Prognostic significance of ?mmunhistochemical axl expression in pancreas ductal adenocarcinomas

Introduction and Aim: Pancreas Ductal Adenocarcinomas (PDACs) are among the leading causes of cancer-related death. Tyrosine kinase receptors (TKRs) are responsible for cell plasticity, chemoresistance, immunosuppression and metastasis potential. Axl is a receptor of the TKR family, and it has come to the fore in cancer treatment in the last decade. This study aimed to investigate the relationship of immunohistochemical Axl expression with histological features and its prognostic importance in PDACs. Materials and Methods: Fifty-three patients who were operated on for PDAC between 2006-2017 were evaluated retrospectively. Features of tumors; size, lymphovascular invasion (LVI), perineural invasion (PNI), resection margin (RM), lymph node metastasis (LNM), differentiation, tumor-infiltrating lymphocyte, stage and overall survival were recorded. Immunohistochemically, membranous and or cytoplasmic staining was considered positive for Axl. Statistically, Pearson Chi-Square, Cox regression and Kaplan Mayer tests were used in the SPSS 21.0 program. Results: Axl was positive in 28 patients (52.8%). Axl positivity was found to be associated with the presence of LVI (P = 0.009) and LNM (P = 0.002) and was an independent prognostic factor in short survival (P = 0.006). Conclusion: It was found that increased expression of Axl, which is known to increase EMT-mediated metastasis in carcinogenesis, may be an indicator of local spread and poor prognosis in PDAC patients. In this respect, it can be promising as a targeted molecule in PDAC patient's individualized treatments.

Aberrometría corneal en el queratocono subclínico

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 % y especificidad del 88,9 %. 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.

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 % and specificity of 88.9 %. Conclusions: Coma posterior to 90º (aberrometric parameter) presents high sensitivity and specificity for the diagnosis of subclinical keratoconus, using Pentacam AXL tomographic analysis.

Clinical Significance of co-expression of RNA Binding Protein PTBP1 and p-AXL in Osteosarcoma / 中山大学学报(医学科学版)

ObjectiveTo explore the co-expression of PTBP1 and p-AXL in osteosarcoma and its clinicopathological significance for prognosis evaluation. MethodsThe expression of PTBP1 and AXL and their prognostic value in osteosarcoma were analyzed by GEO and Target data. Paraffin biopsy specimens and clinical information from 76 cases of osteosarcoma and 37 cases of non-malignant bone tissue （callus， osteofibrous dysplasia and osteoid ostema） were obtained from the First Affiliated Hospital of Sun Yat-sen University from March 2016 to October 2020. The expressions of PTBP1 and p-AXL proteins in osteosarcoma were detected by immunohistochemistry. ResultsGEO database showed that the expression levels of PTBP and AXL in osteosarcoma tumor group were higher than those in normal tissues， but did not reach statistical significance. Target database showed that the high expression of PTBP1 had shorter Overall survival（OS） and Progression-free survival（PFS） than low PTBP1 expression， but did not reach statistical significance （P=0.064； P=0.134）. Immunohistochemical staining included 76 cases of osteosarcoma and 37 cases of non-malignant bone tissue. The expression rate of PTBP1 and p-AXL protein in osteosarcoma tissues was higher than that in non-malignant bone tissue. The expression of p-AXL is correlated with lung metastasis （P=0.025）. Kaplan-Meier analysis showed that lung metastasis， recurrence， PTBP1 expression， co-expression of PTBP1/p-AXL influence the prognosis of patients in OS. Multivariate Cox regression analysis showed that lung metastasis （P<0.000 1） and positive expression of PTBP1 （P=0.041） were independent risk factors for osteosarcoma patients in OS. Co-expression of PTBP1 and p-AXL had shorter OS （P=0.017） and PFS （P=0.043） than non-coexpression osteosarcoma patients. ConclusionsPTBP1 and p-AXL were highly expressed in osteosarcoma tissues. The co-expression of PTBP1 and p-AXL was associated with poor prognosis of patients， and PTBP1 could be used as an independent prognostic indicator of patients with osteosarcoma.

