RESUMO
Epidermodysplasia verruciformis (EDV) is a rare genodermatosis that predisposes individuals to persistent infection with ß-human papillomavirus (HPV) genotypes. The term EDV acanthoma may be applied to lesions with incidental findings of EDV-defining histopathological features without clinical signs of EDV. We report a case of HPV-14- and -21-positive EDV acanthoma arising in association with condyloma in a female patient with a history of low-grade squamous intraepithelial lesion of the cervix positive for high-risk HPV (non-16/18), chronic kidney disease, and systemic lupus erythematosus. The patient had no family or personal history of EDV, but the patient was on immunosuppressive therapy with mycophenolate mofetil and prednisone. A biopsy specimen from one of the perianal lesions revealed histopathologic changes consistent with EDV in the setting of condyloma. Molecular testing showed HPV-14 and -21, which supported the coexistence of condyloma with EDV acanthoma.
Assuntos
Acantoma , Condiloma Acuminado , Epidermodisplasia Verruciforme , Infecções por Papillomavirus , Neoplasias Cutâneas , Humanos , Feminino , Acantoma/complicações , Papillomavirus Humano , Epidermodisplasia Verruciforme/complicações , Epidermodisplasia Verruciforme/patologia , Infecções por Papillomavirus/patologia , Condiloma Acuminado/complicações , Papillomaviridae , Neoplasias Cutâneas/complicaçõesRESUMO
BACKGROUND: Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine cutaneous carcinoma aetiologically linked to the Merkel cell polyomavirus (MCPyV). Immune checkpoint inhibitors are currently the first-line therapy for metastatic MCC; however, the treatment is effective in only about half of patients, highlighting the need for alternative therapies. Selinexor (KPT-330) is a selective inhibitor of nuclear exportin 1 (XPO1) and has been shown to inhibit MCC cell growth in vitro, but the pathogenesis has not been established. Decades of research have established that cancer cells significantly upregulate lipogenesis to meet an increased demand for fatty acids and cholesterol. Treatments that inhibit lipogenic pathways may halt cancer cell proliferation. AIM: To determine the effect of increasing doses of selinexor on fatty acid and cholesterol synthesis in MCPyV-positive MCC (MCCP) cell lines and aid in elucidating the mechanism by which selinexor prevents and reduces MCC growth. METHODS: MKL-1 and MS-1 cell lines were treated with increasing doses of selinexor for 72â h. Protein expression quantification was determined using chemiluminescent Western immunoblotting and densitometric analysis. Fatty acids and cholesterol were quantified using free fatty acid assay and cholesterol ester detection kits. RESULTS: Selinexor causes statistically significant reductions of the lipogenic transcription factors sterol regulatory element-binding proteins 1 and 2, and lipogenic enzymes acetyl-CoA carboxylase, fatty acid synthase, squalene synthase and 3ß-hydroxysterol Δ-24-reductase in a dose-dependent manner in two MCCP cell lines. Although inhibiting the fatty acid synthesis pathway results in meaningful decreases in fatty acids, the cellular cholesterol levels did not demonstrate such reductions. CONCLUSION: For patients with metastatic MCC refractory to immune checkpoint inhibitors, selinexor may provide clinical benefit through the inhibition of the lipogenesis pathway; however, further research and clinical trials are needed to evaluate these findings.
Assuntos
Carcinoma de Célula de Merkel , Neoplasias Cutâneas , Humanos , Carcinoma de Célula de Merkel/patologia , Inibidores de Checkpoint Imunológico , Lipogênese , Linhagem Celular , Neoplasias Cutâneas/patologia , Ácidos GraxosRESUMO
TSPyV is a viral agent linked to Trichodysplasia spinulosa, a disfiguring human skin disease which presents with hyperkeratotic spicule eruption in immunocompromised hosts. This proliferative disease state requires extensive modulation of the host cell environment. While the small T (sT) antigen of TSPyV has been postulated to cause widespread cellular perturbation, its specific substrates and their mechanistic connection are unclear. To identify the cellular substrates and pathways perturbed by TSPyV sT and propose a nuanced model that reconciles the multiple arms of TSPyV pathogenesis, changes in expression of several proteins and phospho-proteins in TSPyV sT expressing and TSPyV sT deletion mutant-expressing cell lysates were interrogated using Western blot assays. TSPyV sT expression exploits the DNA damage response pathway, by inducing hyperphosphorylation of ATM and 53BP1 and upregulation of BMI-1. Concurrently, sT dysregulates the S6 protein translation pathway via hyperphosphorylation of CDC2, p70 S6 kinase, S6, and PP1α. The S6S244/247 and p-PP1αT320 phospho-forms are points of overlap between the DDR and S6 networks. We propose a mechanistic rationale for previous reports positioning sT antigen as the key driver of TSPyV pathogenesis. We illuminate novel targets in the S6 and DDR pathways and recognize a potential synergy between these pathways. TSPyV may sensitize the cell to both unrestricted translation and genomic instability. This multi-pronged infection model may inform future therapeutic modalities against TSPyV and possibly other viruses with overlapping host substrates.
