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Sex differences in intestinal morphology and increase in diencephalic neuropeptide Y gene expression in female but not male Pekin ducks exposed to chronic heat stress. 暴露于慢性热应激的雌性而非雄性北京鸭肠道形态的性别差异和间脑神经肽 Y 基因表达的增加
IF 3.3 4区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-07-03 DOI: 10.1111/jne.13424
E M Oluwagbenga, M Bergman, K M Ajuwon, G S Fraley

The impact of heat stress (HS) on production is intricately linked with feed intake. We investigated the effects of HS on intestines and diencephalic genes in Pekin ducks. One hundred and sixty adult ducks were allocated to two treatment rooms. The control room was maintained at 22°C and the HS room at 35°C for the first 10 h of the day then reduced to 29.5°C. After 3 weeks, 10 hens and 5 drakes were euthanized from each room and jejunum and ileum collected for histology. Brains were collected for gene expression analysis using qRT-PCR. Intestinal morphology data were analyzed with two-way ANOVA and diencephalic gene data were analyzed with Kruskal-Wallis test. There was an increase in villi width in the ileum (p = .0136) and jejunum (p = .0019) of HS hens compared to controls. HS drakes showed a higher crypt depth (CD) in the jejunum (p = .0198) compared to controls. There was an increase in crypt goblet cells (GC) count in the ileum (p = .0169) of HS drakes compared to HS hens. There was higher villi GC count (p = .07) in the jejunum of HS drakes compared to controls. There was an increase in the crypt GC density (p = .0054) in the ileum, not jejunum, of HS drakes compared to HS hens. Further, there were no differences in the proopiomelanocortin gene expression in either sex but there was an increase in the expression of neuropeptide Y (NPY) gene in HS hens (p = .031) only and a decrease in the corticotropin releasing hormone gene in the HS drakes (p = .037) compared to controls. These data show that there are sex differences in the effect of HS on gut morphology while the upregulation in NPY gene may suggest a role in mediating response to chronic HS.

热应激(HS)对生产的影响与采食量密切相关。我们研究了热应激对北京鸭肠道和间脑基因的影响。160 只成年鸭被分配到两个处理室。对照室的温度保持在 22°C,HS 室的温度保持在 35°C,每天前 10 小时,然后降至 29.5°C。3 周后,对每个房间的 10 只母鸭和 5 只公鸭实施安乐死,收集空肠和回肠进行组织学检查。收集大脑,使用 qRT-PCR 进行基因表达分析。肠道形态学数据采用双向方差分析,脑膜基因数据采用 Kruskal-Wallis 检验。与对照组相比,HS母鸡回肠(p = .0136)和空肠(p = .0019)的绒毛宽度有所增加。与对照组相比,HS雌鸽的空肠隐窝深度(CD)更高(p = .0198)。与 HS 雌鸽相比,HS 雄鸽回肠隐窝腺泡细胞 (GC) 数量增加(p = .0169)。与对照组相比,HS 雄鸽空肠中的绒毛 GC 数量较高(p = .07)。与 HS 雌鸽相比,HS 雄鸽回肠(而非空肠)隐窝 GC 密度增加(p = .0054)。此外,与对照组相比,HS雌鸽和HS雄鸽的前绒毛膜促皮质素基因表达均无差异,但仅HS雄鸽的神经肽Y(NPY)基因表达增加(p = .031),而HS雌鸽的促肾上腺皮质激素释放激素基因表达减少(p = .037)。这些数据表明,HS 对肠道形态的影响存在性别差异,而 NPY 基因的上调可能表明其在调解对慢性 HS 的反应方面发挥了作用。
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引用次数: 0
NETest in advanced high-grade gastroenteropancreatic neuroendocrine neoplasms 晚期高级别胃肠胰神经内分泌肿瘤的 NETest。
IF 3.3 4区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-06-27 DOI: 10.1111/jne.13428
H. Sorbye, G. O. Hjortland, L. W. Vestermark, A. Sundlov, J. Assmus, A. Couvelard, A. Perren, S. W. Langer

