[Show abstract][Hide abstract] ABSTRACT: Background
Psoriasis is a multifactorial, chronic disease of skin affecting 2-3 % of the world¿s population. Genetic studies of psoriasis have identified a number of susceptibility genes that are involved in anti-viral immunity. Furthermore, physiological studies have also found an increase in anti-viral proteins in psoriatic skin. These findings suggest the presence of an anti-viral state in psoriatic skin. However, the triggers for this anti-viral cascade and its consequences for host immunity are not known. Endogenous retroviruses have previously been described in many autoimmune diseases including psoriasis.Methods
In the present study we examined the humoral immune response against human endogenous retrovirus-K (HERV-K) proteins and the cutaneous expression levels of multiple HERV-K genes in psoriasis patients and healthy controls.ResultsIn psoriatic sera we observed a significant decrease in IgM response against three HERV-K proteins: Env surface unit (SU), Env transmembrane protein (TM), and Gag capsid (CA) in comparison to sera obtained from blood bank healthy controls. A decrease in IgG response was also observed against CA. Furthermore, using quantitative RT-PCR we observed a decrease in the expression of HERV-K Env, Gag, Pol and Rec as well as ERV-9 genes in lesional psoriatic skin as compared to healthy skin.Conclusions
Together, our results suggest that the pro-inflammatory, anti-viral state in psoriasis is associated with diminished expression of HERV-K gene transcripts and a concomitant decrease in humoral responses to HERV-K. Our results indicate that a simple model where continuous, minimally changing HERV-K expression serves as an antigenic trigger in psoriasis might not be correct and further studies are needed to decipher the possible relationship between psoriasis and HERVs.
Journal of Translational Medicine 09/2014; 12(1):256. · 3.99 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Nonmelanoma skin cancer (NMSC) is the most common cancer in the U.S.A. The two most common NMSCs are basal cell carcinoma and squamous cell carcinoma. The associations of single-nucleotide polymorphisms (SNPs) in pigmentation pathway genes with NMSC are not well characterized. There is a series of epidemiological studies that have tested these relationships, but there is no recent summary of these findings. To explain overarching trends, we undertook a systematic review of published studies. The summarized data support the concept that specific SNPs in the pigmentation pathway are of importance for the pathogenesis of NMSC. The SNPs with the most promising evidence include MC1R rs1805007(T) (Arg151Cys) and rs1805008(T) (Arg160Trp), and ASIP AH haplotype [rs4911414(T) and rs1015362(G)]. There are a few other SNPs found in TYR, OCA2 and SLC45A2 that may show additional correlation after future research. With additional research there is potential for the translation of future findings to the clinic in the form of SNP screenings, where patients at high risk for NMSC can be identified beyond their phenotype by genotypically screening for predisposing SNPs.
British Journal of Dermatology 09/2014; · 3.76 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Fitzpatrick skin phototype (FSPT) is the most common method used to assess sunburn risk and is an independent predictor of skin cancer risk. Because of a conventional assumption that FSPT is predictable based on pigmentary phenotypes, physicians frequently estimate FSPT based on patient appearance.
Journal of the American Academy of Dermatology 06/2014; · 5.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Targeted therapies for cutaneous squamous cell carcinoma (cSCC) remain limited. Extensive genetic heterogeneity complicates a robust molecular characterization of the evolution of cSCC. Nonetheless, potential targeted therapies for this cancer are under investigation, including the inhibition of epidermal growth factor receptor (EGFR), which may yield promising results. In addition, the emergence of immune checkpoint blockade therapy and vaccine-based methods may provide novel treatment strategies for cSCC that are tailored to the individual patient. Ultimately, a combination of such methods may yield a multi-pronged targeted approach to personalize the treatment of cSCC.
Seminars in Cutaneous Medicine and Surgery 06/2014; 33(2):72-75. · 2.40 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Advanced basal cell carcinomas (BCC) are neoplasms with high-risk clinical characteristics that can develop as locally advanced disease or metastasis. Treatment of advanced BCC may result in significant morbidity due to the technical challenges of size and/or location or in which surgery and radiation therapy may be contraindicated. No standard of care exists for the management of advanced BCC. As such, the difficulty in managing these tumors necessitates a multidisciplinary approach to patient care.
We report four cases of advanced BCC that benefited from a multidisciplinary approach, as well as highlight treatment considerations and factors in the development of advanced BCC.
All four complex cases of advanced BCC presented to a multidisciplinary non-melanoma skin cancer tumor board with extensive tumor involvement. Treatment of disease was effective in preventing recurrence while optimizing aesthetic outcomes.
The multidisciplinary tumor board has a central and important role in the evaluation and management of advanced BCC.
J Drugs Dermatol. 2014;13(5):601-606.