Assuntos
Infecções por Polyomavirus , Polyomavirus , Antígenos Virais de Tumores/genética , Dano ao DNA , Humanos , Polyomavirus/genética , Biossíntese de ProteínasRESUMO
Sinonasal inverted papillomas (IPs) are rare tumours arising from the nasal epithelial mucosa. Most lesions are benign, but a subset of IPs progress to dysplasia and squamous cell carcinoma. Although the epidemiology and clinical features of IPs are well known, the pathogenesis is still unclear. Given the established role of human papillomaviruses (HPVs) in the formation of other mucosal tumours including cervical and oropharyngeal cancer, some have suggested the virus may play a role in IP development. However, the association between HPV and IPs has not yet been proven, and the variable detection of HPV DNA in IPs has cast uncertainty on whether the virus plays a major role in pathogenesis. In this review, we summarize early clinical reports and synthesize recent studies that may elucidate the association between HPV and IPs. We also discuss the role HPV may have in the progression of benign IP to dysplasia and malignancy, as well as potential pathological mechanisms. We hope that synthesizing the initial and recent studies on this topic will not only lead to a better understanding of research in the role of HPV in IP development, but also help guide and contextualize future studies.
Assuntos
Alphapapillomavirus/isolamento & purificação , Neoplasias Nasais/virologia , Papiloma Invertido/virologia , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus , Neoplasias dos Seios Paranasais/virologia , Humanos , Neoplasias Nasais/patologia , Papiloma Invertido/patologia , Papillomaviridae/genética , Infecções por Papillomavirus/complicações , Neoplasias dos Seios Paranasais/patologiaRESUMO
Epidermodysplasia verruciformis (EDV) is a rare genodermatosis that predisposes affected individuals to persistent infection with certain types of human papillomavirus (HPV), particularly those that belong to the genus beta-HPV, including HPV-5 and HPV-8, which carry high oncogenic potential. There are three main HPV-related viral cytopathic changes in cutaneous verrucae in terms of intracytoplasmic inclusion bodies (ICBs), namely, granular, filamentous, and homogeneous type ICBs. To date, only HPV-4, HPV-60, and HPV-65 have been found in association with homogeneous ICBs. We report a unique case of HPV-49-associated EDV in a 41-year-old woman with common variable immunodeficiency, mycosis fungoides, and multiple cutaneous malignancies, including squamous cell carcinoma and Merkel cell carcinoma who presented with multiple pink papules and hyperpigmented macules on the left upper extremity. One of the skin lesions histopathologically revealed keratinocytic nuclear enlargement with abundant blue-gray cytoplasm, accompanied by hypergranulosis, characteristic of EDV, along with peculiar bright eosinophilic and homogeneous ICBs. To the best of our knowledge, this is the first reported case of EDV with detection of HPV-49 by genotyping, which features eosinophilic homogeneous ICBs, like those seen in the setting of HPV-4, HPV-60, or HPV-65 infection.
