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Fibroblast Activation Protein is a GH Target: A Prospective Study of Patients with Acromegaly Before and After Treatment.

成纤维细胞激活蛋白是 GH 靶点: 肢端肥大症患者治疗前后的前瞻性研究。

  • 影响因子:5.19
  • DOI:10.1210/clinem/dgz033
  • 作者列表:"Arlien-Søborg MC","Grøndahl C","Bæk A","Dal J","Madsen M","Høgild ML","Pedersen SB","Bjerre M","Jørgensen JOL
  • 发表时间:2020-01-01
Abstract

BACKGROUND:Fibroblast growth factor 21 (FGF21) is a circulating hormone with pleiotropic metabolic effects, which is inactivated by fibroblast activation protein (FAP). Data regarding interaction between FGF21, FAP, and growth hormone (GH) are limited, but it is noteworthy that collagens are also FAP substrates, since GH potently stimulates collagen turnover. AIM:To measure circulating FGF21 components, including FAP, in patients with acromegaly before and after disease control. METHODS:Eighteen patients with active acromegaly were studied at the time of diagnosis and ≥ 6 months after disease control by either surgery or medical treatment. Serum levels of total and active FGF21, β-klotho, FAP, and collagen turnover markers were measured by immunoassays. Expression of putative FGF21-dependent genes were measured in adipose tissue by reverse transcriptase-polymerase chain reaction, body composition assessed by dual-energy x-ray absorptiometry scan, and insulin sensitivity estimated with homeostatic model assessment of insulin resistance (HOMA-IR). RESULTS:Total FGF21, active FGF21 and β-klotho remained unchanged. Insulin sensitivity and body fat mass increased after disease control but neither correlated with active FGF21. Expression of FGF21-dependent genes did not change after treatment. FAP levels (µg/L) were markedly reduced after treatment [105.6 ± 29.4 vs 62.2 ± 32.4, P < 0.000]. Collagen turnover markers also declined significantly after treatment and ΔFAP correlated positively with ΔProcollagen Type I (P < 0.000) and Type III (P < 0.000). CONCLUSION:1) Circulating FGF21 and β-klotho do not change in response to acromegaly treatment, 2) FAP concentrations in serum decrease after disease control and correlate positively with collagen turnover markers, and 3) FAP is a hitherto unrecognized GH target linked to collagen turnover. CLINICAL TRIALS REGISTRATION:NCT00647179.

摘要

背景: 成纤维细胞生长因子 21 (FGF21) 是一种具有多效性代谢作用的循环激素,被成纤维细胞激活蛋白 (FAP) 灭活。关于 FGF21 、 FAP 和生长激素 (GH) 之间相互作用的数据有限,但值得注意的是胶原也是 FAP 底物,因为 GH 强烈刺激胶原周转。 目的: 检测肢端肥大症患者疾病控制前后循环 FGF21 成分,包括 FAP。 方法: 对 18 例活动性肢端肥大症患者在确诊时和经手术或药物治疗后 ≥ 6 个月进行研究。通过免疫测定法测定总和活性 FGF21 、 β-klotho 、 FAP 和胶原转换标志物的血清水平。通过逆转录聚合酶链反应测定脂肪组织中假定的 FGF21-dependent 基因的表达,通过双能 x 线吸收扫描评估身体成分,和用稳态模型评估胰岛素抵抗 (HOMA-IR) 估计的胰岛素敏感性。 结果: 总 FGF21 、活性 FGF21 和 β-klotho 保持不变。疾病控制后胰岛素敏感性和体脂量增加,但与活性 fgf21 均不相关。治疗后 FGF21-dependent 基因表达无变化。FAP 水平 (µ g/L) 在治疗后显著降低 [105.6 ± 29.4 vs 62.2 ± 32.4,P <0.000]。治疗后胶原转换标志物也显著下降,Δ fap 与 Δ ⅰ 型前胶原 (P < 0.000) 和 III 型前胶原 (P < 0.000) 呈正相关。 结论: 1) 循环 FGF21 和 β-klotho 在肢端肥大症治疗后没有变化,2) 疾病控制后血清 FAP 浓度降低,与胶原转换标志物呈正相关,3) FAP 是迄今为止未被认识的 GH 靶点,与胶原周转有关。 临床试验注册: NCT00647179.

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影响因子:3.03
发表时间:2020-01-02
来源期刊:Pituitary
DOI:10.1007/s11102-019-01023-0
作者列表:["Galm, Brandon P.","Buckless, Colleen","Swearingen, Brooke","Torriani, Martin","Klibanski, Anne","Bredella, Miriam A.","Tritos, Nicholas A."]

