ADAM23在小鼠脑组织的表达

目的:观察整合素-金属蛋白水解酶23(ADAM23)在成年小鼠脑组织的表达及分布。方法:RT-PCR克隆ADAM23全长序列,体外逆转录合成地高辛标记的RNA探针;原位杂交法检测ADAM23在脑各组织的表达。结果:ADAM23 mRNA在小鼠大脑皮层区、海马CA3区、小脑的浦肯野细胞层(Purkinje cell)区、舌下神经核区高表达;而小脑、下丘的中央核、小脑核侧部区等弱表达。结论:ADAM23在成年小鼠脑组织的广泛表达尤其中枢神经系统的高表达,预示着ADAM23在中枢神经系统内有重要作用。     

The expression of ADAM23 and its correlation with promoter methylation in non-small-cell lung carcinoma

ADAM23, a member of a disintegrin and metalloprotease (ADAM) family, has been reported to be expressed in several types of tumours. The exact role of ADAM23 and the possible mechanisms in which it is involved in non-small-cell lung carcinoma (NSCLC) remains unclear. Therefore, this study was designed to explore the expression of ADAM23 and its correlation with promoter methylation in NSCLC. Immunohistochemistry and RT-PCR together with Western blotting methods were used to analyse the expression of ADAM23 in 52 cancer tissue samples and eight benign pulmonary lesions as well as four cell lines. The methylated status of ADAM23 gene was determined with methylation-specific PCR (MSP). The results of immunohistochemistry showed that the expression of ADAM23 protein was lower in NSCLC than that in corresponding normal tissues and benign pulmonary lesions (38.5%vs. 86.5% and 87.5%, P < 0.05), and decreased as NSCLC progressed. Meanwhile, methylation of ADAM23 gene was observed in 21 of 52 NSCLC tissues (40.4%), much higher than that of adjacent normal tissues (7.6%) and benign pulmonary lesions (0/8). In the cancer tissues of ADAM23-negative samples, the rate of ADAM23 gene methylation was 50.3% (17/32). ADAM23 expression and its promoter methylation were negatively associated (r = -0.328, P = 0.017). Moreover, weak expression of ADAM23 in methylated cancer cells increased after treatment with 5-aza-2'-deoxycytidine (5-Aza-2'-dC), confirming that methylation was responsible for the gene downregulation. Our results demonstrate that the expression level of ADAM23 is likely to be involved in the progression of NSCLC and its downregulation is probably correlated with promoter methylation. These findings may provide potential diagnostic and prognostic information about NSCLC.     

Low levels of ADAM23 expression in epithelial ovarian cancer are associated with poor survival

Background

ADAM23, a member of the disintegrin and metalloprotease (ADAM) family, has been reported to be expressed in several types of tumours. Nevertheless, the exact role of ADAM23 in epithelial ovarian cancer (EOC) remains unclear. The aim of this study was to investigate ADAM23 expression in EOC and evaluate its clinicopathological and prognostic significance.

Characterization of a specific interaction between ADAM23 and cellular prion protein

ADAMs are transmembrane proteins implicated in several biological functions, including cytokine and growth factor shedding, fertilization, muscle and nervous system development. Here, we show for the first time that ADAM23, which is predominantly expressed in the central nervous system, co-localizes with cellular prion protein (PrP^C) at plasma membrane of mouse hippocampal neurons and neuroblastoma cells. Co-immunoprecipitation and pull-down assay showed a physical interaction between ADAM23 and both recombinant and endogenous PrP^C. Glycosylation seems to be not relevant to the observed interaction since both ADAM23 and PrP^C recombinant proteins expressed in bacteria or extracted from eukaryotic cells treated with tunicamycin are still able to bind each other. In vitro binding assays also suggested that the disintegrin domain of ADAM23 is able to interact directly with PrP^C. Taken together, these findings point out PrP^C as a novel molecular partner for ADAM23 in the nervous systems.     

Analysis of the disintegrin-metalloproteinases family reveals ADAM29 and ADAM7 are often mutated in melanoma

We performed a mutational analysis of the 19 disintegrin-metalloproteinases (ADAMs) genes in human cutaneous metastatic melanoma and identified eight to be somatically mutated in 79 samples, affecting 34% of the melanoma tumors analyzed. Functional analysis of the two frequently mutated ADAM genes, ADAM29 and ADAM7 demonstrated that the mutations affect adhesion of melanoma cells to specific extracellular matrix proteins and in some cases increase their migration ability. This suggests that mutated ADAM genes could play a role in melanoma progression.     