Molecular blood biomarkers are lacking for high-grade (HG) gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN). To histologically distinguish between neuroendocrine carcinoma (NEC), neuroendocrine tumors G3 (NET G3), adenocarcinoma and MINEN is often challenging. The mRNA-based NETest has diagnostic, prognostic and predictive value in neuroendocrine tumors G1-2 but has not been studied in HG GEP-NEN. Patients with advanced HG GEP-NEN were prospectively included in an observational study. A blood sample was collected before the start of chemotherapy and pseudonymised before NETest was performed. NETest results are expressed as an activity index (NETest score) from 0 to 100. The normal score cut-off is 20. Histological sections were pseudonymised before centralized pathological re-evaluation. Samples from 60 patients were evaluable with the NETest. Main primary tumor sites were colon (14), rectum (12), pancreas (11) and esophagus (7). Re-classification: 30 NEC, 12 NET G3, 3 HG-NEN ambiguous morphology, 8 MiNEN, 3 adenocarcinomas with neuroendocrine differentiation (ADNE), 3 adenocarcinomas and 1 NET G2. Elevated NETest (>20) was seen in 38/45 (84%) HG GEP-NEN, all 17 large-cell NEC (100%), 11/13 (85%) small-cell NEC, all ambiguous cases and 7/12 (64%) NET G3. NETest was elevated in 5/8 (63%) MiNEN, 2/3 ADNE, however not in 3 adenocarcinomas. Median survival was 10.2 months (9.6–10.8 95%CI) for evaluable HG GEP-NEN treated with palliative chemotherapy (n = 39), and survival was significantly shorter in patients with NETest >60 with an OS of only 6.5 months. This is the first study to evaluate use of the NETest in advanced HG GEP-NEN. The NETest was almost always elevated in GEP-NEC and in all large-cell NEC. The NETest was also frequently elevated in NET G3 and MiNEN, however cases were limited. Baseline NETest was not predictive for benefit of chemotherapy, however a NETest >60 was prognostic with a shorter survival for patients receiving chemotherapy.

高级(HG)胃肠胰(GEP)神经内分泌肿瘤(NEN)缺乏分子血液生物标记物。从组织学角度区分神经内分泌癌(NEC)、神经内分泌肿瘤 G3(NET G3)、腺癌和 MINEN 通常具有挑战性。基于 mRNA 的 NETest 对神经内分泌肿瘤 G1-2 具有诊断、预后和预测价值,但尚未对 HG GEP-NEN 进行研究。一项前瞻性观察研究纳入了晚期 HG GEP-NEN 患者。化疗开始前采集血液样本,化名后进行NETest检测。NETest结果以活动指数(NETest得分)表示,从0到100。正常分值为 20 分。组织学切片在集中病理再评估前进行化名。60 名患者的样本可通过 NETest 进行评估。主要原发肿瘤部位为结肠(14 例)、直肠(12 例)、胰腺(11 例)和食道(7 例)。重新分类:30例NEC、12例NET G3、3例HG-NEN形态不清、8例MiNEN、3例神经内分泌分化腺癌(ADNE)、3例腺癌和1例NET G2。38/45(84%)例 HG GEP-NEN、所有 17 例大细胞 NEC(100%)、11/13(85%)例小细胞 NEC、所有不明确病例和 7/12 (64%)例 NET G3 均出现 NETest 升高(>20)。5/8(63%)例 MiNEN 和 2/3 例 ADNE 中的 NETest 升高,但 3 例腺癌中的 NETest 没有升高。接受姑息化疗的可评估 HG GEP-NEN 的中位生存期为 10.2 个月(9.6-10.8 95%CI)(n = 39),NETest >60 的患者生存期明显较短,仅为 6.5 个月。这是第一项评估在晚期 HG GEP-NEN 中使用 NETest 的研究。在 GEP-NEC 和所有大细胞 NEC 中,NETest 几乎总是升高。NETest 在 G3 和 MiNEN 中也经常升高,但病例有限。基线NETest不能预测化疗的疗效,但NETest>60则预示接受化疗的患者生存期缩短。
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引用次数: 0
Role of neoadjuvant peptide receptor radionuclide therapy in unresectable and metastatic gastro-entero-pancreatic neuroendocrine neoplasms: A scoping review. 新辅助肽受体放射性核素疗法在不可切除和转移性胃肠胰神经内分泌肿瘤中的作用:范围综述。
IF 3.3 4区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-06-27 DOI: 10.1111/jne.13425
Raghava Kashyap, Senthil Raja, Ajay Adusumilli, Murali Mohan Reddy Gopireddy, Benjamin P T Loveday, Ramin Alipour, Grace Kong