Impact of tear optics on the repeatability of Pentacam AXL wave and iTrace in measuring anterior segment parameters and aberrations

Purpose: To assess impact of tear optics on repeatability of a Scheimpflug device with a Hartmann Shack aberrometer and a ray tracing aberrometer. Methods: One hundred healthy and 100 postrefractive surgery eyes underwent dry eye evaluation including Schirmer抯 test and tear film break?up time (TBUT). They underwent optical quality analyzer (OQAS, Visio metrics S.L, Terrassa, Spain) to assess objective scatter index (OSI), three scans each on Pentacam AXL wave (OCULUS Optikgerate Gmbh, Wetzlar, Germany), iTrace (Tracey� Technologies, Texas, USA) for flat, steep keratometry, thinnest corneal thickness, root mean square higher?order aberrations (RMS HOA), RMS lower?order aberrations (LOA), spherical aberrations, RMS COMA. Repeatability of Pentacam AXL wave and iTrace in healthy and postrefractive eyes (OSI >1 vs OSI <1) was studied using within?subject standard deviation (Sw) test杛etest repeatability (TRT), coefficient of variation (COV). Results: OSI showed an inverse association with TBUT (P < 0.001). All measurements with Pentacam AXL wave with OSI < 1 had excellent repeatability, intraclass correlation coefficient (ICC) ranging from 0.88 for HOA, to 0.92 for LOA. The Sw, TRT, and COV of all aberration measurements were significantly lower (better) than those of iTrace. In eyes with OSI ?1, the repeatability with Pentacam AXL wave dropped with ICC ranging from 0.77 for HOA, to 0.84 for LOA with lower Sw, TRT, and COV of all aberration measurements as compared to iTrace. Maximum variation was seen with HOA and minimum with LOA. Conclusion: Tear optics affected repeatability of Pentacam wave and iTrace. Pentacam wave had better repeatability in eyes with a poor tear film as compared to iTrace. Thus, the tear film can impact repeatability of an instrument and it is important to assess the tear film prior to imaging patients, which can change the way we interpret and image these patients.

The FAP α -activated prodrug Z-GP-DAVLBH inhibits the growth and pulmonary metastasis of osteosarcoma cells by suppressing the AXL pathway

Osteosarcoma is a kind of bone tumor with highly proliferative and invasive properties, a high incidence of pulmonary metastasis and a poor prognosis. Chemotherapy is the mainstay of treatment for osteosarcoma. Currently, there are no molecular targeted drugs approved for osteosarcoma treatment, particularly effective drugs for osteosarcoma with pulmonary metastases. It has been reported that fibroblast activation protein alpha (FAPα) is upregulated in osteosarcoma and critically associated with osteosarcoma progression and metastasis, demonstrating that FAPα-targeted agents might be a promising therapeutic strategy for osteosarcoma. In the present study, we reported that the FAPα-activated vinblastine prodrug Z-GP-DAVLBH exhibited potent antitumor activities against FAPα-positive osteosarcoma cells in vitro and in vivo. Z-GP-DAVLBH inhibited the growth and induced the apoptosis of osteosarcoma cells. Importantly, it also decreased the migration and invasion capacities and reversed epithelial-mesenchymal transition (EMT) of osteosarcoma cells in vitro and suppressed pulmonary metastasis of osteosarcoma xenografts in vivo. Mechanistically, Z-GP-DAVLBH suppressed the AXL/AKT/GSK-3β/β-catenin pathway, leading to inhibition of the growth and metastatic spread of osteosarcoma cells. These findings demonstrate that Z-GP-DAVLBH is a promising agent for the treatment of FAPα-positive osteosarcoma, particularly osteosarcoma with pulmonary metastases.

Function of AXL and molecular mechanisms in regulation of nasopharyngeal carcinoma / 中南大学学报(医学版)

