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1.
J Immunol ; 211(8): 1216-1223, 2023 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-37672029

RESUMO

Bullous pemphigoid (BP) is the most common autoimmune bullous skin disease of humans and is characterized by eosinophilic inflammation and circulating and tissue-bound IgG and IgE autoantibodies directed against two hemidesmosomal proteins: BP180 and BP230. The noncollagenous 16A domain (NC16A) of BP180 has been found to contain major epitopes recognized by autoantibodies in BP. We recently established the pathogenicity of anti-NC16A IgE through passive transfer of patient-derived autoantibodies to double-humanized mice that express the human high-affinity IgE receptor, FcεRI, and human NC16A domain (FcεRI/NC16A). In this model, anti-NC16A IgEs recruit eosinophils to mediate tissue injury and clinical disease in FcεRI/NC16A mice. The objective of this study was to characterize the molecular and cellular events that underlie eosinophil recruitment and eosinophil-dependent tissue injury in anti-NC16A IgE-induced BP. We show that anti-NC16A IgEs significantly increase levels of key eosinophil chemoattractants, eotaxin-1 and eotaxin-2, as well as the proteolytic enzyme matrix metalloproteinase-9 (MMP-9) in the lesional skin of FcεRI/NC16A mice. Importantly, neutralization of eotaxin-1, but not eotaxin-2, and blockade of the main eotaxin receptor, CCR3, drastically reduce anti-NC16A IgE-induced disease activity. We further show that anti-NC16A IgE/NC16A immune complexes induce the release of MMP-9 from eosinophils, and that MMP-9-deficient mice are resistant to anti-NC16A IgE-induced BP. Lastly, we find significantly increased levels of eotaxin-1, eotaxin-2, and MMP-9 in blister fluids of BP patients. Taken together, this study establishes the eotaxin-1/CCR3 axis and MMP-9 as key players in anti-NC16A IgE-induced BP and candidate therapeutic targets for future drug development and testing.


Assuntos
Penfigoide Bolhoso , Humanos , Camundongos , Animais , Metaloproteinase 9 da Matriz , Quimiocina CCL24 , Imunoglobulina E , Quimiocina CCL11 , Receptores CCR3 , Colágenos não Fibrilares , Autoantígenos , Imunoglobulina G , Autoanticorpos , Receptores de IgE
2.
Med Care ; 61(12): 829-835, 2023 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-37708348

RESUMO

BACKGROUND: Previous studies of hospital-based patients with metastatic melanoma suggest sociodemographic factors, including insurance type, may be associated with the receipt of systemic treatments. OBJECTIVES: To examine whether insurance type is associated with the receipt of systemic treatment among patients with melanoma in a broad cohort of patients in North Carolina. METHODS: We conducted a retrospective cohort study between 2011 and 2017 of patients with stages III-IV melanoma using data from the North Carolina Central Cancer Registry linked to Medicare, Medicaid, and private health insurance claims across the state. The primary outcome was the receipt of any systemic treatment, and the secondary outcome was the receipt of immunotherapy. RESULTS: A total of 372 patients met the inclusion criteria. The average age was 68 years old (interquartile range: 56-76) and 61% were male. Within the cohort 48% had Medicare only, 29% had private insurance, 12% had both Medicare and Medicaid, and 11% had Medicaid only. A total of 186 (50%) patients received systemic treatment for melanoma, 125 (67%) of whom received immunotherapy. The use of systemic therapy, including immunotherapy, increased significantly over time. Having Medicaid-only insurance was independently associated with a 45% lower likelihood of receiving any systemic treatment [0.55 (95% CI: 0.35, 0.85)] and a 43% lower likelihood of receipt of immunotherapy [0.57 (95% CI: 0.34, 0.95)] compared with private insurance. CONCLUSIONS: Stage III-IV melanoma patients with Medicaid-only insurance were less likely to receive systemic therapy or immunotherapy than patients with private insurance or Medicare insurance. This finding raises concerns about insurance-based disparities in treatment access.


