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Adjuvant and neoadjuvant therapy with cyclin-dependent kinase 4 and 6 inhibitors in hormone receptor-positive, human epidermal growth factor receptor 2-negative early breast cancer: a systematic review and meta-analysis. 激素受体阳性、人表皮生长因子受体2阴性的癌症早期应用细胞周期依赖性激酶4和6抑制剂的辅助和新辅助治疗:一项系统综述和荟萃分析。
IF 3.9 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-07-11 Print Date: 2023-08-01 DOI: 10.1530/ERC-22-0365
Meilin Zhang, Jian Song, Shigang Guo, Feng Jin, Ang Zheng

Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have shown advantages in hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer. This study aimed to evaluate the efficacy and safety of CDK4/6 inhibitors combined with endocrine therapy (ET) in patients with HR+, HER2- early breast cancer. The PubMed, Embase, Cochrane Library, and Web of Science databases were searched for randomized controlled trials (RCTs) related to CDK4/6 inhibitors combined with ET. Literature conforming to the research content was identified according to the inclusion and exclusion criteria. The efficacy endpoints included invasive disease-free survival (IDFS), distant relapse-free survival (DRFS), and overall survival (OS) with adjuvant therapy. The efficacy endpoint of neoadjuvant therapy was complete cell cycle arrest (CCCA). The safety outcomes included the incidence of adverse events (AEs) and grade 3-4 hematological and non-hematological AEs. Data analysis was performed using Review Manager software (version 5.3). A statistical model (fixed-effects model or random-effects model) was selected based on the level of heterogeneity, and a sensitivity analysis was performed if strong heterogeneity existed. Subgroup analyses were performed based on the baseline patient characteristics. Nine articles (including six RCTs) were included in the study. In adjuvant therapy, compared with the control group, CDK4/6 inhibitors combined with ET showed no statistically significant difference in IDFS (hazard ratio = 0.83, 95% confidence interval (CI) = 0.64-1.08, P = 0.17) and DRFS (hazard ratio = 0.83, 95% CI = 0.52-1.31, P = 0.42). In neoadjuvant therapy, CDK4/6 inhibitors combined with ET significantly improved CCCA compared with the control group (odds ratio = 9.00, 95% CI = 5.42-14.96, P < 0.00001). In terms of safety, the combination treatment group had a significantly increased incidence of grade 3-4 hematological AEs in patients, especially grade 3-4 neutropenia (risk ratio (RR) = 63.90, 95% CI = 15.44-264.41, P < 0.00001) and grade 3-4 leukopenia (RR = 85.89, 95% CI = 19.12-385.77, P < 0.00001), with statistically significant differences. In patients with HR+, HER2- early breast cancer, the addition of CDK4/6 inhibitors may prolong IDFS and DRFS in adjuvant therapy, especially in high-risk patients. Further follow-up is needed to establish whether OS can be improved with CDK4/6 inhibitors plus ET. CDK4/6 inhibitors also showed effective anti-tumor proliferation activity in neoadjuvant therapy. Regular monitoring of routine blood tests in patients using CDK4/6 inhibitors is essential.

