Extension of Survival in Bilaterally Adrenalectomized Mice by Implantation of SF-1/Ad4BP-Induced Steroidogenic Cells.


  • 影响因子:3.62
  • DOI:10.1210/endocr/bqaa007
  • 作者列表:"Tanaka T","Aoyagi C","Mukai K","Nishimoto K","Kodama S","Yanase T
  • 发表时间:2020-03-01

:Mesenchymal stroma/stem cells (MSCs) exist in adult tissues, such as adipose tissue and bone marrow, and differentiate into cells of multiple lineages. In previous studies, we found that MSCs differentiate into steroidogenic cells by forced expression of steroidogenic factor 1 (SF-1)/adrenal 4 binding protein (Ad4BP), the master regulator of steroidogenesis and differentiation of pituitary gonadotrophs, adrenal glands, and gonads. In this study, SF-1/Ad4BP-induced steroidogenic cells derived from mouse adipose tissue-derived MSCs (ADSCs) were implanted under the kidney capsule of bilateral adrenalectomized (bAdx) mice. bAdx mice did not survive after 7 days. However, 4 of 9 bAdx mice implanted with SF-1/Ad4BP-induced steroidogenic cells, 1 of 10 bAdx mice transplanted with control ADSCs, and bAdx mice transplanted with an adrenal gland survived for 30 days. Plasma corticosterone levels in bAdx mice implanted with SF-1/Ad4BP-induced steroidogenic cells and control ADSCs were 5.41 ± 2.26 ng/mL (mean ± SEM) and undetectable at 7 days after implantation, respectively. After removal of the kidney bearing the graft from the surviving mice at 30 days after implantation, plasma corticosterone was not detected in any of the samples. Immunohistochemical staining revealed SF-1/Ad4BP-positive cells under the capsule of the kidney. Although we performed an adrenocorticotropin (ACTH) loading test on bAdx mice implanted with SF-1/Ad4BP-induced steroidogenic cells, ACTH responsiveness was not observed. Implantation of steroidogenic cells derived from ADSCs into bAdx mice increased the basal plasma corticosterone level and extended the survival of bAdx mice, suggesting the capability of restoring steroidogenic cells by cell transplantation therapy for adrenal insufficiency.


: 间充质基质/干细胞 (msc) 存在于成人组织,如脂肪组织和骨髓中,并分化为多个谱系的细胞。在以前的研究中,我们发现MSCs通过强迫表达类固醇生成因子1 (SF-1)/肾上腺4结合蛋白 (Ad4BP) 分化为类固醇生成细胞,这是类固醇生成和垂体促性腺激素、肾上腺和性腺分化的主要调控因子。在本研究中,将来源于小鼠脂肪组织来源的msc (ADSCs) 的SF-1/Ad4BP-induced类固醇生成细胞植入双侧肾上腺切除 (bAdx) 小鼠的肾被膜下。bAdx小鼠在7天后没有存活。然而,植入SF-1/Ad4BP-induced类固醇生成细胞的9只bAdx小鼠中的4只、移植有对照adsc的10只bAdx小鼠中的1只和移植有肾上腺的bAdx小鼠存活30天。植入SF-1/Ad4BP-induced类固醇生成细胞的bAdx小鼠和对照adsc的血浆皮质酮水平分别为5.41 ± 2.26 ng/mL (平均值 ± sem),植入后7天检测不到。在植入后30天从存活的小鼠取出带有移植物的肾后,在任何样品中均未检测到血浆皮质酮。免疫组化染色显示肾被膜下有SF-1/Ad4BP-positive个细胞。尽管我们对植入了SF-1/Ad4BP-induced类固醇生成细胞的bAdx小鼠进行了促肾上腺皮质激素 (ACTH) 负荷试验,但没有观察到ACTH反应性。将来源于ADSCs的类固醇生成细胞植入bAdx小鼠增加了基础血浆皮质酮水平并延长了bAdx小鼠的存活,表明通过细胞移植治疗肾上腺功能不全恢复类固醇生成细胞的能力。



作者列表:["Prendergast KM","Smith PM","Tran TB","Postlewait LM","Maithel SK","Prescott JD","Pawlik TM","Wang TS","Glenn J","Hatzaras I","Shenoy R","Phay JE","Shirley LA","Fields RC","Jin LX","Weber SM","Salem A","Sicklick JK","Gad S","Yopp AC","Mansour JC","Duh QY","Seiser N","Votanopoulos KI","Levine EA","Poultsides GA","Solórzano CC","Kiernan CM"]