Assuntos
Medicare , Melanoma , Humanos , Masculino , Idoso , Estados Unidos , Feminino , North Carolina , Estudos Retrospectivos , Seguro Saúde , Medicaid , Melanoma/terapia , Melanoma Maligno Cutâneo
3.
J Immunol ; 205(10): 2786-2794, 2020 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-32998984

RESUMO

BP180 (also termed type XVII collagen) is a hemidesmosomal protein and plays a critical role in cell-cell matrix adhesion in the skin; however, its other biological functions are largely unclear. In this study, we generated a BP180 functional-deficient mouse strain by deleting its extracellular domain of humanized NC16A (termed ΔNC16A mice). We found that BP180 is expressed by bone marrow mesenchymal stem cells (BM-MSC), and its functional deficiency leads to myeloid hyperplasia. Altered granulopoiesis in ΔNC16A mice is through bone marrow stromal cells evidenced by bone marrow transplantation. Furthermore, the level of G-CSF in bone marrow and circulation were significantly increased in ΔNC16A mice as compared with wild-type mice. The increased G-CSF was accompanied by an increased activation of the NF-κB signaling pathway in bone marrow and BM-MSC of ΔNC16A mice. Blockade of G-CSF restored normal granulopoiesis in ΔNC16A mice. Inhibition of NF-κB signaling pathway significantly reduces the release of G-CSF from ΔNC16A BM-MSC in vitro and the level of serum G-CSF in ΔNC16A mice. To our knowledge, these findings provide the first direct evidence that BP180 plays an important role in granulopoiesis through regulating NF-κB signaling pathway in BM-MSC.


Assuntos
Autoantígenos/metabolismo , Medula Óssea/patologia , Leucopoese/imunologia , Células-Tronco Mesenquimais/metabolismo , Neutrófilos/fisiologia , Colágenos não Fibrilares/metabolismo , Animais , Autoantígenos/genética , Medula Óssea/efeitos dos fármacos , Medula Óssea/metabolismo , Diferenciação Celular/imunologia , Modelos Animais de Doenças , Fator Estimulador de Colônias de Granulócitos/antagonistas & inibidores , Fator Estimulador de Colônias de Granulócitos/sangue , Fator Estimulador de Colônias de Granulócitos/metabolismo , Humanos , Hiperplasia/genética , Hiperplasia/imunologia , Camundongos , Camundongos Transgênicos , NF-kappa B/metabolismo , Colágenos não Fibrilares/genética , Domínios Proteicos/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Colágeno Tipo XVII
4.
Hum Mutat ; 41(10): 1751-1760, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32643855

RESUMO

We hypothesized that human genes differ by their sensitivity to ultraviolet (UV) exposure. We used somatic mutations detected by genome-wide screens in melanoma and reported in the Catalog Of Somatic Mutations In Cancer. As a measure of UV sensitivity, we used the number of silent mutations generated by C>T transitions in pyrimidine dimers of a given transcript divided by the number of potential sites for this type of mutations in the transcript. We found that human genes varied by UV sensitivity by two orders of magnitude. We noted that the melanoma-associated tumor suppressor gene CDKN2A was among the top five most UV-sensitive genes in the human genome. Melanoma driver genes have a higher UV-sensitivity compared with other genes in the human genome. The difference was more prominent for tumor suppressors compared with oncogene. The results of this study suggest that differential sensitivity of human transcripts to UV light may explain melanoma specificity of some driver genes. Practical significance of the study relates to the fact that differences in UV sensitivity among human genes need to be taken into consideration whereas predicting melanoma-associated genes by the number of somatic mutations detected in a given gene.


Assuntos
Melanoma , Neoplasias Cutâneas , Genoma Humano , Humanos , Melanoma/genética , Mutação , Oncogenes , Mutação Silenciosa , Neoplasias Cutâneas/genética , Raios Ultravioleta
5.
Am J Dermatopathol ; 41(4): 264-272, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30211730