Peptide receptor radionuclide therapy (PRRT) is an established therapy for metastatic neuroendocrine neoplasms (NEN). The role of PRRT as a neoadjuvant treatment prior to surgery or other local therapies is uncertain. This scoping review aimed to define the landscape of evidence available detailing the utility of PRRT in the neo-adjuvant setting, including the clinical contexts, efficacy, and levels of evidence. A comprehensive literature search of PUBMED, SCOPUS, and EMBASE through to December 2022 was performed to identify reports of PRRT use as neoadjuvant therapy prior to local therapies. Observational studies and clinical trials were included. A total of 369 records were identified by the initial search, and 17 were included in the final analysis, comprising 179 patients treated with neoadjuvant PRRT. Publications included case reports, retrospective cohort series and a phase 2 trial. Definitions of unresectable disease were variable. Radioisotopes used included 177Lu (n = 142) and 90Y (n = 36), used separately (n = 178) or in combination (n = 1). A combination of PRRT with chemotherapy was also explored (n = 2). Toxicity data was reported in 11/17 studies. Survival analysis was reported in 3/17 studies. Surgical resection following PRRT was reported for both the primary tumor (n = 71) and metastases (n = 12). Resection rates could not be calculated as not all publications reported whether resection was completed. Published literature exploring the use of PRRT in the neoadjuvant setting is mostly limited to case reports and retrospective cohort studies. From these limited data there is reported to be a role of PRRT in neoadjuvant setting in the literature. However, the low quality of evidence precludes any definite conclusion on the grade of disease, site of primary, isotope used or use of concomitant chemotherapy that can benefit from this application. Further prospective studies will require collaboration between multiple centers to gain sufficient high-quality evidence.

肽受体放射性核素疗法(PRRT)是一种治疗转移性神经内分泌肿瘤(NEN)的成熟疗法。在手术或其他局部疗法之前,PRRT 作为新辅助疗法的作用尚不确定。本次范围界定综述旨在明确现有证据的范围,详细说明 PRRT 在新辅助治疗中的作用,包括临床背景、疗效和证据级别。我们对截至 2022 年 12 月的 PUBMED、SCOPUS 和 EMBASE 进行了全面的文献检索,以确定在局部治疗前将 PRRT 用作新辅助治疗的报告。研究纳入了观察性研究和临床试验。初步搜索共发现 369 条记录,其中 17 条被纳入最终分析,包括 179 名接受新辅助 PRRT 治疗的患者。文献包括病例报告、回顾性队列系列研究和一项二期试验。不可切除性疾病的定义各不相同。使用的放射性同位素包括177Lu(n = 142)和90Y(n = 36),分别使用(n = 178)或联合使用(n = 1)。还探讨了 PRRT 与化疗的联合应用(n = 2)。11/17 项研究报告了毒性数据。3/17 项研究报告了生存期分析。有报告称,PRRT 治疗后对原发肿瘤(71 例)和转移瘤(12 例)进行了手术切除。由于并非所有文献都报告了切除是否完成,因此无法计算切除率。探讨在新辅助治疗中使用 PRRT 的已发表文献大多局限于病例报告和回顾性队列研究。从这些有限的数据来看,有文献报道 PRRT 在新辅助治疗中的作用。然而,由于证据质量不高,因此无法就可从该应用中获益的疾病分级、原发部位、使用的同位素或同时使用的化疗得出明确结论。进一步的前瞻性研究需要多个中心合作才能获得足够的高质量证据。
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引用次数: 0
The research trend of hyperprolactinemia from 2011 to 2023 was analyzed by bibliometrics 通过文献计量学分析了 2011 至 2023 年高催乳素血症的研究趋势。
IF 3.3 4区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-06-18 DOI: 10.1111/jne.13422
Kaiyan Liu, Jin Zhao, Han Yu, Jing Yang, Yi Ren

The objective of this study is to conduct a bibliometric analysis of research trends in hyperprolactinemia from 2011 to 2023. This analysis aims to provide researchers with insights into the current hotspots and frontiers related to hyperprolactinemia. It is worth noting that there are currently no existing reports on bibliometric analyses of hyperprolactinemia. The Social Science Citation Index (SSCI) and Science Citation Index Expanded (SCIE) databases of the Web of Science Core Collection were systematically searched for “articles” and “review articles” related to the topic of hyperprolactinemia from 2011 to 2023. VOSviewer was employed to conduct bibliometric analysis, aiming to analyze the research trends in hyperprolactinemia over the past 13 years. A total of 1865 eligible articles were retrieved, with contributions from 9544 scholars representing 83 countries in the field of research. The United States had the highest number of publications, followed by China. The keywords were categorized into six clusters: (1) etiology of hyperprolactinemia and other related endocrine and metabolic diseases. (2) Hyperprolactinemia and mental illness. (3) Diagnosis and management of hyperprolactinemia. (4) Treatment of hyperprolactinemia and prolactinoma. (5) Detection of macroprolactin and macroprolactinemia. (6) Symptoms of male hyperprolactinemia. Over the past 13 years, there has been a consistent and slightly increasing trend in the number of research papers focusing on hyperprolactinemia. The primary areas of research focus are centered around the diagnosis and treatment of hyperprolactinemia caused by antipsychotic drugs or prolactinoma.

