Single-nucleotide polymorphisms in 3'-untranslated region inducible costimulator gene and the important roles of miRNA in alopecia areata.

Background: Alopecia areata (AA) spares the stem cell compartment and attacks only the base of the hair follicle, which is surrounded by infiltrating lymphocytes. AA is associated with polymorphisms in immune-related genes and with decreased function of CD4+CD25+ T regulatory (Treg) cells. Treg function is modulated by the costimulatory molecules, like inducible costimulator (ICOS) that are crucial in orienting T cell differentiation and function so that they strongly impact on the immunologic decision between tolerance or autoimmunity development. Objective: The aim of our study was to investigate the possible association of AA with single-nucleotide polymorphisms (SNP) present in the ICOS 3'-untranslated region (3'UTR) region and to elucidate how SNPs modulate ICOS gene expression by affecting miRNA binding sites. Methods: This is a case-control study performed in 184 patients with AA and 200 controls. ICOS gene and miRNA expression were analyzed by real-time polymerase chain reaction. Results: The genotype carrying the rs4404254(C) [p = 0.012, OR (95% CI): 0.5 (0.3-0.8)] and rs4675379(C) [p = 0.015, OR (95% CI): 0.3 (0.1-0.8)] 3' UTR alleles was more frequently observed in AA patients than in controls and correlated with a reduced ICOS expression. miR-1276 significantly suppressed ICOS expression by binding to the 3'UTR of ICOS mRNA. Also, we observed that, miR-101 and miR-27b are upregulated, while miR-103 and miR-2355-3p are downregulated in peripheral blood mononuclear cells of AA patients compared to controls. Conclusion: Our data show that rs4404254 and rs4675379 SNPs of ICOS gene are associated with AA and also reveal that the presence of rs4404254 polymorphism correlates with ICOS post-transcriptional repression by microRNA binding.

Cabozantinib Affects Osteosarcoma Growth Through A Direct Effect On Tumor Cells and Modifications In Bone Microenvironment.

Osteosarcoma (OS) is the most common primary malignant tumor of the bone. Due to its high heterogeneity and to survival signals from bone microenvironment, OS can resist to standard treatments, therefore novel therapies are needed. c-MET oncogene, a tyrosine-kinase receptor, plays a crucial role in OS initiation and progression. The present study aimed to evaluate the effect of c-MET inhibitor cabozantinib (CBZ) on OS both directly and through its action on bone microenvironment. We tested different doses of CBZ in in vitro models of OS alone or in co-culture with bone cells in order to reproduce OS-tumor microenvironment interactions. CBZ is able to decrease proliferation and migration of OS cells, inhibiting ERK and AKT signaling pathways. Furthermore, CBZ leads to the inhibition of the proliferation of OS cells expressing receptor activator of nuclear factor κB (RANK), due to its effect on bone microenvironment, where it causes an overproduction of osteoprotegerin and a decrease of production of RANK ligand by osteoblasts. Overall, our data demonstrate that CBZ might represent a new potential treatment against OS, affecting both OS cells and their microenvironment. In this scenario, RANK expression in OS cells could represent a predictive factor of better response to CBZ treatment.

Erythema gyratum repens is not an obligate paraneoplastic disease: a systematic review of the literature and personal experience.

BACKGROUND: Erythema gyratum repens (EGR) is a rare clinical entity that is considered to be an obligatory paraneoplastic disease. According to the literature, an underlying neoplasm can be detected in 82% of the cases. OBJECTIVES: The aim of this systemic review was to evaluate the association of EGR with malignancies or other non-neoplastic conditions. METHODS: The medical records of patients seen at the Section of Dermatology, University of Genoa between 1990 and 2010, in whom a diagnosis of EGR had been made, were reviewed for evidence of systemic associations. A systematic search of the Cochrane library, EMBASE, Pubmed and MEDLINE databases was also conducted. Key search term used in the review was 'erythema gyratum repens'. RESULTS: Four patients with a diagnosis of EGR have been retrieved from our medical records. One case was idiopathic, one was associated with a bronchial carcinoma and two were associated with drug-intake. One hundred and twelve original cases of EGR were selected from the literature for detailed review. Among these, 58 cases (70%) were associated with an underlying neoplasm, 25 cases (30%) were non-paraneoplastic and 29 cases have been considered as different dermatoses mimicking EGR in their clinical presentation ('EGR-like' eruption). CONCLUSION: EGR should no longer be considered as an obligate paraneoplastic syndrome as the cases that are not associated with neoplasm are more than expected. In addition to searching an underlying neoplasm, dermatologists should be aware about the possibility of other associations including also drug-intake.

Cutaneous sporotrichoid leishmaniasis resistant to pentavalent antimonial therapy: complete resolution with itraconazole.

Sporotrichoid leishmaniasis is a sporadic form of cutaneous leishmaniasis, a protozoal infection, reported particularly in the Middle East. Clinically it occurs as nontender, subcutaneous, slightly erythematous nodules, often associated with lymphangitis, usually on exposed areas of the skin. Sometimes it occurs after treatment with a single dose of antimonials, and in older lesions, the biopsy can be negative for amastigotes. We report a case of cutaneous sporotrichoid leishmaniasis unresponsive to intralesional pentavalent antimonial therapy, which completely resolved after treatment with oral itraconazole. To our knowledge, this is only the third such case reported. We discuss the causes of dissemination of the nodular lesions and the negative results for amastigotes on re-biopsed lesions.

A novel missense mutation in fumarate hydratase in an Italian patient with a diffuse variant of cutaneous leiomyomatosis (Reed's syndrome).

BACKGROUND: The multiple cutaneous and uterine leiomyomatosis syndrome (MCUL) is a rare autosomal dominant condition characterized by cutaneous leiomyomatosis in both sexes and uterine leiomyomas in women. This syndrome overlaps with hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome. METHODS: We report an Italian family in which the finding of multiple cutaneous leiomyomas in the proband, a 46-year-old woman, led to the diagnosis of Reed's syndrome and to a general and genetic screening. RESULTS: DNA sequencing in the proband disclosed a missense mutation designated p.Asp341Tyr that has not been reported previously. Interestingly, the patient's mother had a clear-cell-type renal cancer removed at the age of 57 years. CONCLUSION: Cutaneous leiomyomas are the clinical and histological clue leading to the diagnosis of MCUL or HLRCC. Dermatologists should be aware that a correct evaluation of a patient with cutaneous leiomyomas involves a complete medical and family history, physical examination and a genetic counseling.