Aviv Barzilai

Silencing of a large microRNA cluster on human chromosome 14q32 in melanoma: biological effects of mir-376a and mir-376c on insulin growth factor 1 receptor

BackgroundMetastatic melanoma is a devastating disease with limited therapeutic options. MicroRNAs (miRNAs) are small non coding RNA molecules with important roles in post-transcriptional gene expression regulation, whose aberrant expression has been implicated in cancer.ResultsWe show that the expression of miRNAs from a large cluster on human chromosome 14q32 is significantly down-regulated in melanoma cell lines, benign nevi and melanoma samples relative to normal melanocytes. This miRNA cluster resides within a parentally imprinted chromosomal region known to be important in development and differentiation. In some melanoma cell lines, a chromosomal deletion or loss-of-heterozygosity was observed in the cis-acting regulatory region of this cluster. In several cell lines we were able to re-express two maternally-induced genes and several miRNAs from the cluster with a combination of de-methylating agents and histone de-acetylase inhibitors, suggesting that epigenetic modifications take part in their silencing. Stable over-expression of mir-376a and mir-376c, two miRNAs from this cluster that could be re-expressed following epigenetic manipulation, led to modest growth retardation and to a significant decrease in migration in-vitro. Bioinformatic analysis predicted that both miRNAs could potentially target the 3UTR of IGF1R. Indeed, stable expression of mir-376a and mir-376c in melanoma cells led to a decrease in IGF1R mRNA and protein, and a luciferase reporter assay indicated that the 3UTR of IGF1R is a target of both mir-376a and mir-376c.ConclusionsOur work is the first to show that the large miRNA cluster on chromosome 14q32 is silenced in melanoma. Our results suggest that down-regulation of mir-376a and mir-376c may contribute to IGF1R over-expression and to aberrant negative regulation of this signaling pathway in melanoma, thus promoting tumorigenesis and metastasis.

Low-dose methotrexate treatment for moderate-to-severe atopic dermatitis in adults

Backgroundu2002 Atopic dermatitis (AD) is a common inflammatory skin disease. Methotrexate (MTX) was suggested as an effective treatment option in cases of moderate‐to‐severe atopic dermatitis. This study assessed the efficacy and safety of treatment with low weekly doses of methotrexate for moderate‐to‐severe AD in adults.

Diagnosis and classification of autoimmune blistering diseases

Blistering skin diseases are a group of autoimmune disorders that are characterized by autoantibodies against structural proteins of the epidermis or the dermal-epidermal junction and clinically by blisters and erosions on skin and/or mucous membranes. Since clinical criteria and histopathological characteristics are not sufficient for diagnosis, direct immunofluorescence microscopy of a biopsy specimen or serological tests are needed for exact diagnosis. The differentiation between the various disorders became more important since prognosis as well as different treatment options are nowadays available for the various diseases. Moreover, some bullous diseases may indicate the presence of an underlying malignancy. The detection of serum autoantibodies have been shown to correlate with disease activity and thus may be helpful in deciding treatment options for these patients.

Experience with New World cutaneous leishmaniasis in travelers

In recent years, New World cutaneous leishmaniasis has been seen at a higher incidence among returning Israeli travelers. Leishmania braziliensis and related species cause unsightly cutaneous lesions possibly complicated with a mucosal disease. A total of 12 patients with New World cutaneous leishmaniasis were treated in our clinic, 11 of whom (92%) acquired the disease in the Bolivian Amazon Basin. Five (42%) had regional lymphadenopathy in addition to cutaneous lesions. Polymerase chain reaction was performed for 8 patients to identify the causative Leishmania species. In all, 9 patients (75%) were cured by a single course, and 3 (25%) after an additional course of intravenous sodium stibogluconate. The treatment was well tolerated clinically. Laboratory abnormalities, mainly elevation of liver enzymes (58%), were reversible. We concluded that polymerase chain reaction is a useful tool in establishing the species diagnosis of leishmaniasis and that sodium stibogluconate appears to be a safe and effective treatment for L braziliensis infection.

Melanoma miRNA trafficking controls tumour primary niche formation

Melanoma originates in the epidermis and becomes metastatic after invasion into the dermis. Prior interactions between melanoma cells and dermis are poorly studied. Here, we show that melanoma cells directly affect the formation of the dermal tumour niche by microRNA trafficking before invasion. Melanocytes, cells of melanoma origin, are specialized in releasing pigment vesicles, termed melanosomes. In melanoma in situ, we found melanosome markers in distal fibroblasts before melanoma invasion. The melanosomes carry microRNAs into primary fibroblasts triggering changes, including increased proliferation, migration and pro-inflammatory gene expression, all known features of cancer-associated fibroblasts (CAFs). Specifically, melanosomal microRNA-211 directly targets IGF2R and leads to MAPK signalling activation, which reciprocally encourages melanoma growth. Melanosome release inhibitor prevented CAF formation. Since the first interaction of melanoma cells with blood vessels occurs in the dermis, our data suggest an opportunity to block melanoma invasion by preventing the formation of the dermal tumour niche.