RESUMO

Telomerase reverse transcriptase (TERT) promoter mutations are commonly found in malignant melanomas but rare in melanocytic nevi. To assess its potential diagnostic utility for the distinction of melanoma from nevus, we determined the TERT promoter mutation status of 86 primary melanomas, 72 melanocytic nevi, and 40 diagnostically problematic melanocytic proliferations. Of the 86 melanomas, 67 (77.9%) were TERT-positive, defined as harboring a hotspot TERT promoter mutation at positions -124C>T, -124_125CC>TT, -138_139CC>TT, or -146C>T. Of the 72 nevi, only 1 (1.4%) was TERT-positive. Of the 40 diagnostically uncertain melanocytic proliferations, 2 (5.0%) were TERT-positive. TERT positivity as a test for melanoma versus nevus had an accuracy of 87.3% [95% confidence interval (CI), 81.1-92.1], a sensitivity of 77.9% (95% CI, 68.9-85.4), a specificity of 98.6% (95% CI, 95.8-100), a positive predictive value of 98.5% (95% CI, 95.6-100), and a negative predictive value of 78.9% (95% CI, 72.6-85.4). Our results indicate that hotspot TERT promoter mutation status may be a useful ancillary parameter for the diagnosis of melanoma. In particular, the high specificity of these mutations for melanoma indicates the presence of a TERT promoter mutation in a melanocytic neoplasm associated with diagnostic controversy, or uncertainty should increase concern for a melanoma.


Assuntos
Melanoma/diagnóstico , Melanoma/genética , Regiões Promotoras Genéticas/genética , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/genética , Telomerase/genética , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Nevo Pigmentado/diagnóstico , Nevo Pigmentado/genética , Melanoma Maligno Cutâneo
6.
Carcinogenesis ; 37(1): 30-8, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26521212

RESUMO

Factors known to affect melanoma survival include age at presentation, sex and tumor characteristics. Polymorphisms also appear to modulate survival following diagnosis. Result from other studies suggest that vitamin D receptor (VDR) polymorphisms (SNPs) impact survival in patients with glioma, renal cell carcinoma, lung, breast, prostate and other cancers; however, a comprehensive study of VDR polymorphisms and melanoma-specific survival is lacking. We aimed to investigate whether VDR genetic variation influences survival in patients with cutaneous melanoma. The analysis involved 3566 incident single and multiple primary melanoma cases enrolled in the international population-based Genes, Environment, and Melanoma Study. Melanoma-specific survival outcomes were calculated for each of 38 VDR SNPs using a competing risk analysis after adjustment for covariates. There were 254 (7.1%) deaths due to melanoma during the median 7.6 years follow-up period. VDR SNPs rs7299460, rs3782905, rs2239182, rs12370156, rs2238140, rs7305032, rs1544410 (BsmI) and rs731236 (TaqI) each had a statistically significant (trend P values < 0.05) association with melanoma-specific survival in multivariate analysis. One functional SNP (rs2239182) remained significant after adjustment for multiple testing using the Monte Carlo method. None of the SNPs associated with survival were significantly associated with Breslow thickness, ulceration or mitosis. These results suggest that the VDR gene may influence survival from melanoma, although the mechanism by which VDR exerts its effect does not seem driven by tumor aggressiveness. Further investigations are needed to confirm our results and to understand the relationship between VDR and survival in the combined context of tumor and host characteristics.


Assuntos
Melanoma/genética , Receptores de Calcitriol/genética , Neoplasias Cutâneas/genética , Austrália/epidemiologia , Canadá/epidemiologia , Feminino , Genótipo , Haplótipos , Humanos , Itália/epidemiologia , Masculino , Melanoma/mortalidade , Polimorfismo de Nucleotídeo Único , Modelos de Riscos Proporcionais , Neoplasias Cutâneas/mortalidade , Estados Unidos/epidemiologia
7.
Int J Cancer ; 139(6): 1217-22, 2016 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-27101944

RESUMO

Although nevus count is an established risk factor for melanoma, relationships between nevus number and patient and tumor characteristics have not been well studied and the influence of nevus count on melanoma-specific survival is equivocal. Using data from the Genes, Environment and Melanoma (GEM) study, a large population-based study of primary cutaneous melanoma, we evaluated associations between number of nevi and patient features, including sun-sensitivity summarized in a phenotypic index, and tumor characteristics. We also assessed the association of nevus count with melanoma-specific survival. Higher nevus counts were independently and positively associated with male gender and younger age at diagnosis, and they were inversely associated with lentigo maligna histology. We observed a borderline significant trend of poorer melanoma-specific survival with increasing quartile of nevus count, but little or no association between number of nevi and pigmentary phenotypic characteristics or prognostic tumor features.


