A Case of Paradoxical Reactions to Biologic Therapy for Psoriasis.

Introduction: Psoriasis is an immune-mediated chronic inflammatory skin disease. As our understanding of the pathogenesis of psoriasis has improved, biologic agents have become increasingly important in the treatment of psoriasis. However, the use of biologic agents is associated with cutaneous side effects. A new type of side effect called paradoxical reactions is an emerging threat arising from the increasing use of biologic agents. Case: Here, we present a case of paradoxical skin reactions - pyoderma gangrenosum (PG) and eczema - induced by biologic therapy. The case was successfully and eventually treated with baricitinib. Discussion: PG is a rare inflammatory disease characterised by painful and necrotic ulcerations containing neutrophils. It has been associated with autoimmune diseases such as inflammatory bowel disease (IBD). TNF (tumor necrosis factor) -α inhibitors can effectively treat refractory PG, while IL (interleukin) -17A inhibitors may worsen IBD symptoms. The cause of PG in this case was believed to be secukinumab, not adalimumab. The patient was diagnosed with eczematous dermatitis due to TNF-α inhibitors, and baricitinib was added to treat eczematous dermatitis. Conclusion: Paradoxical reactions are unpredictable events that may occur during treatment with biologics at anytime. They need further research in order to formulate personalised treatment.

Comparison of responses of melanocyte lineages from p75(+) and p75(-) human scalp-derived neural crest stem cells under phototherapy.

Phototherapy is an effective therapeutic option in the treatment of vitiligo; however, responses varied among the different types. The underlying mechanism has scarcely been investigated. To investigate and compare the effects of phototherapy on the mutation of melanocyte lineage differentiated from human scalp-derived neural crest stem cells (HS-NCSCs) with p75 neurotrophin receptor expression positive and p75 neurotrophin receptor expression negative group in vitro, the HS-NCSCs were isolated from fetal scalp tissue, which is identified by immunofluorescent staining. The p75(+) and p75(-) cells from HS-NCSCs were isolated by magnetic cell sorting, respectively. The embryonic neural crest stem cell biomarkers were detected by RT-PCR. Narrow-band UVB (NB-UVB) was used to irradiate the cells. Cell proliferation was evaluated by cell count. Tyrosinase, Tyrp1, and Tyrp2 gene expression were measured by quantitative RT-PCR. Tyrosinase and GRCR protein levels were investigated by Western blot analysis. The electrophoretic strip showed that Sox2, Oct4, Sox10, and Nestin of p75(+) HS-NCSCs were brighter than the p75(-) HS-NCSCs. After the same dose radiation with NB-UVB, the cell proliferation of p75(+) group showed less inhibitory rate compared with the p75(-) HS-NCSCs. The tyrosinase mRNA and protein expression of differentiated melanocytes increased significantly in the group of p75(+) HS-NCSCs compared with the p75(-) group. The melanocytic mutation of p75(+) HS-NCSCs increased significantly compared with the p75(-) HS-NCSCs under NB-UVB, which indicated there were more melanocyte precursors in the differentiated cells from p75(+) HS-NCSCs. This may provide new insights for the different repigmentation efficacy of segmental and non-segmental vitiligo.

NB-UVB Induces Melanocytic Differentiation of Human Hair Follicle Neural Crest Stem Cells.

BACKGROUND: Phototherapy is an important method to treat vitiligo. However, it is unclear how phototherapy affects melanocyte precursors and skin neural crest stem cells. OBJECTIVE: To investigate the underlying mechanisms of narrow-band ultraviolet B (NB-UVB) induced melanocyte lineage differentiated from human scalp-derived neural crest stem cells (HS-NCSCs). METHODS: HS-NCSCs were expanded from scalp hair follicles. The c-Kit-/CD57- HS-NCSCs were isolated by cell sorting. Different doses of NB-UVB were used to irradiate these HS-NCSCs. Cell ultrastructure was examined by transmission electron microscope. Melanocyte marker expression was analyzed by Quantitative RT-PCR and Western blot. Cell proliferation and migration were also evaluated. RESULTS: The c-Kit-/CD57- HS-NCSCs expressed embryonic NCSC biomarkers. NB-UVB at a dose of 100 mJ of NB-UVB had little effect on the cell proliferation of differentiated melanocytes from c-Kit-/CD57- HS-NCSCs, while 700 mJ inhibited cell proliferation significantly. The dendritic processes of differentiated melanocytes increased after radiation. The tyrosinase and Melanocortin 1 receptor (Mc1R) expression of differentiated melanocytes increased after NB-UVB exposure. The effect of NB-UVB on tyrosinase expression was modulated by signaling inhibitors H89 and PD98059 as well as Mc1R level in the cells. The migration ability of differentiated melanocytes was enhanced under 100 mJ exposure. CONCLUSION: These data demonstrate that NB-UVB facilitates melanocytic differentiation of the HS-NCSCs and enhances migration of these cells. Mc1R and cAMP pathway play a critical role in NB-UVB induced melanocytic differentiation.