细胞周期依赖性激酶4和6(CDK4/6)抑制剂在激素受体阳性(HR+)、人表皮生长因子受体2阴性(HER2-)晚期癌症中显示出优势。本研究旨在评估CDK4/6抑制剂联合内分泌治疗(ET)治疗HR+、HER2-早期癌症患者的有效性和安全性。在PubMed、Embase、Cochrane Library和Web of Science数据库中搜索与CDK4/6抑制剂联合ET相关的随机对照试验(RCT)。根据纳入和排除标准确定符合研究内容的文献。疗效终点包括侵袭性无病生存期(IDFS)、远处无复发生存期(DRFS)和辅助治疗的总生存期(OS)。新辅助治疗的疗效终点是完全细胞周期阻滞(CCCA)。安全性结果包括不良事件(AE)的发生率以及3-4级血液学和非血液学AE。使用Review Manager软件(5.3版)进行数据分析。根据异质性水平选择统计模型(固定效应模型或随机效应模型),如果存在强异质性,则进行敏感性分析。根据基线患者特征进行亚组分析。本研究纳入了9篇文章(包括6篇随机对照试验)。在辅助治疗中,与对照组相比,CDK4/6抑制剂联合ET在IDFS(危险比=0.83,95%可信区间(CI)=0.64-1.08,P=0.17)和DRFS(危险比=0.83,95%CI=0.52-1.31,P=0.42)方面没有统计学显著差异,与对照组相比,CDK4/6抑制剂联合ET显著改善了CCCA(比值比=9.00,95%CI=5.42-14.96,P<0.00001)。就安全性而言,联合治疗组患者3-4级血液学AE的发生率显著增加,尤其是3-4级中性粒细胞减少症(风险比(RR)=63.90,95%CI=15.44-264.41,P<0.00001)和3-4级白细胞减少症(RR=85.89,95%CI=19.12-385.77,P<0.0001),差异有统计学意义。在HR+、HER2-早期癌症患者中,添加CDK4/6抑制剂可能会延长辅助治疗中的IDFS和DRFS,尤其是在高危患者中。需要进一步的随访来确定CDK4/6抑制剂加ET是否可以改善OS。CDK4/6抑制物在新辅助治疗中也显示出有效的抗肿瘤增殖活性。定期监测使用CDK4/6抑制剂的患者的常规血液检查是至关重要的。
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引用次数: 0
PRB inhibited cell proliferation through let-7b-E2F1 in breast cancer. PRB通过let-7b-E2F1抑制乳腺癌细胞增殖。
IF 3.9 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-07-01 DOI: 10.1530/ERC-22-0204
Teeranut Asavasupreechar, Ryoko Saito-Koyama, Yasuhiro Miki, Keiichi Tamai, Jiro Abe, Chihiro Inoue, Ikuro Sato, Viroj Boonyaratanakornkit, Hironobu Sasano

The presence of progesterone receptor (PR) and PR isoform B (PRB) in breast cancer is generally correlated with better clinical outcomes. Additionally, the significance of hormone-independent effects of PR/PRB correlated with better prognosis has been reported in non-small cell lung cancer (NSCLC). However, the detailed mechanism of that still remains unclear. In this study, we examined how microRNAs (miRNAs) could contribute to tumor inhibition via PR/PRB expression, in order to find miRNAs that have tumor-agnostic effects between breast cancer and NSCLC. We obtained miRNA data using human tissues of breast cancer and NSCLC from The Cancer Genome Atlas (TCGA) database and PCR array from NSCLC patients of our cohort. Subsequently, we examined the function of the miRNA through in vitro study using breast cancer cell lines. As a result, only let-7b expression was significantly correlated with PR expression in both cancers. Additionally, the expression of let-7b significantly inhibited cell proliferation by inducing PR and PRB expression in breast cancer cell lines. However, the positive correlation of let-7b and PRB required a mediated factor, E2 promoter binding factor 1 (E2F1), obtained from TCGA database analysis. In vitro experiments showed that let-7b significantly inhibited E2F1, and E2F1 significantly inhibited PRB. This study revealed that PRB inhibits the proliferation of breast cancer cells by the let-7b-E2F1 interaction. In addition, the immunohistochemical analysis in NSCLC was also consistent with these in vitro data. Our results could contribute to developing novel therapeutic strategies for patients with PR/PRB-positive cancer by targeting let-7b or PRB expression in breast cancer and possibly NSCLC.

孕激素受体(PR)和孕激素异构体B (PRB)在乳腺癌中的存在通常与较好的临床结果相关。此外,在非小细胞肺癌(NSCLC)中,PR/PRB的激素独立效应与较好的预后相关的意义也有报道。然而,其具体机制尚不清楚。在这项研究中,我们研究了microRNAs (miRNAs)如何通过PR/PRB表达促进肿瘤抑制,以发现在乳腺癌和非小细胞肺癌之间具有肿瘤不可知作用的miRNAs。我们使用来自癌症基因组图谱(TCGA)数据库的乳腺癌和非小细胞肺癌的人体组织以及来自我们队列的非小细胞肺癌患者的PCR阵列获得miRNA数据。随后,我们通过乳腺癌细胞系的体外研究检测了miRNA的功能。因此,在两种癌症中,只有let-7b表达与PR表达显著相关。此外,let-7b的表达通过诱导乳腺癌细胞系中PR和PRB的表达显著抑制细胞增殖。然而,let-7b与PRB的正相关需要一个介导因子,E2启动子结合因子1 (E2F1),该因子从TCGA数据库分析中获得。体外实验表明,let-7b显著抑制E2F1, E2F1显著抑制PRB。本研究表明,PRB通过let-7b-E2F1相互作用抑制乳腺癌细胞的增殖。此外,非小细胞肺癌的免疫组织化学分析也与这些体外数据一致。我们的研究结果可能有助于通过靶向let-7b或PRB在乳腺癌和可能的非小细胞肺癌中的表达,为PR/PRB阳性癌症患者开发新的治疗策略。
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引用次数: 0
Long-term safety of growth hormone replacement therapy in survivors of cancer and tumors of the pituitary region. 生长激素替代疗法在垂体区肿瘤和癌症幸存者中的长期安全性。
IF 3.9 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-07-01 DOI: 10.1530/ERC-23-0026
Melissa Bolier, Aart-Jan Van der Lelij, Geert Janssens, Marry M van den Heuvel-Eibrink, Sebastian J C M M Neggers