Assuntos
Melanoma/mortalidade , Melanoma/patologia , Nevo Pigmentado/patologia , Fenótipo , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Melanoma/epidemiologia , Pessoa de Meia-Idade , Razão de Chances , Vigilância da População , Prognóstico , Modelos de Riscos Proporcionais , Fatores de Risco , Neoplasias Cutâneas , Melanoma Maligno Cutâneo
8.
Cancer Treat Res ; 167: 17-49, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26601858

RESUMO

The epidemiology of melanoma is complex, and individual risk depends on sun exposure, host factors, and genetic factors, and in their interactions as well. Sun exposure can be classified as intermittent, chronic, or cumulative (overall) exposure, and each appears to have a different effect on type of melanoma. Other environmental factors, such as chemical exposures-either through occupation, atmosphere, or food-may increase risk for melanoma, and this area warrants further study. Host factors that are well known to be important are the numbers and types of nevi and the skin phenotype. Genetic factors are classified as high-penetrant genes, moderate-risk genes, or low-risk genetic polymorphisms. Subtypes of tumors, such as BRAF-mutated tumors, have different risk factors as well as different therapies. Prevention of melanoma has been attempted using various strategies in specific subpopulations, but to date optimal interventions to reduce incidence have not emerged.


Assuntos
Melanoma/etiologia , Melanoma/prevenção & controle , Interação Gene-Ambiente , Humanos , Melanoma/epidemiologia , Melanoma/genética , Mutação , Exposição Ocupacional/efeitos adversos , Fatores de Risco , Luz Solar/efeitos adversos
10.
J Health Commun ; 21(5): 564-74, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-27115046

RESUMO

Tanning bed use before age 35 has been strongly associated with several types of skin cancer. The current study sought to advance an understanding of audience segmentation for indoor tanning among young women. Panhellenic sorority systems at two universities in the Southeastern United States participated in this study. A total of 1,481 young women took the survey; 421 (28%) had tanned indoors in the previous 12 months and were the focus of the analyses reported in this article. Results suggested two distinct tanner types: regular (n = 60) and irregular (n = 353) tanners. Regular tanners tanned more frequently (M = 36.2 vs. 8.6 times per year) and reported significantly higher positive outcome expectations (p < .001) and lower negative outcome expectations (p < .01) than irregular tanners, among other significant differences. Hierarchical logistic regression analysis revealed several significant (p < .001) predictors of regular tanning type, with tanning dependence emerging as the strongest predictor of this classification (OR = 2.25). Implications for developing anti-tanning messages directed at regular and irregular tanners are discussed.


Assuntos
Banho de Sol/psicologia , Banho de Sol/estatística & dados numéricos , Adolescente , Pesquisa Empírica , Feminino , Promoção da Saúde , Humanos , Neoplasias Cutâneas/epidemiologia , Neoplasias Cutâneas/prevenção & controle , Sudeste dos Estados Unidos/epidemiologia , Inquéritos e Questionários , Universidades , Adulto Jovem
11.
Int J Cancer ; 136(11): 2659-67, 2015 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-25382380

RESUMO

Melanocortin-1 receptor (MC1R) is a marker of melanoma risk in populations of European ancestry. However, MC1R effects on survival are much less studied. We investigated associations between variation at MC1R and survival in an international, population-based series of single primary melanoma patients enrolled into the Genes, Environment, and Melanoma study. MC1R genotype data was available for 2,200 participants with a first incident primary melanoma diagnosis. We estimated the association of MC1R genotypes with melanoma-specific survival (i.e., death caused by melanoma) and overall survival using COX proportional hazards modeling, adjusting for established prognostic factors for melanoma. We also conducted stratified analyses by Breslow thickness, tumor site, phenotypic index, and age. In addition, we evaluated haplotypes involving polymorphisms near the Agouti signaling protein gene (ASIP) locus for their impacts on survival. Melanoma-specific survival was inversely associated with carriage of MC1R variants in the absence of consensus alleles compared to carriage of at least one consensus allele (hazard ratio (HR) = 0.60; 95% confidence interval (CI): 0.40, 0.90). MC1R results for overall survival were consistent with no association. We did not observe any statistical evidence of heterogeneity of effect estimates in stratified analyses. We observed increased hazard of melanoma-specific death among carriers of the risk haplotype TG near the ASIP locus (HR = 1.37; 95% CI: 0.91, 2.04) when compared to carriers of the most common GG haplotype. Similar results were noted for overall survival. Upon examining the ASIP TG/TG diplotype, we observed considerably increased hazard of melanoma-specific death (HR = 5.11; 95% CI: 1.88, 13.88) compared to carriers of the most common GG/GG diplotype. Our data suggest improved melanoma-specific survival among carriers of two inherited MC1R variants.


