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1.
Nat Commun ; 11(1): 2711, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32483135

RESUMO

p16INK4a (CDKN2A) is a central tumor suppressor, which induces cell-cycle arrest and senescence. Cells expressing p16INK4a accumulate in aging tissues and appear in premalignant lesions, yet their physiologic effects are poorly understood. We found that prolonged expression of transgenic p16INK4a in the mouse epidermis induces hyperplasia and dysplasia, involving high proliferation rates of keratinocytes not expressing the transgene. Continuous p16INK4a expression increases the number of epidermal papillomas formed after carcinogen treatment. Wnt-pathway ligands and targets are activated upon prolonged p16INK4a expression, and Wnt inhibition suppresses p16INK4a-induced hyperplasia. Senolytic treatment reduces p16INK4a-expressing cell numbers, and inhibits Wnt activation and hyperplasia. In human actinic keratosis, a precursor of squamous cell carcinoma, p16INK4a-expressing cells are found adjacent to dividing cells, consistent with paracrine interaction. These findings reveal that chronic p16INK4a expression is sufficient to induce hyperplasia through Wnt-mediated paracrine stimulation, and suggest that this tumor suppressor can promote early premalignant epidermal lesion formation.


Assuntos
Transformação Celular Neoplásica/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Epiderme/metabolismo , Via de Sinalização Wnt/genética , Animais , Proliferação de Células/genética , Transformação Celular Neoplásica/metabolismo , Células Cultivadas , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Humanos , Hiperplasia/genética , Hiperplasia/metabolismo , Queratinócitos/metabolismo , Ceratose/genética , Ceratose/metabolismo , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Papiloma/genética , Papiloma/metabolismo , Papiloma/patologia
3.
PLoS One ; 15(3): e0222619, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32150577

RESUMO

Ion channels have recently attracted attention as potential mediators of skin disease. Here, we explored the consequences of genetically encoded induction of the cell volume-regulating Ca2+-activated KCa3.1 channel (Kcnn4) for murine epidermal homeostasis. Doxycycline-treated mice harboring the KCa3.1+-transgene under the control of the reverse tetracycline-sensitive transactivator (rtTA) showed 800-fold channel overexpression above basal levels in the skin and solid KCa3.1-currents in keratinocytes. This overexpression resulted in epidermal spongiosis, progressive epidermal hyperplasia and hyperkeratosis, itch and ulcers. The condition was accompanied by production of the pro-proliferative and pro-inflammatory cytokines, IL-ß1 (60-fold), IL-6 (33-fold), and TNFα (26-fold) in the skin. Treatment of mice with the KCa3.1-selective blocker, Senicapoc, significantly suppressed spongiosis and hyperplasia, as well as induction of IL-ß1 (-88%) and IL-6 (-90%). In conclusion, KCa3.1-induction in the epidermis caused expression of pro-proliferative cytokines leading to spongiosis, hyperplasia and hyperkeratosis. This skin condition resembles pathological features of eczematous dermatitis and identifies KCa3.1 as a regulator of epidermal homeostasis and spongiosis, and as a potential therapeutic target.


Assuntos
Eczema/genética , Epiderme/patologia , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/genética , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/metabolismo , Ceratose/genética , Pele/metabolismo , Transgenes , Acetamidas/farmacologia , Animais , Citocinas/metabolismo , Doxiciclina/farmacologia , Eczema/tratamento farmacológico , Feminino , Homeostase/genética , Hiperplasia/tratamento farmacológico , Hiperplasia/genética , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/antagonistas & inibidores , Queratinócitos/metabolismo , Ceratose/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Transativadores/metabolismo , Compostos de Tritil/farmacologia
5.
J Dairy Sci ; 103(2): 1843-1855, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31759610