MicroRNA-204-3p modulates epithelial-mesenchymal transition by targeting paired box gene 2 in human melanoma A-375 cells.

BACKGROUND: Paired box 2 gene promoted the progression of subsequent epithelial-mesenchymal transition (EMT) in malignant melanoma, which is the most dangerous type of skin cancer. We aimed to investigate the functional role of miR-204-3p in metastatic melanoma. METHODS: To study the effects of overexpressed miR-204-3p on the melanoma cells, miR-204-3p mimic vector were transfected into A-375 cells for detecting the cell viability using CCK-8 kit. Wound healing and Transwell assays were performed to assess the migration and invasion capacities of melanoma cells. TargetScan and miRTarBase were used to predict the potential target of miR-204-3p, which was subsequently verified by dual-luciferase assay. The expressions of several EMT-associated genes were determined by quantitative real-time polymerase chain (qRT-PCR) and Western blot. RESULTS: The expression of miR-204-3p in several melanoma cell lines was lower than that in HaCaT cells. After transfecting with the miR-204-3p mimic vector, the cell viability of A-375 cells decreased over time and significantly reduced at 48 h (P<0.01). Overexpression of miR-204-3p noticeably suppressed the migration and invasion abilities of A-375 cells (P<0.01). PAX2 and guanine nucleotide binding protein (G protein) q polypeptide (GNAQ) were the potential targets of miR-204-3p, which could effectively silence PAX2 rather than GNAQ. MiR-204-3p overexpression could upregulate the epithelial cadherin (E-cadherin) and downregulate the vimentin, matrix metalloproteinase 2 (MMP2) and MMP-9 at transcriptional and posttranscriptional levels. CONCLUSIONS: Our results revealed that miR-204-3p had inhibitory effects on the migratory and invasive capacities and EMT progression in malignant melanoma through targeting PAX2.

Yes-Associated Protein (YAP) Promotes Tumorigenesis in Melanoma Cells Through Stimulation of Low-Density Lipoprotein Receptor-Related Protein 1 (LRP1).

YAP is a critical protein in cancer development and can induce transformative phenotypes in mammary epithelial cells. Previous studies have provided evidence that YAP can contribute to the metastatic behavior of melanoma, since specific knockdown of YAP leads to reduced metastatic and invasive capacity in vitro. However, the mechanism by which YAP regulates the function of melanoma is unknown. Here, we identified that YAP has a positive impact on the expression of LRP1, which also plays critical roles in cancer. Mechanically, knockdown of YAP resulted in a significant down-regulation of LRP1 at both the protein and mRNA levels. Tissue microarray analysis (TMA) also showed a positive correlation between YAP and LRP1 expression. In addition, reduction of YAP-impaired pro-carcinogenic phenotypes could be partially reversed by simultaneous overexpression of LRP1, suggesting that LRP1 is functionally important in YAP-induced melanoma tumorigenesis. Furthermore, we found that LRP1 was regulated by YAP through a transcription- and promoter-dependent mechanism. Taken together, our results suggest that YAP regulates LRP1 through stimulation of the LRP1 promoter and that LRP1 may be an important target for influencing YAP in melanoma.

Effects of exercise intervention in breast cancer survivors: a meta-analysis of 33 randomized controlled trails.

BACKGROUND: Exercise is associated with favorable outcomes in cancer survivors. The purpose of this meta-analysis is to comprehensively summarize the effects of exercise intervention in breast cancer survivors. METHODS: A systematic search of PubMed, Elsevier, and Google scholar was conducted up to March 2015. References from relevant meta-analyses and reviews were also checked. RESULTS: Thirty-three randomized controlled trials were included in this meta-analysis, including 2,659 breast cancer survivors. Compared with the control group, quality of life was significantly improved in exercise intervention group, especially in mental health and general health subscales of short form 36 questionnaire, as well as emotion well-being and social well-being subscales of the Functional Assessment of Cancer Therapy. Besides, exercise alleviated the symptoms of depression and anxiety in the exercise group. Furthermore, exercise was also associated with positive outcomes in body mass index, lean mass, and muscle strength. In addition, the serum concentration of insulin, insulin-like growth factor-II, and insulin-like growth factor binding protein-1 was significantly reduced in exercise intervention group. However, based on the current data of this meta-analysis, there were no significant differences in sleep dysfunction or fatigue between groups. CONCLUSION: Our study suggested that exercise intervention was beneficial to breast cancer survivors. Therefore, exercise should be recommended to this patient group.

Prognostic value of melanoma cell adhesion molecule expression in cancers: a meta-analysis.