Growth hormone deficiency (GHD) is a common complication in survivors of cancer and patients with tumors of the pituitary region. Growth hormone replacement therapy (GHT) has proven beneficial effects, including increased growth velocity, positive effects on body composition and skeletal integrity, and increased quality of life. However, due to known pro-proliferative, angiogenic, and anti-apoptotic properties of growth hormone, there are still some concerns about the safety of GHT in survivors. This narrative review aims to provide an overview of the long-term sequelae, and subsequently long-term safety, of GHT in survivors of (childhood) cancer and patients with tumors of the pituitary region. We identified predominantly reassuring results regarding the safety of survivors with GHT, although we must take into account the shortcomings of some studies and limited information on adult cancer survivors. Besides the already increased risk for second neoplasms, recurrences, or mortality in survivors due to host-, disease-, and treatment-related factors, we could not identify an increased risk due to GHT in particular. Therefore, we support the consensus that GHT can be considered in survivors after careful individual risk/benefit analysis and in open discussion with the patients and their families, taking into account the known morbidity of untreated GHD in cancer survivors and the positive effects of GHT.

生长激素缺乏症(GHD)是癌症幸存者和垂体区肿瘤患者的常见并发症。生长激素替代疗法(GHT)已被证明是有益的,包括增加生长速度,对身体成分和骨骼完整性的积极影响,以及提高生活质量。然而,由于已知的生长激素的促增殖、血管生成和抗凋亡特性,仍然存在一些关于GHT在幸存者中的安全性的担忧。这篇叙述性综述旨在概述GHT在(儿童)癌症幸存者和垂体区肿瘤患者中的长期后遗症和长期安全性。尽管我们必须考虑到一些研究的缺点和关于成年癌症幸存者的有限信息,但我们确定了关于GHT幸存者安全性的主要令人放心的结果。除了因宿主、疾病和治疗相关因素而增加的二次肿瘤、复发或幸存者死亡的风险外,我们还不能确定GHT特别增加的风险。因此,我们支持这样的共识,即在仔细的个体风险/收益分析和与患者及其家属的公开讨论后,考虑到癌症幸存者中未经治疗的GHD的已知发病率和GHT的积极作用,可以考虑在幸存者中使用GHT。
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引用次数: 0
Intratumoral dendritic cells and T cells predict survival in gastroenteropancreatic neuroendocrine neoplasms. 瘤内树突状细胞和T细胞预测胃肠胰腺神经内分泌肿瘤的生存。
IF 3.9 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-07-01 DOI: 10.1530/ERC-22-0357
Wiebke Werner, Katharina Detjen, Alix Bruneau, Isabella Lurje, Natalie Nestel, Henning Jann, Frank Tacke, Bertram Wiedenmann, Christoph Roderburg, Linda Hammerich

