• 【招募华裔美国老年人进入痴呆症研究: 加州大学旧金山分校ADRC的经验。】 复制标题 收藏 收藏
    DOI:10.1093/geront/gnr033 复制DOI
    作者列表:Chao SZ,Lai NB,Tse MM,Ho RJ,Kong JP,Matthews BR,Miller BL,Rosen HJ
    BACKGROUND & AIMS: PURPOSE:To describe the results of efforts to recruit Asian Americans into longitudinal research on cognitive decline in aging. DESIGN AND METHODS:Recruitment strategies include clinics for assessment of cognitive impairment at the University of California, San Francisco campus and San Francisco's Chinatown, lectures to local health care providers and community members, participation in community events, and publications in mass media. RESULTS:Over 200 Chinese patients were evaluated in our outreach clinic. Many were primarily Chinese speaking with low levels of education. One hundred and twenty-five participants enrolled, and annual follow-up has been 88%. Among enrollees, 36% were recruited from our clinical service; 30% via word of mouth; and the rest from community lectures and events, flyers, and mass media. Participants who enrolled were relatively highly educated, tended to be interested in learning about their cognitive abilities, and were supportive of the goals of research. IMPLICATIONS:Despite the significant cultural and linguistic barriers, Chinese Americans can be successfully recruited into longitudinal studies of aging and cognitive impairment. Clinical services are a critical component of such an effort, and low education and other factors that may be associated with it are clear barriers to research participation.
    背景与目标:
  • 【血浆神经丝光在佛罗里达阿尔茨海默病研究中心 (ADRC) 的应用。】 复制标题 收藏 收藏
    DOI:10.3233/JAD-200901 复制DOI
    作者列表:
    BACKGROUND & AIMS: BACKGROUND:Plasma NfL (pNfL) levels are elevated in many neurological disorders. However, the utility of pNfL in a clinical setting has not been established. OBJECTIVE:In a cohort of diverse older participants, we examined: 1) the association of pNfL to age, sex, Hispanic ethnicity, diagnosis, and structural and amyloid imaging biomarkers; and 2) its association to baseline and longitudinal cognitive and functional performance. METHODS:309 subjects were classified at baseline as cognitively normal (CN) or with cognitive impairment. Most subjects had structural MRI and amyloid PET scans. The most frequent etiological diagnosis was Alzheimer's disease (AD), but other neurological and neuropsychiatric disorders were also represented. We assessed the relationship of pNfL to cognitive and functional status, primary etiology, imaging biomarkers, and to cognitive and functional decline. RESULTS:pNfL increased with age, degree of hippocampal atrophy, and amyloid load, and was higher in females among CN subjects, but was not associated with Hispanic ethnicity. Compared to CN subjects, pNfL was elevated among those with AD or FTLD, but not those with neuropsychiatric or other disorders. Hippocampal atrophy, amyloid positivity and higher pNfL levels each added unique variance in predicting greater functional impairment on the CDR-SB at baseline. Higher baseline pNfL levels also predicted greater cognitive and functional decline after accounting for hippocampal atrophy and memory scores at baseline. CONCLUSION:pNfL may have a complementary and supportive role to brain imaging and cognitive testing in a memory disorder evaluation, although its diagnostic sensitivity and specificity as a stand-alone measure is modest. In the absence of expensive neuroimaging tests, pNfL could be used for differentiating neurodegenerative disease from neuropsychiatric disorders.
    背景与目标:
  • 【阿尔茨海默病的心血管损害: Bryan ADRC的尸检结果。】 复制标题 收藏 收藏
    DOI:10.1155/JBB.2005.189 复制DOI
    作者列表:Corder EH,Ervin JF,Lockhart E,Szymanski MH,Schmechel DE,Hulette CM
    BACKGROUND & AIMS:
    背景与目标:
  • 【脂肪来源的再生细胞 (ADRC) 富集脂肪移植治疗部分乳房切除术缺陷的前瞻性试验: RESTORE-2试验。】 复制标题 收藏 收藏
    DOI:10.1016/j.ejso.2012.02.178 复制DOI
    作者列表:Pérez-Cano R,Vranckx JJ,Lasso JM,Calabrese C,Merck B,Milstein AM,Sassoon E,Delay E,Weiler-Mithoff EM
    BACKGROUND & AIMS: AIMS:Women undergoing breast conservation therapy (BCT) for breast cancer are often left with contour defects and few acceptable reconstructive options. RESTORE-2 is the first prospective clinical trial using autologous adipose-derived regenerative cell (ADRC)-enriched fat grafting for reconstruction of such defects. This single-arm, prospective, multi-center clinical trial enrolled 71 patients post-BCT with defects ≤150 mL. METHODS:Adipose tissue was collected via syringe lipoharvest and then processed during the same surgical procedure using a closed automated system that isolates ADRCs and prepares an ADRC-enriched fat graft for immediate re-implantation. ADRC-enriched fat graft injections were performed in a fan-shaped pattern to prevent pooling of the injected fat. Overall procedure times were less than 4 h. The RESTORE-2 protocol allowed for up to two treatment sessions and 24 patients elected to undergo a second procedure following the six month follow-up visit. RESULTS:Of the 67 patients treated, 50 reported satisfaction with treatment results through 12 months. Using the same metric, investigators reported satisfaction with 57 out of 67 patients. Independent radiographic core laboratory assessment reported improvement in the breast contour of 54 out of 65 patients based on blinded assessment of MRI sequence. There were no serious adverse events associated with the ADRC-enriched fat graft injection procedure. There were no reported local cancer recurrences. Injection site cysts were reported as adverse events in ten patients. CONCLUSION:This prospective trial demonstrates the safety and efficacy of the treatment of BCT defects utilizing ADRC-enriched fat grafts.
