Hung Q. Doan

Coxsackievirus A6 associated hand, foot and mouth disease in adults: Clinical presentation and review of the literature

BACKGROUND Hand, foot, and mouth disease (HFMD) is generally considered a rare illness in adults. Classically, HFMD has been strongly associated with coxsackievirus strain A16 and enterovirus 71. The coxsackievirus A6 (CVA6) strain has been linked to severe worldwide outbreaks since 2008. CVA6 is associated with a more severe and profound course of disease, affecting both children and adults. OBJECTIVES To present a series of five adult patients diagnosed with HFMD due to CVA6. We investigate method of diagnosis and compare clinical presentation of adult cases to those in children. STUDY DESIGN Each patient underwent a full-body skin exam as well as inspection of the oral cavity. Rapid plasma reagin (RPR) and serologic assays by complement fixation against coxsackievirus B (1-6) and A (2,4,7,9,10,16) were performed as indicated. As standard serological testing does not detect CVA6, real-time reverse transcription-polymerase chain reaction (qRT-PCR) of serum, buccal swabs, and skin scrapings were performed by the Centers for Disease Control and Prevention (CDC). RESULTS Each patient had clinical findings consistent with various stages of HFMD. One patient presented with delayed onychomadesis and desquamation of the palms and soles. RPR and serologic assays by complement fixation against CVB (1-6) and CVA (2,4,7,9,10,16) were mostly negative, although elevated in two patients due to cross-reactivity. qRT-PCR identified CVA6 genetic material in samples from all patients. CONCLUSION This series demonstrates that there is a wide array of disease presentation of CVA6 associated HFMD in adults.

Physical and Functional Antagonism between Tumor Suppressor Protein p53 and Fortilin, an Anti-apoptotic Protein

Tumor suppressor protein p53, our most critical defense against tumorigenesis, can be made powerless by mechanisms such as mutations and inhibitors. Fortilin, a 172-amino acid polypeptide with potent anti-apoptotic activity, is up-regulated in many human malignancies. However, the exact mechanism by which fortilin exerts its anti-apoptotic activity remains unknown. Here we present significant insight. Fortilin binds specifically to the sequence-specific DNA binding domain of p53. The interaction of fortilin with p53 blocks p53-induced transcriptional activation of Bax. In addition, fortilin, but not a double point mutant of fortilin lacking p53 binding, inhibits p53-dependent apoptosis. Furthermore, cells with wild-type p53 and fortilin, but not cells with wild-type p53 and the double point mutant of fortilin lacking p53 binding, fail to induce Bax gene and apoptosis, leading to the formation of large tumor in athymic mice. Our results suggest that fortilin is a novel p53-interacting molecule and p53 inhibitor and that it is a logical molecular target in cancer therapy.

Antibiotic overuse and resistance in dermatology.

Antibiotics have a significant role in dermatology, treating a wide range of diseases, including acne, rosacea, inflammatory skin conditions and skin structure infections, such as cellulitis, folliculitis, carbuncles, and furuncles. Because of their consistent use, utility, and availability, antibiotics are susceptible to overuse within the medical practice, and, specific to this discussion, in the dermatologic setting. The issue of continuously increasing risk of antibiotic resistance remains an important concern to the dermatologist. The scope of this review will be to provide an overview of the common antibiotics used in the dermatologic setting with an emphasis on identifying areas of overuse, reported bacterial resistance, and discussion of clinical management aimed at decreasing antibiotic resistance

Zostavax: a subcutaneous vaccine for the prevention of herpes zoster

Introduction: Herpes zoster (HZ) occurs as a reactivation of dormant varicella zoster virus (VZV), and occurs more frequently in the aging population or the immunocompromised due to waning cell-mediated immunity. Up to 1 million cases of HZ are reported annually in the USA with an estimated 10 – 30% of the population being affected by shingles in their lifetime. HZ is a debilitating illness, and while mortality is low, morbidity remains a significant cause for concern with prevention efforts aimed at reducing VZV reactivation and its complications. The HZ vaccine was approved by the US Food and Drug Administration for individuals aged 50-years or older. However, the Center for Disease Control and Preventions Advisory Committee for Immunization Practices recommends the vaccine in individuals aged 60-years or older. Areas covered: Recent literature investigating the efficacy and indications of live attenuated zoster vaccine. Expert opinion: Live attenuated zoster vaccine is safe and efficacious in preventing HZ and decreasing the morbidity associated with postherpetic neuralgia. The vaccine is FDA approved in individuals aged 50-years or older but further studies are warranted to investigate the vaccines efficacy in immunosuppressed and immunocompromised patients.

