Several approaches to active immunotherapy for melanoma, including peptide‐based vaccines (PVs), autologous tumour cell vaccines (TCVs), allogeneic TCVs and autologous dendritic cell vaccines (DCVs), have been investigated in clinical trials. However, comprehensive evidence comparing these interventions remains unavailable. The objective of this study was to expand previous work to compare and rank the immunotherapeutic strategies for melanoma in terms of overall survival and toxic effects with a Bayesian network meta‐analysis. Methodologically, we performed a network meta‐analysis of head‐to‐head randomized controlled trials comparing and ranking cancer vaccine approaches for patients with melanoma. PubMed, MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, the WHO International Clinical Trials Registry Platform and ClinicalTrials.gov were searched up to 31 July 2020. We estimated summary hazard ratios for death and risk ratios for toxicity. The effects of the underlying prognostic variable on survival benefits were examined by meta‐regression. We performed subgroup analysis for the outcomes based on metastatic categories. Overall, we identified 4776 citations, of which 15 head‐to‐head randomized controlled trials (3162 participants) were included in the analysis. In terms of efficacy, allogeneic tumour cell vaccines plus immunotherapy adjuvants, peptide‐based vaccines plus immunotherapy adjuvants and standard therapy were more effective than peptide vaccines. The proportion of women was inversely associated with mortality risk. For safety, all treatments were inferior to allogeneic tumour cell vaccines except for allogeneic tumour cell vaccines plus chemotherapy. Peptide vaccines plus immunotherapy adjuvants led to an increased risk of adverse events compared to allogeneic tumour cell vaccines plus immunotherapy adjuvants. These results suggest that allogeneic TCV and autologous DCV are better than standard therapy. PV plus immune modulators are the most effective strategy among all comparable strategies but is associated with increased toxicity. Any combination regimens for cancer therapeutic vaccines need to be balanced between risk and benefit profiles.

Dermographism manifests as a secondary temporal linear cutaneous wheal after scratching, stroking, or rubbing the skin. It is a debilitating condition with profound effects on quality of life, but the underlying causes and mechanisms remain obscure.1 Relevant study on the association of environmental factors with dermographism was limited. Lefebvre et al. found that the prevalence of dermographism was higher in polluted areas, but could not confirm the causality.2 Therefore, we conducted this study to investigate the effect of previous exposure to air pollutants on dermographism.

BackgroundPsoriasis is a chronic inflammatory skin disease, which holds a high incidence in China. However, professional dermatologists who can diagnose psoriasis early and correctly are insufficient in China, especially in the rural areas. A smart approach to identify psoriasis by pictures would be highly adaptable countrywide and could play a useful role in early diagnosis and regular treatment of psoriasis. ObjectivesDesign and evaluation of a smart psoriasis identification system based on clinical images (without relying on a dermatoscope) that works effectively similar to a dermatologist. MethodsA set of deep learning models using convolutional neural networks (CNNs) was explored and compared in the system for automatic identification of psoriasis. The work was carried out on a standardized dermatological dataset with 8021 clinical images of 9 common disorders including psoriasis along with full electronic medical records of patients built over the last 9 years in China. A two-stage deep neural network was designed and developed to identify psoriasis. In the first stage, a multilabel classifier was trained to learn the visual patterns for each individual skin disease. In the second stage, the output of the first stage was utilized to distinguish psoriasis from other skin diseases. ResultsThe area under the curve (AUC) of the two-stage model reached 0.981 0.015, which outperforms a single-stage model. And, the classifier showed superior performance (missed diagnosis rate: 0.03, misdiagnosis rate: 0.04) than 25 Chinese dermatologists (missed diagnosis rate: 0.19, misdiagnosis rate: 0.10) in the diagnosis of psoriasis on 100 clinical images. ConclusionsUsing clinical images to identify psoriasis is feasible and effective based on CNNs, which also builds a solid technical base for smart care of skin diseases especially psoriasis using mobile/tablet applications for teledermatology in China.