Clinical management of gastroenteropancreatic neuroendocrine neoplasms remains challenging. We recently introduced the FMS-like tyrosine kinase 3 ligand (FLT3LG) as a possible biomarker for a proinflammatory tumor microenvironment. Here, we put a spotlight on the quantitative assessment of classical dendritic cells (cDC) and T cells in the context of FLT3LG mRNA levels in a retrospective study on neuroendocrine tumor (NET) G2/G3 and neuroendocrine carcinoma (NEC) of pancreatic and gastric origin. The abundance of cDC and T cells and their relevant subpopulations were determined by immunofluorescent staining and correlated with FLT3LG mRNA levels as well as clinical outcomes. Immune cell counts attested to highly variable infiltration densities. Samples with the presence of cDC or high numbers of T cells exhibited increased FLT3LG expression. Abundance of cDC, defined as HLA-DR+CD11c+ cells with CLEC9a (cDC1) or CD1c (cDC2), as well as T cells correlated with FLT3LG mRNA levels and predicted disease-specific survival. Combining FLT3LG and T cell counts further improved this prediction. Therefore, tumor-infiltrating cDC and T cells are prognostic markers in NET G2/G3 or NEC and FLT3LG mRNA may serve as a simple-to-use biomarker for a quantitative estimate of their abundance, mandating prospective evaluation in the context of immune-targeted therapies.

胃肠胰神经内分泌肿瘤的临床治疗仍然具有挑战性。我们最近介绍了fms样酪氨酸激酶3配体(FLT3LG)作为促炎肿瘤微环境的可能生物标志物。本文通过对胰腺和胃源性神经内分泌肿瘤(NET) G2/G3和神经内分泌癌(NEC)的回顾性研究,对经典树突状细胞(cDC)和T细胞在FLT3LG mRNA水平下的定量评估进行了研究。cDC和T细胞及其相关亚群的丰度通过免疫荧光染色测定,并与FLT3LG mRNA水平和临床结果相关。免疫细胞计数证明浸润密度变化很大。存在cDC或大量T细胞的样本显示FLT3LG表达增加。cDC的丰度,定义为HLA-DR+CD11c+细胞与CLEC9a (cDC1)或CD1c (cDC2),以及T细胞与FLT3LG mRNA水平相关,并预测疾病特异性生存。结合FLT3LG和T细胞计数进一步改善了这一预测。因此,肿瘤浸润性cDC和T细胞是NET G2/G3或NEC的预后标志物,FLT3LG mRNA可以作为一种简单使用的生物标志物,用于定量估计它们的丰度,要求在免疫靶向治疗的背景下进行前瞻性评估。
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引用次数: 0
Risk of complications after core needle biopsy in pheochromocytoma/paraganglioma. 嗜铬细胞瘤/副神经节瘤核心穿刺活检术后并发症的风险。
IF 3.9 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-07-01 DOI: 10.1530/ERC-22-0354
Liang Zhang, Tobias Åkerström, Kazhan Mollazadegan, Felix Beuschlein, Karel Pacak, Britt Skogseid, Joakim Crona

Core needle biopsy (CNB) has been used with caution in pheochromocytoma and paraganglioma (PPGL) due to concerns about catecholamine-related complications. While it is unclear what scientific evidence supports this claim, it has limited the acquisition of biological samples for diagnostic purposes and research, especially in metastatic PPGL. We performed a systematic review and individual patient meta-analysis to evaluate the risk of complications after CNB in PPGL patients. The primary and secondary objectives were to investigate the risk of death and the occurrence of complications requiring intervention or hospitalization, respectively. Fifty-six articles describing 86 PPGL patients undergoing CNB were included. Of the patients (24/71), 34% had metastases and 53.4% (31/58) had catecholamine-related symptoms before CNB. Of the patients (14/41), 34.1% had catecholamine excess testing prior to the biopsy. No CNB-related deaths were reported. Four patients (14.8%, 4/27) experienced CNB-related complications requiring hospitalization or intervention. One case had a temporary duodenal obstruction caused by hematoma, two cases had myocardial infarction, and one case had Takotsubo cardiomyopathy. Eight patients (32%, 8/25) had CNB-related catecholamine symptoms, mainly transient hypertension, excessive diaphoresis, tachycardia, or hypertensive crisis. The scientific literature does not allow us to make any firm conclusion on the safety of CNB in PPGL. However, it is reasonable to argue that CNB could be conducted after thorough consideration, preparation, and with close follow-up for PPGL patients with a strong clinical indication for such investigation.

