RESUMO
Langerhans cell histiocytosis (LCH) is characterized by an expansion and accumulation of pathological histiocytes expressing langerin (CD207) and CD1a in different organs under an inflammatory milieu. The origin of pathognomonic precursors of LCH is widely debated, but monocytes and pre-dendritic cells (pre-DC) play a significant role. Remarkably, we found an expansion of AXLhigh cells in the CD11c+ subset of patients with active LCH, which also express the pathognomonic CD207 and CD1a. Moreover, we obtained a monocyte-derived LC-like (mo-LC-like) expressing high levels of AXL when treated with inflammatory cytokine, or plasma of patients with active disease. Intriguingly, inhibiting the mTOR pathway at the initial stages of monocyte differentiation to LC-like fosters the pathognomonic LCH program, highly increasing CD207 levels, together with NOTCH1 induction. We define here that AXLhigh could also be taken as a strong pathognomonic marker for LCH, and the release of Langerin and NOTCH1 expression depends on the inhibition of the mTOR pathway.
Assuntos
Antígenos CD , Receptor Tirosina Quinase Axl , Histiocitose de Células de Langerhans , Lectinas Tipo C , Lectinas de Ligação a Manose , Proteínas Proto-Oncogênicas , Receptores Proteína Tirosina Quinases , Serina-Treonina Quinases TOR , Feminino , Humanos , Masculino , Antígenos CD/metabolismo , Antígenos CD1/metabolismo , Biomarcadores , Diferenciação Celular , Histiocitose de Células de Langerhans/metabolismo , Lectinas Tipo C/metabolismo , Lectinas de Ligação a Manose/metabolismo , Monócitos/metabolismo , Monócitos/imunologia , Células Mieloides/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas/genética , Receptores Proteína Tirosina Quinases/metabolismo , Receptor Notch1/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismoRESUMO
Objetivo: Determinar parámetros aberrométricos de la córnea para la detección del queratocono subclínico. Métodos: Se realizó un estudio observacional, analítico de corte transversal que incluyó 36 pacientes con queratocono subclínico (grupo de estudio) y 36 estudiantes con córneas aparentemente sanas (grupo control), que asistieron a la consulta de córnea del Instituto Cubano de Oftalmología Ramón Pando Ferrer, entre mayo de 2018 y junio de 2022. Se analizaron topografía y aberrometría corneal con el tomógrafo corneal Pentacam AXL. Resultados: El grupo queratocono subclínico mostró valores similares para la queratometría, asfericidad corneal, paquimetría y el valor total de desviación en comparación con el grupo normal. Hubo diferencias estadísticamente significativas en los parámetros aberrométricos, como el coma a 90º (Z3 -1), y la raíz cuadrada media de las aberraciones de alto orden, de cara anterior, posterior y total corneal, en queratocono subclínico en comparación con el grupo normal. El coma posterior a 90º presentó un área bajo la curva (0,894) mayor dentro de las aberrometrías, con un punto de corte de -0,013 µm, con sensibilidad del 86,1 por ciento y especificidad del 88,9 por ciento. Conclusiones: El coma posterior a 90º (parámetro aberrométrico) presenta una alta sensibilidad y especificidad para el diagnóstico de queratocono subclínico, mediante el análisis tomográfico Pentacam AXL(AU)
Objective: To determine corneal aberrometric parameters for the detection of subclinical keratoconus. Methods: An observational, analytical, cross-sectional study was performed including 36 patients with subclinical keratoconus (study group) and 36 students with apparently healthy corneas (control group), who attended the cornea consultation at the Cuban Institute of Ophthalmology Ramón Pando Ferrer, between May 2018 and June 2022. Corneal topography and aberrometry were analyzed with the Pentacam AXL corneal tomographer. Results: The subclinical keratoconus group showed similar values for keratometry, corneal asphericity, pachymetry and total deviation value compared to the normal group. There were statistically significant differences in aberrometric parameters, such as coma at 90° (Z3-1), and root mean square of high-order anterior, posterior and total corneal aberrations in subclinical keratoconus compared to the normal group. The 90° posterior coma presented a higher area under the curve (0.894) within the aberrometries, with a cutoff point of -0.013 µm, with sensitivity of 86.1 percent and specificity of 88.9 percent. Conclusions: Coma posterior to 90º (aberrometric parameter) presents high sensitivity and specificity for the diagnosis of subclinical keratoconus, using Pentacam AXL tomographic analysis(AU)
Assuntos
Humanos , Feminino , Córnea/anormalidades , Aberrometria/métodos , Ceratocone/etiologia , Estudos Observacionais como AssuntoRESUMO
INTRODUCTION: Zika virus (ZIKV) is a human teratogen that causes congenital Zika syndrome (CZS). AXL, TLR3, and STAT2 are proteins involved in the ZIKV's entry into cells (AXL) and host's immune response (TLR3 and STAT2). In this study, we evaluated the role of genetic polymorphisms in these three genes as risk factors to CZS, and highlighted which proteins that interact with them could be important for ZIKV infection and teratogenesis. MATERIALS AND METHODS: We evaluate eighty-eight children exposed to ZIKV during the pregnancy, 40 with CZS and 48 without congenital anomalies. The evaluated polymorphisms in AXL (rs1051008), TLR3 (rs3775291), and STAT2 (rs2066811) were genotyped using TaqMan® Genotyping Assays. A protein-protein interaction network was created in STRING database and analyzed in Cytoscape software. RESULTS: We did not find any statistical significant association among the polymorphisms and the occurrence of CZS. Through the analyses of the network composed by AXL, TLR3, STAT2 and their interactions targets, we found that EGFR and SRC could be important proteins for the ZIKV infection and its teratogenesis. CONCLUSION: In summary, our results demonstrated that the evaluated polymorphisms do not seem to represent risk factors for CZS; however, EGFR and SRC appear to be important proteins that should be investigated in future studies.