Assuntos
Proteína Agouti Sinalizadora/genética , Melanoma/genética , Melanoma/mortalidade , Receptor Tipo 1 de Melanocortina/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Estudos de Associação Genética , Variação Genética , Genótipo , Hereditariedade , Humanos , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Modelos de Riscos Proporcionais , Adulto Jovem
12.
PLoS Genet ; 8(10): e1002927, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23055936

RESUMO

Holoprosencephaly (HPE) is a failure of the forebrain to bifurcate and is the most common structural malformation of the embryonic brain. Mutations in SHH underlie most familial (17%) cases of HPE; and, consistent with this, Shh is expressed in midline embryonic cells and tissues and their derivatives that are affected in HPE. It has long been recognized that a graded series of facial anomalies occurs within the clinical spectrum of HPE, as HPE is often found in patients together with other malformations such as acrania, anencephaly, and agnathia. However, it is not known if these phenotypes arise through a common etiology and pathogenesis. Here we demonstrate for the first time using mouse models that Hedgehog acyltransferase (Hhat) loss-of-function leads to holoprosencephaly together with acrania and agnathia, which mimics the severe condition observed in humans. Hhat is required for post-translational palmitoylation of Hedgehog (Hh) proteins; and, in the absence of Hhat, Hh secretion from producing cells is diminished. We show through downregulation of the Hh receptor Ptch1 that loss of Hhat perturbs long-range Hh signaling, which in turn disrupts Fgf, Bmp and Erk signaling. Collectively, this leads to abnormal patterning and extensive apoptosis within the craniofacial primordial, together with defects in cartilage and bone differentiation. Therefore our work shows that Hhat loss-of-function underscrores HPE; but more importantly it provides a mechanism for the co-occurrence of acrania, holoprosencephaly, and agnathia. Future genetic studies should include HHAT as a potential candidate in the etiology and pathogenesis of HPE and its associated disorders.


Assuntos
Aciltransferases/genética , Proteínas Hedgehog/metabolismo , Holoprosencefalia/genética , Holoprosencefalia/metabolismo , Anormalidades Maxilomandibulares/genética , Anormalidades Maxilomandibulares/metabolismo , Mutação , Defeitos do Tubo Neural/genética , Defeitos do Tubo Neural/metabolismo , Transdução de Sinais , Aciltransferases/metabolismo , Animais , Apoptose/genética , Expressão Gênica , Holoprosencefalia/embriologia , Anormalidades Maxilomandibulares/embriologia , Camundongos , Camundongos Transgênicos , Crista Neural/embriologia , Crista Neural/metabolismo , Defeitos do Tubo Neural/embriologia , Receptores Patched , Receptor Patched-1 , Fenótipo , Receptores de Superfície Celular/metabolismo
13.
Health Commun ; 30(2): 164-74, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25470441

RESUMO

The lack of a theory-based understanding of indoor tanning is a major impediment to the development of effective messages to prevent or reduce this behavior. This study applied the Comprehensive Indoor Tanning Expectations (CITE) scale in an analysis of indoor tanning behavior among sorority women (total N = 775). Confirmatory factor analyses indicated that CITE positive and negative expectations were robust, multidimensional factors and that a hierarchical structure fit the data well. Social cognitive theory-based structural equation models demonstrated that appearance-oriented variables were significantly associated with outcome expectations. Outcome expectations were, in turn, significantly associated with temptations to tan, intention to tan indoors, and indoor tanning behavior. The implications of these findings for the development of messages to prevent and reduce indoor tanning behavior are discussed in two domains: (a) messages that attempt to change broader societal perceptions about tan skin, and (b) messages that focus more narrowly on indoor tanning-challenging positive expectations, enhancing negative expectations, and encouraging substitution of sunless tanning products.