Assuntos
Alphapapillomavirus , Epidermodisplasia Verruciforme , Infecções por Papillomavirus , Adulto , Epidermodisplasia Verruciforme/complicações , Feminino , Humanos , Corpos de Inclusão/patologia , Papillomaviridae/genéticaRESUMO
Merkel cell carcinoma (MCC) is a highly lethal cutaneous carcinoma, which in ~80% of cases in the USA is aetiologically linked to Merkel cell polyomavirus (MCPyV). Immune checkpoint inhibitors (ICIs) can successfully treat ~50% of patients with metastatic MCC, but some MCCs are refractory to ICIs, possibly due to altered DNA damage response (DDR). Selinexor, an anticancer therapy that is currently approved in combination with chemotherapy for multiple myeloma, downregulates the small T and large T tumour antigens in MCC through selective inhibition of nuclear exportin 1 (XPO1). We examined the effect of varying doses of selinexor on DDR protein expression in MCPyV-positive and MCPyV-negative MCC cells. Selinexor was found to inhibit DDR protein expression in both MCPyV-positive and MCPyV-negative cells. Addition of selinexor alone or combined with ICI may be a promising treatment for MCC, but further in vivo research and clinical trials are required to validate these findings.
Assuntos
Carcinoma de Célula de Merkel , Poliomavírus das Células de Merkel , Neoplasias Cutâneas , Carcinoma de Célula de Merkel/tratamento farmacológico , Carcinoma de Célula de Merkel/patologia , Dano ao DNA , Humanos , Hidrazinas , Poliomavírus das Células de Merkel/genética , Neoplasias Cutâneas/genética , TriazóisRESUMO
The DDR is a complex signaling network responsible for the preservation of genomic integrity. Beta human papillomaviruses (ß-HPVs) are able to destabilize the host genome by attenuating the DDR machinery at the molecular scale following expression of the oncogenes E6 and E7. In the event of ß-HPV infection, the E6- and E7-mediated inhibition of the DDR enhances the oncogenicity of UV-induced mutations to enable carcinogenesis in an otherwise immunocompetent host, marking an important mechanistic divergence from the alpha genus of HPVs. In this review, we summarize recent updates to build upon the 'hit-and-run' hypothesis of ß-HPV pathomechanism and highlight strain-dependent variations. Simultaneously, we illuminate points within the ß-HPV-DDR interface that may unravel new insights for HPV viral genetics, genus-specific mechanistic models, and developments in targeted molecular therapy of ß-HPV-related cancers.
Assuntos
Betapapillomavirus/fisiologia , Carcinogênese , Dano ao DNA , Interações entre Hospedeiro e Microrganismos , Infecções por Papillomavirus/genética , Humanos , Proteínas Oncogênicas Virais/genéticaRESUMO
The human DNA damage response (DDR) is a complex signaling network constituting many factors responsible for the preservation of genomic integrity. Human polyomaviruses (HPyVs) are able to harness the DDR machinery during their infectious cycle by expressing an array of tumor (T) antigens. These molecular interactions between human polyomavirus T antigens and the DDR create conditions that promote viral replication at the expense of host genomic stability to cause disease as well as carcinogenesis in the cases of the Merkel cell polyomavirus and BK polyomavirus. This review focuses on the six HPyVs with disease association, emphasizing strain-dependent differences in their selective manipulation of the DDR. Appreciation of the HPyV-DDR interface at a molecular scale is conducive to the development of novel therapeutic approaches.
Assuntos
Antígenos Transformantes de Poliomavirus/genética , Vírus BK/genética , Poliomavírus das Células de Merkel/genética , Infecções por Polyomavirus/genética , Vírus BK/patogenicidade , Carcinogênese/genética , Dano ao DNA/genética , Instabilidade Genômica/genética , Interações Hospedeiro-Patógeno/genética , Humanos , Poliomavírus das Células de Merkel/patogenicidade , Neoplasias/genética , Neoplasias/virologia , Infecções por Polyomavirus/patologia , Infecções por Polyomavirus/virologia , Infecções Tumorais por VírusRESUMO
Trichodysplasia Spinulosa (TS) is a rare proliferative skin disease that occurs primarily in immunocompromised patients, specifically organ transplant recipients. TS is characterized by uncontrolled inner root sheath cell proliferation and folliculocentric papular eruption that can progress to disfiguring leonine facies when left untreated. TS presents with distinct histological features including the presence of large eosinophilic, trichohyaline granules within hyperproliferating inner root sheath cells of the hair bulb. The discovery of the Trichodysplasia Spinulosa Polyomavirus (TSPyV) and recent studies highlighting the role of TSPyV tumor antigens in cell proliferation pathways have provided new insight into the mechanisms of TS development. In this review, we discuss the expansion of our understanding of TS, specifically over the past 5 years. We summarize novel cases of TS and recent developments in the mechanisms underlying TSPyV-mediated disease progression. We also evaluate advancements in diagnostic methods and treatment options. As the incidence of TS continues to rise, it is becoming critical for clinicians to understand the clinical features of TS and emerging research regarding pathogenesis and therapeutics for early treatment of this potentially disfiguring disease.