解整合素金属蛋白酶19/ADAM19在子痫前期胎盘组织中的表达及其对滋养细胞分泌MMPs的调节

目的通过对子痫前期及正常孕妇胎盘组织中解整合素金属蛋白酶19（ADAM19）的检测及ADAM19对绒毛滋养细胞分泌MMP2,9的调节,探讨ADAM19与子痫前期发病的关系。方法应用免疫组织化学（免疫组化）链霉素抗生物素-过氧化物酶法、免疫印迹技术和RT-PCR技术检测24例正常胎盘组织及46例子痫前期（其中26例为重度子痫前期,20例为轻度子痫前期）胎盘组织中ADAM19蛋白及mRNA的表达;用明胶酶谱方法检测抗ADAM19抗体作用后滋养细胞MMP2,9的分泌变化。结果胎盘组织中,ADAM19主要分布在多种滋养层细胞中,包括细胞滋养层细胞、合体滋养层细胞一和些绒毛间质结缔组织细胞、毛细血管中,其阳性信号不仅定位于细胞膜上,在细胞质中也有分布。正常胎盘中ADAM19的蛋白表达量为0.372±0.016,重度和轻度子痫前期组ADAM19蛋白定量分别为0.766±0.029和0.693±0.041,轻、重度子痫前期组分别与正常组比较,差异均有统计学意义（P〈0.01）,轻度子痫前期与重度子痫前期比较,差异无统计学意义（P〉0.05）。ADAM19mRNA在正常组胎盘中的量为0.205±0.084,在重度和轻度子痫前期组中分别为0.481±0.057和0.454±0.033,轻、重度子痫前期组分别与正常组比较,差异均有统计学意义（P〈0.01）,轻度子痫前期与重度子痫前期比较,差异无统计学意义（P〉0.05）。在体外培养的滋养层细胞中,100μg/L浓度的抗ADAM19抗体在作用12h即可以抑制滋养细胞MMP2,MMP9的分泌,其作用呈浓度依赖。结论子痫前期胎盘组织中ADAM19过表达可能与子痫前期的发生和发展有关;在子痫前期的发生中,ADAM19可能是在妊娠早期抑制滋养细胞的浸润而导致胎盘浅着床的。     

Extracting MRS discriminant functional features of brain tumors

The current challenge in automatic brain tumor classification based on MRS is the improvement of the robustness of the classification models that explicitly account for the probable breach of the independent and identically distributed conditions in the MRS data points. To contribute to this purpose, a new algorithm for the extraction of discriminant MRS features of brain tumors based on a functional approach is presented. Functional data analysis based on region segmentation (RSFDA) is based on the functional data analysis formalism using nonuniformly distributed B splines according to spectral regions that are highly correlated. An exhaustive characterization of the method is presented in this work using controlled and real scenarios. The performance of RSFDA was compared with other widely used feature extraction methods. In all simulated conditions, RSFDA was proven to be stable with respect to the number of variables selected and with respect to the classification performance against noise and baseline artifacts. Furthermore, with real multicenter datasets classification, RSFDA and peak integration (PI) obtained better performance than the other feature extraction methods used for comparison. Other advantages of the method proposed are its usefulness in selecting the optimal number of features for classification and its simplified functional representation of the spectra, which contributes to highlight the discriminative regions of the MR spectrum for each classification task. Copyright © 2012 John Wiley & Sons, Ltd.     

解聚素和金属蛋白酶19在早孕绒毛中的表达及其与自然流产的相关性研究

目的通过对解聚素和金属蛋白酶19（ADAM19）在早孕自然流产和正常早孕绒毛中表达的研究,探讨其在妊娠过程中的作用及其与流产的关系。方法早期妊娠和难免流产的绒毛组织各30例,应用免疫组织化学链霉素抗生物素-过氧化物酶法,检测ADAM19的表达。结果在正常妊娠的绒毛中,ADAM19主要表达在细胞膜上,在细胞滋养细胞、细胞滋养层细胞柱中均有较强的表达,表达强度均强于合体滋养细胞;在流产组绒毛中,ADAM19在细胞滋养细胞、细胞滋养层细胞柱中的表达均明显低于正常绒毛组,二者比较差异有统计学意义（P〈0.01）。结论ADAM19在妊娠早期滋养细胞的侵入中有重要的作用,早期流产的发生与绒毛中ADAM19水平下降有关。     

CD23 shedding: requirements for substrate recognition and inhibition by dipeptide hydroxamic acids