Assuntos
Comunicação em Saúde , Modelos Psicológicos , Neoplasias Cutâneas/prevenção & controle , Banho de Sol/psicologia , Cognição , Análise Fatorial , Feminino , Humanos , Intenção , Teoria Psicológica , Reprodutibilidade dos Testes , Pesquisa , Teoria Social , Inquéritos e Questionários , Adulto Jovem
14.
J Cutan Pathol ; 41(9): 724-32, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24917033

RESUMO

BACKGROUND: BRAF mutation status, and therefore eligibility for BRAF inhibitors, is currently determined by sequencing methods. We assessed the validity of VE1, a monoclonal antibody against the BRAF V600E mutant protein, in the detection of mutant BRAF V600E melanomas as classified by DNA pyrosequencing. METHODS: The cases were 76 metastatic melanoma patients with only one known primary melanoma who had had BRAF codon 600 pyrosequencing of either their primary (n = 19), metastatic (n = 57) melanoma, or both (n = 17). All melanomas (n = 93) were immunostained with the BRAF VE1 antibody using a red detection system. The staining intensity of these specimens was scored from 0 to 3+ by a dermatopathologist. Scores of 0 and 1+ were considered as negative staining while scores of 2+ and 3+ were considered positive. RESULTS: The VE1 antibody showed a sensitivity of 85% and a specificity of 100% as compared to DNA pyrosequencing results. There was 100% concordance between VE1 immunostaining of primary and metastatic melanomas from the same patient. V600K, V600Q, and V600R BRAF melanomas did not positively stain with VE1. CONCLUSIONS: This hospital-based study finds high sensitivity and specificity for the BRAF VE1 immunostain in comparison to pyrosequencing in detection of BRAF V600E in melanomas.


Assuntos
Anticorpos Monoclonais , Imuno-Histoquímica , Melanoma/diagnóstico , Proteínas Proto-Oncogênicas B-raf/metabolismo , Neoplasias Cutâneas/diagnóstico , Biomarcadores Tumorais/metabolismo , Humanos , Melanoma/genética , Melanoma/metabolismo , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Sensibilidade e Especificidade , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismo
15.
Adv Exp Med Biol ; 810: 342-58, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25207375

RESUMO

Solar UV radiation (UVR) exposure is clearly associated with increased mortality from nonmelanoma skin cancer--usually squamous cell carcinoma. However, the association with cutaneous melanoma is unclear from the evidence in ecologic studies and several analytic studies have conflicting results regarding the effect of high levels of intermittent UV exposure prior to diagnosis on mortality. Understanding this conundrum is critical to present coherent public health messages and to improve the mortality rates from melanoma.


Assuntos
Carcinoma de Células Escamosas/mortalidade , Melanoma/mortalidade , Neoplasias Induzidas por Radiação/mortalidade , Neoplasias Cutâneas/mortalidade , Pele/efeitos da radiação , Vitamina D/metabolismo , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Relação Dose-Resposta à Radiação , Estudos Epidemiológicos , Humanos , Melanoma/metabolismo , Melanoma/patologia , Neoplasias Induzidas por Radiação/metabolismo , Neoplasias Induzidas por Radiação/patologia , Especificidade de Órgãos , Pele/metabolismo , Pele/patologia , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Análise de Sobrevida , Raios Ultravioleta/efeitos adversos
16.
Appl Biochem Biotechnol ; 196(2): 923-948, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37273094