    背景与目标:
  • 【阿尔茨海默氏病患者一级亲属的风险模式。】 复制标题 收藏 收藏
    DOI:10.1001/archpsyc.1994.03950070069012 复制DOI
    作者列表:Silverman JM,Li G,Zaccario ML,Smith CJ,Schmeidler J,Mohs RC,Davis KL
    BACKGROUND & AIMS: BACKGROUND:Although an increased cumulative risk for primary progressive dementia (PPD) has been repeatedly demonstrated in relatives of probands with Alzheimer's disease (AD), an examination of their rates of illness at different ages has not been previously undertaken. Such an examination might reveal possible age-related characteristics associated with a more familial variety of AD. METHODS:Using family history interviews and survival analysis, the cumulative risk for and 5-year age-specific hazard rates of PPD were assessed in the first-degree relatives of 200 probands with AD and two nondemented control groups--179 elderly ascertained through the Alzheimer's Disease Research Center (ADRC-derived controls) and 427 elderly ascertained from community senior centers (community controls). RESULTS:The PPD risk curve for the relatives of probands with AD rose to about 30% and was significantly higher than the curves for the relatives of the ADRC-derived and community controls, where comparable rates were observed (approximately 12%). The age-specific hazard rates of PPD were calculated in three groups of relatives for each 5-year interval from ages 45 to 49 years through ages 85 to 89 years. The age-specific relative risk (RRi) for PPD in the relatives of probands with AD began to steadily diminish from the 75- to 79-year age interval (RRi = 13.49) through the 85- to 89-year age interval (RRi = 0.96) compared with the relatives of ADRC-derived controls and from the 60- to 64-year age interval (RRi = 16.15) through the 85- to 89-year age interval (RRi = 2.03) compared with the relatives of the community controls. CONCLUSIONS:These data indicate that, for relatives of probands with AD, while the lifetime risk for PPD is greater than in relatives of controls, the familial contribution to the risk for PPD decreases with increasing age. The higher risk for PPD in relatives of probands with AD may be substantially diminished or even eliminated by the latter half of the ninth decade.
    背景与目标:
  • 【心肌细胞在急性心肌梗死中通过网格蛋白介导的内吞作用捕获干细胞衍生的抗凋亡microRNA-214。】 复制标题 收藏 收藏
    DOI:10.1074/jbc.RA119.007537 复制DOI
    作者列表:Eguchi S,Takefuji M,Sakaguchi T,Ishihama S,Mori Y,Tsuda T,Takikawa T,Yoshida T,Ohashi K,Shimizu Y,Hayashida R,Kondo K,Bando YK,Ouchi N,Murohara T
    BACKGROUND & AIMS: :Extracellular vesicles (EVs) have emerged as key mediators of intercellular communication that have the potential to improve cardiac function when used in cell-based therapy. However, the means by which cardiomyocytes respond to EVs remains unclear. Here, we sought to clarify the role of exosomes in improving cardiac function by investigating the effect of cardiomyocyte endocytosis of exosomes from mesenchymal stem cells on acute myocardial infarction (MI). Exposing cardiomyocytes to the culture supernatant of adipose-derived regenerative cells (ADRCs) prevented cardiomyocyte cell damage under hypoxia in vitro. In vivo, the injection of ADRCs into the heart simultaneous with coronary artery ligation decreased overall cardiac infarct area and prevented cardiac rupture after acute MI. Quantitative RT-PCR-based analysis of the expression of 35 known anti-apoptotic and secreted microRNAs (miRNAs) in ADRCs revealed that ADRCs express several of these miRNAs, among which miR-214 was the most abundant. Of note, miR-214 silencing in ADRCs significantly impaired the anti-apoptotic effects of the ADRC treatment on cardiomyocytes in vitro and in vivo To examine cardiomyocyte endocytosis of exosomes, we cultured the cardiomyocytes with ADRC-derived exosomes labeled with the fluorescent dye PKH67 and found that hypoxic culture conditions increased the levels of the labeled exosomes in cardiomyocytes. Chlorpromazine, an inhibitor of clathrin-mediated endocytosis, significantly suppressed the ADRC-induced decrease of hypoxia-damaged cardiomyocytes and also decreased hypoxia-induced cardiomyocyte capture of both labeled EVs and extracellular miR-214 secreted from ADRCs. Our results indicate that clathrin-mediated endocytosis in cardiomyocytes plays a critical role in their uptake of circulating, exosome-associated miRNAs that inhibit apoptosis.