由于担心儿茶酚胺相关并发症,在嗜铬细胞瘤和副神经节瘤(PPGL)中谨慎使用核心针活检(CNB)。虽然尚不清楚有什么科学证据支持这一说法,但它限制了用于诊断和研究目的的生物样本的获取,特别是在转移性PPGL中。我们进行了系统回顾和个体患者荟萃分析,以评估PPGL患者CNB后并发症的风险。主要和次要目的分别是调查死亡风险和需要干预或住院治疗的并发症的发生。56篇文章描述了86例接受CNB的PPGL患者。其中,34%(24/71)的患者有转移,53.4%(31/58)的患者在CNB前有儿茶酚胺相关症状。在14/41的患者中,34.1%的患者在活检前进行了儿茶酚胺过量检测。没有与cnb相关的死亡报告。4例患者(14.8%,4/27)出现cnb相关并发症,需要住院或干预。血肿引起暂时性十二指肠梗阻1例,心肌梗死2例,Takotsubo心肌病1例。8例(32%,8/25)患者出现与cnb相关的儿茶酚胺症状,主要是短暂性高血压、过度出汗、心动过速或高血压危象。科学文献不允许我们对CNB在PPGL中的安全性做出任何确定的结论。然而,我们有理由认为,对于临床适应症较强的PPGL患者,经过充分的考虑、准备和密切的随访后,可以进行CNB。
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引用次数: 2
Genome-wide association studies in advanced prostate cancer: KYUCOG-1401-A study. 晚期前列腺癌的全基因组关联研究:KYUCOG-1401-A研究
IF 3.9 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-07-01 DOI: 10.1530/ERC-23-0044
Masaki Shiota, Shuichi Tatarano, Toshiyuki Kamoto, Hideyasu Matsuyama, Hideki Sakai, Tsukasa Igawa, Tomomi Kamba, Naohiro Fujimoto, Yuya Sekine, Hiroko Kimura, Shintaro Narita, Naoki Terada, Yukihide Momozawa, Shusuke Akamatsu, Tomonori Habuchi, Akira Yokomizo, Seiji Naito, Masatoshi Eto

Androgen-deprivation therapy (ADT) has been widely used for the treatment of advanced prostate cancer. However, prognosis and adverse events (AEs) vary among patients. This study aimed to identify genetic markers able to predict the outcome of ADT. Japanese patients treated with primary ADT for advanced prostate cancer in the KYUCOG-1401 trial were enrolled as a development set. A distinct population of advanced prostate cancer cases treated with ADT was included as a validation set. Single-nucleotide polymorphisms (SNPs) associated with radiographic progression-free survival (rPFS) at 1 year and AEs including de novo diabetes mellitus (DM), arthralgia, and de novo dyslipidemia were identified in the development set by a genome-wide association study (GWAS). The SNPs associated with rPFS in the development study were then genotyped in the validation set. GWAS followed by validation identified SNPs (rs76237622 in PRR27 and rs117573572 in MTAP) that were associated with overall survival (OS) in ADT. A genetic prognostic model using these SNPs showed excellent predictive efficacy for PFS and OS in ADT. In addition, GWAS showed that several SNPs were associated with de novo DM, arthralgia, and de novo dyslipidemia in ADT. This study identified novel multiple SNPs that correlated with outcomes in ADT. Future studies on correlations affecting the therapeutic efficacy of ADT-based combination therapies would make a valuable contribution to the development of personalized medicine.

雄激素剥夺疗法(ADT)已广泛应用于晚期前列腺癌的治疗。然而,患者的预后和不良事件(ae)各不相同。本研究旨在鉴定能够预测ADT预后的遗传标记。KYUCOG-1401试验中接受原发性ADT治疗晚期前列腺癌的日本患者被纳入研究。一组接受ADT治疗的晚期前列腺癌病例被纳入验证组。在一项全基因组关联研究(GWAS)中,发现了与1年放射学无进展生存期(rPFS)和ae相关的单核苷酸多态性(snp),包括新发糖尿病(DM)、关节痛和新发血脂异常。发育研究中与rPFS相关的snp随后在验证集中进行基因分型。GWAS验证后发现了与ADT总生存期(OS)相关的snp (PRR27中的rs76237622和MTAP中的rs117573572)。使用这些snp的遗传预后模型对ADT的PFS和OS具有良好的预测效果。此外,GWAS显示几个snp与ADT患者的新发DM、关节痛和新发血脂异常有关。本研究发现了与ADT预后相关的新的多个snp。未来对影响以adt为基础的联合治疗疗效的相关性的研究将为个性化医疗的发展做出宝贵的贡献。
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引用次数: 0
Thyroid autoimmunity, thyroglobulin autoantibodies, and thyroid cancer prognosis. 甲状腺自身免疫、甲状腺球蛋白自身抗体与甲状腺癌预后。
IF 3.9 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-07-01 DOI: 10.1530/ERC-23-0042
Nicola Viola, Laura Agate, Sonia Caprio, Loredana Lorusso, Alessandro Brancatella, Debora Ricci, Daniele Sgrò, Clara Ugolini, Paolo Piaggi, Paolo Vitti, Rossella Elisei, Ferruccio Santini, Francesco Latrofa