The role of IVIg treatment in severe pemphigus vulgaris

Backgroundu2002 High‐dose intravenous immunoglobulin (IVIg) has become a part of the treatment armentarium in pemphigus vulgaris (PV). Some consider IVIg as an adjuvant steroid sparing agent in PV, while others as disease modifying that can be used as monotherapy.

Population-Specific Association between a Polymorphic Variant in ST18, Encoding a Pro-Apoptotic Molecule, and Pemphigus Vulgaris

Pemphigus vulgaris (PV) is a severe autoimmune blistering disease caused by anti-epithelial antibodies, leading to disruption of cell-cell adhesion. Although the disease is exceedingly rare worldwide, it is known to be relatively prevalent in Jewish populations. The low prevalence of the disease represents a significant obstacle to a genome-wide approach to the mapping of susceptibility genes. We reasoned that the study of a genetically homogeneous cohort characterized by a high prevalence of PV may help exposing associated signals while reducing spurious results due to population sub-structure. We performed a genome-wide association study using 300K single-nucleotide polymorphisms (SNPs) in a case-control study of 100 PV patients of Jewish descent and 397 matched control individuals, followed by replication of significantly associated SNPs in three additional cohorts of Jewish, Egyptian, and German origin. In addition to the major histocompatibility complex locus, a genomic segment on 8q11.23 that spans the ST18 gene was also found to be significantly associated with PV. This association was confirmed in the Jewish and Egyptian replication sets but not in the German sample, suggesting that ST18-associated variants may predispose to PV in a population-specific manner. ST18 regulates apoptosis and inflammation, two processes of direct relevance to the pathogenesis of PV. Further supporting the relevance of ST18 to PV, we found this gene to be overexpressed in the skin of PV patients as compared with healthy individuals.

UVB in the management of early stage mycosis fungoides

Backgroundu2002 Several options for treatment of early mycosis fungoides (MF) offer similar success rates. Previous small studies have shown UVB to be at least as effective as PUVA.

Liposomal amphotericin B in comparison to sodium stibogluconate for Leishmania braziliensis cutaneous leishmaniasis in travelers

BACKGROUNDnNew World cutaneous leishmaniasis is mostly acquired in the Amazon Basin of Bolivia where L viannia (V) braziliensis is endemic. Treatment with systemic pentavalent antimonial compounds has been shown to be effective in achieving clinical cure in only 75% of cases.nnnOBJECTIVEnWe sought to assess the efficacy and safety of liposomal amphotericin B (L-AmB) treatment for primary infection of cutaneous L (V) braziliensis.nnnMETHODSnA prospective observational evaluation was performed for cutaneous leishmaniasis due to L (V) braziliensis which was treated with L-AmB, 3 mg/kg, for 5 consecutive days, and a sixth dose on day 10. This therapy regimen was compared with the treatment regimen of sodium stibogluconate (SSG) 20 mg/kg for 3 weeks.nnnRESULTSnOur study was divided into two groups; 34 patients received L-AmB and 34 received SSG treatment. Almost all patients were infected in Bolivia. In the L-AmB group, 29 patients (85%) had complete cure compared with 70% in the SSG group (P = not significant), 4 other patients were slow healers, and only one patient needed additional treatment with SSG. No relapses were seen during a mean 29-month follow-up period. Failure rate was 3% in the L-AmB versus 29% in the SSG group (P = .006). Treatment was interrupted in 65% of patients taking SSG because of adverse events, whereas all patients receiving L-AmB completed treatment.nnnLIMITATIONSnThis was a non-blinded comparative study.nnnCONCLUSIONSnComparison of L-Amb to SSG treatment for L (V) braziliensis shows that the former is effective, better tolerated, and more cost effective. L-AmB should therefore be considered as the first-line treatment option for cutaneous L (V) braziliensis infection.

Treatment of cutaneous leishmaniasis with intralesional sodium stibogluconate.

Backgroundu2002 Cutaneous leishmaniasis is endemic in Israel. Leishmania major is the most prevalent species that cause cutaneous leishmaniasis. Current treatment options are limited and there are few investigations in search of alternative ones.