Assuntos
Teratogênese , Infecção por Zika virus , Zika virus , Gravidez , Criança , Feminino , Humanos , Infecção por Zika virus/genética , Zika virus/fisiologia , Receptor Tirosina Quinase Axl , Receptor 3 Toll-Like/genética , Receptor 3 Toll-Like/metabolismo , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas/genética , Mapas de Interação de Proteínas/genética , Receptores ErbB/metabolismo , Fator de Transcrição STAT2/genética , Fator de Transcrição STAT2/metabolismoRESUMO
Objetivo: Comparar las mediciones biométricas realizadas con el IOL Master 700 y el Pentacam AXL en pacientes miopes con cirugía fotoablativa previa. Métodos: Se realizó un estudio transversal en 103 ojos de 103 pacientes miopes con cirugía fotoablativa previa, atendidos en el período de enero 2019 a enero 2020, en el Instituto Cubano de Oftalmología "Ramón Pando Ferrer". Las variables estudiadas fueron: edad, sexo, equivalente esférico y características biométricas posoperatorias (longitud axial, profundidad de la cámara anterior y queratometrías), así como su relación, aportadas automáticamente por el IOL master 700 y el pentacam AXL para evitar los factores dependientes del operador, tres meses después de la cirugía. El análisis estadístico se realizó con la prueba t para datos pareados, utilizando una significación del 95 por ciento. Resultados: La edad promedio fue de 25,72 ± 4,26 años. Se analizaron 53 ojos derechos y 50 izquierdos, todos tratados con láser de superficie. El equivalente esférico medio fue de -0,06 ± 0,34 dioptrías y el tiempo entre la cirugía y los exámenes fue de 6,32 ± 3,56 meses. No hubo diferencia estadísticamente significativa (p > 0,05) entre la longitud axial y la profundidad de la cámara anterior; mientras que sí la hubo (p < 0,01) con las queratometrías obtenidas con el IOL Master 700, en comparación con los del pentacam AXL. Conclusión: En pacientes miopes con cirugía fotoablativa previa, el IOL Master 700 y el pentacam AXL proveen mediciones biométricas similares, como la longitud axial y la profundidad de la cámara anterior, no así con la queratometría, la cual es diferente(AU)
Objective: Compare the biometric measurements taken with IOL Master 700 and Pentacam AXL in myopic patients with previous photoablative surgery. Methods: A cross-sectional study was conducted of 103 eyes of 103 myopic patients undergoing photoablative surgery at Ramón Pando Ferrer Cuban Institute of Ophthalmology from January 2019 to January 2020. The variables analyzed were age, sex, spherical equivalent and preoperative biometric characteristics (axial length, anterior chamber depth and keratometries) and the relationship to one another, automatically supplied by IOL Master 700 and Pentacam AXL to avoid operator-dependent factors. The analysis was performed three months after surgery. Statistical analysis was based on the paired Student's t-test with a significance level of 95 percent. Results: Mean age was 25.72 ± 4.26 years. Fifty-three right eyes and 50 left eyes were studied, all of them treated with surface laser. Mean spherical equivalent was -0.06 ± 0.34 diopters; the time elapsed between surgery and the tests was 6.32 ± 3.56 months. No statistically significant differences (p > 0.05) were found between axial length and anterior chamber depth, but statistically significant differences (p < 0.01) were observed between the keratometries obtained with IOL Master 700 and Pentacam AXL. Conclusion: IOL Master 700 and Pentacam AXL provide similar biometric measurements for axial length and anterior chamber depth in myopic patients with previous photoablative surgery, but keratometric measurements are different(AU)
Assuntos
Humanos , Adulto , Interpretação Estatística de Dados , Paquimetria Corneana/métodos , Lasers , Miopia/etiologia , Estudos TransversaisRESUMO