本研究旨在对 2011 年至 2023 年高泌乳素血症的研究趋势进行文献计量分析。该分析旨在让研究人员深入了解当前与高催乳素血症相关的热点和前沿领域。值得注意的是,目前还没有关于高催乳素血症的文献计量分析报告。我们在科学网核心数据库的社会科学引文索引(SSCI)和科学引文索引扩展(SCIE)数据库中系统检索了 2011 年至 2023 年与高泌乳素血症相关的 "文章 "和 "综述文章"。采用 VOSviewer 进行文献计量分析,旨在分析过去 13 年中有关高泌乳素血症的研究趋势。共检索到1865篇符合条件的文章,来自83个国家的9544名学者参与了该领域的研究。美国的论文数量最多,其次是中国。关键词分为六组:(1)高催乳素血症及其他相关内分泌和代谢疾病的病因学。(2) 高催乳素血症与精神疾病。(3) 高泌乳素血症的诊断和治疗。(4) 高泌乳素血症和泌乳素瘤的治疗。(5) 巨泌乳素和巨泌乳素血症的检测。(6) 男性高催乳素血症的症状。在过去 13 年中,以高泌乳素血症为重点的研究论文数量一直呈略微增长趋势。研究重点主要围绕抗精神病药物或催乳素瘤引起的高泌乳素血症的诊断和治疗。
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引用次数: 0
Dyslipidaemia in women with polycystic ovary syndrome referred to a teaching hospital in Cape Town, South Africa 南非开普敦一家教学医院转诊的多囊卵巢综合征妇女的血脂异常。
IF 3.3 4区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-06-10 DOI: 10.1111/jne.13414
Adrian David Marais, Anne Hoffman, Diane Mary Blackhurst, Zephne Margeret van der Spuy

The polycystic ovary syndrome (PCOS) imparts health risks including dyslipidaemia, diabetes and cardiovascular disease that are amenable to lifestyle adjustment and/or medication. We describe dyslipidaemia in women referred to a gynaecological endocrine clinic. Clinical data and endocrine and lipoprotein investigations comprising fasting triglyceride (TG), total cholesterol (TC), high density lipoprotein cholesterol (HDLC) and calculated low density lipoprotein cholesterol (LDLC) were studied along with electrophoresis patterns of apolipoprotein B-containing lipoproteins. The 1721 participants comprised black, mixed ancestry, white and Indian individuals (9.8%, 83.2%, 5.8% and 1.2%, respectively). The mean ± standard deviation of the age, body mass index (BMI) and waist/hip ratio were 26.0 ± 5.9 years, 32.3 ± 8.3 kg/m2 and waist/hip ratio 0.88 ± 0.11, respectively. Overweight status (BMI 26–30 kg/m2) and obesity (BMI >30 kg/m2) involved 272 (15.8%) and 1010 (58.7%) individuals, respectively. Morbid obesity (BMI >40 kg/m2) was present in 309 (17.9%) individuals. The TG, TC, HDLC and LDLC concentrations were 1.22 ± 0.86, 4.77 ± 1.02, 1.3 ± 0.36, 2.94 ± 0.94 mmol/L, respectively. LDL hypercholesterolaemia occurred in 753 (43.7%) and exceeded 5 mmol/L in 39 (2.3%) women. Low HDLC (<0.9 mmol/L) affected 122 (7%), hypertriglyceridaemia (>1.7 mmol/L) affected 265 (15.4%) and exceeded 2.5 mmol/L in 91 (5.3%) women. Mixed hyperlipidaemia (TG >1.7, TC >5.0 mmol/L) occurred in 176 (10.2%). Electrophoresis revealed small LDL particles in 79 (4.6%) and dysbetalipoproteinaemia in 13 (0.76%) of the cohort. Small LDL associated with obesity, blood pressure, TG and glucose concentration and higher androgenic state. Many women with PCOS had unfavourable lipoprotein results: mostly moderate changes in TG, HDLC and LDLC. Small LDL is not rare, may aid risk assessment and is best determined directly. Incidental monogenic disorders of lipoprotein metabolism included dysbetalipoproteinaemia, familial hypercholesterolaemia and severe hypertriglyceridaemia. Dyslipidaemia in PCOS requires more careful diagnosis, individualised management and research.