RESUMO

A systematic review was conducted to elucidate the role of teat-end hyperkeratosis (THK) as a risk factor for clinical mastitis (CM) or subclinical mastitis (SCM). Scientific papers on the subject were identified by means of a database search. All types of peer-reviewed analytical studies, observational or experimental and published in English, could be included in the review, regardless of publication year. Of 152 identified records, 18 articles were selected, of which 8 were prospective cohort studies, 9 were cross-sectional, and 1 was a hybrid case-control study. Internal validity of studies was assessed using a score system ranging from 0 to 6, based on design, risk of bias, and statistical methods. The most frequent study limitation was improper use of statistical methods to avoid confounding of associations between THK and CM or SCM. The 3 studies that used CM as outcome (all with high validity scores) showed positive associations with THK (especially severe), although the magnitude and statistical significance of the estimates differed among them. Most studies that used SCM as the primary outcome (based on microbiological examination of milk) reported that only severe THK was associated with SCM. Two studies with high validity scores reported moderate to strong associations between severe THK and incidence or prevalence of Staphylococcus aureus intramammary infection. Two studies with high validity scores reported that only severe THK was associated with the risk of somatic cell count (SCC) ≥200,000 cells/mL and increased mean SCC, respectively. Although 4 cross-sectional studies reported positive associations between THK and SCC, these associations were possibly spurious because confounding factors, such as parity, were not considered in the analyses. Results of the reviewed studies suggest that severe THK is a risk factor for both CM and SCM, as defined by microbiological examination of milk, SCC thresholds, or mean SCC. The effect of severe THK on both contagious (especially Staphylococcus aureus) and environmental CM or SCM emphasizes the importance of teat health for mastitis control. Four studies demonstrated that quarters with mild THK had lower prevalence of intramammary infection or lower mean SCC than quarters with no THK, suggesting that development of mild THK, as a physiological response to milking, can have a protective effect. Dairy consultants should focus on monitoring and minimizing occurrence of severe THK to prevent CM and SCM.


Assuntos
Ceratose/veterinária , Mastite Bovina/epidemiologia , Leite/microbiologia , Infecções Estafilocócicas/veterinária , Staphylococcus aureus/isolamento & purificação , Animais , Calosidades/epidemiologia , Calosidades/veterinária , Estudos de Casos e Controles , Bovinos , Contagem de Células/veterinária , Estudos Transversais , Indústria de Laticínios , Feminino , Ceratose/epidemiologia , Glândulas Mamárias Animais/microbiologia , Mastite Bovina/microbiologia , Gravidez , Prevalência , Estudos Prospectivos , Fatores de Risco , Infecções Estafilocócicas/epidemiologia , Infecções Estafilocócicas/microbiologia
6.
J Dtsch Dermatol Ges ; 17(12): 1227-1238, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31846220

RESUMO

Loricrin downregulation has been associated with age-related changes as well as inherited and inflammatory skin diseases. We hypothesize that changes in loricrin could be more related to altered barrier function and consequently disorders that affect epithelial cells, such as psoriasis, atopic dermatitis (AD), erythrokeratoderma, loricrin keratoderma (LK) and periodontitis. The aim of this review is to summarize what is known about the association between loricrin downregulation and epithelial-related disorders (ERDs). A search was performed on the following databases: Medline, Cochrane Library, PubMed, EMBASE, Lilacs, Scopus and Google Scholar, resulting in 16 included articles. Loricrin keratoderma was the ERD most frequently associated with loricrin mutations (730insG, 709insC and 578insG; 5/7 cases - 71.44 %). Atopic dermatitis was the ERD most frequently associated with loricrin downregulation (2/7 cases - 28.6 %). Mutilating palmoplantar keratoderma, progressive symmetrical erythrokeratoderma and a new type of erythrokeratoderma were not associated with any mutations. At the gene level, periodontitis patients showed the highest decrease (-6.89x), followed by AD (-6.5x) and psoriasis patients (-0.5x). In summary, loricrin mutation and downregulation were associated with several ERDs. The diversity in disease presentation is likely related to whether there is a total loss of loricrin, mislocalization and/or if the mutant form of loricrin causes dysfunction of other proteins and/or changes in cornification.


Assuntos
Proteínas de Membrana/metabolismo , Mutação , Dermatopatias/metabolismo , Análise Mutacional de DNA , Regulação para Baixo , Feminino , Expressão Gênica , Humanos , Ceratose/genética , Ceratose/metabolismo , Masculino , Proteínas de Membrana/genética , Membrana Mucosa/metabolismo , Psoríase/genética , Psoríase/metabolismo , RNA Mensageiro/metabolismo , Dermatopatias/genética
9.
Dermatol Online J ; 25(10)2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31735011

RESUMO

Follicular spicules are a very rare but highly characteristic cutaneous manifestation of multiple myeloma. The spicules typically appear as hyperkeratotic horns in the follicular openings of the face, most commonly on or around the nose and forehead. The pathophysiology of this condition has not been fully elucidated and remains an active area of research and debate. Herein we describe a patient who presented with follicular spicules in the context of unintentional weight loss, anemia, and elevated inflammatory markers. We discuss the diagnostic work-up for such a presentation, review the classification of follicular spicules of multiple myeloma, and describe approaches to manage this uncommon skin condition.


