Detection of structural abnormalities of cortical and subcortical gray matter in patients with MRI-negative refractory epilepsy using neurite orientation dispersion and density imaging

PurposeNODDI (Neurite Orientation Dispersion and Density Imaging) and DTI (Diffusion tensor imaging) may be useful in identifying abnormal regions in patients with MRI-negative refractory epilepsy. The aim of this study was to determine whether NODDI and DTI maps including neurite density (ND), orientation dispersion index (ODI), mean diffusivity (MD) and fractional anisotropy (FA) can detect structural abnormalities in cortical and subcortical gray matter (GM) in these patients. The correlation between these parameters and clinical characteristics of the disease was also investigated.MethodsNODDI and DTI maps of 17 patients were obtained and checked visually. Region of interest (ROI) was drawn on suspected areas and contralateral regions in cortex. Contrast-to-noise ratio (CNR) was determined for each region. Furthermore volumetric data and mean values of ND, ODI, FA and MD of subcortical GM structures were calculated in both of the patients and controls. Finally, the correlations of these parameters in the subcortical with age of onset and duration of epilepsy were investigated.ResultsCortical abnormalities on ODI images were observed in eight patients qualitatively. CNR of ODI was significantly greater than FA and MD. The subcortical changes including decrease of FA and ND and increase of ODI in left nucleus accumbens and increase of the volume in right amygdala were detected in the patients.ConclusionsThe results revealed that NODDI can improve detection of microstructural changes in cortical and subcortical GM in patients with MRI negative epilepsy.     

A syngeneic glioma model to assess the impact of neural progenitor target cell age on tumor malignancy

Human glioma incidence, malignancy, and treatment resistance are directly proportional to patient age. Cell intrinsic factors are reported to contribute to human age-dependent glioma malignancy, but suitable animal models to examine the role of aging are lacking. Here, we developed an orthotopic syngeneic glioma model to test the hypothesis that the age of neural progenitor cells (NPCs), presumed cells of glioma origin, influences glioma malignancy. Gliomas generated from transformed donor 3-, 12-, and 18-month-old NPCs in same-aged adult hosts formed highly invasive glial tumors that phenocopied the human disease. Survival analysis indicated increased malignancy of gliomas generated from older 12- and 18-month-old transformed NPCs compared with their 3-month counterparts (median survival of 38.5 and 42.5 vs. 77 days, respectively). This study showed for the first time that age of target cells at the time of transformation can affect malignancy and demonstrated the feasibility of a syngeneic model using transformed NPCs for future examination of the relative impacts of age-related cell intrinsic and cell-extrinsic factors in glioma malignancy.     

Cytoplasmic suppression of malignancy

Summary Using both normal and transformed rat liver epithelial cells to prepare cytoplasmic hybrids (cybrids) we have found evidence to support the theory that the cytoplasm from a normal cell can suppress tumorigenicity. A unique aspect of this study is that all of the cells utilized, both normal and malignantly transformed, were derived from an original cloned cell. We found that fusing cytoplasts from normal cells to malignantly transformed whole cells resulted in cybrid clones which, when injected into newborn rat pups, isogenic with those from which the cell culture was initiated, yielted tumors in 51% of the animals injected compared to 92% of the animals injected with the tumorigenic parent. Those animals that did develop tumors from the cybrid cells survived longer than those injected with cells from the tumorigenic parent. Thus, the cybrid, formed of cytoplasm from both parents, was less tumorigenic than the malignantly transformed parent cell. When reconstituted cells were prepared by fusing cytoplasts from normal cells with karyoplasts from malignantly transformed cells, a situation in which essentially all of the cytoplasm of the reconstituted cell is derived from normal cells, the tumorigenic phenotype was extinguished. This work was supported in part by United States Public Health Service grant CA12056, and grant CA09100 from the National Cancer Institute, Bethesda, MD. This work is partial fulfillment for the degree of Doctor of Philosophy for B.A.I.     

Increased age of transformed mouse neural progenitor/stem cells recapitulates age‐dependent clinical features of human glioma malignancy

Increasing age is the most robust predictor of greater malignancy and treatment resistance in human gliomas. However, the adverse association of clinical course with aging is rarely considered in animal glioma models, impeding delineation of the relative importance of organismal versus progenitor cell aging in the genesis of glioma malignancy. To address this limitation, we implanted transformed neural stem/progenitor cells (NSPCs), the presumed cells of glioma origin, from 3‐ and 18‐month‐old mice into 3‐ and 20‐month host animals. Transplantation with progenitors from older animals resulted in significantly shorter (P ≤ 0.0001) median survival in both 3‐month (37.5 vs. 83 days) and 20‐month (38 vs. 67 days) hosts, indicating that age‐dependent changes intrinsic to NSPCs rather than host animal age accounted for greater malignancy. Subsequent analyses revealed that increased invasiveness, genomic instability, resistance to therapeutic agents, and tolerance to hypoxic stress accompanied aging in transformed NSPCs. Greater tolerance to hypoxia in older progenitor cells, as evidenced by elevated HIF‐1 promoter reporter activity and hypoxia response gene (HRG) expression, mirrors the upregulation of HRGs in cohorts of older vs. younger glioma patients revealed by analysis of gene expression databases, suggesting that differential response to hypoxic stress may underlie age‐dependent differences in invasion, genomic instability, and treatment resistance. Our study provides strong evidence that progenitor cell aging is responsible for promoting the hallmarks of age‐dependent glioma malignancy and that consideration of progenitor aging will facilitate development of physiologically and clinically relevant animal models of human gliomas.     