多囊卵巢综合征(PCOS)带来的健康风险包括血脂异常、糖尿病和心血管疾病,这些疾病都可以通过调整生活方式和/或药物治疗来解决。我们描述了转诊到妇科内分泌诊所的妇女的血脂异常情况。我们研究了临床数据、内分泌和脂蛋白检查,包括空腹甘油三酯(TG)、总胆固醇(TC)、高密度脂蛋白胆固醇(HDLC)和计算得出的低密度脂蛋白胆固醇(LDLC),以及含脂蛋白 B 的脂蛋白的电泳模式。1721 名参与者包括黑人、混血儿、白人和印度人(分别占 9.8%、83.2%、5.8% 和 1.2%)。年龄、体重指数(BMI)和腰围/臀围比的平均值(± 标准差)分别为 26.0 ± 5.9 岁、32.3 ± 8.3 kg/m2 和腰围/臀围比 0.88 ± 0.11。超重(体重指数 26-30 kg/m2)和肥胖(体重指数大于 30 kg/m2)分别涉及 272 人(15.8%)和 1010 人(58.7%)。病态肥胖(BMI >40 kg/m2)有 309 人(17.9%)。TG、TC、HDLC 和 LDLC 的浓度分别为 1.22 ± 0.86、4.77 ± 1.02、1.3 ± 0.36、2.94 ± 0.94 mmol/L。753名(43.7%)妇女患有低密度脂蛋白高胆固醇血症,39名(2.3%)妇女的低密度脂蛋白超过5毫摩尔/升。低 HDLC(1.7 毫摩尔/升)影响到 265 名(15.4%)妇女,91 名(5.3%)妇女的 HDLC 超过 2.5 毫摩尔/升。176人(10.2%)患有混合型高脂血症(TG >1.7,TC >5.0 mmol/L)。电泳结果显示,79 人(4.6%)体内存在小低密度脂蛋白颗粒,13 人(0.76%)体内存在脂蛋白异常。小低密度脂蛋白与肥胖、血压、TG 和葡萄糖浓度以及较高的雄激素状态有关。许多患有多囊卵巢综合症的妇女都有不利的脂蛋白结果:主要是总胆固醇、高密度脂蛋白和低密度脂蛋白的中度变化。小低密度脂蛋白并不罕见,可能有助于风险评估,最好直接测定。偶发的单基因脂蛋白代谢紊乱包括脂蛋白血症、家族性高胆固醇血症和严重的高甘油三酯血症。多囊卵巢综合症患者的血脂异常需要更仔细的诊断、个体化管理和研究。
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引用次数: 0
Restoring function to inactivating G protein-coupled receptor variants in the hypothalamic–pituitary–gonadal axis† 恢复下丘脑-垂体-性腺轴中失活 G 蛋白偶联受体变体的功能1。
IF 3.3 4区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-06-09 DOI: 10.1111/jne.13418
Tarryn Radomsky, Ross C. Anderson, Robert P. Millar, Claire L. Newton

G protein-coupled receptors (GPCRs) are central to the functioning of the hypothalamic–pituitary–gonadal axis (HPG axis) and include the rhodopsin-like GPCR family members, neurokinin 3 receptor, kappa-opioid receptor, kisspeptin 1 receptor, gonadotropin-releasing hormone receptor, and the gonadotropin receptors, luteinizing hormone/choriogonadotropin receptor and follicle-stimulating hormone receptor. Unsurprisingly, inactivating variants of these receptors have been implicated in a spectrum of reproductive phenotypes, including failure to undergo puberty, and infertility. Clinical induction of puberty in patients harbouring such variants is possible, but restoration of fertility is not always a realisable outcome, particularly for those patients suffering from primary hypogonadism. Thus, novel pharmaceuticals and/or a fundamental change in approach to treating these patients are required. The increasing wealth of data describing the effects of coding-region genetic variants on GPCR function has highlighted that the majority appear to be dysfunctional as a result of misfolding of the encoded receptor protein, which, in turn, results in impaired receptor trafficking through the secretory pathway to the cell surface. As such, these intracellularly retained receptors may be amenable to ‘rescue’ using a pharmacological chaperone (PC)-based approach. PCs are small, cell permeant molecules hypothesised to interact with misfolded intracellularly retained proteins, stabilising their folding and promoting their trafficking through the secretory pathway. In support of the use of this approach as a viable therapeutic option, it has been observed that many rescued variant GPCRs retain at least a degree of functionality when ‘rescued’ to the cell surface. In this review, we examine the GPCR PC research landscape, focussing on the rescue of inactivating variant GPCRs with important roles in the HPG axis, and describe what is known regarding the mechanisms by which PCs restore trafficking and function. We also discuss some of the merits and obstacles associated with taking this approach forward into a clinical setting.