Melanoma cell adhesion molecule (MACM) has been reported in many studies as a novel bio-marker for its prognosis value in cancers. But the prognosis significance of MACM expression in cancer remains inconclusive. Therefore, we conducted a system review and meta-analysis to assess its prognosis value in cancers. A systematic search through Pubmed, EMBASE and Cochran Library database was conducted. Hazard Ratios (HRs) and 95% confidence intervals (CIs) were used to evaluate the prognosis value of MACM expression. Eleven studies with 2657 cases were included after sorting out 462 articles for this meta-analysis. The results of the fixed-model depending on the heterogeneity in studies demonstrated that MACM expression was significantly associated with overall survival (OS) in cancer (HR=2.84, 95% CI: 1.10-7.31, P<0.00001). Furthermore, subgroup analysis indicated that high expressed MACM predicted a poor OS in both Asian (HR=2.52, 95% CI: 1.80-3.52, P<0.00001) and Caucasian (HR=2.40, 95% CI: 2.01-2.88, P<0.00001). In conclusion, high expression of MACM was significantly associated with a poor prognostic outcome in cancer. MACM can be regarded as a novel bio-marker in different types of cancers and can be used to evaluate the prognosis of therapeutic effect during clinical practices.

Efficacy and safety of secukinumab in the treatment of moderate to severe plaque psoriasis: a meta-analysis of randomized controlled trials.

Psoriasis is a chronic inflammatory skin disease with high rate of recurrence. New anti-interleukin-17 (IL-17) and anti-IL17RA biologics are in Phase 3 clinical trials and may prove to be more effective than existing biologic drugs. Now we perform a meta-analysis on efficacy and safety of secukinumab in the treatment of moderate-to-severe plaque psoriasis. In this meta-analysis, data analysis was performed with the Cochrane Collaboration's RevMan 5.0 software. Eight randomized controlled trials (RCTs) with a total of 3,213 psoriasis cases were included in the meta-analysis. Co-primary endpoints (week 12) were ≥ 75%/90% improvement in psoriasis area and a score of 0 (clear) or 1 (almost clear) on a 5-point Investigator's Global Assessment scale (IGA mod 2011 0/1) versus placebo [1]. The overall efficacy in the meta-analysis was as follows: PASI 75: for secukinumab 150 mg versus placebo, fixed-effects OR = 49.25, 95% CI: 33.67-72.06, Z = 20.07, P < 0.00001; PASI 90: for secukinumab 150 mg versus placebo, fixed-effects OR = 44.92, 95% CI: 24.72-81.62, Z = 12.49, P < 0.00001; IGA mod 2011 0/1: for secukinumab 150 mg versus placebo, random-effects OR = 22.25, 95% CI: 7.63-64.84, Z = 5.68, P < 0.00001; Compared with placebo, there were no significant adverse effects in the secukinumab groups, demonstrating safety in the treatment of moderate to severe plaque psoriasis. The proportion of patients who achieved 75%, 90% and IGA mod 2011 0/1 reductions respectively was significant in the secukinumab groups, demonstrating a rapid clinical improvement accompanied by a favorable short-term safety profile.

The tumor necrosis factor receptor superfamily member 1B polymorphisms predict response to anti-TNF therapy in patients with autoimmune disease: A meta-analysis.

Numerous published data on the tumor necrosis factor receptor superfamily member 1B (TNFRSF1B) gene polymorphisms are shown to be associated with response or non-response to anti-TNF therapy in autoimmune diseases such as rheumatoid arthritis (RA), psoriasis and Crohn's Disease (CD). The aim of this study is to investigate whether the TNFRSF1B rs1061622 T/G or TNFRSF1A A/G rs767455 polymorphisms can predict the response to anti-TNF-based therapy in patients with autoimmune diseases. We conducted a meta-analysis of studies on the association between TNFRSF1B rs1061622 T/G polymorphism or TNFRSF1A A/G rs767455 polymorphism and non-responsiveness to anti-TNF therapy in autoimmune diseases. A total of 8 studies involving 929 subjects for TNFRSF1B rs1061622 and 564 subjects for TNFRSF1A rs767455 were finally considered. These studies consisted of seven studies on the TNFRSF1B polymorphism and four studies on the TNFRSF1A polymorphism. Meta-analysis showed significant association between the TNFRSF1B rs1061622 allele and non-responders to anti-TNF therapy [T/G odds ratio (OR) 0.72, 95% confidence interval (CI) 0.57-0.93, p=0.01]. Stratification by disease type indicated an association between the TNFRSF1B rs1061622 allele and non-responders to TNF antagonist in RA (T/G OR 0.69, 95% CI 0.48-0.99, p<0.05) and psoriasis (T/G OR 0.39, 95% CI 0.23-0.67, p<0.001), but not in CD (T/G OR 1.14, 95% CI 0.57-0.93, p=0.57). And there was no association between TNFRSF1A rs767455 genotype and non-responders to the anti-TNF therapy (A/G OR 0.93, 95% CI 0.70-1.23, p=0.59). This meta-analysis demonstrates that TNFRSF1B T allele carriers show a better response to anti-TNF therapy, and individuals carrying TNFRSF1A A allele have no relationship with the response to anti-TNF therapy for autoimmune diseases. The genotyping of this polymorphism could help to optimize the treatment by identifying patients with a likely poor response to biological drugs.