CD23 (low affinity IgE receptor, FcεRII) is expressed as a Type II extracellular protein on a variety of cells such as B cells, monocytes and macrophages and is cleaved from the cell surface to generate several distinct fragments. The expression of CD23 on the cell surface as well as the generation of soluble fragments of CD23 has been shown to be involved in regulation of IgE synthesis. CD23 is released from the cell surface by a metalloprotease, analogous to the cleavage of other cell surface molecules such as TNF-α. This activity has been extensively studied with respect to biochemical characterization and ability to cleave specific mutants of CD23. Both local sequence and distal domains have been shown to affect cleavage of CD23. Selective dipeptide hydroxamic acid inhibitors of CD23 processing have been identified and demonstrated to very potently and selectively inhibit CD23 processing.     

CAR T cells for brain tumors: Lessons learned and road ahead

Malignant brain tumors, including glioblastoma, represent some of the most difficult to treat of solid tumors. Nevertheless, recent progress in immunotherapy, across a broad range of tumor types, provides hope that immunological approaches will have the potential to improve outcomes for patients with brain tumors. Chimeric antigen receptors (CAR) T cells, a promising immunotherapeutic modality, utilizes the tumor targeting specificity of any antibody or receptor ligand to redirect the cytolytic potency of T cells. The remarkable clinical response rates of CD19‐targeted CAR T cells and early clinical experiences in glioblastoma demonstrating safety and evidence for disease modifying activity support the potential of further advancements ultimately providing clinical benefit for patients. The brain, however, is an immune specialized organ presenting unique and specific challenges to immune‐based therapies. Remaining barriers to be overcome for achieving effective CAR T cell therapy in the central nervous system (CNS) include tumor antigenic heterogeneity, an immune‐suppressive microenvironment, unique properties of the CNS that limit T cell entry, and risks of immune‐based toxicities in this highly sensitive organ. This review will summarize preclinical and clinical data for CAR T cell immunotherapy in glioblastoma and other malignant brain tumors, including present obstacles to advancement.     

Genetic and epigenetic alterations of 9p21 gene products in benign and malignant tumors of the head and neck

The multistep process of tumorigenesis has not been decoded to date, although numerous investigations into probable molecular changes have meanwhile been conducted. However, not only DNA changes or loss of alleles cause deregulation of gene function, but also epigenetic alterations (e.g. methylation) result in functional loss. The INK4a-ARF (CDKN2A) locus, located on chromosome 9p21, encodes two functionally distinct tumor suppressor genes, p14ARF and p16INK4a, which play active roles in the p53 and Rb tumor suppressive pathways. We therefore examined not only p16 and p14 proteins, but also alterations of the INK4a-ARF locus, including methylation and loss of heterozygosity in benign and malignant tumors of the head and neck (squamous cell carcinomas and pleomorphic adenomas). In benign pleomorphic adenomas, methylation of p14ARF was found in 1 out of 42 (2%) cases, whereas alterations of p16INK4a occurred in 12/42 (29%) pleomorphic adenomas. In HNSCC, methylation of p16INK4a occurred in 16 out of 50 (32%) carcinomas. P14ARF was found to be methylated in 8 out of 50 cases (16%). Our results demonstrate that alterations of the INK4a-ARF locus are frequent and important events not only in the carcinogenesis of malignant, but also in benign tumors.     

Functional MRI activation patterns of cerebellum in patients with epilepsy and brain tumors

Function of cerebellum in control and coordination of motor function has been well established for several years. Recent functional magnetic resonance imaging (MRI) studies reveal activation of cerebellum with memory, speech and language tasks. We hypothesize that during every function in the brain signals are relayed to cerebellum. We seek to analyze cognitive, emotional and social functions of cerebellum in patients with brain tumors and epilepsy utilizing functional Magnetic Resonance Imaging. Fifty‐one consecutive adult patients who underwent functional MRI examination were retrospectively analyzed for various activation patterns involving cerebellum. The neuropsychological battery of tasks assessed motor, language, memory, visual and auditory functions. Cognitive ability of all participants was assessed by Montreal cognitive assessment (MOCA). Patterns were analyzed for specific lobes and locations in the cerebellum. We found that simultaneous cerebellar activation is a consistent finding with brain activation during every functional MRI task that we tested except visual task. The patterns of functional MRI cerebellar activation were similar in both patient subgroups and control subjects compared to previously described patterns in normal subjects. Clin. Anat. 32:1053–1060, 2019. © 2019 Wiley Periodicals, Inc.     