OBJECTIVES@#Nasopharyngeal carcinoma (NPC) is a highly invasive epithelial malignant tumor with unique geographical and ethnic distribution characteristics. NPC is mostly found in south China and Southeast Asia, and its treatment mainly depends on radiotherapy and chemotherapy. However, NPC is usually found in the late stage, and local recurrence and distant metastasis are common, leading to poor prognosis. The receptor tyrosine kinase AXL is up-regulated in various tumors and it is involved in tumor proliferation, migration, invasion, and other processes, which are associated with poor prognosis of tumors. This study aims to detect the expression of AXL in NPC cell lines and tissues, and to investigate its biological function of AXL and the underlying molecular mechanisms in regulation of NPC.@*METHODS@#The expression levels of AXL in normal nasopharyngeal epithelial tissues and NPC tissues were analyzed by GSE68799, GSE12452, and GSE53819 data sets based on Gene Expression Omnibus (GEO) database. The Cancer Genome Atlas (TCGA) database was used to analyze the relationship between AXL and prognosis of head and neck squamous cell carcinoma (HNSC). The indicators of prognosis included overall survival (OS), disease-free interval (DFI), disease-specific survival (DSS), and progression-free interval (PFI). Western blotting assay was used to detect the AXL protein expression levels in normal nasopharyngeal epithelial cell line and NPC cell lines. Immunohistochemical method was used to detect AXL expression levels in normal nasopharyngeal epithelial tissues and NPC tissues. Cell lines with stable AXL knockdown were established by infecting 5-8F and Fadu cells with lentivirus interference vector, and cell lines with stable AXL overexpression were established by infecting C666-1 and HK-1 cells with lentivirus expression vector. Real-time PCR and Western blotting were used to detect the efficiency of knockdown and overexpression in stable cell lines. The effects of AXL knockdown or overexpression on proliferation, migration, and invasion of NPC cells were detected by CCK-8, plate colony formation, and Transwell assays, and the effect of AXL knockdown on tumor growth in nude mice was detected by subcutaneous tumor formation assay. The sequence of AXL upstream 2.0 kb promoter region was obtained by UCSC online database. The PROMO online database was used to predict AXL transcription factors with 0% fault tolerance, and the JASPAR online database was used to predict the binding sites of ETS1 to AXL. Real-time PCR and Western blotting were used to detect the effect of ETS1 on AXL protein and mRNA expression. The AXL upstream 2.0 kb promoter region was divided into 8 fragments, each of which was 250 bp in length. Primers were designed for 8 fragments. The binding of ETS1 to AXL promoter region was detected by chromatin immuno-precipitation (ChIP) assay to determine the direct regulatory relationship between ETS1 and AXL. Rescue assay was used to determine whether ETS1 affected the proliferation, migration, and invasion of NPC cells through AXL.@*RESULTS@#Bioinformatics analysis showed that AXL was highly expressed in NPC tissues (P<0.05), and AXL expression was positively correlated with OS, DFI, DSS, and PFI in HNSC patients. Western blotting and immunohistochemical results showed that AXL was highly expressed in NPC cell lines and tissues compared with the normal nasopharyngeal epithelial cell line and tissues. Real-time PCR and Western blotting results showed that knockdown and overexpression efficiency in the stable cell lines met the requirements of subsequent experiments. The results of CCK-8, plate colony formation, Transwell assays and subcutaneous tumor formation in nude mice showed that down-regulation of AXL significantly inhibited the proliferation, migration, invasion of NPC cells and tumor growth (all P<0.05), and the up-regulation of AXL significantly promoted the proliferation, migration, and invasion of NPC cells (all P<0.05).As predicted by PROMO and JASPAR online databases, ETS1 was a transcription factor of AXL and had multiple binding sites in the AXL promoter region. Real-time PCR and Western blotting results showed that knockdown or overexpression of ETS1 down-regulated or up-regulated AXL protein and mRNA expression levels. ChIP assay result showed that ETS1 bound to AXL promoter region and directly regulate AXL expression. Rescue assay showed that AXL rescued the effects of ETS1 on proliferation, migration and invasion of NPC cells (P<0.05).@*CONCLUSIONS@#AXL is highly expressed in NPC cell lines and tissues, which can promote the malignant progression of NPC, and its expression is regulated by transcription factor ETS1.

Mediciones biométricas en pacientes miopes con cirugía fotoablativa previa / Biometric measurements in myopic patients with previous photoablative surgery

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)

Comparación entre las mediciones biométricas del IOL Master 500 y el Pentacam AXL en la biometría ocular / Comparison of biometric measurements taken with IOL Master 500 and Pentacam AXL for ocular biometry

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)

Research advances in the association of the tyrosine kinase receptor Axl and its ligand Gas6 with hepatocellular carcinoma / 临床肝胆病杂志

As one of the tyrosine kinase receptors, Axl is an important downstream regulator of epithelial-mesenchymal transition (EMT) and can bind to its ligand Gas6 protein. By activating the downstream signal transduction pathways, Axl is closely associated with vascular invasion, tumor metastasis, recurrence, and low survival rate of hepatocellular carcinoma. Current studies on the Gas6/Axl signaling pathway have confirmed that Axl inhibitors play an important role in the treatment of liver cancer and the Gas6/Axl signaling pathway may be a potential therapeutic target for liver cancer. This article mainly introduces the association of Axl and its ligand Gas6 with the development and progression of liver cancer and their application in the diagnosis and treatment of liver cancer, in order to provide new ideas for the early diagnosis of liver cancer and clinical research on anti-cancer treatment.