RESUMO

Polyunsaturated Fatty Acids (PUFAs) are important nutrients for human health. We aimed to evaluate the efficiency of marine water fungus Aspergillus sp. (Accession no: MZ505709) for lipid biosynthesis. The Yeast Extract Glucose (YEG) medium was supplemented with different concentration of Borassus flabellifer Endocarps Hydrolysate (BFEH; 1-5%) to evaluate the fungal biomass and its lipid accumulation. The combination of glucose and BFEH as carbon source increased the fresh weight (25.43 ± 0.33 g/L), dry weight (21.39 ± 0.77 g/L) and lipid yield (3.14 ± 0.09 g/L) of fungal biomass. The lipid content of dried fungal biomass has shown 91.08 ± 5.07 mg cod liver oil equivalents/g and 125.98 ± 5.96 mg groundnut oil equivalents/g biomass. GC-MS and NMR spectrometry analysis revealed the compounds involved in fatty acid metabolism and lipid signaling pathways along with the presence of linolenic acid. Interestingly, fungus grown in BFEH enriched medium has recorded the maximum amount of lipids with major fatty acid derivatives. Increase in the growth rate of Artemia franciscana was observed, when the extracted fungal lipid was supplemented as a food supplement. Therefore, this study suggests that marine fungal lipid may serve as potential natural compound as nutraceuticals and aquafeeds.


Assuntos
Ácidos Graxos Insaturados , Ácidos Graxos , Humanos , Ácidos Graxos/metabolismo , Biomassa , Aspergillus/metabolismo , Glucose/metabolismo
17.
ArXiv ; 2024 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-38800658

RESUMO

Automated region of interest detection in histopathological image analysis is a challenging and important topic with tremendous potential impact on clinical practice. The deep-learning methods used in computational pathology may help us to reduce costs and increase the speed and accuracy of cancer diagnosis. We started with the UNC Melanocytic Tumor Dataset cohort that contains 160 hematoxylin and eosin whole-slide images of primary melanomas (86) and nevi (74). We randomly assigned 80% (134) as a training set and built an in-house deep-learning method to allow for classification, at the slide level, of nevi and melanomas. The proposed method performed well on the other 20% (26) test dataset; the accuracy of the slide classification task was 92.3% and our model also performed well in terms of predicting the region of interest annotated by the pathologists, showing excellent performance of our model on melanocytic skin tumors. Even though we tested the experiments on the skin tumor dataset, our work could also be extended to other medical image detection problems to benefit the clinical evaluation and diagnosis of different tumors.

18.
J Invest Dermatol ; 144(1): 24-32.e1, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37437774

RESUMO

Linear IgA bullous dermatosis (LABD) is an acquired autoimmune subepidermal blistering skin disease characterized by circulating and tissue-bound IgA autoantibodies that recognize epitopes within the hemidesmosomal protein BP180, including its NC16A domain. Histologically, LABD has long been defined by neutrophil infiltration and dermal-epidermal separation. However, the pathogenic roles of anti-NC16A IgA and neutrophils in LABD, as well as their interactions, have not been thoroughly studied. We show that passive transfer of patient-derived anti-NC16A IgA induce clinical and histologic LABD pathology in humanized NC16A mice that are reconstituted locally or systemically with human neutrophils. The lesional skin of mice exhibits significantly elevated levels of the neutrophil chemoattractants CXCL-1 and CXCL-2. Furthermore, we show significantly increased levels of the neutrophil chemoattractant IL-8 in blister fluids of patients with LABD. This study provides direct evidence that anti-NC16A IgA in patients with LABD are pathogenic and interact with neutrophils to mediate tissue injury and subepidermal blister formation. This study further corroborates the importance of neutrophil-mediated tissue injury in LABD disease physiology and establishes a clinically relevant in vivo model system that can be used to systematically dissect the immunopathogenesis of LABD.


Assuntos
Doenças Autoimunes , Dermatose Linear Bolhosa por IgA , Humanos , Animais , Camundongos , Dermatose Linear Bolhosa por IgA/patologia , Neutrófilos/patologia , Vesícula , Autoanticorpos , Imunoglobulina A
19.
Plant Physiol Biochem ; 211: 108644, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38710114

