ARF6 promotes hepatocellular carcinoma proliferation through activating STAT3 signaling.

BACKGROUND: Hepatocellular Carcinoma (HCC) possesses the high mortality in cancers worldwide. Nevertheless, the concrete mechanism underlying HCC proliferation remains obscure. In this study, we show that high expression of ARF6 is associated with a poor clinical prognosis, which could boost the proliferation of HCC. METHODS: Immunohistochemistry and western blotting were used to detect the expression level of ARF6 in HCC tissues. We analyzed the clinical significance of ARF6 in primary HCC patients. We estimated the effect of ARF6 on tumor proliferation with in vitro CCK8, colony formation assay, and in vivo nude mouse xenograft models. Immunofluorescence was conducted to investigate the ARF6 localization. western blotting was used to detect the cell cycle-related proteins with. Additionally, we examined the correlation between ARF6 and STAT3 signaling in HCC with western blotting, immunohistochemistry and xenograft assay. RESULTS: ARF6 was upregulated in HCC tissues compared to adjacent normal liver tissues. The increased expression of ARF6 correlated with poor tumor differentiation, incomplete tumor encapsulation, advanced tumor TNM stage and poor prognosis. ARF6 obviously promoted HCC cell proliferation, colony formation, and cell cycle progression. In vivo nude mouse xenograft models showed that ARF6 enhanced tumor growth. Furthermore, ARF6 activated the STAT3 signaling and ARF6 expression was positively correlated with phosphorylated STAT3 level in HCC tissues. Furthermore, after intervening of STAT3, the effect of ARF6 on tumor-promoting was weakened, which demonstrated ARF6 functioned through STAT3 signaling in HCC. CONCLUSIONS: Our results indicate that ARF6 promotes HCC proliferation through activating STAT3 signaling, suggesting that ARF6 may serve as potential prognostic and therapeutic targets for HCC patients.

Prognostic significance and molecular mechanisms of adenosine triphosphate-binding cassette subfamily C members in gastric cancer.

Gastric cancer (GC) is one of the major leading causes of tumor-related deaths worldwide. Adenosine triphosphate-binding cassette subfamily C (ABCC) consists of 13 members, ABCC1 to 13, which were examined for their associations with GC.The online Kaplan-Meier Plotter database was used to determine the prognostic significance of ABCC subfamily members in GC. Stratified analyses were performed using gender, disease stage, degree of tumor differentiation, expression of human epidermal growth factor receptor 2 (HER2), and Lauren classification. Molecular mechanisms were examined using the database for annotation, visualization, and integrated discovery database.ABCC1, ABCC3, ABCC7, ABCC8, ABCC9, and ABCC10 expression showed prognostic significance in the whole population and in male and female subpopulations (all P ≤ .05). Furthermore, high expression of most ABCC family members always suggested a poor prognosis, except for ABCC7 (P > .05). Stratified analyses revealed that ABCC1, ABCC3, ABCC7, ABCC8, ABCC9, and ABCC10 expression showed prognostic significance for the whole population, as well as male and female populations. ABCC2 and ABCC9 were significantly correlated with all disease stages, while ABCC2 and ABCC6 were significantly correlated with all Lauren classifications. Expression of ABCC1, ABCC3, ABCC5, ABCC7, ABCC8, ABCC9, and ABCC10 was significantly correlated with either negative or positive of HER2 status (all P ≤ .05). Enrichment analysis indicated that these genes were involved in ATPase activity, transmembrane transport, or were ABC transporters (all P ≤ .05).ABCC1, ABCC3, ABCC7, ABCC8, ABCC9, and ABCC10 may be potential prognosis biomarkers for GC, acting as ABC transporters and via ATPase activity.

Sublingual immunotherapy of atopic dermatitis in mite-sensitized patients: a multi-centre, randomized, double-blind, placebo-controlled study.

Allergen-specific immunotherapy is widely used for allergic rhinitis and asthma treatment worldwide. This study explored the efficacy and safety of sublingual immunotherapy (SLIT) with the extracts of Dermatophagoides Farinae (D. farinae Drops) on house dust mites (HDM)-induced atopic dermatitis (AD). 239 patients with HDM-induced AD were recruited and exposure to a multi-centre, randomized, double-blind, and placebo-controlled clinical trials for 36 weeks, which were randomly divided into placebo and sublingual D. farinae Drops groups (high-dose, medium-dose and low-dose), respectively. Statistical analysis was performed in three groups: Full Analysis Set, Per Protocol Set and Safety Set. 48 cases have withdrawn from the study before the end of study. As primary outcomes, significant decreases in scoring atopic dermatitis and total medication score were showed in medium-dose and high-dose D. farinae Drops groups. In the sixth visit, the skin lesion area showed a statistically significant difference between high-dose/medium-dose D. farinae Drops group and placebo group (p < .05). Most adverse events are slight, and no life-threatening adverse drug reaction happened. Our research demonstrates the beneficial effect of SLIT with high or medium dose D. farinae Drops on AD, and the treatment was well tolerated.