The relevance of thyroid autoimmunity to the prognosis of papillary thyroid carcinoma is still unsettled. We decided to investigate the impact of thyroid autoimmunity on the prognosis of papillary thyroid carcinoma and the handling of TgAbs. We evaluated the clinical course of a large group of patients according to the presence (PTC-LT) or absence (PTC) of lymphocytic thyroiditis at histology. We studied 194 consecutive patients with a diagnosis of PTC and treated them with total thyroidectomy plus ¹³¹I ablation between 2007 and 2009. Median follow-up (with 25th-75th percentiles) was 84.0 (56.4-118.0) months. The remission criteria were: basal Tg < 0.2 ng/mL (or stimulated Tg: < 1), TgAbs < 8 IU/mL (otherwise 'decreasing TgAb trend', a decline of ≥20% in sequential TgAb measurements) and unremarkable imaging. PTC-LT and PTC patients had comparable treatment.TgAbs were detectable in 72.5% of PTC-LT and 16.5% of PTC patients. Time to remission was longer in the detectable than in the undetectable TgAb cohort (28.5 vs· 7.5 months (median); HR: 0.54, CI: 0.35-0.83, P = 0.005). When comparing PTC-LT to PTC patients, the difference was maintained in the detectable TgAb (29.3 vs 13.0 months; HR: 0.38, CI: 0.18-0.80; P = 0.01) but not in the undetectable TgAb cohort (7.7 vs 7.3 months; HR: 0.90, CI: 0.55-1.47; P = 0.68). Using the decreasing TgAb trend, the influence of detectable TgAbs on time to remission was abolished. Thyroid autoimmunity does not influence the prognosis of papillary thyroid carcinoma. A decreasing TgAb trend seems an appropriate criterion to establish the remission of papillary thyroid carcinoma.

甲状腺自身免疫与甲状腺乳头状癌预后的关系尚不明确。我们决定研究甲状腺自身免疫对甲状腺乳头状癌预后的影响以及对tgab的处理。我们根据组织学上淋巴细胞性甲状腺炎的存在(PTC- lt)或不存在(PTC)来评估一大组患者的临床病程。我们研究了2007年至2009年间连续诊断为PTC的194例患者,并对他们进行了甲状腺全切除术加1³1消融治疗。中位随访(25 -75百分位)为84.0(56.4-118.0)个月。缓解标准为:基础Tg < 0.2 ng/mL(或刺激Tg < 1), TgAb < 8 IU/mL(否则TgAb呈下降趋势,连续TgAb测量下降≥20%)和无明显影像学表现。PTC- lt和PTC患者的治疗具有可比性。在72.5%的PTC- lt和16.5%的PTC患者中检测到tgab。可检测TgAb组的缓解时间比不可检测TgAb组的更长(28.5个月vs·7.5个月);Hr: 0.54, ci: 0.35-0.83, p = 0.005)。当PTC- lt患者与PTC患者进行比较时,可检测的TgAb保持差异(29.3 vs 13.0个月;Hr: 0.38, ci: 0.18-0.80;P = 0.01),但在无法检测到的TgAb队列中没有(7.7 vs 7.3个月;Hr: 0.90, ci: 0.55-1.47;P = 0.68)。利用TgAb下降的趋势,可检测到的TgAb对缓解时间的影响被消除。甲状腺自身免疫不影响甲状腺乳头状癌的预后。TgAb下降趋势似乎是确定甲状腺乳头状癌缓解的适当标准。
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引用次数: 1
Non-pituitary GH regulation of the tissue microenvironment. 非垂体GH对组织微环境的调节。
IF 3.9 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-07-01 DOI: 10.1530/ERC-23-0028
Vera Chesnokova, Shlomo Melmed

Non-pituitary growth hormone (npGH) expression is well established in extrapituitary tissues, but an understanding of the physiological role of npGH remains rather limited. Pro-tumorigenic npGH impacting the tumor microenvironment has been reviewed. We focus here on autocrine/paracrine npGH effects in non-tumorous tissues and discuss its mechanisms of action in the normal tissue microenvironment. We address the tissue-specific effects of npGH in regulating stem, endothelial, immune, and epithelial cells and highlight the related role of npGH-associated changes in tissue aging.