Assuntos
Doenças do Cabelo , Hospedeiro Imunocomprometido , Infecções por Polyomavirus , Antígenos de Neoplasias , Proliferação de Células , Progressão da Doença , Doenças do Cabelo/virologia , Humanos , Polyomavirus , Infecções por Polyomavirus/complicações , PeleRESUMO
Merkel cell carcinoma (MCC) is an aggressive neuroendocrine cancer of the skin with high rates of metastasis and mortality. Besides well-established factors including genetic mutations and UV-induced DNA damage in Merkel cell carcinogenesis, the recent discovery of the Merkel cell polyomavirus (MCPyV) has shed light on the viral etiology of MCC. In the current study, we provide novel evidence that MCPyV small T (sT) antigen induces the DNA damage response (DDR) pathway. Our data show that in human MCC cells, the presence of MCPyV is associated with hyperphosphorylation of histone H2AX, a marker for DNA damage. We observed that overexpression of MCPyV sT antigen induced the phosphorylation of histone H2AX as well as the activation of ataxia telangiectasia mutant (ATM), an upstream kinase important for H2AX phosphorylation. Moreover, we observed that MCPyV sT expression also induced the hyperphosphorylation of other ATM downstream molecules (including 53BP1 and CHK2) as well as the hypermethylation of histone 3 and histone 4. These findings disclose a novel link between MCPyV sT and the DDR pathway in MCC. Given that measurement of DDR is clinically useful for evaluating treatment response to radio- and chemotherapy, our findings warrant further investigation to evaluate the potential implications of this pathway for MCC management.
Assuntos
Antígenos Virais de Tumores/genética , Carcinoma de Célula de Merkel/virologia , Dano ao DNA , Expressão Gênica , Poliomavírus das Células de Merkel , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Células HEK293 , Histonas/metabolismo , Humanos , Células de Merkel/virologia , Fosforilação , Neoplasias Cutâneas/virologiaRESUMO
In 1964, the first human oncovirus, Epstein-Barr virus, was identified in Burkitt lymphoma cells. Since then, 6 other human oncoviruses have been identified: human papillomavirus, Merkel cell polyomavirus, hepatitis B and C viruses, human T-cell lymphotropic virus-1, and human herpesvirus-8. These viruses are causally linked to 12% of all cancers, many of which have mucocutaneous manifestations. In addition, oncoviruses are associated with multiple benign mucocutaneous diseases. Research regarding the pathogenic mechanisms of oncoviruses and virus-specific treatment and prevention is rapidly evolving. Preventative vaccines for human papillomavirus and hepatitis B virus are already available. This review discusses the mucocutaneous manifestations, pathogenesis, diagnosis, treatment, and prevention of oncovirus-related diseases. The first article in this continuing medical education series focuses on diseases associated with human papillomavirus and Merkel cell polyomavirus, while the second article in the series focuses on diseases associated with hepatitis B and C viruses, human T-cell lymphotropic virus-1, human herpesvirus-8, and Epstein-Barr virus.
Assuntos
Poliomavírus das Células de Merkel/patogenicidade , Papillomaviridae/patogenicidade , Retroviridae/patogenicidade , Neoplasias Cutâneas/virologia , Infecções Tumorais por Vírus/epidemiologia , Biópsia por Agulha , Educação Médica Continuada , Feminino , Humanos , Imuno-Histoquímica , Masculino , Poliomavírus das Células de Merkel/isolamento & purificação , Invasividade Neoplásica/patologia , Papillomaviridae/isolamento & purificação , Prevenção Primária , Prognóstico , Retroviridae/isolamento & purificação , Medição de Risco , Neoplasias Cutâneas/epidemiologia , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/terapia , Análise de Sobrevida , Infecções Tumorais por Vírus/fisiopatologia , Infecções Tumorais por Vírus/terapia , Infecções Tumorais por Vírus/virologiaRESUMO
BRAF inhibitors are highly effective therapies in treating a subset of melanomas but are associated with induction of secondary cutaneous squamous cell carcinoma (cSCC). Recently, Human Polyomavirus 6 (HPyV6) was found to actively express viral proteins in BRAF inhibitor-induced cSCCs; however, the specific cellular mechanisms by which HPyV6 may facilitate neoplastic cell growth require further investigation. The current study describes a novel pathogenic mechanism of action for HPyV6 small tumor (sT) antigen which involves binding to protein phosphatase 2A (PP2A) via its WFG motif and zinc binding sites. Our findings demonstrate an important role of HPyV6 sT for activation of PP2A's downstream oncogenic pathways (MEK/ERK/c-Jun), which may underlie the pathogenesis of BRAF inhibitor-induced neoplasms. J. Med. Virol. 89:742-747, 2017. © 2016 Wiley Periodicals, Inc.