    背景与目标: : 细胞外囊泡 (ev) 已成为细胞间通讯的关键介质,当用于基于细胞的治疗时,它们具有改善心脏功能的潜力。然而,心肌细胞对EVs的反应方式尚不清楚。在这里,我们试图通过研究间充质干细胞外泌体的心肌细胞内吞作用对急性心肌梗死 (MI) 的影响来阐明外泌体在改善心脏功能中的作用。将心肌细胞暴露于脂肪来源的再生细胞 (ADRCs) 的培养上清液可防止体外缺氧条件下心肌细胞损伤。在体内,在冠状动脉结扎的同时向心脏注射ADRCs可减少整个心脏梗塞面积,并防止急性MI后心脏破裂。基于rt-pcr的定量分析35个已知的抗凋亡和分泌的microrna (mirna) 在ADRCs中的表达表明,ADRCs表达了其中的几种mirna,其中miR-214是最丰富的。值得注意的是,ADRCs中的miR-214沉默显着损害了ADRC治疗对体外和体内心肌细胞的抗凋亡作用,以检查外泌体的心肌细胞内吞作用,我们用荧光染料PKH67标记的ADRC衍生的外泌体培养了心肌细胞,发现低氧培养条件增加了心肌细胞中标记外泌体的水平。氯丙嗪是网格蛋白介导的内吞作用的抑制剂,可显着抑制ADRC诱导的缺氧损伤心肌细胞的减少,并减少缺氧诱导的心肌细胞捕获标记的ev和ADRC分泌的细胞外miR-214。我们的结果表明,网格蛋白介导的心肌细胞内吞作用在其吸收循环的,抑制凋亡的外泌体相关mirna中起关键作用。
  • 【心理状态短期测验和蒙特利尔认知评估在整个认知范围内的比较。】 复制标题 收藏 收藏
    DOI:10.1016/j.mayocp.2019.01.043 复制DOI
    作者列表:Townley RA,Syrjanen JA,Botha H,Kremers WK,Aakre JA,Fields JA,Machulda MM,Graff-Radford J,Savica R,Jones DT,Knopman DS,Petersen RC,Boeve BF
    BACKGROUND & AIMS: OBJECTIVE:To compare the Short Test of Mental Status (STMS) with the Montreal Cognitive Assessment (MoCA) for predicting and detecting mild cognitive impairment (MCI). PARTICIPANTS AND METHODS:Participants from the community-based Mayo Clinic Study of Aging (MCSA) (November 24, 2010, through May 19, 2012) and an academic referral Alzheimer's Disease Research Center (ADRC) (March 16, 2015, through September 5, 2018) were analyzed. All participants were evaluated using a standardized neuropsychological battery, and a multidisciplinary consensus diagnosis was assigned. The MCSA and ADRC samples included 313 and 106 stable cognitively normal (CN) participants, 72 and 8 CN participants at baseline who developed incident MCI or dementia, 114 and 96 participants with prevalent MCI, and 25 and 132 participants with dementia, respectively. RESULTS:There were no statistically significant differences between the 2 tests in 6 of 7 diagnostic comparisons across academic referral and community populations. The STMS had a better area under the curve (0.90; 95% CI, 0.87-0.93) for differentiating prevalent MCI from CN participants in the MCSA cohort compared with the MoCA cohort (0.85; 95% CI, 0.81-0.89; P=.01). In addition, 53% of the stable CN participants (222 of 419) scored less than 26 on the MoCA, with specificity of 47% for diagnosing prevalent MCI. CONCLUSION:We provide evidence that the STMS performs similarly to the MoCA in a variety of settings and neurodegenerative syndromes. These results suggest that the current recommended MoCA cutoff score may be overly sensitive, consistent with previous studies. We also provide a conversion table for comparing the 2 cognitive tests.