非垂体生长激素(npGH)的表达在垂体外组织中得到了很好的证实,但对npGH的生理作用的了解仍然相当有限。促瘤性npGH对肿瘤微环境的影响已作了综述。我们将重点研究npGH在非肿瘤组织中的自分泌/旁分泌作用,并讨论其在正常组织微环境中的作用机制。我们讨论了npGH在调节干细胞、内皮细胞、免疫细胞和上皮细胞中的组织特异性作用,并强调了npGH在组织衰老中的相关作用。
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引用次数: 3
BRAFV600E restructures cellular lactylation to promote anaplastic thyroid cancer proliferation. BRAFV600E重组细胞乳酸化,促进间变性甲状腺癌增殖。
IF 3.9 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-06-28 Print Date: 2023-08-01 DOI: 10.1530/ERC-22-0344
Xumeng Wang, Tianxing Ying, Jimeng Yuan, Yue Wang, Xingyun Su, Shitu Chen, Yurong Zhao, Yuanyuan Zhao, Jinghao Sheng, Lisong Teng, Chi Luo, Weibin Wang

Anaplastic thyroid cancer (ATC) is a rare but fatal cancer with BRAF mutation ranging from 30 to 50%. Histone lysine lactylation represents a novel epigenetic mark that translates cellular metabolic signals into transcriptional regulation. It is not clear whether the Warburg effect can promote the proliferation of ATC with BRAFV600E mutation via metabolite-mediated histone lactylation. Our study aimed at illustrating how BRAFV600E restructures the cellular protein lactylation landscape to boost ATC proliferation, and determining whether blockade of protein lactylation can sensitize mutant ATC to BRAFV600E inhibitors. Western blotting was used to evaluate lactylation status. Aerobic glycolysis was intervened by adding cell-permeable ethyl lactate or using metabolic inhibitors. Chromatin immunoprecipitation and RT-qPCR were applied to analyze the expression of growth-related genes. Different chemical inhibitors were used to inhibit BRAFV600E and other enzymes. ATC cell line-derived xenograft model was employed to examine the efficacy of mono and combinatorial therapies. The results showed that aerobic glycolysis in ATC increased global protein lactylation via improving cellular lactate availability. In particular, lactylation on Histone 4 Lysine 12 residue (H4K12La) activated the expression of multiple genes essential for ATC proliferation. Furthermore, oncogenic BRAFV600E boosted glycolytic flux to restructure the cellular lactylation landscape, leading to H4K12La-driven gene transcription and cell cycle deregulation. Accordingly, the blockade of cellular lactylation machinery synergized with BRAFV600E inhibitor to impair ATC progression both in vitro and in vivo. Our results demonstrated an extra beneficial effect of aerobic glycolysis on ATC, revealing a novel metabolism-epigenetics axis suitable for combinatorial therapy with BRAFV600E inhibition.