Apoptotic Gene Expression in Sinecatechins-Treated External Genital and Perianal Warts

External genital and perianal warts (EGW)—the most common viral sexually transmitted disease in the United States—are caused by the human papillomavirus (HPV), a family of DNA viruses with more than 150 genotypes characterized to date (7). In 2006, sinecatechins ointment 15% (trade name Veregen ) was approved by the Food and Drug Administration for the treatment of EGW. Sinecatechins ointment is comprised of a proprietary blend of eight different catechins, the chief family of flavonoids believed to account for the wide array of health benefits attributed to green tea (12). In decreasing order of concentration, the four major catechins found in green tea are epigallocatechin gallate, epigallocatechin, epicatechin gallate, and epicatechin. Prior to their application for treating viral disease, catechins had been associated with a wide array of health benefits (10). Although it is believed that the majority of these health benefits are due to the catechins’ antioxidative activity, green tea catechins have also displayed poorly understood antiproliferative and antiviral properties (10). In vitro, epigallocatechin gallate can induce apoptotic growth inhibition of four HPV-infected tumor cell lines, and in vivo, green tea catechins were found to be effective in treating cervical HPV lesions, as determined by positive morphological changes of cervical lesions and a decrease of HPV DNA levels following treatment (8,11). However, despite these observations and FDA approval nearly a decade ago, the mechanism of action of sinecatechins-induced growth inhibition of EGW is unknown. To begin to answer this question, we performed an openlabel, single-site study enrolling subjects with a clinical diagnosis of EGW, and used specialized microarrays to determine the expression-level changes specific to apoptosis of EGW before and after sinecatechins treatment. A total of 30 subjects were recruited for the study, 24 male and 6 female, with a mean age of 39.2 – 10.6 years. Of these, 18 subjects remained enrolled and were available for follow-up for the duration of the study. Veregen ointment, 15%, was dispensed to the patient with instructions to apply to the target warts three times daily for 16 weeks. Three biopsies were taken from each patient—excised at baseline (B1), at the first visit with 50% or more clearance of target warts (B2), and at the first visit with complete clearance of target lesions (B3). Tissue samples were stored in RNAlater (Ambion) solution until processing, and nucleic acids were extracted from the samples using Trizol reagent (Sigma). HPV types from extracted DNA samples were detected by a nested polymerase chain reaction (PCR) approach as previously described (1), and copy number was determined with a custom-made real time PCR kit (Quantification of HPV6_15979, L1 protein, L1 gene, PrimerDesign Ltd.). Extracted and applied RNA, measured at A260/A280 nm, produced a ratio between 1.8 and 2.0. Subjects were stratified based on their response to treatment, which was quantitatively determined by measuring change in viral copy number between B1 and B3. Subjects were classified as virological responders (VR) if viral copy number decreased by at least 60% from B1, and were classified as virological nonresponders (VNR) if viral copy number remained the same or increased from B1. Of these, seven were found to be VR, and 11 were defined as VNR. In addition to the detection of HPV-6 in all lesions, one VR and three VNR were positive for co-infection with other HPV types (VR: HPV-18 and -35; VNR: HPV-7, -8, and -35). Next, the Applied Biosystems High Capacity RNAto-cDNA master mix was utilized for cDNA synthesis, and analysis of apoptotic gene expressions was then performed using TaqMan array 96-well plates. Initially, gene expression level was surveyed individually as an independent variable, and subsequently, group-based response values were generated using DataAssist v3.01 Software. Quantification of group-based responses for each gene were determined by calculating a fold change from biopsy 1 to biopsy 2 (B1_2), from biopsy 1 to biopsy 3 (B1_3), and from biopsy 2 to biopsy 3 (B2_3). Gene expression changes were categorized as biologically significant if there was at least a twofold change. To determine statistical significance of these fold changes, the statistical significance of these fold changes was evaluated using a nonparametric two-sided Wilcoxon signed-rank test with a significance level of p< 0.05.

Fortilin potentiates the peroxidase activity of Peroxiredoxin-1 and protects against alcohol-induced liver damage in mice

Fortilin, a pro-survival molecule, inhibits p53-induced apoptosis by binding to the sequence-specific DNA-binding domain of the tumor suppressor protein and preventing it from transcriptionally activating Bax. Intriguingly, fortilin protects cells against ROS-induced cell death, independent of p53. The signaling pathway through which fortilin protects cells against ROS-induced cell death, however, is unknown. Here we report that fortilin physically interacts with the antioxidant enzyme peroxiredoxin-1 (PRX1), protects it from proteasome-mediated degradation, and keeps it enzymatically active by blocking its deactivating phosphorylation by Mst1, a serine/threonine kinase. At the whole animal level, the liver-specific overexpression of fortilin reduced PRX1 phosphorylation in the liver, enhanced PRX1 activity, and protected the transgenic animals against alcohol-induced, ROS-mediated, liver damage. These data suggest the presence of a novel oxidative-stress-handling pathway where the anti-p53 molecule fortilin augments the peroxidase PRX1 by protecting it against degradation and inactivation of the enzyme. Fortilin-PRX1 interaction in the liver could be clinically exploited further to prevent acute alcohol-induced liver damage in humans.