    背景与目标:
  • 【前体蛋白的突变是泛素阳性额颞叶变性的主要原因。】 复制标题 收藏 收藏
    DOI:10.1093/hmg/ddl241 复制DOI
    作者列表:
    BACKGROUND & AIMS: :Null mutations in the progranulin gene (PGRN) were recently reported to cause tau-negative frontotemporal dementia linked to chromosome 17. We assessed the genetic contribution of PGRN mutations in an extended population of patients with frontotemporal lobar degeneration (FTLD) (N=378). Mutations were identified in 10% of the total FTLD population and 23% of patients with a positive family history. This mutation frequency dropped to 5% when analysis was restricted to an unbiased FTLD subpopulation (N=167) derived from patients referred to Alzheimer's Disease Research Centers (ADRC). Among the ADRC patients, PGRN mutations were equally frequent as mutations in the tau gene (MAPT). We identified 23 different pathogenic PGRN mutations, including a total of 21 nonsense, frameshift and splice-site mutations that cause premature termination of the coding sequence and degradation of the mutant RNA by nonsense-mediated decay. We also observed an unusual splice-site mutation in the exon 1 5' splice site, which leads to loss of the Kozac sequence, and a missense mutation in the hydrophobic core of the PGRN signal peptide. Both mutations revealed novel mechanisms that result in loss of functional PGRN. One mutation, c.1477C>T (p.Arg493X), was detected in eight independently ascertained familial FTLD patients who were shown to share a common extended haplotype over the PGRN genomic region. Clinical examination of patients with PGRN mutations revealed highly variable onset ages with language dysfunction as a common presenting symptom. Neuropathological examination showed FTLD with ubiquitin-positive cytoplasmic and intranuclear inclusions in all PGRN mutation carriers.
    背景与目标: : 最近据报道,progranulin基因 (PGRN) 的零突变会导致与17号染色体相关的tau阴性额颞叶痴呆。我们评估了PGRN突变在额颞叶变性 (FTLD) 患者的扩展人群中的遗传贡献 (N = 378)。在总FTLD人群的10% 和具有阳性家族史的患者的23% 中鉴定出突变。当分析限于来自转诊至阿尔茨海默氏病研究中心 (ADRC) 的患者的无偏FTLD亚群 (N = 167) 时,该突变频率降至5%。在ADRC患者中,PGRN突变与tau基因 (MAPT) 突变同样频繁。我们鉴定了23种不同的致病性PGRN突变,包括总共21种无义,移码和剪接位点突变,这些突变会导致编码序列过早终止并通过无义介导的衰变降解突变RNA。我们还观察到外显子1 5' 剪接位点的异常剪接位点突变,导致Kozac序列丢失,以及PGRN信号肽疏水核心的错义突变。这两个突变都揭示了导致功能性PGRN丧失的新机制。在八名独立确定的家族性FTLD患者中检测到一个突变c.1477C>T (p.Arg493X),这些患者在PGRN基因组区域上具有共同的扩展单倍型。PGRN突变患者的临床检查显示,发病年龄高度可变,语言功能障碍是常见的症状。神经病理学检查显示,在所有PGRN突变携带者中,FTLD具有泛素阳性的细胞质和核内包涵体。
  • 【评估阿尔茨海默氏病的遗传结构在记忆力下降的风险。】 复制标题 收藏 收藏
    DOI:10.3233/JAD-170834 复制DOI
    作者列表:Del-Aguila JL,Fernández MV,Schindler S,Ibanez L,Deming Y,Ma S,Saef B,Black K,Budde J,Norton J,Chasse R,Alzheimer’s Disease Neuroimaging Initiative (ADNI).,Harari O,Goate A,Xiong C,Morris JC,Cruchaga C
    BACKGROUND & AIMS: :Many genetic studies for Alzheimer's disease (AD) have been focused on the identification of common genetic variants associated with AD risk and not on other aspects of the disease, such as age at onset or rate of dementia progression. There are multiple approaches to untangling the genetic architecture of these phenotypes. We hypothesized that the genetic architecture of rate of progression is different than the risk for developing AD dementia. To test this hypothesis, we used longitudinal clinical data from ADNI and the Knight-ADRC at Washington University, and we calculated PRS (polygenic risk score) based on the IGAP study to compare the genetic architecture of AD risk and dementia progression. Dementia progression was measured by the change of Clinical Dementia Rating Sum of Boxes (CDR)-SB per year. Out of the 21 loci for AD risk, no association with the rate of dementia progression was found. The PRS rate was significantly associated with the rate of dementia progression (β= 0.146, p = 0.03). In the case of rare variants, TREM2 (β= 0.309, p = 0.02) was also associated with the rate of dementia progression. TREM2 variant carriers showed a 23% faster rate of dementia compared with non-variant carriers. In conclusion, our results indicate that the recently identified common and rare variants for AD susceptibility have a limited impact on the rate of dementia progression in AD patients.