METHODS:Purpose Given the paucity of reliable predictors of tumor recurrence, progression, or response to somatostatin receptor ligand (SRL) therapy in acromegaly, we attempted to determine whether preoperative MR image texture was predictive of these clinical outcomes. We also determined whether image texture could differentiate somatotroph adenomas from non-functioning pituitary adenomas (NFPAs). Methods We performed a retrospective study of patients with acromegaly due to a macroadenoma who underwent transsphenoidal surgery at our institution between 2007 and 2015. Clinical data were extracted from electronic medical records. MRI texture analysis was performed on preoperative non-enhanced T1-weighted images using ImageJ (NIH). Logistic and Cox models were used to determine if image texture parameters predicted outcomes. Results Eighty-nine patients had texture parameters measured, which were compared to that of NFPAs, while 64 of these patients had follow-up and were included in the remainder of analyses. Minimum pixel intensity, skewness, and kurtosis were significantly different in somatotroph adenomas versus NFPAs (area under the receiver operating characteristic curve, 0.7771, for kurtosis). Furthermore, those with a maximum pixel intensity above the median had an increased odds of IGF-I normalization on SRL therapy (OR 5.96, 95% CI 1.33–26.66), which persisted after adjusting for several potential predictors of response. Image texture did not predict tumor recurrence or progression. Conclusion Our data suggest that MRI texture analysis can distinguish NFPAs from somatotroph macroadenomas with good diagnostic accuracy and can predict normalization of IGF-I with SRL therapy.

关键词: 暂无
翻译标题与摘要 下载文献
影响因子:4.48
发表时间:2020-01-01
DOI:10.1016/j.trsl.2019.07.013
作者列表:["Xiong Y","Tang Y","Fan F","Zeng Y","Li C","Zhou G","Hu Z","Zhang L","Liu Z"]

METHODS::Growth hormone-secreting pituitary adenoma (GHPA), a benign endocrine tumor located in the base of the skull, results in acromegaly. In addition to the mass effect of the tumor itself in the sellar region, GHPA can lead to the overgrowth of almost every organ. Previous findings indicated that the processes underlying acromegaly were partly attributable to hyperactivity of the growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis. However, the mechanisms driving this syndrome remains largely unknown. Additionally, the roles of GHPA-derived exosomes, which contain functional microRNAs and proteins that manipulate target cell proliferation and differentiation in distal extremities, are also unknown. In this study, we demonstrated that GHPA exosomes promote bone formation in vitro and trabecula number in vivo. The mechanism of increased trabecula formation may be attributable to GHPA exosome-induced osteoblast proliferation via increased cell viability and DNA replication. We further discovered that exosomal hsa-miR-21-5p plays a distinct role from the GH/IGF-1 axis in these processes. Accordingly, the results of this study provide a novel mechanism whereby GHPA influences distal extremities and a new perspective for treating GHPA.

关键词: 暂无
翻译标题与摘要 下载文献
影响因子:5.19
发表时间:2020-01-01
DOI:10.1210/clinem/dgz033
作者列表:["Arlien-Søborg MC","Grøndahl C","Bæk A","Dal J","Madsen M","Høgild ML","Pedersen SB","Bjerre M","Jørgensen JOL"]

METHODS:BACKGROUND:Fibroblast growth factor 21 (FGF21) is a circulating hormone with pleiotropic metabolic effects, which is inactivated by fibroblast activation protein (FAP). Data regarding interaction between FGF21, FAP, and growth hormone (GH) are limited, but it is noteworthy that collagens are also FAP substrates, since GH potently stimulates collagen turnover. AIM:To measure circulating FGF21 components, including FAP, in patients with acromegaly before and after disease control. METHODS:Eighteen patients with active acromegaly were studied at the time of diagnosis and ≥ 6 months after disease control by either surgery or medical treatment. Serum levels of total and active FGF21, β-klotho, FAP, and collagen turnover markers were measured by immunoassays. Expression of putative FGF21-dependent genes were measured in adipose tissue by reverse transcriptase-polymerase chain reaction, body composition assessed by dual-energy x-ray absorptiometry scan, and insulin sensitivity estimated with homeostatic model assessment of insulin resistance (HOMA-IR). RESULTS:Total FGF21, active FGF21 and β-klotho remained unchanged. Insulin sensitivity and body fat mass increased after disease control but neither correlated with active FGF21. Expression of FGF21-dependent genes did not change after treatment. FAP levels (µg/L) were markedly reduced after treatment [105.6 ± 29.4 vs 62.2 ± 32.4, P < 0.000]. Collagen turnover markers also declined significantly after treatment and ΔFAP correlated positively with ΔProcollagen Type I (P < 0.000) and Type III (P < 0.000). CONCLUSION:1) Circulating FGF21 and β-klotho do not change in response to acromegaly treatment, 2) FAP concentrations in serum decrease after disease control and correlate positively with collagen turnover markers, and 3) FAP is a hitherto unrecognized GH target linked to collagen turnover. CLINICAL TRIALS REGISTRATION:NCT00647179.

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