Interleukin-6 particularly plays a critical role in number of biological events. Different cancer cells, cancer-associated cells and resistant cancer cells overexpress and secrete IL-6 in tumor microenvironment. While, IL6 which was originally identified as a B-cell differentiation factor, is a multifunctional cytokine that regulates the immune response, the acute phase response and inflammation. There are increasing evidences showed that IL-6 can initial promoting anti-tumor immunity to inhibit cancer progress. Those contradictory view urge us to explore the function of IL6 in melanoma. We report that IL6 was overexpression in melanoma patients and melanoma cell lines. Patients with high IL6 expression in melanoma species conferred a worse prognosis. Knock down IL6 markedly attenuated melanoma cell proliferation, invasion and metastasis in vitro and in vivo. Anti-IL6 antibody siltuximab can treat subcutaneous tumorigenic nude mice effectively. To further investigate the mechanism of IL6 promote invasion in melanoma. We downregulated IL6 and found the cell cycle were mainly prolonged in G1 phase and shortened in S phase, DNA damage was increase. Human phosphor-kinase array showed a significant decrease in stat3 and p-stat3, MMP9. Taken together, above findings indicated that IL6 stimulates tumor invasion and metastasis by adjust cell cycle, apoptosis, and STAT3/MMP9 expression and these actions can be inhibited by a neutralising anti-IL6 antibody siltuximab, which serves as a new understanding of the function of IL6 in melanoma, and enhanced the basis of IL6 as a melanoma target.

Skin cancer is the most common type of cancer. The main types of skin cancer are nevus, basal cell carcinoma (BCC),squamous cell carcinoma(SCC), and malignant melanoma(MM) et al. According to the diagnostic criteria, skin cancer can be divided into benign, low degree and high degree malignancy. In current clinical practice, diagnosis of benign and malignant tumors often needs biopsy and pathological examination. Many patients are unable to get inexpensive access to accurate diagnosis, which might cause delays in the optimal treatment. In order to aid primary doctors to predict the malignant degree of the skin cancer more conveniently and conduct the preliminary screening before diagnosis, we attempted the automatic scoring of malignant degree by clinical skin cancer images using deep learning models. Xiangya Hospital accumulated pathologically verified and annotated dataset for 9 years (from 2010 to 2018). 10 kinds of skin cancer diseases, including 4,500 images, were selected and divided into three levels: Junctional nevus, Intradermal nevus, Dermatofibroma, Lipoma and Seborrheic keratosis is benign, BCC, Bowen's disease and Solar keratosis is low degree of malignancy, SCC and MM is high degree of malignancy. We used the Xception architecture to classify the three degrees, and the over-all accuracy could reach 82.7%. The area under the receiver operating curve (ROC) values corresponding to the three degrees could reach 0.959, 0.919 and 0.947 respectively. Our scoring algorithm was compared with 10 professional dermatologists, and the results showed that the performance of computer assessment was highly consistent with those of the professional dermatologists.

PURPOSE: OSAHS is associated with the pathogenesis of metabolic abnormalities, including NAFLD. The aim of study was to study the association of chemokine fractalkine with liver injury in male OSAHS patients. METHODS: We studied 25 male patients with newly diagnosed OSAHS, who were free of alcohol and other diseases, had never been treated for OSAHS, and were taking no medications. We compared fractalkine measurements and liver function in these patients to measurements obtained in 20 control subjects who were matched for age, sex and body mass index, and in whom occult OSAHS was excluded. The OSAHS patients received one month nCPAP treatment. The association between fractalkine and liver injury was analyzed. RESULTS: Plasma fractalkine and ALT, AST, TG were significantly higher in OSAHS patients than in controls. Fractalkine were associated with AHI (r=0.777; P<0.001), lowest oxygen saturation (r=-0.556, P<0.001), mean oxygen saturation (r=-0.545, P<0.001) and ALT (r=0.500; P<0.001). The severity of OSAHS was an independent factor predicting the plasma fractalkine. Plasma fractalkine levels were significantly decreased in patients with OSAHS after one month nCPAP (454.92±84.00 versus 396.83±96.24 pg/ml, P=0.001) , and ALT(43.57±22.10 versus 33.00±18.21 u/L; p<0.001), AST(33.99 ± 15.03 versus 25.71±12.12 u/L; p<0.001), TG (84±39.8 versus 70± 11.9 mg/dL,p<0.001) were significantly decreased after one month nCPAP . CONCLUSIONS: In male patients, OSAHS can independently contribute to elevated level of fractalkine, a marker of inflammation associated with liver injury . CLINICAL IMPLICATIONS: OSAHS may increase the risks of liver injury through inflammation, which may provide a strategy for attenuating the progression of NAFLD in patients with OSAHS.