Assuntos
Ceratose/patologia , Mieloma Múltiplo/patologia , Síndromes Paraneoplásicas/patologia , Pele/patologia , Humanos , Ceratose/etiologia , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/complicações , Mieloma Múltiplo/diagnóstico
10.
Drug Discov Ther ; 13(5): 294-296, 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31656251

RESUMO

Graham Little Piccardi Lassueur syndrome (GLPLS) is a rare dermatosis characterized by patchy cicatricial alopecia of scalp, rapidly developing keratosis pilaris like follicular papules over trunk and extremities, and noncicatricial loss of axillary and pubic hair. This syndrome which is mostly seen in middle aged post-menopausal females (between ages 30-70)has rarely ever been described in the pediatric age group. We report a case of a 15 year old girl presenting to us with this rare syndrome.


Assuntos
Alopecia/complicações , Ceratose/complicações , Adolescente , Feminino , Humanos , Síndrome
16.
J Photochem Photobiol B ; 198: 111565, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31374350

RESUMO

The incidence of skin cancers has increased worldwide, requiring more prevention of this type of cancer. The use of sunscreen and the control of the time of exposure to sunlight are the recognized forms of prevention. However, new substances have been researched in order to develop formulations with more efficient protective activity. Citral is a natural compound with lemon scent that is used in food and cosmetic industries. The present work evaluated the chemoprotective effect of citral during UVB-induced skin carcinogenesis. Male hairless mice HRS/J, 8-12 weeks old, were exposed to UVB irradiation for 24 weeks, with a cumulative radiation dose of 13.875 J/cm2. Citral (0.1, 0.5 and 1%) was applied to the skin at a dosage of 0.1 g/animal, 5 min after UVB exposure. At the end of the experiment, the number of lesion/animal, and size of lesions were measured. The histological sections of the skin were evaluated for the presence and intensity of actinic keratosis and squamous cell carcinoma. TUNEL assay was performed for apoptosis evaluation. Skin samples were used for the measurement of oxidative stress parameters (total radical-trapping antioxidant parameter of skin, glutathione, catalase activity and malondialdehyde), and cytokines levels (IL-1ß, IL-4, IL-10, IL-23, TNF-α, and IFNγ). Citral 1% completely inhibited UVB-induced skin carcinogenesis by reducing levels of oxidative stress and pro-inflammatory cytokines, increasing apoptotic rate in the skin.


Assuntos
Carcinoma de Células Escamosas/patologia , Monoterpenos/farmacologia , Neoplasias Cutâneas/patologia , Pele/efeitos dos fármacos , Raios Ultravioleta , Monoterpenos Acíclicos , Animais , Antioxidantes/metabolismo , Carcinoma de Células Escamosas/prevenção & controle , Catalase/metabolismo , Citocinas/metabolismo , Glutationa/metabolismo , Ceratose/patologia , Masculino , Malondialdeído/metabolismo , Camundongos , Camundongos Pelados , Monoterpenos/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/efeitos da radiação , Pele/metabolismo , Pele/efeitos da radiação , Neoplasias Cutâneas/prevenção & controle
17.
Cutis ; 103(6): 340-342, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31348447

RESUMO

A 53-year-old woman presented with an asymptomatic nodule on the distal subungual right fifth fingernail that had slowly enlarged over the last year. An excisional biopsy showed an acanthotic epidermis surmounted by hyperkeratotic scale as well as a fibrotic dermis with collagen bundles assuming a vertical orientation to the long axis of the epidermis, characteristic of an acquired digital fibrokeratoma (ADF). There was no sign of recurrence 4 months following excision. There are no known associations or risk factors for development of ADF, though prior trauma might play a role. This case describes the clinical and histopathological features of ADF and the differential diagnosis and treatment options. It is important to consider ADF when examining subungual nodules, and to be able to identify and differentiate between other benign and malignant nail tumors.


Assuntos
Ceratose/diagnóstico , Unhas/patologia , Dermatopatias/diagnóstico , Biópsia , Diagnóstico Diferencial , Feminino , Dedos , Humanos , Ceratose/patologia , Pessoa de Meia-Idade , Dermatopatias/patologia
18.
J Foot Ankle Surg ; 58(5): 1036-1039, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31350140

RESUMO

Digital fibrokeratoma (DF) is an uncommon, benign, soft tissue tumor. It usually occurs sporadically in adult males, and its recurrence is rare when treated by means of surgical removal. To the best of our knowledge, we report here the first case of recurrent female familial DF. The mother's first DF, on her right hallux, was removed when she was 32 years of age, and her second fibrokeratoma, on the left fifth toe, was removed when she was 49 years of age, and then relapsed 3 years later. The daughter's first DF, on her left fifth toe, was excised when the daughter was 24 years of age and recurred 1 year later. Both the mother's and daughter's recurrent lesions were surgically excised and pathologically diagnosed as DF. Because both the mother's and daughter's DF occurred at relatively early ages, we believe that genetic factors might play a role in the tumorigenesis of DF in this family.