Receptor tyrosine kinase AXL in tumor immunotherapy / 中国肿瘤生物治疗杂志

@#AXL是受体酪氨酸激酶TAM（TYRO3-AXL-MERTK）家族中的一员，被认为是一种癌基因，不仅在多种癌症中高表达，而且也表达于包括NK细胞、树突状细胞（DC）、T细胞在内的多种免疫细胞，且可以通过调节其下游的信号通路影响免疫细胞的发育及功能。AXL作为一种“免疫检查点”参与抗肿瘤免疫反应的调控，或将成为肿瘤免疫治疗的新靶点。本文主要介绍AXL在不同免疫细胞中的生物学功能，以及目前靶向AXL相关药物的研究进展，以期为研发AXL靶向药物和制定联合用药策略提供新思路。

Analise dos dados biométricos gerados por interferometria comparada com Scheimpflug / Analysis of biometric data generated by interferometry compared with Scheimpflug

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.

Molecular mechanisms of tobacco induced oral and oropharyngeal cancer: Results of a tissue microarray and immunohistochemistry-based study from a tertiary cancer center in India

Background: It is well established that chronic exposure to tobacco induces head and neck cancers but the exact etiopathogenesis is not known. Though studies have shown expression of TIMP1, EPS8 and AXL in cancers, their role in tobacco-induced cancers is not known. We aimed this study to evaluate the role of these molecules in oral and oropharyngeal squamous cell cancers (SCC). Materials and Methods: In this single institutional study, 31 patients of oral and oropharyngeal SCC with history of chewing tobacco were included. Smokers were excluded from the study. After informed consent biopsies were taken from affected and contralateral normal mucosa. Paraffin blocks were made and tissue microarray (TMA) were constructed using these blocks. Immunohistochemistry (IHC) for TIMP1, EPS8, AXL kinase was carried out on these tissue microarrays. The intensity of staining was scored from 0 to 3+, related to expression of each of the three molecules. Results: The expression of TIMP1, EPS8 and AXL kinase was significantly more in the cancerous mucosa versus non-cancerous mucosa (P = 0.000 in all three) in oral and oropharyngeal SCC exposed to chewing tobacco. Conclusion: Immunohistochemical expression of these molecular markers in oral and oropharyngeal SCC correlated with their molecular based studies. Significant IHC expression of TIMP1, EPS8 and AXL establishes their role in the pathogenesis of oral and oropharyngeal squamous cell carcinomas. Novel targeted therapies may be researched that can detect and target these molecules at an earlier stage of pathogenesis of these tumors.

Overcoming the Intrinsic Gefitinib-resistance via Downregulation of AXL in Non-small Cell Lung Cancer

BACKGROUND: Resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib, is a limited factor in the treatment of non-small-cell lung cancer (NSCLC) patients. Therefore, ongoing studies are trying to identify EGFR-TKIs-resistant mechanisms and to discover novel therapeutic strategies and targets for NSCLC treatment.METHODS: In the present study, the possibility of overcoming intrinsic gefitinib-resistance was examined by regulating the expression of AXL. A natural product-derived antitumor agent, yuanhuadine (YD) was employed to modulate the expression of AXL in the cells.RESULTS: Treatment with YD effectively downregulated AXL expression in AXL-overexpressed gefitinib-resistant H1299 cells. The combination of gefitinib and YD exhibited a synergistic grwoth-inhibitory activity in H1299 cells by downregulation of AXL expression.CONCLUSIONS: Based on these findings, AXL was found to be a promising therapeutic target to overcome the intrinsic resistance to gefitinib in NSCLC. Furthermore, YD is able to effectively regulate the expression of AXL and thus it may be applicable as a potential lead compound for the treatment of gefitinib-resistant NSCLC.

Role of receptor tyrosine kinase AXL in tumor drug resistance / 上海交通大学学报（医学版）

AXL is a member of TAM (TYRO3-AXL-MER) family of receptor tyrosine kinases, which is overexpressed in many cancers, including nonsmall cell lung cancer, breast cancer and ovarian cancer. It can mediate the occurrence of epithelial-mesenchymal transition, and plays an important role in tumor drug resistance. In addition, AXL can also mediate the occurrence of targeted agents resistance by regulating the signaling pathway and influencing tumor microenviroment. As a result, AXL is an attractive candidate not only as a prognostic indicator in malignancy but also as a target for anti-cancer therapy. Several multi-target small molecule inhibitors against AXL have been approved, and varieties of inhibitors with higher specificity are in clinical or preclinical studies. This article focused on the role of AXL in tumor drug resistance and summarized the research profiles of different small molecule inhibitors against AXL to provide new ideas for anti-tumor research and therapy.