G 蛋白偶联受体(GPCRs)是下丘脑-垂体-性腺轴(HPG 轴)功能的核心,包括类罗丹明 GPCR 家族成员、神经激肽 3 受体、卡帕类阿片受体、kisspeptin 1 受体、促性腺激素释放激素受体,以及促性腺激素受体、黄体生成素/绒毛促性腺激素受体和卵泡刺激素受体。毫不奇怪,这些受体的失活变体与一系列生殖表型有关,包括无法进入青春期和不育症。临床上可以诱导携带此类变异体的患者进入青春期,但恢复生育能力并非总能实现,尤其是对那些患有原发性性腺功能减退症的患者而言。因此,需要新型药物和/或从根本上改变治疗这些患者的方法。描述编码区基因变异对 GPCR 功能影响的数据越来越丰富,这些数据突出表明,大多数基因变异似乎是由于编码的受体蛋白折叠错误而导致功能障碍,这反过来又会导致受体通过分泌途径向细胞表面的转运功能受损。因此,这些滞留在细胞内的受体可能可以通过基于药理学伴侣(PC)的方法进行 "拯救"。PC 是一种具有细胞渗透性的小分子,据推测能与折叠错误的细胞内滞留蛋白相互作用,稳定它们的折叠并促进它们通过分泌途径进行运输。为了支持将这种方法作为一种可行的治疗方案,我们观察到许多被拯救的变体 GPCR 在被 "拯救 "到细胞表面时至少保留了一定程度的功能。在本综述中,我们审视了 GPCR PC 的研究现状,重点关注在 HPG 轴中发挥重要作用的失活变异 GPCR 的拯救,并介绍了 PC 恢复贩运和功能的已知机制。我们还讨论了将这种方法应用于临床的一些优点和障碍。
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引用次数: 0
Clinical impact of using [18F]AlF-NOTA-octreotide PET/CT instead of [68Ga]Ga-DOTA-SSA PET/CT: Secondary endpoint analysis of a multicenter, prospective trial 使用[18F]AlF-NOTA-奥曲肽 PET/CT 代替[68Ga]Ga-DOTA-SSA PET/CT 的临床影响:一项多中心前瞻性试验的次要终点分析。
IF 3.3 4区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-06-04 DOI: 10.1111/jne.13420
Hannes Leupe, Elin Pauwels, Timon Vandamme, Bliede Van den Broeck, Willem Lybaert, Jeroen Dekervel, Filip Van Herpe, Joris Jaekers, Frederik Cleeren, Johannes Hofland, Adrienne Brouwers, Michel Koole, Guy Bormans, Eric Van Cutsem, Karen Geboes, Annouschka Laenen, Chris Verslype, Sigrid Stroobants, Christophe M. Deroose

