RESUMO
Digital squamous cell carcinoma (SCC) presents a diagnostic challenge because of its relatively rare occurrence and mimicry of benign conditions. Although low-risk human papillomavirus (HPV) subtypes are commonly associated with benign digital verrucae, digital SCC can be associated with high-risk, oncogenic HPV subtypes. We report 7 patients, including 4 HIV-positive patients, who presented with 10 lesions of digital SCC in situ. Six of 10 lesions were typed for HPV by immunostain or polymerase chain reaction. Multiple high-risk oncogenic subtypes were found, including HPV-16, -33, -51, and -73. The majority of reports linking HPV and digital SCCs have implicated the HPV-16 subtype. This case series highlights the diversity of oncogenic HPV types that may be associated with digital SCCs. Because the high rate of recurrence of digital SCCs may be a result of persistence of oncogenic HPV at the margins of resection, aggressive treatment of individual lesions and of genital reservoirs for HPV on patients and their sexual partners is warranted.
Assuntos
Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/virologia , Dedos , Infecções por Papillomavirus/complicações , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/virologia , Adulto , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/cirurgia , Feminino , Papillomavirus Humano 16 , Humanos , Queratinócitos/patologia , Masculino , Pessoa de Meia-Idade , Infecções por Papillomavirus/virologia , Reação em Cadeia da Polimerase , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/cirurgiaRESUMO
A20 is a NF-kappaB-dependent gene that has dual anti-inflammatory and antiapoptotic functions in endothelial cells (EC). The function of A20 in smooth muscle cells (SMC) is unknown. We demonstrate that A20 is induced in SMC in response to inflammatory stimuli and serves an anti-inflammatory function via blockade of NF-kappaB and NF-kappaB-dependent proteins ICAM-1 and MCP-1. A20 inhibits SMC proliferation via increased expression of cyclin-dependent kinase inhibitors p21waf1 and p27kip1. Surprisingly, A20 sensitizes SMC to cytokine- and Fas-mediated apoptosis through a novel NO-dependent mechanism. In vivo, adenoviral delivery of A20 to medial rat carotid artery SMC after balloon angioplasty prevents neointimal hyperplasia by blocking SMC proliferation and accelerating re-endothelialization, without causing apoptosis. However, expression of A20 in established neointimal lesions leads to their regression through increased apoptosis. This is the first demonstration that A20 exerts two levels of control of vascular remodeling and healing. A20 prevents neointimal hyperplasia through combined anti-inflammatory and antiproliferative functions in medial SMC. If SMC evade this first barrier and neointima is formed, A20 has a therapeutic potential by uniquely sensitizing neointimal SMC to apoptosis. A20-based therapies hold promise for the prevention and treatment of neointimal disease.
Assuntos
Hiperplasia/prevenção & controle , Músculo Liso Vascular/citologia , Músculo Liso Vascular/fisiologia , NF-kappa B/antagonistas & inibidores , Proteínas/fisiologia , Proteínas/uso terapêutico , Túnica Íntima/patologia , Adenoviridae , Animais , Aorta , Apoptose , Ciclo Celular , Divisão Celular , Primers do DNA , Proteínas de Ligação a DNA , Endotélio Vascular/fisiologia , Regulação da Expressão Gênica , Vetores Genéticos , Humanos , Molécula 1 de Adesão Intercelular/genética , Peptídeos e Proteínas de Sinalização Intracelular , Proteínas Nucleares , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Suínos , Proteína 3 Induzida por Fator de Necrose Tumoral alfa , Doenças Vasculares/prevenção & controleRESUMO
Rotaviruses, segmented double-stranded RNA viruses, co-opt the eukaryotic translation machinery with the aid of nonstructural protein 3 (NSP3), a rotaviral functional homolog of the cellular poly(A) binding protein (PABP). NSP3 binds to viral mRNA 3' consensus sequences and circularizes mRNA via interactions with eIF4G. Here, we present the X-ray structure of the C-terminal domain of NSP3 (NSP3-C) recognizing a fragment of eIF4GI. Homodimerization of NSP3-C yields a symmetric, elongated, largely alpha-helical structure with two hydrophobic eIF4G binding pockets at the dimer interface. Site-directed mutagenesis and isothermal titration calorimetry documented that NSP3 and PABP use analogous eIF4G recognition strategies, despite marked differences in tertiary structure.
Assuntos
Fatores de Iniciação de Peptídeos/química , RNA Mensageiro/metabolismo , Proteínas não Estruturais Virais/química , Sequência de Aminoácidos , Animais , Sítios de Ligação , Proteínas de Transporte/química , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Dimerização , Fator de Iniciação Eucariótico 4G , Humanos , Modelos Moleculares , Dados de Sequência Molecular , Fatores de Iniciação de Peptídeos/metabolismo , Estrutura Quaternária de Proteína , Proteínas de Ligação a RNA/química , Proteínas de Ligação a RNA/metabolismo , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Alinhamento de Sequência , Proteínas não Estruturais Virais/metabolismoRESUMO
Rotaviruses, the cause of life-threatening diarrhea in humans and cattle, utilize a functional homolog of poly(A) binding protein (PABP) known as nonstructural protein 3 (NSP3) for translation of viral mRNAs. NSP3 binds to viral mRNA 3' consensus sequences and circularizes the mRNA via interactions with eIF4G. The X-ray structure of the NSP3 RNA binding domain bound to a rotaviral mRNA 3' end has been determined. NSP3 is a novel, heart-shaped homodimer with a medial RNA binding cleft. The homodimer is asymmetric, and contains two similar N-terminal segments plus two structurally different C-terminal segments that intertwine to create a tunnel enveloping the mRNA 3' end. Biophysical studies demonstrate high affinity binding leading to increased thermal stability and slow dissociation kinetics, consistent with NSP3 function.