Relationship between receptor tyrosine kinase Axl and apoptosis relative proteins in osteosarcoma / 临床与实验病理学杂志

Purpose To identify the role of tyrosine kinase receptor Axl for anti-apoptosis which was induced by cisplatin (DDP) and methotrexate (MTX) chemotherapy and to analyze the relationship between P-Axl and apoptosis-related proteins in osteosarcoma.Methods Osteosarcoma cell lines MG63,143B and U2OS were used in apoptosis assays,Axl siRNA transfection,cytotoxicity assays,cell cycle analysis,etc.A total of 41 cases of osteosarcom patients were included for immunohistochemistry of EnVision two-step staining and clinico-pathological relative analysis.TUNEL assay was performed in ten cases for apoptosis detection.Results Among the osteosarcoma cell lines,Gas6/Axl could obviously protect tumor cells from apoptosis induced by DDP and MTX (P ＜ 0.05).Axl siRNA transfection enhanced cell apoptosis,whereas Gas6 prone to function upon previous knockdown by Axl siRNA.Among the 41 cases,the positive rate of P-Axl,BCL-2,and Bax was 85.4％,70.7％,and 36.6％,respectively.In contrast,the positive rate of them was 22.2％,11.1％,and 11.1％ in osteofibrous dysplasia,respectively.The expression levels of these apoptosisrelated factors were significantly higher in osteosarcoma than in osteofibrous dysplasia (P ＜ 0.05).Through clinico-pathological analysis,there were significant relationships between the survival status and BCL-2 or Bax expression (P ＜ 0.05).Pearson correlation analysis demonstrated that BCL-2 was positively correlated to P-Axl with statistical significance (r =0.842,P ＜ 0.0001).By Cox univariate analysis,BCL-2 or Bax was correlated with the patients' prognosis.TUNEL assay also demonstrated that P-Axl high expression inhibited apoptosis in osteosarcoma tissues.Conclusion Gas6/Axl protects osteosarcoma cells from the apoptosis induced by DDP and MTX chemotherapy and inhibits apoptosis in osteosarcoma tissue,possibly through the regulation of apoptosis-related protein BCL-2.

Research progress of receptor tyrosine kinase AXL in tumor / 实用肿瘤学杂志

AXL is a member of the TAM receptor tyrosine kinase family,and AXL has been shown to beassociated with a variety of cancers such as lung cancer,breast cancer,thyroid cancer,prostate cancer and pancre-atic cancer.The latest evidence suggests that AXL can promote the growth,invasion and metastasis of varioustumors,and its inhibitors can also inhibit tumor formation,suggesting that AXL may be a potential target for anti-tumor therapy,and the use of AXL kinase inhibitors may become the new strategy of anti-tumor therapy.This ar-ticle reviews the progress of AXL and tumor.

The clinical significance of soluble Axl and Tyro3 receptor tyrosine kinase in systemic lupus erythematosus / 中华风湿病学杂志