无定形甲状腺癌症(ATC)是一种罕见但致命的癌症,BRAF突变范围在30%至50%之间。组蛋白赖氨酸乳酸化是一种新的表观遗传学标记,可将细胞代谢信号转化为转录调控。目前尚不清楚Warburg效应是否能通过代谢产物介导的组蛋白乳酸化促进BRAFV600E突变ATC的增殖。我们的研究旨在阐明BRAFV600E如何重组细胞蛋白乳酸化景观以促进ATC增殖,并确定阻断蛋白乳酸化是否能使突变体ATC对BRAFV600E抑制剂敏感。蛋白质印迹法用于评估乳酸化状态。通过添加可渗透细胞的乳酸乙酯或使用代谢抑制剂来干预好氧糖酵解。染色质免疫沉淀和RT-qPCR分析生长相关基因的表达。使用不同的化学抑制剂来抑制BRAFV600E和其他酶。采用ATC细胞系衍生的异种移植物模型来检查单一和组合疗法的疗效。结果表明,ATC中的有氧糖酵解通过提高细胞乳酸的可用性来增加全局蛋白质乳酸化。特别地,组蛋白4赖氨酸12残基(H4K12La)上的乳酸化激活了ATC增殖所必需的多个基因的表达。此外,致癌BRAFV600E增加了糖酵解流量,以重组细胞乳酸化景观,导致H4K12La驱动的基因转录和细胞周期失调。因此,细胞乳酰化机制的阻断与BRAFV600E抑制剂协同作用,在体外和体内损害ATC进展。我们的研究结果证明了有氧糖酵解对ATC的额外有益作用,揭示了一种新的代谢表观遗传学轴,适用于BRAFV600E抑制的组合治疗。
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引用次数: 2
lncRNA DIRC3 regulates invasiveness and insulin-like growth factor signaling in thyroid cancer cells. lncRNA DIRC3调节甲状腺癌细胞的侵袭性和胰岛素样生长因子信号。
IF 3.9 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-06-26 Print Date: 2023-08-01 DOI: 10.1530/ERC-23-0058
Piotr T Wysocki, Karol Czubak, Anna A Marusiak, Monika Kolanowska, Dominika Nowis
Differentiated thyroid cancers (DTCs) are malignancies that demonstrate strong but largely uncharacterized heritability. Germline variants that influence the risk of DTCs localize in disrupted in renal carcinoma 3 (DIRC3), a poorly described long non-coding RNA gene. Here, we investigated the function of DIRC3 in DTCs. Using patient-matched thyroid tissue pairs and The Cancer Genome Atlas data we established that DIRC3 is downregulated in DTCs, whereas high expression of DIRC3 in tumors may reduce the risk of cancer recurrence. DIRC3 transcripts were enriched in cell nuclei, where they upregulated insulin-like growth factor binding protein 5 (IGFBP5), a gene that modulates the cellular response to insulin-like growth factor 1 (IGF1). Silencing DIRC3 in thyroid cancer cell lines (MDA-T32 and MDA-T120) had a dichotomous phenotypic influence: augmented cell migration and invasiveness, reduced apoptosis, but abrogated the MTT reduction rate. Transcriptomic profiling and gene rescue experiments indicated the functional redundancy in the activities of DIRC3 and IGFBP5. Moreover, the reduced level of DIRC3 enhanced the susceptibility of thyroid cancer cells to IGF1 stimulation and promoted Akt signaling via downregulation of the IGFBP5 protein. In conclusion, DIRC3 expression alters the phenotype of thyroid cancer cells and regulates the activity of the IGFBP5/IGF1/Akt axis. Our findings suggest that an interplay between DIRC3 and IGF signaling may play a role in promoting thyroid carcinogenesis.
分化型甲状腺癌(DTC)是一种恶性肿瘤,表现出强烈但很大程度上不典型的遗传性。影响DTC风险的种系变异定位于肾癌3(DIRC3),这是一种描述不清的长非编码RNA基因。在这里,我们研究了DIRC3在DTC中的作用。利用患者匹配的甲状腺组织对和癌症基因组图谱数据,我们确定DIRC3在DTC中下调,而DIRC3在肿瘤中的高表达可能降低癌症复发的风险。DIRC3转录物在细胞核中富集,在细胞核中它们上调胰岛素样生长因子结合蛋白5(IGFBP5),这是一种调节细胞对胰岛素样生长因数1(IGF1)反应的基因。甲状腺癌症细胞系(MDA-T32和MDA-T120)中的DIRC3沉默具有双重表型影响:增加细胞迁移和侵袭性,减少细胞凋亡,但消除了MTT减少率。转录组学分析和基因拯救实验表明DIRC3和IGFBP5的活性存在功能冗余。此外,DIRC3水平的降低增强了甲状腺癌症细胞对IGF1刺激的易感性,并通过下调IGFBP5蛋白促进了Akt信号传导。总之,DIRC3的表达改变了甲状腺癌症细胞的表型,并调节IGFBP5/IGF1/Akt轴的活性。我们的研究结果表明,DIRC3和IGF信号之间的相互作用可能在促进甲状腺癌变中发挥作用。
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引用次数: 0
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Endocrine-related cancer
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