[18F]AlF-NOTA-octreotide ([18F]AlF-OC) is a promising alternative for [68Ga]Ga-DOTA-somatostatin analogs (SSAs) in positron emission tomography (PET) imaging of the somatostatin receptor (SSTR). Our aim is to assess changes in TNM staging and differences in patient management between [18F]AlF-OC PET/CT and [68Ga]Ga-DOTA-SSA PET/CT in the work-up of neuroendocrine tumor (NET) patients. Patients who underwent both [18F]AlF-OC and [68Ga]Ga-DOTA-TATE or [68Ga]Ga-DOTA-NOC PET/CT in our multicenter study (Pauwels et al., J Nucl Med.2023;63:632–638) with a NET were included for analysis. TNM staging was determined and compared for both tracers. For each patient, the blinded [68Ga]Ga-DOTA-SSA or [18F]AlF-OC PET/CT images were presented in random order at a multidisciplinary team board. The images were presented together with clinical information and compared with previous SSTR and [18F]FDG PET/CT imaging. After a consensus decision for patient management was recorded, the board was presented with the PET/CT images from the other SSTR tracer and a decision was made for the second tracer. Differences in management were classified as major if it entailed an intermodality change and minor if it led to an intramodality change. Compared with [68Ga]Ga-DOTA-SSA, the use of [18F]AlF-OC led to a change in 16/75 patients: TNM staging changes in 10/75 patients (13.3%; downstaging in 3/10, upstaging in 7/10) and differences in clinical management were seen in 10/75 patients (13.3%), leading to a major difference in 7/10 cases and a minor change in 3/10 cases. All 10 cases with a difference in patient management between both PET tracers were caused by additional lesion detection by [18F]AlF-OC. The use of [18F]AlF-OC did not impact TNM staging or clinical management in the large majority of the patients (86.7%), further validating the potential for routine clinical use of [18F]AlF-OC PET/CT as an alternative for [68Ga]Ga-DOTA-SSA PET/CT. The trial is registered under ClinicalTrials.gov identifier NCT04552847 and EudraCT 2020–000549-15.

[18F]AlF-NOTA-octreotide([18F]AlF-OC)是[68Ga]Ga-DOTA-索马司他汀类似物(SSA)在体生长激素受体(SSTR)正电子发射断层扫描(PET)成像中的一种很有前途的替代品。我们的目的是评估[18F]AlF-OC PET/CT和[68Ga]Ga-DOTA-SSA PET/CT在神经内分泌肿瘤(NET)患者检查中TNM分期的变化和患者管理的差异。我们的多中心研究(Pauwels 等人,J Nucl Med.2023;63:632-638)纳入了同时接受[18F]AlF-OC和[68Ga]Ga-DOTA-TATE或[68Ga]Ga-DOTA-NOC PET/CT检查的NET患者进行分析。两种示踪剂的 TNM 分期均已确定并进行了比较。在多学科小组委员会上,按随机顺序展示每位患者的盲法[68Ga]Ga-DOTA-SSA或[18F]AlF-OC PET/CT图像。图像与临床信息一起展示,并与之前的 SSTR 和 [18F]FDG PET/CT 图像进行比较。在记录了对患者管理的一致决定后,向委员会展示另一种 SSTR 示踪剂的 PET/CT 图像,并就第二种示踪剂做出决定。如果管理上的差异导致了模式间的改变,则被归类为重大差异;如果导致了模式内的改变,则被归类为轻微差异。与[68Ga]Ga-DOTA-SSA相比,使用[18F]AlF-OC导致16/75例患者的病情发生变化:10/75例患者的TNM分期发生了变化(13.3%;3/10例患者分期下调,7/10例患者分期上调),10/75例患者的临床管理发生了变化(13.3%),其中7/10例患者的临床管理发生了重大变化,3/10例患者的临床管理发生了轻微变化。两种 PET 示踪剂在患者管理方面存在差异的所有 10 个病例都是由于[18F]AlF-OC 发现了额外的病灶。在绝大多数患者(86.7%)中,使用[18F]AlF-OC不会影响TNM分期或临床治疗,这进一步验证了[18F]AlF-OC PET/CT作为[68Ga]Ga-DOTA-SSA PET/CT的常规临床应用潜力。该试验已在 ClinicalTrials.gov 标识符 NCT04552847 和 EudraCT 2020-000549-15 下注册。
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引用次数: 0
Pharmacologic blockade of nicotinic receptors in the suprachiasmatic nucleus increases ovarian atresia and inhibits follicular growth 药物阻断蛛网膜上核的烟碱受体可增加卵巢闭锁并抑制卵泡生长。
IF 3.3 4区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-06-03 DOI: 10.1111/jne.13421
Elizabeth Vieyra, Roberto Calderón, Rosa Linares, Gabriela Rosas, Deyra A. Ramírez, Julieta A. Espinoza, Andrea Chaparro, Carlos-Camilo Silva, Roberto Domínguez, Leticia Morales-Ledesma