Objetivo: Comparar las mediciones biométricas realizadas con el IOL Master 500 y el Pentacam AXL. Métodos: Se realizó un estudio transversal en 99 ojos de 99 pacientes miopes con criterio de cirugía fotoablativa, atendidos en el período de enero del año 2019 a enero de 2020, en el Servicio de Cirugía Refractiva del Instituto Cubano de Oftalmología "Ramón Pando Ferrer". Las variables estudiadas fueron edad, sexo, equivalente esférico y características biométricas preoperatorias (longitud axial, profundidad de la cámara anterior y queratometrías), así como su relación, aportadas automáticamente por el IOL Master 500 y el Pentacam AXL para evitar los factores dependientes del operador. El análisis estadístico se realizó con la Prueba t para datos pareados, utilizando una significación del 95 por ciento. Una diferencia con un valor de p < 0,05 fue considerado estadísticamente significativo. Resultados: El 60,61 por ciento de los pacientes eran de sexo femenino y el 39,39 por ciento del masculino, con una edad promedio de 25,67 ± 4,30 años. Se analizaron 51 ojos derechos y 48 izquierdos. El equivalente esférico medio fue de -3,30 ± 1,53 dioptrías. No hubo diferencia estadísticamente significativa entre los valores biométricos (longitud axial, profundidad de la cámara anterior y queratometrías) obtenidos con el IOL Master 500, en comparación con los del Pentacam-AXL (p > 0,05). Conclusión: Las mediciones biométricas (longitud axial, profundidad de la cámara anterior y queratometrías) obtenidas con el IOL Master 500 y el Pentacam-AXL son similares(AU)
Objective: Compare biometric measurements taken with IOL Master 500 and Pentacam AXL. Methods: A cross-sectional study was conducted of 99 eyes of 99 myopic patients with indication of photoablative surgery attending the Refractive Surgery Service at Ramón Pando Ferrer Cuban Institute of Ophthalmology from January 2019 to January 2020. The variables analyzed were age, sex, spherical equivalent and preoperative biometric characteristics (axial length, anterior chamber depth and keratometries) and the relationship to one another, automatically supplied by IOL Master 500 and Pentacam AXL to avoid operator-dependent factors. Statistical analysis was based on the paired T-test with a significance level of 95%. A difference with a p-value < 0.05 was considered to be statistically significant. Results: Of the patients studied, 60.61 percent were female and 39.39 percent were male; mean age was 25.67± 4.30 years. A total 51 right eyes and 48 left eyes were analyzed. Mean spherical equivalent was -3.30 ± 1.53 diopters. No statistically significant difference was found between the biometric values (axial length, anterior chamber depth and keratometries) obtained with IOL Master 500 versus Pentacam AXL (p > 0.05). Conclusion: Similar biometric measurements (axial length, anterior chamber depth and keratometries) are obtained with IOL Master 500 and Pentacam AXL(AU)
Assuntos
Humanos , Masculino , Feminino , Adulto , Biometria/métodos , Procedimentos Cirúrgicos Refrativos/métodos , Câmara Anterior/diagnóstico por imagem , Estudos TransversaisRESUMO
Resumo Objetivo: Observar o grau de concordância das variáveis analisadas entre os dispositivos IOL Master 500 e Pentacam AXL e descrever as medias Métodos: Foram analisados 35 prontuários, totalizando 61 olhos. Todos os pacientes se submeteram à avaliação biométrica nos dois dispositivos, no período de agosto de 2018 a agosto de 2019. Os dados coletados foram: idade, sexo, profundidade da câmara anterior, comprimento axial, K1, K2, poder dióptrico da LIO e alvo refracional. Resultados: As médias das variáveis analisadas entre os dispositivos de biométricos óptica em questão tiveram diferença estatisticamente significante (p<0,05). A regressão linear não apontou influência de nenhuma das variáveis da câmara anterior na diferença de valores do poder dióptrico da LIO e do alvo refracional entre os dispositivos. Conclusão: Não houve concordância estatística entre os dispositivos para as variáveis analisadas. Portanto, deve se evitar intercambiar o uso do Pentacam AXL com o IOL Master 500.