The cytologic criteria of malignancy

Cytology and cell biology are two separate fields that share a focus on cancer. Cancer is still diagnosed based on morphology, and surprisingly little is known about the molecular basis of the defining structural features. Cytology uses the smallest possible biopsy for diagnosis by reducing morphologic “criteria of malignancy” to the smallest scale. To begin to develop common ground, members of the American Society of Cytopathology Cell Biology Liaison Working Group classify some of the “criteria of malignancy” and review their relation to current cell biology concepts. The criteria of malignancy are extremely varied, apparently reflecting many different pathophysiologies in specific microenvironments. Criteria in Group 1 comprise tissue‐level alterations that appear to relate to resistance to anoikis, alterations in cell adhesion molecules, and loss of apical–basal polarity. Criteria in Group 2 reflect genetic instability, including chromosomal and possibly epigenetic instability. Criteria in Groups 3 are subcellular structural changes involving cytoplasmic components, nuclear lamina, chromatin and nucleoli that cannot be accounted for by genetic instability. Some distinct criteria in Group 3 are known to be induced by cancer genes, but their precise structural basis remains obscure. The criteria of malignancy are not closely related to the histogenetic classification of cancers, and they appear to provide an alternative, biologically relevant framework for establishing common ground between cytologists and cell biologists. To understand the criteria of malignancy at a molecular level would improve diagnosis, and likely point to novel cell physiologies that are not encompassed by current cell biology concepts. J. Cell. Biochem. 110: 795–811, 2010. © 2010 Wiley‐Liss, Inc.     

Mathematical modeling of the malignancy of cancer using graph evolution

We report a novel computational method based on graph evolution process to model the malignancy of brain cancer called glioma. In this work, we analyze the phases that a graph passes through during its evolution and demonstrate strong relation between the malignancy of cancer and the phase of its graph. From the photomicrographs of tissues, which are diagnosed as normal, low-grade cancerous and high-grade cancerous, we construct cell-graphs based on the locations of cells; we probabilistically generate an edge between every pair of cells depending on the Euclidean distance between them. For a cell-graph, we extract connectivity information including the properties of its connected components in order to analyze the phase of the cell-graph. Working with brain tissue samples surgically removed from 12 patients, we demonstrate that cell-graphs generated for different tissue types evolve differently and that they exhibit different phase properties, which distinguish a tissue type from another.     

Spatial characteristics of newly diagnosed grade 3 glioma assessed by magnetic resonance metabolic and diffusion tensor imaging

The spatial heterogeneity in magnetic resonance (MR) metabolic and diffusion parameters and their relationship were studied for patients with treatment-naive grade 3 gliomas. MR data were evaluated from 51 patients with newly diagnosed grade 3 gliomas. Anatomic, diffusion, and metabolic imaging data were considered. Variations in metabolite levels, apparent diffusion coefficient (ADC), and fractional anisotropy (FA) were evaluated in regions of gadolinium enhancement and T2 hyperintensity as well as regions with abnormal metabolic signatures. Contrast enhancement was present in only 21 of the 51 patients. When present, the enhancing component of the lesion had higher choline-to-N-acetylaspartate index (CNI), higher choline, lower N-acetylaspartate, similar creatine, similar ADC and FA, and higher lactate/lipid than the nonenhancing lesion. Regions with CNI ≥ 4 had higher choline, lower N-acetylaspartate, higher lactate/lipid, higher ADC, and lower FA than normal-appearing white matter and regions with intermediate CNI values. For lesions that exhibited gadolinium enhancement, the metabolite levels and diffusion parameters in the region of enhancement were consistent with it corresponding to the most abnormal portion of the tumor. For nonenhancing lesions, areas with CNI ≥ 4 were the most abnormal in metabolic and diffusion parameters. This suggests that the region with the highest CNI might provide a good target for biopsies for nonenhancing lesions to obtain a representative histologic diagnosis of its degree of malignancy. Metabolic and diffusion parameter levels may be of interest not only for directing tissue sampling but also for defining the targets for focal therapy and assessing response to therapy.     