RESUMO

In this study, we have investigated the effect of carbon quantum dots (FM-CQDs) synthesized from marine fungal extract on Curcuma longa to improve the plant growth and curcumin production. The isolated fungus, Aspergillus flavus has produced a high amount of indole-3-acetic acid (IAA) (0.025 mg g-1), when treated with tryptophan. CQDs were synthesized from the A. flavus extract and it was characterized using ultraviolet visible spectrophotometer (UV-Vis) and high-resolution transmission electron microscopy (HR-TEM). The synthesized CQDs were excited at 365 nm in an UV-Vis and the HR-TEM analysis showed approximately 7.4 nm in size with a spherical shape. Both fungal crude extract (FCE) at 0-100 mg L-1 and FM-CQDs 0-5 mg L-1 concentrations were tested on C. longa. About 80 mg L-1 concentration FCE treated plants has shown a maximum height of 21 cm and FM-CQDs at 4 mg L-1 exhibited a maximum height of 25 cm compared to control. The FM-CQDs significantly increased the photosynthetic pigments such as total chlorophyll (1.08 mg g-1 FW) and carotenoids (17.32 mg g-1 FW) in C. longa. Further, antioxidant enzyme analysis confirmed that the optimum concentrations of both extracts did not have any toxic effects on the plants. FM-CQDs treated plants increased the curcumin content up to 0.060 mg g-1 by HPLC analysis. Semi quantitative analysis revealed that FCE and FM-CQDs significantly upregulated ClCURS1 gene expression in curcumin production.


Assuntos
Aspergillus flavus , Carbono , Curcuma , Curcumina , Pontos Quânticos , Pontos Quânticos/química , Curcuma/metabolismo , Curcuma/microbiologia , Carbono/metabolismo , Carbono/farmacologia , Curcumina/metabolismo , Curcumina/farmacologia , Aspergillus flavus/metabolismo , Aspergillus flavus/crescimento & desenvolvimento , Ácidos Indolacéticos/metabolismo , Endófitos/metabolismo
20.
Int J Radiat Oncol Biol Phys ; 117(3): 738-749, 2023 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-37451472

RESUMO

PURPOSE: The manual segmentation of organ structures in radiation oncology treatment planning is a time-consuming and highly skilled task, particularly when treating rare tumors like sacral chordomas. This study evaluates the performance of automated deep learning (DL) models in accurately segmenting the gross tumor volume (GTV) and surrounding muscle structures of sacral chordomas. METHODS AND MATERIALS: An expert radiation oncologist contoured 5 muscle structures (gluteus maximus, gluteus medius, gluteus minimus, paraspinal, piriformis) and sacral chordoma GTV on computed tomography images from 48 patients. We trained 6 DL auto-segmentation models based on 3-dimensional U-Net and residual 3-dimensional U-Net architectures. We then implemented an average and an optimally weighted average ensemble to improve prediction performance. We evaluated algorithms with the average and standard deviation of the volumetric Dice similarity coefficient, surface Dice similarity coefficient with 2- and 3-mm thresholds, and average symmetric surface distance. One independent expert radiation oncologist assessed the clinical viability of the DL contours and determined the necessary amount of editing before they could be used in clinical practice. RESULTS: Quantitatively, the ensembles performed the best across all structures. The optimal ensemble (volumetric Dice similarity coefficient, average symmetric surface distance) was (85.5 ± 6.4, 2.6 ± 0.8; GTV), (94.4 ± 1.5, 1.0 ± 0.4; gluteus maximus), (92.6 ± 0.9, 0.9 ± 0.1; gluteus medius), (85.0 ± 2.7, 1.1 ± 0.3; gluteus minimus), (92.1 ± 1.5, 0.8 ± 0.2; paraspinal), and (78.3 ± 5.7, 1.5 ± 0.6; piriformis). The qualitative evaluation suggested that the best model could reduce the total muscle and tumor delineation time to a 19-minute average. CONCLUSIONS: Our methodology produces expert-level muscle and sacral chordoma tumor segmentation using DL and ensemble modeling. It can substantially augment the streamlining and accuracy of treatment planning and represents a critical step toward automated delineation of the clinical target volume in sarcoma and other disease sites.


Assuntos
Cordoma , Aprendizado Profundo , Humanos , Cordoma/diagnóstico por imagem , Cordoma/radioterapia , Tomografia Computadorizada por Raios X/métodos , Algoritmos , Músculos , Processamento de Imagem Assistida por Computador/métodos
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