Objective To explore the expression and clinical significance of soluble Axl and Tyro3 receptor tyrosine kinase in systemic lupus erythematosus (SLE).Methods Sandwich enzyme linked immunosorbent assay (ELISA) was used to detect sAxlTK and sTyro3TK in the serum of 140 SLE patients,150 disease controls and 100 healthy controls (HC).The relationships between the serum levels of sAxlTK/sTyro3TK and clinical manifestations,laboratory parameters,disease activity were analyzed in SLE patients.Analysis of variance,Dunnett's t-test,chi-square test and spearman's test were used for statistical analysis.Results The concentrations of sAxlTK [(56±18) ng/ml] and sTyro3TK [(3.9±1.6) ng/ml] were both elevated in serum of SLE patients,which were significantly higher than disease controls [sAxlTK:(41±17) ng/ml;sTyro3TK:(2.6± 1.2) ng/ml] and healthy controls [sAxlTK:(37±10) ng/ml;sTyro3TK:(2.1±0.7) ng/ml].The SLE sAxlTK levels were negatively correlated with lymphocyte count (r=-0.266,P=0.002),hemoglobin (r=-0.480,P＜0.01),platelet count (r=-0.374,P＜0.01),albumin (r=-0.465,P＜0.01),estimated glomerular filtration rate (eGFR,r=-0.230,P=0.006),complement C3 (r=-0.399,P＜0.01) and complement C4 (r=-0.374,P＜0.01).However,the levels of sAxlTK in SLE patients were positively correlated with D-dimer (r=0.371,P＜0.01),creatinine (r=0.278,P＜0.01),24-hour urinary protein quantification (r=0.383,P＜0.01),erythrocyte sedimentation rate (r=0.422,P＜0.01),titre of anti-nuclear antibodies (r=0.271,P=0.002),anti-dsDNA antibody (r=0.299,P＜0.01),anti-nucleosome antibody (r=0.263,P=0.013) and anti-cardiolipin antibody (r=0.309,P＜0.01).In addition,the levels of serum sAxlTK in SLE patients showed positive correlation with the scores of SLEDAI (r=0.307,P＜0.01).Comparisons of sAxlTK levels between patients with high and low disease activity demonstrated a higher level of sAxlTK in the former [(64±17) ng/ml vs (52±16) ng/ml;t=-3.939,P＜0.01].Conclusion The levels of sAxlTK and sTyro3TK are elevated in the serum of SLE patients.The concentration of sAxlTK is correlated with autoantibodies production,hematological and renal involvement in SLE,which may be a serolgical marker for disease activity.

Axl-targeting drugs in tumor therapy:research advances / 国际药学研究杂志

Axl belongs to the family of receptor tyrosine kinase. Axl and its ligand Gas6 are aberrantly over-expressed in numerous human cancers. The binding of Gas6 and Axl could activate multiple signaling pathways,which take part in the development and progression of cancer,including cell survival,migration,invasion,and angiogenesis. In recent years,Axl and Gas6 have been considered as a promising novel target for cancer therapeutics. Several Axl inhibitors,including small-molecule tyrosine kinase inhibi?tors and anti-Axl monoclonal antibodies are currently under research. In this paper ,we review the development of Axl-targeting drugs in tumor therapy.

Serum sex hormone and growth arrest-specific protein 6 levels in male patients with coronary heart disease / 亚洲男科学杂志(英文版)

Epidemiological studies have shown a high prevalence of low serum testosterone levels in men with cardiovascular disease. Moreover, the tyrosine kinase receptor Axl, the ligand of which is growth arrest-specific protein 6 (GAS6), is expressed in the vasculature, and serum GAS6 levels are associated with endothelial dysfunction and cardiovascular events. Testosterone regulates GAS6 gene transcription directly, which inhibits calcification of vascular smooth muscle cells and provides a mechanistic insight into the cardioprotective action of androgens. This study was designed to determine the correlation between serum GAS6 and testosterone levels in male patients with coronary heart disease (CHD). We recruited 225 patients with CHD and 102 apparently healthy controls. Serum concentrations of GAS6 and soluble Axl were quantified by an enzyme-linked immunosorbent assay. Levels of high-sensitivity C-reactive protein, testosterone, estradiol, and other routine biochemical markers were also measured. Testosterone decreased from 432.69 ± 14.40 to 300.76 ± 6.23 ng dl-1 (P < 0.001) and GAS6 decreased from 16.20 ± 0.31 to 12.51 ± 0.19 ng ml-1 (P < 0.001) in patients with CHD, compared with control subjects. Multiple linear regression analysis showed that serum testosterone and GAS6 levels were positively associated in male patients with CHD. Alterations in GAS6 levels may influence the development of CHD. Downregulation of GAS6/Axl signaling in the presence of low sex hormone levels during disease progression is a potential mechanism by which GAS6 affects CHD. This study provides novel results regarding the influence of sex hormones on serum GAS6 levels in patients with CHD.

Axl-targeting drugs in tumor therapy: Research advances / 国际药学研究杂志

Axl belongs to the family of receptor tyrosine kinase. Axl and its ligand Gas6 are aberrantly over-expressed in numerous human cancers. The binding of Gas6 and Axl could activate multiple signaling pathways, which take part in the development and progression of cancer, including cell survival, migration, invasion, and angiogenesis. In recent years, Axl and Gas6 have been considered as a promising novel target for cancer therapeutics. Several Axl inhibitors, including small-molecule tyrosine kinase inhibitors and anti-Axl monoclonal antibodies are currently under research. In this paper, we review the development of Axl-targeting drugs in tumor therapy.