Abstract Objective: Observe the agreement between IOL Master 500 and Pentacam AXL and describe the averages. Methods: We analyzed 35 medical records, totaling 61 eyes. All patients underwent biometric evaluation on both devices from August 2018 to August 2019. The data collected were: age, gender, anterior chamber depth, axial length, K1, K2, biometrics and IOL target. Results: The averages of the variables analyzed between the optical biometric devices in question had a statistically significant difference (p <0.05). Linear regression showed no influence of any anterior chamber variables on the difference in biometrics and target values between the devices. Conclusion: There was no statistical agreement between the devices for the analyzed variables. Therefore, the interchange of Pentacam AXL with IOL Master 500 should be avoided.
Assuntos
Humanos , Masculino , Pessoa de Meia-Idade , Idoso , Refração Ocular , Biometria , Comprimento Axial do Olho , Lentes Intraoculares Multifocais , InterferometriaRESUMO
BACKGROUND: Renal cell carcinoma (RCC) represents 2%-3% of all cancers of the Western countries. Currently, sunitinib, a receptor tyrosine kinase inhibitor, particularly of PDGF and VEGF receptors, is the first-line therapy for metastatic RCC (mRCC), with significant improvement in clinical outcome. However, there is a lack of predictive biomarkers of sunitinib response. Recently, others and our group suggested that the receptor tyrosine kinase AXL may modify the response to sunitinib. OBJECTIVE: To study the expression of AXL in a series patients with of mRCC treated with sunitinib and to correlate it with patient's clinic-pathological features and therapeutic response. MATERIAL AND METHODS: Sixty-four patients with mRCC (51 clear cell carcinomas (CCCs) and 13 non-CCCs) were evaluated for AXL expression by immunohistochemistry in the primary tumor. RESULTS: AXL positivity was observed in 47% (30/64) of cases, namely in 43% (22/51) of CCCs and 61% (8/13) of non-CCC. Considering only the clear cell subtype, the univariate analysis showed that AXL expression was statistically associated with a poor prognosis, with a median overall survival of 13 months vs. 43 months in patients with negative AXL. In this subtype, along with the AXL positivity, other prognostic factors were absence of nephrectomy, Karnofsky performance status, more than 1 site of metastasis and liver metastasis. Moreover, AXL expression was associated with shorter progression to sunitinib. Overall, the multivariate survival analysis showed that absence of nephrectomy (HR = 4.85, P = 0.001), more than 1 site of metastasis (HR = 2.99, P = 0.002), bone metastasis (HR = 2.95, P = 0.001), together with AXL expression (HR = 2.01, P = 0.048) were independent poor prognostic factor in patients with mRCC. CONCLUSION: AXL expression was associated with worse clinical outcome and may be an important prognostic biomarker in sunitinib-treated patients with metastatic renal cell carcinoma.
Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Imuno-Histoquímica/métodos , Indóis/uso terapêutico , Pirróis/uso terapêutico , Receptores Proteína Tirosina Quinases/metabolismo , Antineoplásicos/farmacologia , Carcinoma de Células Renais/patologia , Feminino , Humanos , Indóis/farmacologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Pirróis/farmacologia , Sunitinibe , Resultado do TratamentoRESUMO
Based on currently available genomic data, most head and neck squamous cell carcinoma have few targetable aberrations and immediate clinical translation is challenging. However, potential therapeutic agents listed in this article need to be thoroughly evaluated because there are compelling scientific rationales supporting their development. Concerted effort is required to identify better predictive biomarkers of clinical benefit and improve the therapeutic index. Clinicians need to better understand resistance mechanisms, generate novel hypotheses for appropriate combination regimens and dosing schedules, develop more accurate model systems, and conduct innovative clinical trials.