    背景与目标: : 许多针对阿尔茨海默氏病 (AD) 的遗传学研究都集中在与AD风险相关的常见遗传变异的鉴定上,而不是该疾病的其他方面,例如发病年龄或痴呆进展速度。有多种方法可以解开这些表型的遗传结构。我们假设进展速度的遗传结构与发生AD痴呆的风险不同。为了验证这一假设,我们使用了来自ADNI和华盛顿大学Knight-ADRC的纵向临床数据,并基于IGAP研究计算了PRS (多基因风险评分),以比较AD风险和痴呆进展的遗传结构。通过每年临床痴呆评分总和 (CDR)-SB的变化来衡量痴呆的进展。在21个AD风险位点中,未发现与痴呆进展率相关。PRS率与痴呆进展率显著相关 (β =   0.146,p   =   0.03)。在罕见变异的情况下,TREM2 (β =   0.309,p   =   0.02) 也与痴呆的进展率相关。与非变异携带者相比,TREM2变异携带者的痴呆发生率23% 快。总之,我们的结果表明,最近发现的AD易感性的常见和罕见变异对AD患者痴呆进展率的影响有限。
  • 【通过非欧几里得小波的多分辨率形状特征: 在皮层厚度统计分析中的应用。】 复制标题 收藏 收藏
    DOI:10.1016/j.neuroimage.2014.02.028 复制DOI
    作者列表:Kim WH,Singh V,Chung MK,Hinrichs C,Pachauri D,Okonkwo OC,Johnson SC,Alzheimer's Disease Neuroimaging Initiative.
    BACKGROUND & AIMS: :Statistical analysis on arbitrary surface meshes such as the cortical surface is an important approach to understanding brain diseases such as Alzheimer's disease (AD). Surface analysis may be able to identify specific cortical patterns that relate to certain disease characteristics or exhibit differences between groups. Our goal in this paper is to make group analysis of signals on surfaces more sensitive. To do this, we derive multi-scale shape descriptors that characterize the signal around each mesh vertex, i.e., its local context, at varying levels of resolution. In order to define such a shape descriptor, we make use of recent results from harmonic analysis that extend traditional continuous wavelet theory from the Euclidean to a non-Euclidean setting (i.e., a graph, mesh or network). Using this descriptor, we conduct experiments on two different datasets, the Alzheimer's Disease NeuroImaging Initiative (ADNI) data and images acquired at the Wisconsin Alzheimer's Disease Research Center (W-ADRC), focusing on individuals labeled as having Alzheimer's disease (AD), mild cognitive impairment (MCI) and healthy controls. In particular, we contrast traditional univariate methods with our multi-resolution approach which show increased sensitivity and improved statistical power to detect a group-level effects. We also provide an open source implementation.
    背景与目标: : 对任意表面网格 (例如皮质表面) 进行统计分析是了解脑部疾病 (例如阿尔茨海默氏病 (AD)) 的重要方法。表面分析可能能够识别与某些疾病特征相关或表现出组间差异的特定皮质模式。本文的目标是使表面信号的组分析更加敏感。为此,我们推导了多尺度形状描述符,这些描述符以不同的分辨率水平表征每个网格顶点 (即其局部上下文) 周围的信号。为了定义这样的形状描述符,我们利用谐波分析的最新结果,将传统的连续小波理论从欧几里得扩展到非欧几里得设置 (即图,网格或网络)。使用此描述符,我们在两个不同的数据集上进行实验,即阿尔茨海默氏病神经成像计划 (ADNI) 数据和在威斯康星州阿尔茨海默氏病研究中心 (w-adrc) 获得的图像,重点是标记为患有阿尔茨海默氏病 (AD) 的个体,轻度认知障碍 (MCI) 和健康对照。特别是,我们将传统的单变量方法与我们的多分辨率方法进行了对比,后者显示出更高的灵敏度和更高的统计能力来检测组水平的影响。我们还提供了一个开源实现。
  • 【自体脂肪再生细胞的治疗性血管生成: 与骨髓单核细胞的比较。】 复制标题 收藏 收藏
    DOI:10.1152/ajpheart.00310.2014 复制DOI
    作者列表:Hao C,Shintani S,Shimizu Y,Kondo K,Ishii M,Wu H,Murohara T
    BACKGROUND & AIMS: :Transplantation of adipose-derived regenerative cell (ADRC) enhances ischemia-induced angiogenesis, but the underlying mechanism remains unknown. Here, we compared the efficacy between ADRC and bone marrow mononuclear cell (BM-MNC) transplantation in rabbits model of hindlimb ischemia and examined the possible roles of alternative phenotypic macrophages polarization in ADRC-mediated angiogenesis using mice model of hindlimb ischemia. ADRCs and BM-MNCs were isolated from New Zealand White rabbits and C57BL/6J mice. In rabbit studies, our data showed that ADRCs could incorporate into the endothelial vasculature in vitro and in vivo. Both ADRC-conditioned media (CM) and BM-MNC-CM enhanced the migratory ability and interrupted the process of apoptosis in human umbilical vein endothelial cells. Four weeks after cell transplantation, augmentation of postnatal neovascularization was observed in the ischemic muscle injected with either ADRCs or BM-MNCs. In mice studies, we presented that ADRCs polarized into the IL-10-releasing M2 macrophages through PGE2-EP2/4 axis and suppressed the expressions of TNF-α and IL-6 in the ischemic muscle. Gene expressions of several angiogenic cytokines were amplified in the macrophages cultured in ADRC-CM rather than BM-MNC-CM. Blockade of IL-10 using neutralizing MAb attenuated the ADRC-mediated angiogenesis and caused muscle apoptosis in vivo. In conclusion, ADRC transplantation harvested similar effect of neovascularization augmentation compared with BM-MNC in experimental rabbit model of hindlimb ischemia; ADRC displayed a unique immunoregulatory manner of accelerating IL-10-releasing M2 macrophages polarization through the PGE2-EP2/4 axis.