Journal of drugs in dermatology: JDD 05/2014; 13(5):601-6. · 1.32 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cutaneous SCC (cSCC) is the most frequent skin cancer with metastatic potential and can manifest rapidly as a common side effect in patients receiving systemic kinase inhibitors. Here we use massively parallel exome and targeted level sequencing 132 sporadic cSCC, 39 squamoproliferative lesions and cSCC arising in patients receiving the BRAF inhibitor vemurafenib, as well as 10 normal skin samples to identify significant NOTCH1 mutation as an early event in squamous cell carcinogenesis. Bisected vemurafenib induced lesions revealed surprising heterogeneity with different activating HRAS and NOTCH1 mutations identified in two halves of the same cSCC suggesting polyclonal origin. Immunohistochemical analysis using an antibody specific to nuclear NOTCH1 correlates with mutation status in sporadic cSCC and regions of NOTCH1 loss or down-regulation are frequently observed in normal looking skin. Our data indicate that NOTCH1 acts as a gatekeeper in human cSCC.Journal of Investigative Dermatology accepted article preview online, 24 March 2014; doi:10.1038/jid.2014.154.
Journal of Investigative Dermatology 03/2014; · 6.19 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Previous studies have suggested a role for pathogens as a trigger of systemic sclerosis (SSc), though neither a pathogen nor a mechanism of pathogenesis is known. Here we show enrichment of Rhodotorula sequences in the skin of patients with early, diffuse SSc compared to normal controls. RNA-seq was performed on four SSc and four controls, to a depth of 200 million reads per patient. Data were analyzed to quantify the non-human sequence reads in each sample. We found little difference between bacterial microbiome and viral read counts, but found a significant difference between the read counts for a mycobiome component, R. glutinis. Normal samples contained almost no detected R. glutinis or other Rhodotorula sequence reads (mean score 0.021 for R. glutinis, 0.024 for all Rhodotorula). In contrast, SSc samples had a mean score of 5.039 for R. glutinis (5.232 for Rhodotorula). We were able to assemble the D1-D2 hypervariable region of the 28 S rRNA of R. glutinis from each of the SSc samples. Taken together, these results suggest R. glutinis may be present in the skin of early SSc patients at higher levels than normal skin, raising the possibility that it may be triggering the inflammatory response found in SSc.Journal of Investigative Dermatology accepted article preview online, 7 March 2014; doi:10.1038/jid.2014.127.
Journal of Investigative Dermatology 03/2014; · 6.19 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Regulatory T cells (Tregs), which are characterized by expression of the transcription factor Foxp3, are a dynamic and heterogeneous population of cells that control immune responses and prevent autoimmunity. We recently identified a subset of Tregs in murine skin with properties typical of memory cells and defined this population as memory Tregs (mTregs). Due to the importance of these cells in regulating tissue inflammation in mice, we analyzed this cell population in humans and found that almost all Tregs in normal skin had an activated memory phenotype. Compared with mTregs in peripheral blood, cutaneous mTregs had unique cell surface marker expression and cytokine production. In normal human skin, mTregs preferentially localized to hair follicles and were more abundant in skin with high hair density. Sequence comparison of TCRs from conventional memory T helper cells and mTregs isolated from skin revealed little homology between the two cell populations, suggesting that they recognize different antigens. Under steady-state conditions, mTregs were nonmigratory and relatively unresponsive; however, in inflamed skin from psoriasis patients, mTregs expanded, were highly proliferative, and produced low levels of IL-17. Taken together, these results identify a subset of Tregs that stably resides in human skin and suggest that these cells are qualitatively defective in inflammatory skin disease.
The Journal of clinical investigation 02/2014; · 15.39 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
The role of human papillomavirus (HPV) in cutaneous squamous cell carcinoma (cuSCC) is not well defined, with past studies showing conflicting results.
We sought to determine if there is a significant association between HPV and cuSCC and whether cuSCC from immunosuppressed patients are more likely to carry HPV than cuSCC from immunocompetent patients.
We performed a systematic review and abstracted data from articles that included: skin samples by biopsy, HPV detection by polymerase chain reaction, and a minimum of 10 cases and 10 controls. Pooled effect size and 95% confidence intervals were calculated using random effects meta-analysis using the inverse variance method.
cuSCC were more likely to carry HPV than normal-appearing skin (pooled effect size [ES] 3.43, 95% confidence interval 1.97-5.98, P < .0001) in all patients. An increase in HPV prevalence was found in tumors from immunosuppressed patients compared with immunocompetent patients (pooled ES 3.01, 95% confidence interval 2.00-4.52, P < .0001).
The greatest limitation is the heterogeneity of the studies included. The association of higher HPV prevalence in squamous cell carcinoma compared with normal-appearing skin does not imply causality.
These results contribute to evidence that HPV is associated with cuSCC. Higher HPV burden in tumors from immunosuppressed patients compared with immunocompetent patients may have therapeutic implications.