Assuntos
Antineoplásicos/farmacologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/metabolismo , Terapia de Alvo Molecular , Animais , Antineoplásicos/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/patologia , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Ensaios Clínicos como Assunto , Dano ao DNA/efeitos dos fármacos , Dano ao DNA/genética , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Transdução de Sinais/efeitos dos fármacos , Carcinoma de Células Escamosas de Cabeça e Pescoço , Resultado do TratamentoRESUMO
Receptor tyrosine kinase (RTK) targeted therapy has been explored for glioblastoma treatment. However, it is unclear which RTK inhibitors are the most effective and there are no predictive biomarkers available. We recently identified the RTK AXL as a putative target for the pan-RTK inhibitors cediranib and sunitinib, which are under clinical trials for glioblastoma patients. Here, we provide evidence that AXL activity can modulate sunitinib response in glioblastoma cell lines. We found that AXL knockdown conferred lower sensitivity to sunitinib by rescuing migratory defects and inhibiting apoptosis in cells expressing high AXL basal levels. Accordingly, overactivation of AXL by its ligand GAS6 rendered AXL positive glioblastoma cells more sensitive to sunitinib. AXL knockdown induced a cellular rewiring of several growth signaling pathways through activation of RTKs, such as EGFR, as well as intracellular pathways such as MAPK and AKT. The combination of sunitinib with a specific AKT inhibitor reverted the resistance of AXL-silenced cells to sunitinib. Together, our results suggest that sunitinib inhibits AXL and AXL activation status modulates therapy response of glioblastoma cells to sunitinib. Moreover, it indicates that combining sunitinib therapy with AKT pathway inhibitors could overcome sunitinib resistance.
Assuntos
Inibidores da Angiogênese/farmacologia , Indóis/farmacologia , Proteínas Proto-Oncogênicas/fisiologia , Pirróis/farmacologia , Receptores Proteína Tirosina Quinases/fisiologia , Linhagem Celular Tumoral , Movimento Celular , Sobrevivência Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Ativação Enzimática , Receptores ErbB/metabolismo , Técnicas de Silenciamento de Genes , Glioblastoma , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Transdução de Sinais , Sunitinibe , Receptor Tirosina Quinase AxlRESUMO
In this study, a novel concise series of molecules based on the structure of goniothalamin (1) was synthesized and evaluated against a highly metastatic human pancreatic cancer cell line (Panc-1). Among them, derivative 8 displayed a low IC50 value (2.7 µM) and its concentration for decreasing colony formation was 20-fold lower than goniothalamin (1). Both compounds reduced the levels of the receptor tyrosine kinase (AXL) and cyclin D1 which are known to be overexpressed in pancreatic cancer cells. Importantly, despite the fact that goniothalamin (1) and derivative 8 caused pancreatic cancer cell cycle arrest and cell death, only derivative 8 was able to downregulate pro-survival and proliferation pathways mediated by mitogen activated protein kinase ERK1/2. Another interesting finding was that Panc-1 cells treated with derivative 8 displayed a strong decrease in the transcription factor (c-Myc), hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) protein levels. Notably, the molecular effects caused by derivative 8 might not be related to ROS generation, since no significant production of ROS was observed in low concentrations of this compound (from 1.5 up to 3 µM). Therefore, the downregulation of important mediators of pancreatic cancer aggressiveness by derivative 8 reveals its great potential for the development of new chemotherapeutic agents for pancreatic cancer treatment.
Assuntos
Compostos Aza/química , Regulação para Baixo/efeitos dos fármacos , Neoplasias Pancreáticas/patologia , Pironas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Acilação , Animais , Linhagem Celular , Neoplasias Pancreáticas/metabolismo , Pironas/químicaRESUMO
Pancreatic cancer ranks fourth among cancer-related causes of death in North America. Minimal progress has been made in the diagnosis and treatment of patients with late-stage tumors. Moreover, pancreatic cancer aggressiveness is closely related to high levels of pro-survival mediators, which can ultimately lead to rapid disease progression, resistance and metastasis. The main goal of this study was to define the mechanisms by which calix[6]arene, but not other calixarenes, efficiently decreases the aggressiveness of a drug resistant human pancreas carcinoma cell line (Panc-1). Calix[6]arene was more potent in reducing Panc-1 cell viability than gemcitabine and 5-fluorouracil. In relation to the underlying mechanisms of cytotoxic effects, it led to cell cycle arrest in the G0/G1 phase through downregulation of PIM1, CDK2, CDK4 and retinoblastoma proteins. Importantly, calix[6]arene abolished signal transduction of Mer and AXL tyrosine kinase receptors, both of which are usually overexpressed in pancreatic cancer. Accordingly, inhibition of PI3K and mTOR was also observed, and these proteins are positively modulated by Mer and AXL. Despite decreasing the phosphorylation of AKT at Thr308, calix[6]arene caused an increase in phosphorylation at Ser473. These findings in conjunction with increased BiP and IRE1-α provide a molecular basis explaining the capacity of calix[6]arene to trigger endoplasmic reticulum stress and autophagic cell death. Our findings highlight calix[6]arene as a potential candidate for overcoming pancreatic cancer aggressiveness. Importantly, we provide evidence that calix[6]arene affects a broad array of key targets that are usually dysfunctional in pancreatic cancer, a highly desirable characteristic for chemotherapeutics.