Assuntos
Ceratose/etiologia , Ceratose/patologia , Dedos do Pé , Adulto , Feminino , Fibrose , Humanos , Ceratose/cirurgia , Pessoa de Meia-Idade , Recidiva
19.
Oral Dis ; 25(7): 1707-1714, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31295753

RESUMO

OBJECTIVES: To identify molecular characteristics of keratosis of unknown significance and to nominate pathways of molecular progression to oral cancer. Our work could provide a rationale for monitoring and treating these lesions definitively. METHODS: Patients with oral leukoplakia were eligible for our prospective observational study. We correlated alterations in cancer-associated genes with clinical and histopathologic variables (keratosis of unknown significance vs. moderate-to-severe dysplasia) and compared these alterations to a previously molecularly characterized oral cancer population. RESULTS: Of 20 enrolled patients, 13 (65%) had evidence of keratosis of unknown significance, while seven (35%) had dysplasia. Nine patients (45%) developed oral cancer (4/13 with keratosis of unknown significance, 5/7 with dysplasia). At a median follow-up of 67 (range 22-144) months, median overall survival was significantly shorter for patients with dysplasia (hazard ratio 0.11, p = .02). KMT2C and TP53 alterations were most frequent (75% and 35%, respectively). There were molecular similarities between keratosis of unknown significance and dysplasia patients, with no significant differences in mutational frequency among genes with ≥15% rate of alteration. CONCLUSIONS: Among patients with leukoplakia, both patients with keratosis of unknown significance and patients with dysplasia developed oral cancer. Molecular alterations between these two groups were similar at this sample size.


Assuntos
Ceratose/epidemiologia , Leucoplasia Oral/etiologia , Neoplasias Bucais/genética , Lesões Pré-Cancerosas/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Genômica , Humanos , Ceratose/patologia , Leucoplasia Oral/epidemiologia , Leucoplasia Oral/genética , Leucoplasia Oral/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/epidemiologia , Lesões Pré-Cancerosas/patologia , Estudos Prospectivos
20.
Oral Dis ; 25(7): 1715-1723, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31295760

RESUMO

OBJECTIVE: The molecular mechanisms underlying the development of dysplasia in leukoplakia are unknown. We used RNA sequencing to examine the molecular and biological pathway differences in oral leukoplakia with and without oral epithelial dysplasia. MATERIALS AND METHODS: Excisional biopsy specimens (25) were taken from 24 patients with oral leukoplakia diagnosed histopathologically as either oral epithelial dysplasia (13) or epithelial hyperplasia and keratosis without dysplasia (12). Transcriptome analysis used RNA sequencing, differential expression and hierarchical clustering. Biological signalling was examined by gene ontology, pathway and protein-protein interaction analysis. RESULTS: Differential expression analysis showed distinction between the two groups identifying 47 genes as altered in leukoplakia with dysplasia, including SAA1, SAA2, KRT31, KRT37, KRT76, ROBO2, DNAJB5 and DNAJA4. Using hierarchical clustering, dysplastic leukoplakia readily segregated from leukoplakia without dysplasia. Pathway and ontology enrichment analysis provided evidence that downregulation of extracellular matrix (ECM) pathways was a feature of dysplastic lesions. CONCLUSION: Our results suggest that there are detectable changes in the molecular profile of oral leukoplakia exhibiting dysplasia including downregulated ECM as a distinguishing feature of dysplastic lesions. This suggests that reactive changes in stroma may be an early manifestation of dysplastic development. Our study also demonstrates the feasibility of detecting such molecular changes in oral leukoplakia, providing avenues for further investigation of molecular mechanisms of oral dysplasia.


Assuntos
Carcinoma in Situ/patologia , Hiperplasia/patologia , Ceratose/patologia , Leucoplasia Oral/patologia , Neoplasias Bucais/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma in Situ/genética , Feminino , Perfilação da Expressão Gênica , Humanos , Hiperplasia/genética , Ceratose/genética , Leucoplasia Oral/genética , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/genética , Análise de Sequência de RNA
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