    背景与目标: 脂肪来源的再生细胞 (ADRC) 的移植增强了缺血诱导的血管生成,但其潜在机制仍然未知。在这里,我们比较了ADRC和骨髓单核细胞 (bm-mnc) 移植在兔后肢缺血模型中的功效,并使用后肢缺血小鼠模型研究了替代表型巨噬细胞极化在ADRC介导的血管生成中的可能作用。从新西兰白兔和C57BL/6J小鼠中分离出adrc和BM-mnc。在兔研究中,我们的数据表明ADRCs可以在体外和体内掺入内皮血管系统。ADRC条件培养基 (二1212) 和BM-MNC二1212均增强了人脐静脉内皮细胞的迁移能力并中断了凋亡过程。细胞移植后四周,在注射adrc或BM-mnc的缺血肌肉中观察到出生后新血管形成的增强。在小鼠研究中,我们提出ADRCs通过PGE2-EP2/4轴极化到IL-10-releasing M2巨噬细胞中,并抑制缺血肌肉中TNF-α 和IL-6的表达。在ADRC二1212而不是BM-MNC-二1212中培养的巨噬细胞中扩增了几种血管生成细胞因子的基因表达。使用中和MAb阻断IL-10会减弱ADRC介导的血管生成并在体内引起肌肉凋亡。总之,在后肢缺血的实验性兔模型中,ADRC移植获得了与bm-mnc相似的新血管形成增强作用; ADRC显示出通过PGE2-EP2/4轴加速IL-10-releasing M2巨噬细胞极化的独特免疫调节方式。
  • 【脂肪来源的再生细胞疗法治疗烧伤创面愈合: 两种递送方法的比较。】 复制标题 收藏 收藏
    DOI:10.1089/wound.2015.0672 复制DOI
    作者列表:Foubert P,Gonzalez AD,Teodosescu S,Berard F,Doyle-Eisele M,Yekkala K,Tenenhaus M,Fraser JK
    BACKGROUND & AIMS: :Objective: The use of noncultured autologous stromal vascular fraction or clinical grade adipose-derived regenerative cells (ADRCs) is a promising strategy to promote wound healing and tissue repair. Nevertheless, issues regarding the optimal mode of administration remain unclear. The purpose of this study was to compare the effects of local injection and topical spray delivery of ADRCs in a porcine model of thermal burns. Approach: Full-thickness thermal burns were created on the dorsum of 10 Gottingen minipigs. Two days following injury, wounds underwent fascial excision and were randomized to receive control vehicle or freshly isolated autologous ADRCs delivered by either multiple injections into or surrounding the wound bed, or by spray onto the wound surface (0.25 × 106 viable cells/cm2). Healing was evaluated by planimetry, histopathology, and immunohistochemistry at day 7, 12, 16, 21, and 28 posttreatment. Results:In vitro analysis demonstrated that there was no substantial loss of cell number or viability attributable to the spray procedure. Planimetric assessment revealed that delivery of ADRCs by either local injection or topical spray increased wound reepithelialization relative to control at day 14. No significant difference in wound reepithelialization was observed between both delivery approaches. In addition, on day 7 posttreatment, blood vessel density was greater in wounds receiving local or topical spray ADRCs than in the wounds treated with vehicle control. Histopathologic analysis suggests that ADRC treatment may modulate the inflammatory response by reducing neutrophil infiltration at day 7 and 12 posttreatment, irrespective of the route of administration. Conclusions: These data demonstrate that local injection and spray delivery of ADRCs modulate inflammation and improve wound angiogenesis and epithelialization. Importantly, both delivery routes exhibited similar effects on wound healing. Given the greater ease-of-use associated with topical spray delivery, these data support the use of a spray system for autologous ADRC delivery.
