A 10-year review of otic lichen planus: the Mayo Clinic experience.

IMPORTANCE: Lichen planus is an autoimmune inflammatory dermatosis that typically affects the skin but can also involve the stratified squamous epithelium of the external auditory canals and tympanic membranes. Here we report our experience with the clinical presentation, diagnosis, and management of otic lichen planus. OBSERVATIONS: We retrospectively reviewed medical records from January 1, 2001, through May 31, 2011, of patients with a diagnosis of otic lichen planus. Nineteen cases were identified (mean age at diagnosis, 57 years; 15 women). The most common concerns were persistent otorrhea and hearing loss. Other symptoms included plugging, pruritus, tinnitus, pain, and bleeding. The mean symptom duration was 4.0 years (n = 13). Most patients responded well to topical tacrolimus within several months. One patient had a dramatic positive response to rituximab. CONCLUSIONS AND RELEVANCE: Otic lichen planus can lead to persistent hearing loss and should be considered in the differential diagnosis of relentless otorrhea and external auditory canal stenosis. In our experience, topical tacrolimus is the best primary treatment, but alternative therapies could be instituted in severe cases. Early recognition of the nonspecific symptoms of otic lichen planus may lead to prompt treatment and avoidance of irreparable late sequelae.

A novel G-quadruplex-forming GGA repeat region in the c-myb promoter is a critical regulator of promoter activity.

The c-myb promoter contains multiple GGA repeats beginning 17 bp downstream of the transcription initiation site. GGA repeats have been previously shown to form unusual DNA structures in solution. Results from chemical footprinting, circular dichroism and RNA and DNA polymerase arrest assays on oligonucleotides representing the GGA repeat region of the c-myb promoter demonstrate that the element is able to form tetrad:heptad:heptad:tetrad (T:H:H:T) G-quadruplex structures by stacking two tetrad:heptad G-quadruplexes formed by two of the three (GGA)(4) repeats. Deletion of one or two (GGA)(4) motifs destabilizes this secondary structure and increases c-myb promoter activity, indicating that the G-quadruplexes formed in the c-myb GGA repeat region may act as a negative regulator of the c-myb promoter. Complete deletion of the c-myb GGA repeat region abolishes c-myb promoter activity, indicating dual roles of the c-myb GGA repeat element as both a transcriptional repressor and an activator. Furthermore, we demonstrated that Myc-associated zinc finger protein (MAZ) represses c-myb promoter activity and binds to the c-myb T:H:H:T G-quadruplexes. Our findings show that the T:H:H:T G-quadruplex-forming region in the c-myb promoter is a critical cis-acting element and may repress c-myb promoter activity through MAZ interaction with G-quadruplexes in the c-myb promoter.

Targeting and regulation of the HER-2/neu oncogene promoter with bis-peptide nucleic acids.

Antigene oligonucleotides have the potential to regulate gene expression through site-specific DNA binding. However, in vivo applications have been hindered by inefficient cellular uptake, degradation, and strand displacement. Peptide nucleic acids (PNAs) address several of these problems, as they are resistant to degradation and bind DNA with high affinity. We designed two cationic pyrimidine bis-PNAs (cpy-PNAs) to target the polypurine tract of the HER-2/neu promoter and compared them to an unmodified phosphodiester triplex-forming oligonucleotide (TFO1) and a TFO-nitrogen mustard conjugate (TFO2). PNA1 contains a + 2 charge and bound two adjacent 9-bp target sequences with high affinity and specificity, but only at low pH. PNA2 contains a +5 charge and bound one 11-bp target with high affinity up to pH 7.4, but with lower specificity. The PNA:DNA:PNA triplex formed by these cpy-bis-PNAs presented a stable barrier to DNA polymerase extension. The cpy-bis-PNAs and the TFO-alkylator conjugate prevented HER-2/neu transcription in a reporter gene assay (TFO2 = PNA1 > PNA2 >> TFO1). Both PNAs and TFOs were effective at binding the target sequence in naked genomic DNA, but only the TFO-alkylator (TFO2) and the more cationic PNA (PNA2) were detected at the endogenous HER-2/neu promoter in permeabilized cells. This work demonstrates the potential for preventing HER-2/neu gene expression with cpy-bis-PNAs in tumor cells.