Metabolic differences between primary and recurrent human brain tumors: a 1H NMR spectroscopic investigation

High-resolution proton magnetic resonance spectroscopy was performed on tissue specimens from 33 patients with astrocytic tumors (22 astrocytomas, 11 glioblastomas) and 13 patients with meningiomas. For all patients, samples of primary tumors and their first recurrences were examined. Increased anaplasia, with respect to malignant transformation, resulting in a higher malignancy grade, was present in 11 recurrences of 22 astrocytoma patients. Spectroscopic features of tumor types, as determined on samples of the primary occurrences, were in good agreement with previous studies. Compared with the respective primary astrocytomas, characteristic features of glioblastomas were significantly increased concentrations of alanine (Ala) (p = 0.005), increased metabolite ratios of glycine (Gly)/total creatine (tCr) (p = 0.0001) and glutamate (Glu)/glutamine (Gln) (p = 0.004). Meningiomas showed increased Ala (p = 0.02) and metabolite ratios [Gly, total choline (tCho), Ala] over tCr (p = 0.001) relative to astrocytomas, and N-acetylaspartate and myo-inositol were absent. Metabolic changes of an evolving tumor were observed in recurrent astrocytomas: owing to their consecutive assessments, more indicators of malignant degeneration were detected in astrocytoma recurrences (e.g. Gly, p = 0.029; tCho, p = 0.034; Glu, p = 0.015; tCho/tCr, p = 0.001) in contrast to the comparison of primary astrocytomas with primary glioblastomas. The present investigation demonstrated a correlation of the tCho-signal with tumor progression. Significantly elevated concentrations of Ala (p = 0.037) and Glu (p = 0.003) and metabolite ratio tCho/tCr (p = 0.005) were even found in recurrent low-grade astrocytomas with unchanged histopathological grading (n = 11). This may be related to an early stage of malignant transformation, not yet detectable morphologically, and emphasizes the high sensitivity of 1H NMR spectroscopy in elucidating characteristics of brain tumor metabolism.     

烟酰胺腺嘌呤二核苷酸激酶2在恶性脑肿瘤中的普遍标志性表达

目的 检测烟酰胺腺嘌呤二核苷酸激酶2（NADK2）在恶性脑肿瘤中的表达。 方法 使用免疫组织化学法检测了NADK2在75例恶性脑肿瘤中的表达。结果 本实验检测了NADK2在75例恶性脑肿瘤中的表达情况,包括55例星形细胞瘤、13例少突神经细胞瘤、3例髓母细胞瘤和4例室管膜瘤,74例样本中NADK2的表达都明显高于正常对照组织。对免疫组织化学结果进行吸光度分析,比较NADK2在不同肿瘤类型和不同分级的脑肿瘤中的表达,结果表明,NADK2在恶性脑肿瘤中的表达与肿瘤类型和分级无关。结论 高表达NADK2是恶性脑肿瘤的一个普遍特征。     

三维颅脑容积成像在小儿颅内肿瘤诊断中的价值

目的分析三维颅脑容积成像(3D BRAVO)在小儿颅内良恶性肿瘤鉴别诊断中的价值。方法选取71例颅内肿瘤患儿为观察对象,均行颅脑MRI普通增强扫描和3D BRAVO。观察MRI普通增强扫描和MRI普通增强扫描+3D BRAVO的肿瘤检出情况、不同直径肿瘤检出情况及良恶性肿瘤检出情况。结果MRI普通增强扫描+3D BRAVO的肿瘤检出符合率高于MRI普通增强扫描(χ²=25.101,P=0.001)。MRI普通增强扫描+3D BRAVO对不同直径肿瘤的检出符合率高于MRI普通增强扫描(χ²=3.842,P=0.021)。MRI普通增强扫描+3D BRAVO的良恶性肿瘤检出符合率均明显高于MRI普通增强扫描(χ²=13.940、9.401,P=0.000、0.002)。MRI普通增强扫描+3D BRAVO对肿瘤良恶性鉴别的准确率、敏感度、特异度、阳性预测率、阴性预测率(96.04%、91.43%、98.48%、96.97%、95.59%)均高于MRI普通增强扫描(71.29%、60.00%、77.27%、58.33%、78.46%),差异有统计学意义(χ²=22.638、9.401、13.940、14.430、6.153,P=0.000、0.002、0.000、0.000、0.013)。结论与单独使用MRI普通增强扫描相比,MRI普通增强扫描辅以3D BRAVO在小儿颅内肿瘤诊断中有更高的肿瘤检出符合率和不同直径肿瘤检出符合率,在准确鉴别颅内良恶性肿瘤上更具优势。