Chronic arsenite and ultraviolet (UV) exposure are associated with skin tumor. To investigate the details by low concentrations of arsenite and UV induced carcinogenesis in skin, hTERT-immortalized human keratinocytes were used as a cellular model with exposure to low concentrations of sodium arsenite and UV. The effect of NaAsO 2 on UV treatment-induced apoptosis was measured by flow cytometry and Hoechst staining. We found that the cell apoptosis induced by UV exposure was significantly attenuated after exposure to low-dose arsenite, and knockdown of p53 could block UV-induced apoptosis indicating that this phenomenon depended on p53. Interestingly, the expression of murine double minute 2 (MDM2), including its protein and transcriptional levels, was remarkably high after exposure to low-dose arsenite. Moreover, low-dose arsenite treatment dramatically decreased the MDM2 gene promoter activity, suggesting that this effect has been mediated through transcription. In addition, treatment of PD98059 reversed low-dose arsenite-induced MDM2 expression, and the inhibition of ERK2 expression could significantly block MDM2 expression as a consequence, and p53 expression automatically was increased. To validate the role of p53 in exposure to low-dose arsenite, the expression of p53 was examined by immunohistochemistry in the skin of Sprague−Dawley rats model by chronic arsenite exposure for 6 months and in patients with arsenic keratosis, and the results showed that the expression of p53 was decreased in those samples. Taken together, our results demonstrated that low-dose arsenite-induced resistance to apoptosis through p53 mediated by MDM2 in keratinocytes.

Studies have shown that TNFR1 is a key factor in the tumor microenvironment that is dependent on the TNF-α-initiated cascade for tumorigenesis. In this present study, we found that TNFR1 is over-expressed in ovarian cancer, which is relevant to both clinical survival and disease free status. Knockdown of TNFR1 dramatically attenuates malignant phenotypes, including proliferation and colony growth in soft agar, as well as glycolysis in ovarian cancer cells. Unexpectedly, knocking down TNFR1 blocks EGF-induced p-AKT and p-p70S6K expression and EGF-induced cell transformation through PIK3-p110beta rather than p110alpha expression. Taken together, our data provide evidence that TNFR1 plays a critical role in ovarian cancer and show that the EGF induced signaling pathway is independent of the TNF-α triggering cascade signal. Therefore, TNFR1 may serve as a prognostic molecule in ovarian cancer.

Cyclin-dependent kinase 2 (CDK2) is a known regulator in the cell cycle control of the G1/S and S/G2 transitions. However, the role of CDK2 in tumorigenesis is controversial. Evidence from knockout mice as well as colon cancer cell lines indicated that CDK2 is dispensable for cell proliferation. In this study, we found that ectopic CDK2 enhances Ras (G12V)-induced foci formation and knocking down CDK2 expression markedly decreases epidermal growth factor (EGF)-induced cell transformation mediated through the downregulation of c-fos expression. Interestingly, CDK2 directly phosphorylates ELK4 at Thr194 and Ser387 and regulates the ELK4 transcriptional activity, which serves as a mechanism to regulate c-fos expression. In addition, ELK4 is overexpressed in melanoma and knocking down the ELK4 or CDK2 expression significantly attenuated the malignant phenotype of melanoma cells. Taken together, our study reveals a novel function of CDK2 in EGF-induced cell transformation and the associated signal transduction pathways. This indicates that CDK2 is a useful molecular target for the chemoprevention and therapy against skin cancer.