    背景与目标: 目的: 使用未培养的自体基质血管部分或临床级脂肪源性再生细胞 (ADRCs) 是促进伤口愈合和组织修复的一种有前途的策略。然而,关于最佳管理模式的问题仍然不清楚。这项研究的目的是比较局部注射和局部喷雾递送ADRCs在猪热烧伤模型中的效果。方法: 在10个Gottingen minipigs的背部产生了全层热烧伤。受伤后两天,伤口进行筋膜切除,并随机接受对照载体或新鲜分离的自体ADRCs,通过多次注射进入或围绕伤口床,或通过喷洒到伤口表面 (0.25  ×   106活细胞/cm2)。在治疗后第7、12、16、21和28天,通过平面测定法,组织病理学和免疫组织化学评估愈合情况。结果: 体外分析表明,喷雾过程没有造成细胞数量或活力的实质性损失。平面评估显示,与第14天的对照相比,通过局部注射或局部喷雾递送adrc会增加伤口上皮再形成。在两种递送方法之间,伤口再上皮化均未观察到显着差异。此外,在治疗后的第7天,接受局部或局部喷雾ADRCs的伤口的血管密度比接受媒介物控制的伤口要大。组织病理学分析表明,ADRC治疗可以通过减少治疗后第7天和第12天的中性粒细胞浸润来调节炎症反应,而与给药途径无关。结论: 这些数据表明ADRCs的局部注射和喷雾递送可调节炎症并改善伤口血管生成和上皮形成。重要的是,两种递送途径对伤口愈合均表现出相似的效果。鉴于与局部喷雾递送相关的更大的易用性,这些数据支持使用喷雾系统进行自体ADRC递送。
  • 【发现和合成含硫的6-取代的5,8-二甲氧基-1,4-萘醌肟衍生物作为新的和潜在的抗MDR癌症药物。】 复制标题 收藏 收藏
    DOI:10.1016/j.ejmech.2019.01.005 复制DOI
    作者列表:Huang G,Dong JY,Zhang QJ,Meng QQ,Zhao HR,Zhu BQ,Li SS
    BACKGROUND & AIMS: :Multi-drug resistance (MDR) to anticancer drugs is the primary impediment to successful treatment of cancer. Hunting for new compounds with potent anti-MDR activity is an effectual approach to conquer cancer drug resistance. In this work, 33 new sulfur-containing 1,4-naphthoquinone oxime derivatives were prepared and investigated for their cytotoxicity against a panel of tumor cell lines and fibroblast normal cell line. Cell-based assay showed that most of target compounds displayed more potent cytotoxic potency than positive controls. Meanwhile, all of compounds were non-toxic to normal cells. More importantly, the cytotoxic activity of these oxime derivatives toward drug-resistant cancer cell lines was found to be much stronger than that toward drug-susceptible cell lines (anti-drug resistance coefficient (ADRC) > 1). Of these, compound 12 m was identified as the most effective molecule with IC50 values in the range of 0.29 ± 0.01 to 1.33 ± 0.05 μM toward MDR sublines. Further mechanism studies demonstrated that 12 m could inhibit colony formation, cause G1 phase arrest and promote cell apoptosis mediated by augmenting Bax/Bcl-2 ratio of Bel7402/5-FU cells. Our findings provide promising start points for development of sulfur-containing 1,4-naphthoquinone oxime derivatives as potential anti-MDR agents.