Possible role of fibronectin in malignancy

Frozen sections of tumors induced by injecting virally transformed cells into animals were stained for fibronectin by immunofluorescence. Many tumor cell lines do not express fibronectin in tumors in situ even though some of them express fibronection in culture. Cell shape and hormones appear to influence the expression of fibronectin in culture; however, it is nuclear how fibronection expression is regulated in vivo.     

血液恶性肿瘤患者肠道菌群分析

目的 将血液恶性肿瘤患者肠道菌群与健康个体进行比较,观察血液肿瘤患者肠道菌群结构的变化,探讨肠道菌群与血液恶性肿瘤发生发展的联系。方法 收集血液恶性肿瘤患者与健康志愿者粪便样品,提取样品中菌群总DNA,然后通过变性凝胶梯度电泳（DGGE）技术分析肠道菌群多样性和差异性。结果 血液恶性肿瘤组与健康组肠道菌群的DGGE指纹图谱有明显差异。与正常组相比,患者组肠道大肠埃希菌呈现过度增长趋势,有益菌柔嫩梭菌减少或缺失,某些患者肠道内一些细菌呈现特异性增长,如粪肠球菌、硫磺肠球菌、约氏不动杆菌等。结论 与健康对照组相比,血液恶性肿瘤患者肠道菌群结构与多样性发生改变,这可能为血液恶性肿瘤早期抗感染提供实验依据。     

Parameter comparison of white matter diffusion tensor imaging (DTI) in rhesus macaques (Macaca mulatta)

In this study, we analyzed diffusion tensor imaging(DTI) results of brain white matter in rhesus macaques(Macaca mulatta) with four different parameter settings and found that the sequence A(b=1 000 s/mm2, spatial resolution=1.25 mm×1.25 mm× 1.25 mm, numbers of direction=33, NSA=3) and B(b=800 s/mm2, spatial resolution=1.25 mm×1.25 mm×1.25 mm, numbers of direction=33, NSA=3) could accurately track coarse fibers. The fractional anisotropy(FA) derived from sequence C(b=1 000s/mm2, spatial resolution=0.55 mm×0.55 mm×2.5 mm, direction number=33, NSA=3) was too fuzzy to be used in tracking white matter fibers. By comparison, the high resolution and the FA with high contrast of gray matter and white matter derived from sequence D(b=800 s/mm2, spatial resolution=1.0 mm×1.0 mm ×1.0 mm, numbers of direction=33, NSA=3) qualified in its application in tracking both thick and thin fibers, making it an optimal DTI setting for rhesus macaques.     

国产伏立康唑治疗侵袭性真菌感染6例临床观察

目的观察国产伏立康唑治疗恶性血液病患者侵袭性真菌感染（IFI）的临床疗效和安全性。方法以国产伏立康唑治疗6例发生于恶性血液病患者的侵袭性真菌感染,观察疗效及不良反应。结果6例患者中,有效4例,其中完全反应3例,部分反应1例。1例用药第6天出现低钾血症。结论国产伏立康唑是治疗恶性血液病患者侵袭性真菌感染的安全有效的药物,     

首发为食管鳞癌的多原发癌患者临床特征及生存分析

目的:回顾性分析首发癌为食管鳞癌的多原发癌(ESCCFPM)患者的肿瘤临床特点以及生存预后等临床信息,更好的了解食管鳞癌与其他癌症之间的联系,为指导临床诊治提供相应依据.方法:收集美国国立癌症研究所监测、流行病学和结果数据库(SEER) 2004年1月1日至2016年12月31日ESCCFPM患者临床资料,Kaplan...     

A method of direct-viewing comparative analysis of tumour cell motility in vitro; effect of pH and adhesion on cells of different malignancy

A novel method for the comparative analysis of cell motility by direct viewing was developed and used in a preliminary study of sarcoma cells. Three cell lines from the RPS family of sarcomas in inbred LEW/CUB rats which differ in the incidence of spontaneous metastasis were studied. A system of four different culture conditions, designed to mimic the stress within the tumour, was created by changing and combining two variables: the pH of the medium (with 2% calf serum only), which was either physiological at 7.4 or 6.6; and the adhesiveness of the culture substratum, which was either at a standard level or decreased. It was found that changing the pH from 7.4 to 6.6 in a single step slowed the cells down, and also changed the way in which they moved, from «walking« in random directions to moving in a more directional way. Making the culture surface less adhesive sped up cell locomotion. Decreasing the adhesiveness of the culture substratum and the pH simultaneously stimulated the migration of highly metastasizing cells preferentially. Thus we have found a way to distinguish between highly metastasizing A297Nb sarcoma cells and poorly metastasizing T15 and non-metastasizing K2 sarcoma cells, a distinction that could not be made by a simple examination of the cells. It is concluded that a comparison of cell motility by directly viewing the cells under different conditions may be useful when investigating the in vitro motility properties of malignant cells.     