Assessment of severity of leukoaraiosis: a diffusional kurtosis imaging study.

OBJECTIVE: The objective was to investigate the capabilities of diffusional kurtosis imaging (DKI) in detection of age-related white matter (WM) changes in elderly patients with leukoaraiosis. MATERIAL AND METHODS: Fractional anisotropy (FA), kurtosis, and diffusion parameters in the frontal lobe and parietal lobe were compared between 14 patients at Fazekas scale 0 and 1, and 15 patients at Fazekas scale 2 and 3. RESULTS: FA and DKI parameters were significantly altered in the ischemic lesions vs normal regions of WM in the severe patients. CONCLUSION: DKI can provide sensitive imaging biomarkers for assessing the severity of leukoaraiosis in reference to Fazekas score.

A novel missense mutation in the SLC6A19 gene in a Chinese family with Hartnup disorder.

BACKGROUND: Hartnup disease is a rare autosomal-recessive abnormality of renal and gastrointestinal neutral amino acid transport associated with neurologic, psychiatric, and dermatologic symptoms. Mutations in the SLC6A19 gene have been proposed to be responsible for the underlying changes in this disorder. AIM: To investigate a pedigree with Hartnup disorder and to search for the mutation in the SLC6A19 gene in this pedigree. METHODS: The encoding exons of the SLC6A19 gene were amplified and sequenced from genomic DNA samples. Amino acids were determined in urine samples from the proband and her family members. RESULTS: The proband and her brother had a homozygous mutation of c.850G > A in the SLC6A19 gene, causing G284R in the transmembrane domain of the SLC6A19 transporter, inherited from their parents who were heterozygous carriers. Their urine samples showed increased values of eight neutral amino acids. CONCLUSION: We found a novel homozygous mutation of G284R in the transmembrane domain of the SLC6A19 transporter in the proband, with typical dermatologic and neurologic manifestations and increased levels of urinary neutral amino acids.

Role of autoantibodies against the linker subdomains of envoplakin and periplakin in the pathogenesis of paraneoplastic pemphigus.

BACKGROUND: The presence of autoantibodies against multiple epidermal proteins is an important feature in paraneoplastic pemphigus (PNP). Circulating anti-desmoglein 3 autoantibody, the major pathogenic autoantibody in pemphigus vulgaris (PV), has been proved pathogenic in PNP. Because of many clinical differences between PNP and PV, we speculate about the involvement of other autoantibodies in the pathogenesis of PNP. Envoplakin (EPL) and periplakin (PPL) are recognized by most PNP sera. Their linker subdomains are highly homologous and necessary for the association of intermediate filaments. METHODS: We characterized the autoantibodies against the linker subdomains of EPL and PPL in PNP patients' sera and their associated tumors by enzyme-linked immunosorbent assay (ELISA) and immunofluorence. We also applied the purified autoantibodies against EPL and PPL from PNP sera to cultured human epidermal keratinocytes (HEK), to evaluate the changes of cell-cell adhesion. RESULTS: Autoantibodies against EPL and PPL were detected in most PNP patients by ELISA, and the decrease of these autoantibodies after removal of the tumors was roughly comparable to the improvement of clinical symptoms. Cultured tumor cells from PNP patients secreted these autoantibodies. Specific immunoglobulin receptors for EPL and PPL were found on B lymphocytes in tumors from PNP. Furthermore, purified anti-EPL and anti-PPL autoantibodies from PNP sera were capable of dissociating cultured human epidermal keratinocytes. CONCLUSION: Autoantibodies against EPL and PPL may also be pathogenic in PNP.

Detection of anti-envoplakin and anti-periplakin autoantibodies by ELISA in patients with paraneoplastic pemphigus.

Paraneoplastic pemphigus patients (PNP) develop a group of autoantibodies, among which those against envoplakin and periplakin are almost always found. Epitope mapping has indicated that the linker subdomains of the proteins harbor the major antigenic sites recognized by PNP sera. In order to detect specific autoantibodies for the diagnosis of PNP, we expressed recombinant proteins containing linker subdomains of human periplakin and envoplakin in a human kidney cell line, and used them as the antigens for ELISAs. We found that all of the sera from 16 PNP patients recognized these two recombinant proteins by ELISA, and sera from 20 pemphigus vulgaris (PV), 12 pemphigus foliaceus (PF), 20 bullous pemphigoid (BP), 2 Castleman's tumor without PNP and 20 normal controls showed negative results. We also expressed the extracellular domain of desmoglein 3 (Dsg3) in the cell line, and used this recombinant Dsg3 as the ELISA antigen. Only 11 of our 16 PNP sera were positive, and most PV sera were positive. Our findings indicate that ELISAs using the recombinant proteins containing linker subdomains of envoplakin and periplakin expressed in a human cell line as the antigens are highly sensitive and specific for the diagnosis of PNP.