Malignant melanoma (MM) is one of the most lethal tumors and is characterized by high invasiveness, frequent metastasis, and resistance to chemotherapy. The risk of metastatic MM is accompanied by disordered energy metabolism involving the oxidative phosphorylation (OXPHOS) process, which is largely carried out in mitochondrial complexes. Complex I is the first and largest mitochondrial enzyme complex associated with this process. CD147 is a transmembrane glycoprotein mainly expressed on the cell surface, and also appears in the cytoplasm in some tumors. We found that CD147 is often translocated to the cytoplasm in metastatic MM specimens as compared to primary MM. We also demonstrated high expression of CD147 in isolated mitochondrial fractions of A375 cells. The yeast two-hybrid (Y2H) assay identified NDUFS6 (which encodes a subunit of mitochondrial respiratory chain complex I) as a candidate that interacts with CD147 and depletion of CD147 in A375 cells significantly decreased complex I enzyme activity. We also showed that CD147 increased the viability of A375 cells exposed to berberine-induced mitochondrial damage, and protected them from apoptosis through a mitochondrial-dependent pathway. This finding was confirmed by adding exogenous Bcl-2 to A375 cell cultures. In summary, our results identify the existence of CD147 in human melanoma cell mitochondria. They indicate that CD147 appears to regulate complex I activity and apoptosis in MM by interacting with mitochondrial NDUFS6. Our findings provide new insight into the function of CD147 and identify it as a promising therapeutic target in melanoma through disruption of the energy metabolism.

Hypoxia enhances MMP2 expression and the invasion and metastatic potential of melanoma cells. CD147 has been shown to induce MMP2 in multiple cancers. To investigate the role of CD147 in hypoxiainduced MMP2 activation, we performed immunohistochemistry (IHC) staining in 206 normal and melanoma tissue samples, and analyzed the correlation between HIF1α and CD147. ChIP (chromosome Immunoprecipitation) in melanoma cell lines supports that HIF1α directly binds to CD147 promoter. Moreover, we made a series of deletion mutants of CD147 promoter, and identified a conserved HIF1α binding site. Point mutation in this site significantly decreased CD147 response to hypoxia. Importantly, knocking down CD147 attenuates MMP2 response to hypoxia in melanoma cell lines. MMP2 could not be efficiently activated by hypoxia in CD147 depletion cells. ELISA data showed that MMP2 secretion was reduced in CD147 depletion cells than control under hypoxia condition. To verify the data from cell culture model, we performed in vivo mouse xenograft experiment. IHC staining showed reduced MMP2 level in CD147 depleted xenografts compared to the control group, with the HIF1α level being comparable. Our study demonstrates a novel pathway mediated by CD147 to promote the MMP2 activation induced by hypoxia, and helps to understand the interplay between hypoxia and melanoma progression.

Nascent polypeptide-associated complex α ( α NAC) is reportedly overexpressed in several types of cancers and regulates cell apoptosis under hypoxic conditions in HeLa cells. The aim of our study was to investigate the apoptotic function of α NAC in cancer progression. First, we observed the cellular effects of α NAC depletion. Mouse α NAC was used to restore the protein level and verify the effect. An Annexin V assay, a caspase activity reporter assay, an apoptotic molecular marker, and a colony formation assay were used as markers to investigate the mechanisms of cell death caused by α NAC depletion. The Cancer 10-pathway reporter assay was used to screen downstream pathways. PCR site-directed deletion based on the functional domains of α NAC was used to construct deletion mutants. Those functional domain deletion mutants were used to recover the apoptotic phenotype caused by α NAC depletion. Finally, the role of α NAC in TNF-related apoptosis-inducing ligand (TRAIL) treatment was investigated in vitro . We found that depletion of α NAC in multiple types of cancer cells induce typical apoptotic cell death. This anti-apoptotic function is mediated by the FADD/c-Jun N-terminal kinase pathway. Intact α NAC is required for the direct binding of FADD as well as its anti-apoptosis function. Either α NAC depletion or the deletion of the ubiquitin-associated domain of α NAC sensitizes L929 cancer cells to mTRAIL treatment. Our study revealed a α NAC anti-apoptotic function in multiple types of cancer cells and suggested its potential in cancer therapy.