Assuntos
Antígenos Virais de Tumores/metabolismo , Interações Hospedeiro-Patógeno , Sistema de Sinalização das MAP Quinases , Polyomavirus/patogenicidade , Proteína Fosfatase 2/metabolismo , Humanos , Ligação Proteica , Mapeamento de Interação de ProteínasRESUMO
The co-existence of Darier disease (DD) and acrokeratosis verruciformis of Hopf (AKV) has been noted for decades and the relationship between the 2 entities remains controversial. Although, it has been shown that both diseases are associated with mutations in ATPA2 gene, it is yet to be determined if they are the same disease, or separate but allelic, or interlinked in some other fashion. Herein, the authors report the case of a 13-year-old girl presenting with shiny flat-topped verruca plana-like papules, on the dorsal hands and feet and red-brown crusted papules on her forehead and along the sides of her neck. Histological evaluation of a wart-like lesion shows features of AKV, a verruca plana-like histopathology and focal acantholytic dyskeratosis. Forehead biopsy also demonstrated focal acantholytic dyskeratosis supporting the diagnosis of DD. Polymerase chain reaction for human papillomavirus (HPV) DNA detected HPV-17, a human betapapillomavirus in the verruca plana-like papule. Cytoplasmic expression of the L1 capsid expression was seen in areas of hypergranulosis. The presence of productive betaPV infection in the setting of DD and AKV suggests a susceptibility to HPV infection.
Assuntos
Acrodermatite/complicações , Acrodermatite/genética , Doença de Darier/complicações , Doença de Darier/genética , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/genética , Acrodermatite/patologia , Adolescente , Alelos , Biópsia por Agulha , Doença de Darier/patologia , Feminino , Seguimentos , Predisposição Genética para Doença , Humanos , Imuno-Histoquímica , Mutação , Infecções por Papillomavirus/patologia , Reação em Cadeia da Polimerase/métodos , Doenças RarasRESUMO
Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine skin cancer associated with the Merkel cell polyomavirus (MCPyV). The MCPyV genome, which is clonally integrated in the majority of MCCs, encodes the regulatory small T (sT) antigen. Previously, reports have established MCPyV sT antigen as a potent oncogene capable of inducing cell transformation. In the current study, we demonstrate a distinct role for c-Jun hyperactivation in MCPyV sT antigen pathogenesis. As MCPyV sT antigen's association with aggressive cancer growth has been previously established, this finding may represent a potential therapeutic target for the treatment of MCCs.
Assuntos
Antígenos Virais de Tumores/metabolismo , Carcinoma de Célula de Merkel/virologia , Transformação Celular Neoplásica/metabolismo , Poliomavírus das Células de Merkel/metabolismo , Infecções por Polyomavirus/virologia , Proteínas Proto-Oncogênicas c-jun/metabolismo , Neoplasias Cutâneas/virologia , Antígenos Virais de Tumores/genética , Carcinoma de Célula de Merkel/genética , Carcinoma de Célula de Merkel/imunologia , Carcinoma de Célula de Merkel/metabolismo , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/imunologia , Perfilação da Expressão Gênica , Regulação Viral da Expressão Gênica , Células HEK293 , Humanos , Poliomavírus das Células de Merkel/genética , Poliomavírus das Células de Merkel/imunologia , Fosforilação , Infecções por Polyomavirus/genética , Infecções por Polyomavirus/imunologia , Infecções por Polyomavirus/metabolismo , Proteínas Proto-Oncogênicas c-jun/biossíntese , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/metabolismo , Infecções Tumorais por Vírus/virologiaRESUMO
A 3-year-old African American girl taking sirolimus and tacrolimus for a small bowel transplantation presented with hypopigmented macules and papules throughout her trunk. A biopsy diagnosed epidermodysplasia verruciformis (EV) that was found to be associated with human papillomavirus (HPV) type 14 according to polymerase chain reaction analysis. There are few cases of acquired EV in the setting of organ transplantation. Although there is no standardized treatment for acquired EV, prevention and surveillance for transformation to squamous cell carcinoma are primary concerns.
