagen. Minoxidil is an FDA-approved anti-hypertensive agent that inhibits LH that reduces fibrosis. In this study, we investigated the functional roles of LHs (LH1, LH2, and LH3) in pulmonary fibrosis and the anti-fibrotic effects of minoxidil.Material/MethodsPatient serum samples were examined for their expression of procollagen-lysine, 2-oxoglutarate 5-dioxygenases (PLOD) 1–3, the genes encoding LH 1–3. Mice with bleomycin (BLM 2.5 mg/kg)-induced pulmonary fibrosis were administered a minoxidil solution (30 mg/kg) by oral gavage.ResultsThe PLOD mRNA levels were significantly higher in the IPF patients than in the healthy control subjects. Minoxidil suppressed the BLM-induced pulmonary fibrosis in vivo. These effects were associated with blocking TGF-β1/Smad3 signal transduction and attenuating the expression and activity of LHs, resulting in decreased collagen formation, thus reducing the pulmonary fibrosis. The anti-fibrotic effects of minoxidil may be mediated through competitive inhibition of LHs activity, resulting in decreased pyridine cross-link formation and collagen production and deposition.ConclusionsThe results of this study suggest that LH represents a target to prevent or treat pulmonary fibrosis, and minoxidil may provide an effective agent to inhibit LHs.

Hepatocellular carcinoma is a lethal cancer with high recurrence ratio and lacks effective therapeutics. In the past few years, it has been reported that increased intake of vegetables and fruits could reduce the cancer incidence, which suggests dietary agents might possess anticancer effects. Eriocitrin is a flavonoid isolated from lemon, which is known as a strong antioxidant agent. We here for the first time demonstrated that eriocitrin could inhibit the proliferation of hepatocellular carcinoma cell lines by arresting cell cycle in S phase through up-regulation of p53, cyclin A, cyclin D3 and CDK6. Furthermore, we found that eriocitrin could trigger apoptosis by activating mitochondria-involved intrinsic signaling pathway. Thus, eriocitrin might be regarded as a potential chemopreventive natural product to inhibit the early malignant transformation of hepatocellular carcinoma.