METHODS:BACKGROUND:Adrenocortical carcinoma is a rare, aggressive cancer. We compared features of patients who underwent synchronous versus metachronous metastasectomy. METHODS:Adult patients who underwent resection for metastatic adrenocortical carcinoma from 1993 to 2014 at 13 institutions of the US adrenocortical carcinoma group were analyzed retrospectively. Patients were categorized as synchronous if they underwent metastasectomy at the index adrenalectomy or metachronous if they underwent resection after recurrence of the disease. Factors associated with overall survival were assessed by univariate analysis. RESULTS:In the study, 84 patients with adrenocortical carcinoma underwent metastasectomy; 26 (31%) were synchronous and 58 (69%) were metachronous. Demographics were similar between groups. The synchronous group had more T4 tumors at the index resection (42 vs 3%, P < .001). The metachronous group had prolonged median survival after the index resection (86.3 vs 17.3 months, P < .001) and metastasectomy (36.9 vs 17.3 months, P = .007). Synchronous patients with R0 resections had improved survival compared to patients with R1/2 resections (P = .008). Margin status at metachronous metastasectomy was not associated with survival (P = .452). CONCLUSION:Select patients with metastatic adrenocortical carcinoma may benefit from metastasectomy. Patients with metachronous metastasectomy have a more durable survival benefit than those undergoing synchronous metastasectomy. This study highlights need for future studies examining differences in tumor biology that could explain outcome disparities in these distinct patient populations.

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作者列表:["Fan L","Zhuang Y","Wang Y","Liu X","Liu D","Xiang B","He M","Zhang Z","Li Y","Wang Y","Zhu X","Ye H"]

METHODS::Hypokalemia is a common feature in patients with Cushing's syndrome (CS). Whether the occurrence of hypokalemia is associated with cortisol and adrenocorticotropic hormone (ACTH) levels is still unclear. Approximately 80% of cases of endogenous CS are due to Cushing's disease (CD). The purpose of this study was to determine the association of hypokalemia with cortisol and ACTH levels in patients with CD. The retrospective study included 195 patients with CD referred to our medical center from January 2011 to December 2017. The results show that 25.64% (50/195) of the patients had hypokalemia. The 24-h urinary free cortisol (UFC) and plasma cortisol levels were significantly higher in patients with hypokalemia than those with normokalemia (P < 0.05). Plasma ACTH levels were similar between the patients with hypokalemia and normokalemia (P > 0.05). Cortisol levels were negatively correlated with plasma potassium levels (08:00: r = -0.344 (P < 0.01), 00:00: r = -0.435 (P < 0.01); 24-h UFC: r = -0.281 (P < 0.05)). There was no significant correlation between the plasma ACTH and potassium (08:00: r = -0.093 (P > 0.05), 00:00: r = -0.184 (P > 0.050)). Our current data suggest that cortisol level, instead of ACTH level, is correlated with plasma potassium level. A high cortisol level may be the principal cause of hypokalemia.

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作者列表:["Ghosal S","Das S","Pang Y","Gonzales MK","Huynh TT","Yang Y","Taieb D","Crona J","Shankavaram UT","Pacak K"]

METHODS::Many long intergenic noncoding RNAs (lincRNAs) serve as cancer biomarkers for diagnosis or prognostication. To understand the role of lincRNAs in the rare neuroendocrine tumors pheochromocytoma and paraganglioma (PCPG), we performed first time in-depth characterization of lincRNA expression profiles and correlated findings to clinical outcomes of the disease. RNA-Seq data from patients with PCPGs and 17 other tumor types from The Cancer Genome Atlas and other published sources were obtained. Differential expression analysis and a machine-learning model were used to identify transcripts specific to PCPGs, as well as established PCPG molecular subtypes. Similarly, lincRNAs specific to aggressive PCPGs were identified, and univariate and multivariate analysis was performed for metastasis-free survival. The results were validated in independent samples using RT-PCR. From a pan-cancer context, PCPGs had a specific and unique lincRNA profile. Among PCPGs, five different molecular subtypes were identified corresponding to the established molecular classification. Upregulation of 13 lincRNAs was found to be associated with aggressive/metastatic PCPGs. RT-PCR validation confirmed the overexpression of four lincRNAs in metastatic compared to non-metastatic PCPGs. Kaplan-Meier analysis identified five lincRNAs as prognostic markers for metastasis-free survival of patients in three subtypes of PCPGs. Stratification of PCPG patients with a risk-score formulated using multivariate analysis of lincRNA expression profiles, presence of key driver mutations, tumor location, and hormone secretion profiles showed significant differences in metastasis-free survival. PCPGs thus exhibit a specific lincRNA expression profile that also corresponds to the established molecular subgroups and can be potential marker for the aggressive/metastatic PCPGs.

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