Assuntos
Epidermodisplasia Verruciforme/virologia , Intestino Delgado/transplante , Transplante de Órgãos/efeitos adversos , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/virologia , Pré-Escolar , Epidermodisplasia Verruciforme/diagnóstico , Feminino , Humanos , Infecções por Papillomavirus/diagnóstico , Reação em Cadeia da Polimerase , Pele/patologiaRESUMO
Merkel cell polyomavirus (MCPyV), trichodysplasia spinulosa-associated polyomavirus (TSPyV), human polyomavirus 6 (HPyV6), and human polyomavirus 7 (HPyV7) are implicated in the pathogeneses of distinct hyperproliferative cutaneous growths and encode small tumor (sT) antigens. The current study demonstrates that the four sT antigens differentially regulate 4E-binding protein 1 (4E-BP1) serine 65 hyperphosphorylation. MCPyV and HPyV7 sT antigens were found to promote the presence of the hyperphosphorylated 4E-BP1-δ isoform, while TSPyV and HPyV6 sT antigens had no significant effects. Given that hyperphosphorylated 4E-BP1 is associated with an aggressive cancer phenotype, our findings confirm the previously reported pathogenicity of MCPyV sT and highlight a novel mechanism by which HPyV7 sT may mediate oncogenesis.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Antígenos Transformantes de Poliomavirus/imunologia , Poliomavírus das Células de Merkel/imunologia , Fosfoproteínas/genética , Polyomaviridae/imunologia , Infecções por Polyomavirus/imunologia , Polyomavirus/imunologia , Proteínas de Ciclo Celular , Humanos , Infecções por Polyomavirus/virologia , Neoplasias Cutâneas/virologiaRESUMO
Onycholysis, separation of the nail plate from the nail bed, is etiologically classified as primary (idiopathic) or secondary (eg, caused by psoriasis, squamous cell carcinoma). Repetitive microtrauma plays a role in idiopathic onycholysis and also facilitates human papillomavirus (HPV) infection. Herein, we report a case of persistent primary onycholysis associated with repetitive trauma and infection by a multiplicity of Beta-papillomavirus (Beta-PV) genotypes. An otherwise healthy 27-year-old woman presented with a 6-year history of onycholysis of the halluces and right second toe. Her occupation required wearing steel-toed boots. Fungal cultures were negative and antifungal therapy was ineffective. Punch biopsy of the hallux nail bed revealed epidermal hyperplasia, acanthosis, hypergranulosis, hyperkeratosis, and regions of koilocytosis without significant inflammation. This histopathology implicated chronic irritation and HPV infection. Immunohistochemistry demonstrated productive HPV infection. Nested PCR using degenerate consensus primers revealed infection with 5 known and 1 novel Beta-PV genotypes (HPV 5, HPV 8, HPV 20, HPV 23, HPV 37, and FA25). The histopathology of primary onycholysis is unknown. Based on the aforementioned, we propose that repetitive microtrauma caused by wearing steel-toed boots promoted onycholysis and HPV infection, the latter of which, altered the differentiation of nail bed epithelium, preventing adhesion of nail plate to the nail bed. Lastly, the presence of oncogenic Beta-PV genotypes (ie, HPV 5, 8, and 20) implicates a risk for subungual squamous cell carcinoma, particularly if the nail remains symptomatic and persistently irritated.