Differentiation between glioma and radiation necrosis using molecular magnetic resonance imaging of endogenous proteins and peptides

It remains difficult to distinguish tumor recurrence from radiation necrosis after brain tumor therapy. Here we show that these lesions can be distinguished using the amide proton transfer (APT) magnetic resonance imaging (MRI) signals of endogenous cellular proteins and peptides as an imaging biomarker. When comparing two models of orthotopic glioma (SF188/V+ glioma and 9L gliosarcoma) with a model of radiation necrosis in rats, we could clearly differentiate viable glioma (hyperintense) from radiation necrosis (hypointense to isointense) by APT MRI. When we irradiated rats with U87MG gliomas, the APT signals in the irradiated tumors had decreased substantially by 3 d and 6 d after radiation. The amide protons that can be detected by APT provide a unique and noninvasive MRI biomarker for distinguishing viable malignancy from radiation necrosis and predicting tumor response to therapy.     

脂肪细胞分化及其调控的研究进展

肥胖症等多种代谢疾病在全世界范围内的流行使得人们高度关注脂肪沉积调控的机制研究。在细胞水平上,脂肪组织的沉积是脂肪细胞数目增加和单个细胞体积增大的结果。其中,脂肪细胞数目由多潜能干细胞定向分化为前体脂肪细胞的程度决定,而单个细胞体积则与其分化程度和甘油三酯积累量相关。因此,揭示脂肪细胞分化的细胞和分子机制,将为上述代谢性疾病预防和治疗提供重要的理论基础。本文对脂肪细胞的起源、脂肪细胞分化的体外研究模型、脂肪细胞分化的规律和调控以及脂肪细胞分化研究中关键的问题等方面的研究成果进行总结,综述了近年来关于脂肪细胞分化及其调控的研究进展。     

颈髓损伤的常规MRI表现与DTI技术临床应用

目的：比较不同时期颈髓损伤的MRI表现及DTI的应用价值。方法：收集急性颈髓压迫病例15例、慢性颈髓压迫病例23例、颈髓慢性压迫合并急性压迫病例12例。15例健康志愿者作为对照组。进行常规MRI检查,应用DTI检查测量表现扩散系数（ADC）值和各向异性分数（FA）。比较各组间ADC值和FA值,并进行统计学分析。结果：急性颈髓迫病例,常规MRI显示颈髓增粗,呈等T1长T2信号;慢性颈髓压迫病例,9例呈长T1长T2信号,14例呈等T1长T2信号;慢性颈髓压迫并急性压迫病例颈髓明显增粗,呈等、长T1明显长T2信号。与对照组比较：急性颈髓压迫组的ADC值和FA值均明显降低,两组的差异有显著性;慢性颈髓压迫组的FA值降低,ADC值增高,两组的差异有显著性;慢性脊髓压迫合并急性脊髓压迫组ADC值与对照组比较无差异,FA值低于对照组。颈髓压迫各组间ADC值及FA值比较差异显著。结论：不同时期颈髓损伤常规MRI图像缺乏特异性,根据ADC值及FA值可判断颈髓损伤的时期。     

生长分化因子9基因的分子生物学

生长分化因子9是卵母细胞分泌的一种生长因子,它对卵泡的生长分化起着重要作用。本文介绍了生长分化因子9的结构、功能和调控,生长分化因子9基因的克隆及基因结构、发育性表达和作用、定位和多态性,并讨论了该基因与哺乳动物繁殖性能的关系。     

颈髓损伤的常规MRI表现与DTI技术临床应用

目的:比较不同时期颈髓损伤的MRI表现及DTI的应用价值。方法:收集急性颈髓压迫病例15例、慢性颈髓压迫病例23例、颈髓慢性压迫合并急性压迫病例12例。15例健康志愿者作为对照组。进行常规MRI检查,应用DTI检查测量表观扩散系数(ADC)值和各向异性分数(FA)。比较各组间ADC值和FA值,并进行统计学分析。结果:急性颈髓迫病例,常规MRI显示颈髓增粗,呈等T1长T2信号;慢性颈髓压迫病例,9例呈长T1长T2信号,14例呈等T1长T2信号;慢性颈髓压迫并急性压迫病例颈髓明显增粗,呈等、长T1明显长T2信号。与对照组比较:急性颈髓压迫组的ADC值和FA值均明显降低,两组的差异有显著性;慢性颈髓压迫组的FA值降低,ADC值增高,两组的差异有显著性;慢性脊髓压迫合并急性脊髓压迫组ADC值与对照组比较无差异,FA值低于对照组。颈髓压迫各组间ADC值及FA值比较差异显著。结论:不同时期颈髓损伤常规MRI图像缺乏特异性,根据ADC值及FA值可判断颈髓损伤的时期。