Sonidegib, a novel smoothened inhibitor for the treatment of advanced basal cell carcinoma

Basal cell carcinoma (BCC) is the most common nonmelanoma skin cancer. If left untreated, BCCs can become locally aggressive or even metastasize. Currently available treatments include local destruction, surgery, and radiation. Systemic options for advanced disease are limited. The Hedgehog (Hh) pathway is aberrantly activated in a majority of BCCs and in other cancers. Hh pathway inhibitors are targeted agents that inhibit the aberrant activation of the Hh pathway, with smoothened being a targeted component. Sonidegib is a novel smoothened inhibitor that was recently approved by the US Food and Drug Administration. This review focuses on BCC pathogenesis and the clinical efficacy of sonidegib for the treatment of advanced BCC.

Emerging differential roles of the pRb tumor suppressor in trichodysplasia spinulosa-associated polyomavirus and Merkel cell polyomavirus pathogeneses.

BACKGROUND Merkel cell carcinoma (MCC) and trichodysplasia spinulosa (TS) are two proliferative cutaneous diseases caused by the Merkel cell polyomavirus (MCPyV) and trichodysplasia spinulosa-associated polyomavirus (TSPyV) respectively. Recently, studies have elucidated a key role of the small tumor (sT) antigen in the proliferative pathogenic mechanisms of MCPyV and likely TSPyV. While both sT antigens have demonstrated a capacity in regulating cellular pathways, it remains unknown whether MCPyV and TSPyV sT antigens contribute similarly or differentially to cell proliferation. OBJECTIVES The present study aims to explore the proliferative potential of MCPyV and TSPyV sT antigens by investigating their regulatory effects on the retinoblastoma protein (pRb) tumor suppressor. STUDY DESIGN Inducible cell lines expressing MCPyV sT or TSPyV sT were created using a lentiviral packaging system. Cellular proteins were extracted and subjected to SDS-PAGE followed by Western blot detection and densitometric analysis. RESULTS Expression of TSPyV sT markedly enhanced the phosphorylation of pRb in Western blot experiments. In contrast, expression of MCPyV sT did not alter pRb phosphorylation under the same experimental conditions. Densitometric analysis revealed that TSPyV sT antigen expression nearly doubled the ratio of phosphorylated to total pRb (P<0.001, Students T-test), while MCPyV sT antigen expression did not cause significant change in pRb phosphorylation status. CONCLUSION Given that hyperphosphorylation of pRb is associated with dysregulation of the cell cycle, S-phase induction, and increased cell proliferation, our findings support an important role of TSPyV-mediated pRb deactivation in the development of TS. The observation that the pRb tumor suppressor is inactivated by TSPyV sT but not MCPyV sT provides further insights into the distinct pathobiological mechanisms of MCC and TS.

Expression Patterns of Immune-Associated Genes in External Genital and Perianal Warts Treated with Sinecatechins

The role of human papillomavirus (HPV) in human disease includes external genital and perianal warts (EGW), with some HPV genotypes having oncogenic potential (i.e., HPV-16 and -18). While green-tea extracts have antitumor and antiproliferative effects in vitro, the mechanism of action of sinecatechins in the treatment of EGW is not well understood. To investigate the role of immune-regulated genes further, an open-label, single institution, prospective study was conducted enrolling patients with clinically diagnosed EGW. Thirty subjects were enrolled, and 18 completed the trial. All patients applied sinecatechins 15% ointment to target lesions in the study. RNA expression microarrays were obtained from treated EGW lesions and analyzed for differential gene expression of immune-regulated genes. HPV types were analyzed and, based on copy number, were stratified into virological responders (VR) or nonresponders (VNR). Gene expression analysis of RNA samples was performed using TaqMan arrays for human T cell receptor and CD3 complex (TCR), Toll-like receptors (TLR) pathway, interferon (IFN) pathway, and antigen processing pathway. A total of 256 genes were analyzed across the four arrays. Genes that were significantly regulated between VRs and VNRs were CREB3L4, HIST1H3A, HIST1H3H, IFNA1, IFNA4, IFNA5, IFNA6, IFNA8, IFNA14, IFNG, IFNAR1, IL6, IRF9, MAPK4, MAPK5, MAPK14, NET1, and PIK3C2A in the IFN array. In the TCR array, HLA_B was found to be statistically significantly upregulated in both the VR and VNR groups; concomitantly, CD8A was found to be statistically significantly downregulated only in VRs. In the TLR array, only LBP and MAPK8 were found to be differentially regulated. In the antigen processing array, HLA-A, HLA-C, HLA-DMA, HLA-DMB, HLA-F, PSMA5, PSMB8, and PSMB9 were differentially downregulated. Based on these findings, it was determined that sinecatechins treatment modulates and downregulates genes involved in the pro-inflammatory response to HPV infection.

Cellular signaling in sinecatechins-treated external genital and perianal warts: unraveling the mechanism of action of a botanical therapy

Dear Editor,Derived from green tea leaves,sinecatechins(Veregen)ointment,15%is a topical therapy that is FDA-approved to treat human papillomavirus(HPV)-induced external genital and perianal warts(EGW)in immunocompetent patients aged 18 years and older.In two phase 3 trials enrolling over 1,000 participants with EGW,a 16-week treatment regimen with sinecatechins ointment resulted in higher rates of complete clearance of all warts—both