Assuntos
Betapapillomavirus/isolamento & purificação , Unhas/virologia , Onicólise/complicações , Infecções por Papillomavirus/virologia , Adulto , Betapapillomavirus/genética , Biópsia , DNA Viral/genética , Feminino , Genótipo , Testes de DNA para Papilomavírus Humano , Humanos , Imuno-Histoquímica , Unhas/lesões , Unhas/patologia , Onicólise/diagnóstico , Onicólise/etiologia , Infecções por Papillomavirus/diagnóstico , Reação em Cadeia da PolimeraseRESUMO
Purpose: Trichodysplasia spinulosa (TS) is a rare, disfiguring skin condition which presents with widespread asymptomatic or pruritic, skin-colored papules with white protruding keratin spiculations in immunocompromised individuals. Due to its rarity, there is little data to guide treatment decisions. The purpose of this article is to report a case of TS that completely resolved after treatment with topical cidofovir.Materials and methods: A 19-year-old immunosuppressed female presented with widespread painful, itchy bumps on the nose and face. Upon examination, there were erythematous papules with hyperkeratinized spicules affecting the central face. Biopsy of the lesions was consistent with TS which was confirmed via PCR analysis. The tenderness of this patient's eruption was highly atypical for TS. Once daily topical application of compounded 1% cidofovir cream was prescribed.Results: The patient's symptoms resolved completely after 4 weeks of therapy with topical cidofovir 1% cream, without reduction of immunosuppression.Conclusions: Topical cidofovir 1% cream may be a valuable treatment for this rare disease.
Assuntos
Infecções por Polyomavirus , Dermatopatias , Feminino , Humanos , Adulto Jovem , Cidofovir/uso terapêutico , Hospedeiro Imunocomprometido , Infecções por Polyomavirus/diagnóstico , Infecções por Polyomavirus/patologia , Infecções por Polyomavirus/terapia , Prurido , Dermatopatias/patologiaRESUMO
Tirbanibulin 1% ointment is a synthetic antiproliferative agent approved in 2021 by the European Union for treating actinic keratoses (AK). Topical tirbanibulin has clinically resolved HPV-57 ( +) squamous cell carcinoma (SCC), HPV-16 ( +) vulvar high-grade squamous intraepithelial lesion, epidermodysplasia verruciformis, and condyloma. We examined how tirbanibulin might affect HPV oncoprotein expression and affect other cellular pathways involved in cell proliferation and transformation. We treated the HeLa cell line, containing integrated HPV-18, with increasing doses of tirbanibulin to determine the effects on cell proliferation. Immunoblotting was performed with antibodies against the Src canonical pathway, HPV 18 E6 and E7 transcription regulation, apoptosis, and invasion and metastasis pathways. Cell proliferation assays with tirbanibulin determined the half-maximal inhibitory concentration (IC50) of HeLa cells to be 31.49 nmol/L. Increasing concentrations of tirbanibulin downregulates the protein expression of Src (p < 0.001), phospho-Src (p < 0.001), Ras (p < 0.01), c-Raf (p < 0.001), ERK1 (p < 0.001), phospho-ERK1 (p < 0.001), phospho-ERK2 (p < 0.01), phospho-Mnk1 (p < 0.001), eIF4E (p < 0.01), phospho-eIF4E (p < 0.001), E6 (p < 0.01), E7 (p < 0.01), Rb (p < 0.01), phospho-Rb (p < 0.001), MDM2 (p < 0.01), E2F1 (p < 0.001), phospho-FAK (p < 0.001), phospho-p130 Cas (p < 0.001), Mcl-1 (p < 0.01), and Bcl-2 (p < 0.001), but upregulates cPARP (p < 0.001), and cPARP/fPARP (p < 0.001). These results demonstrate that tirbanibulin may impact expression of HPV oncoproteins via the Src- MEK- pathway. Tirbanibulin significantly downregulates oncogenic proteins related to cell cycle regulation and cell proliferation while upregulating apoptosis pathways.
Tirbanibulin is Promising Novel Therapy for Human Papillomavirus (HPV)-associated Diseases.Tirbanibulin 1% ointment is an approved synthetic topical ointment for treating actinic keratoses (AK), a precancer of skin cancer. Topical tirbanibulin has previously been reported to clinically resolve human papillomavirus (HPV)-( +) diseases.In this study, we examine how tirbanibulin may affect the HPV and pathways associated with cancer.We treated the HeLa cell line to determine the effects on HPV cell proliferation. Increasing the concentration of tirbanibulin statistically significantly affected numerous cellular pathways often associated with cancer.These results demonstrate that tirbanibulin may impact expression of HPV oncoproteins and thereby kill cancer cells.