Journal of the American Academy of Dermatology 01/2014; 70(4):621–629. · 5.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: According to Organ Procurement and Transplantation Network data, 28,051 solid organ transplants were performed in 2012. Due to advancements in immunosuppression and management of infectious disease, survival of organ transplant recipients has substantially increased. Voriconazole is a widely prescribed anti-fungal medication used for prophylaxis and for treatment of invasive fungal infections in organ transplant recipients. Case reports describing skin cancer associated with voriconazole exposure emerged shortly after FDA approval, and it is now established that voriconazole is an independent risk factor for the development of cutaneous malignancy in lung transplant recipients. The mechanism of voriconazole induced skin cancer is still unknown and may involve its primary metabolite, voriconazole N-oxide. This paper will discuss the current data and potential mechanisms of voriconazole associated photosensitivity and carcinogenesis, and identify areas requiring further research.
[Show abstract][Hide abstract] ABSTRACT: Background: A significant factor limiting long-term survival in lung transplant recipients (LT-R) is bronchiolitis obliterans syndrome (BOS). There is growing evidence that infections may play a role in the development of BOS. Scedosporium is an emerging pathogen among solid organ transplant recipients. Our aim was to determine if Scedosporium respiratory colonization or invasive disease (SRCI) are risk factors for BOS and mortality.
Methods: We performed a single-center review of LT-R from February 2000 until March 2012. All lung transplant patients who were free of BOS 90 days after transplant and received sufficient pulmonary function tests to assess for BOS were eligible for analysis. Invasive Scedosporium infection was defined as a positive culture from bronchoalveolar lavage with evidence of disease on imaging, as per modified EORTC/IFICG criteria. Those who had positive cultures for Scedosporium without evidence for invasive infection were considered to be colonized.
Results: In 356 lung transplants performed, 258 were eligible for analysis. Median age at transplant was 57 (interquartile range 46-63), and 84% (218/258) of patients received a bilateral lung transplant. Mean time to onset of BOS was 2.4 years. Seven patients developed Scedosporium colonization, while 8 developed infection. In multivariate Cox regression models that evaluated for transplant type, sex, age at transplant, induction agent, acute rejection, and Aspergillus colonization or invasive infection, SRCI was associated with increased risk for BOS (HR 6.67, 95% CI 1.83-24.29, p=0.004) and death (HR 5.37, 95% CI 2.29-12.59, p<0.0001). This risk persisted when SRCI was considered as a time-dependent predictor in multivariable models.
Conclusion: These data suggest a potential association between SRCI and BOS, in addition to SRCI and mortality. Strategies to prevent Scedosporium and ensure eradication may be useful in preventing allograft lung injury.
IDWeek 2013 Meeting of the Infectious Diseases Society of America; 10/2013
[Show abstract][Hide abstract] ABSTRACT: Robinson et al. report a population-based case–control study to examine the association between a history of photosensitizing medication use and non-melanoma skin cancer. They report an increased risk of basal cell carcinoma with tetracycline use and of squamous cell carcinoma with diuretic use. Appropriate counseling regarding sun exposure may reduce skin cancer in patients exposed to these medications.
Journal of Investigative Dermatology 08/2013; 133(8):1922-1923. · 6.37 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Human papillomavirus (HPV) is ubiquitous in skin and has been associated with nonmelanoma skin cancer. Iannacone et al. investigate the role of HPV in basal cell carcinoma (BCC) by assessing the presence of HPV antibodies, HPV DNA in tumors, and the relationship between these two markers and BCC. In contrast to squamous cell carcinoma (SCC), there is no association between HPV and BCC.
Journal of Investigative Dermatology 06/2013; 133(6):1456-1458. · 6.19 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Voriconazole is an effective anti-fungal triazole commonly used in bone marrow and solid organ transplant recipients. However, reports of accelerated development of aggressive squamous cell carcinomas in immunocompromised patients are documented following voriconazole use. It is hypothesized that voriconazole or its primary N-oxide metabolite, voricinazole-N-oxide increases keratinocyte susceptibility via UV-mediated cell damage. We aimed to investigate whether voriconazole or voriconazole-N-oxide potentiate cell death after UVB irradiation in vitro. Both compounds absorb UVB but voriconazole exhibited weak emission while voriconazole-N-oxide showed no detectable emission in UVA. Exposure of different skin cell lines to these compounds did not show significant reduction in cell survival and regardless whether the cells were exposed to the drugs before or after UVB irradiation. However, in primary human keratinocytes, both drugs caused a small increase in cell survival following drug incubation and UVB irradiation. This is the first report documenting the effect of voriconazole and voriconazole-N-oxide in relation to UVB associated cell death in vitro.
Journal of Clinical & Experimental Dermatology Research. 05/2013; 4(2):173.