    背景与目标: 对抗癌药物的多药耐药性 (MDR) 是成功治疗癌症的主要障碍。寻找具有有效抗MDR活性的新化合物是克服癌症耐药性的有效方法。在这项工作中,制备了33种新的含硫1,4-萘醌肟衍生物,并研究了它们对一组肿瘤细胞系和成纤维细胞正常细胞系的细胞毒性。基于细胞的分析表明,大多数目标化合物显示出比阳性对照更有效的细胞毒性。同时,所有化合物均对正常细胞无毒。更重要的是,发现这些肟衍生物对耐药癌细胞系的细胞毒性比对药物敏感细胞系的细胞毒性强得多 (抗耐药系数 (ADRC) >  1)。其中,化合物12 m被鉴定为最有效的分子,其IC50值在0.29   ±   0.01至1.33   ±   0.05  μ m的范围内。进一步的机制研究表明,12 m可以通过增加Bel7402/5-FU细胞的Bax/Bcl-2比值来抑制集落形成,引起G1期阻滞,促进细胞凋亡。我们的发现为开发含硫的1,4-萘醌肟衍生物作为潜在的抗MDR剂提供了有希望的起点。
  • 【缺血性心肌病患者脂肪来源的再生细胞: 精确试验。】 复制标题 收藏 收藏
    DOI:10.1016/j.ahj.2014.03.022 复制DOI
    作者列表:Perin EC,Sanz-Ruiz R,Sánchez PL,Lasso J,Pérez-Cano R,Alonso-Farto JC,Pérez-David E,Fernández-Santos ME,Serruys PW,Duckers HJ,Kastrup J,Chamuleau S,Zheng Y,Silva GV,Willerson JT,Fernández-Avilés F
    BACKGROUND & AIMS: AIMS:Adipose-derived regenerative cells (ADRCs) can be isolated from liposuction aspirates and prepared as fresh cells for immediate administration in cell therapy. We performed the first randomized, placebo-controlled, double-blind trial to examine the safety and feasibility of the transendocardial injections of ADRCs in no-option patients with ischemic cardiomyopathy. METHODS AND RESULTS:Procedural, postoperative, and follow-up safety end points were monitored up to 36 months. After baseline measurements, efficacy was assessed by echocardiography and single-photon emission computed tomography (6, 12, and 18 months), metabolic equivalents and maximal oxygen consumption (MVO2) (6 and 18 months), and cardiac magnetic resonance imaging (6 months). We enrolled 21 ADRC-treated and 6 control patients. Liposuction was well tolerated, ADRCs were successfully prepared, and transendocardial injections were feasible in all patients. No malignant arrhythmias were seen. Adverse events were similar between groups. Metabolic equivalents and MVO2 values were preserved over time in ADRC-treated patients but declined significantly in the control group. The difference in the change in MVO2 from baseline to 6 and 18 months was significantly better in ADRC-treated patients compared with controls. The ADRC-treated patients showed significant improvements in total left ventricular mass by magnetic resonance imaging and wall motion score index. Single-photon emission computed tomography results suggested a reduction in inducible ischemia in ADRC-treated patients up to 18 months. CONCLUSION:Isolation and transendocardial injection of autologous ADRCs in no-option patients were safe and feasible. Our results suggest that ADRCs may preserve ventricular function, myocardial perfusion, and exercise capacity in these patients.
    背景与目标:
  • 【自体细胞富集脂肪移植用于隆胸。】 复制标题 收藏 收藏
    DOI:10.1007/s00266-011-9727-7 复制DOI
    作者列表:Kamakura T,Ito K
    BACKGROUND & AIMS: :Autologous fat grafting for breast augmentation has faced some historical hurdles. However, in recent years it has been gaining acceptance from the medical community. This prospective, nonrandomized open-label study of 20 Japanese women supports the use of autologous fat grafting in breast augmentation and explores enhancement of fat graft tissue with autologous adipose-derived regenerative cells (ADRCs). After adipose harvesting using syringe liposuction, the tissue is processed in the Celution 800 System(®), which washes the graft and isolates ADRCs. The average cells per gram of harvested adipose tissue was 3.42 × 10(5), and the mean cell viability measured using an automated cell counting system before graft delivery was 85.3%. All patients demonstrated improvement in circumferential breast measurement (BRM) from their baseline state, and breast measurements were stable by 3 months after surgery. The mean BRM 9 months after surgery had increased 3.3 cm from preoperative measurements. Through 9 months, overall physician satisfaction was 69% and patient satisfaction was 75%. No serious or unexpected adverse events were reported, and the procedure was safe and well tolerated in all patients. Postoperative cyst formation was seen in two patients. These prospective results demonstrate that ADRC-enriched fat grafts processed with a closed automated system maintain high cell viability and that the procedure is safe and effective, with all patients showing improvement after a single treatment.
    背景与目标: : 自体脂肪移植隆胸面临一些历史障碍。但是,近年来,它已获得医学界的认可。这项针对20名日本女性的前瞻性,非随机开放标签研究支持在隆胸中使用自体脂肪移植,并探索用自体脂肪来源的再生细胞 (adrc) 增强脂肪移植组织。使用注射器吸脂进行脂肪采集后,在cellution 800系统中处理组织 (®),洗涤移植物并分离ADRCs。每克收获的脂肪组织的平均细胞为3.42 × 10(5),并且85.3% 在移植物递送之前使用自动细胞计数系统测量的平均细胞活力。所有患者的周围乳房测量 (BRM) 均从基线状态改善,并且在术后3个月时乳房测量稳定。手术后9个月的平均BRM与术前测量相比3.3厘米增加。通过9个月,医生的总体满意度69%,患者满意度75%。未报告严重或意外的不良事件,所有患者均安全且耐受性良好。两名患者术后出现囊肿形成。这些前瞻性结果表明,用封闭的自动化系统处理的富含ADRC的脂肪移植物可保持较高的细胞活力,并且该过程是安全有效的,所有患者在单次治疗后均显示出改善。

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