Reproduction in all mammalian species depends on the growth and maturation of ovarian follicles, that is, folliculogenesis. Follicular development can culminate with the rupture of mature follicles and the consequent expulsion of their oocytes (ovulation) or in atresia, characterized by the arrest of development and eventual degeneration. These processes are regulated by different neuroendocrine signals arising at different hypothalamic nuclei, including the suprachiasmatic nucleus (SCN). In the later, the activation of muscarinic receptors (mAChRs) and nicotinic receptors (nAChRs) by acetylcholine is essential for the regulation of the pre-ovulatory signals that stimulate the rupture of mature follicles. To evaluate the participation of the nAChRs in the SCN throughout the oestrous cycle in the regulation of the hypothalamic–pituitary–ovarian axis. For this purpose, 90-day-old adult female rats in metoestrus, dioestrus, proestrus or oestrus were microinjected into the left- or right-SCN with 0.3 μL of saline solution as vehicle or with 0.225 μg of mecamylamine (Mec), a non-selective antagonist of the nicotinic receptors, diluted in 0.3 μL of vehicle. The animals were sacrificed when they presented vaginal cornification, indicative of oestrus stage, and the effects of the unilateral pharmacological blockade of the nAChRs in the SCN on follicular development, ovulation and secretion of oestradiol and follicle-stimulating hormone (FSH) were evaluated. The microinjection of Mec decreased the serum levels of FSH, which resulted in a lower number of growing and healthy follicles and an increase in atresia. The higher percentage of atresia in pre-ovulatory follicles was related to a decrease in the number of ova shed and abnormalities in oestradiol secretion. We also detected asymmetric responses between the left and right treatments that depended on the stage of the oestrous cycle. The present results allow us to suggest that during all the stages of the oestrous cycle, cholinergic signals that act on the nAChRs in the SCN are pivotal to modulate the secretion of gonadotropins and hence the physiology of the ovaries. Further research is needed to determine if such signals are generated by the cholinergic neurons in the SCN or by cholinergic afferents to the SCN.

所有哺乳动物的生殖都依赖于卵泡的生长和成熟,即卵泡生成。卵泡发育的最终结果可能是成熟卵泡破裂并随之排出卵母细胞(排卵),也可能是闭锁,其特点是发育停止并最终退化。这些过程受到不同下丘脑核(包括丘脑上核)发出的不同神经内分泌信号的调控。其中,乙酰胆碱对毒蕈碱受体(mAChRs)和烟碱受体(nAChRs)的激活对于调节刺激成熟卵泡破裂的排卵前信号至关重要。为了评估整个发情周期中 SCN 中的 nAChRs 参与下丘脑-垂体-卵巢轴调节的情况。为此,在处于发情期、二发情期、预发情期或发情期的90天大成年雌性大鼠的左侧或右侧SCN中微量注射了0.3微升生理盐水(作为载体)或0.225微克麦卡明(Mec)(一种非选择性烟碱受体拮抗剂)(稀释于0.3微升载体中)。当动物出现阴道粟粒化(发情期的标志)时将其处死,并评估单侧药物阻断 SCN 中的 nAChRs 对卵泡发育、排卵以及雌二醇和促卵泡激素(FSH)分泌的影响。显微注射 Mec 降低了 FSH 的血清水平,导致生长健康的卵泡数量减少,闭锁的卵泡数量增加。排卵前卵泡闭锁比例较高与卵子脱落数量减少和雌二醇分泌异常有关。我们还发现,左右处理之间的反应不对称,这取决于发情周期的阶段。本研究结果表明,在发情周期的各个阶段,作用于 SCN 中 nAChRs 的胆碱能信号对调节促性腺激素的分泌以及卵巢的生理机能至关重要。要确定这些信号是由 SCN 中的胆碱能神经元产生的,还是由 SCN 的胆碱能传入因子产生的,还需要进一步的研究。
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引用次数: 0
Maternal immune activation with toll-like receptor 7 agonist during mid-gestation alters juvenile and adult developmental milestones and behavior 在妊娠中期使用toll样受体7激动剂进行母体免疫激活会改变青少年和成人的发育里程碑和行为。
IF 3.3 4区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-06-01 DOI: 10.1111/jne.13417
Julietta A. Sheng, Stuart A. Tobet

Infections during pregnancy are associated with increased risk for adult neuropsychiatric disease, such as major depressive disorder, schizophrenia, and autism spectrum disorder. In mouse models of maternal immune activation (MIA), different toll-like receptors (TLRs) are stimulated to initiate inflammatory responses in mother and fetus. The goal of this study was to determine sex-dependent aspects of MIA using a TLR7/8 agonist, Resiquimod (RQ), on neurodevelopment. RQ was administered to timed-pregnant mice on embryonic day (E) 12.5. At E15, maternal/fetal plasma cytokines were measured by enzyme-linked immunosorbent assay (ELISA). Maternal cytokines interleukin (IL)-6 and IL-10 were higher while tumor necrosis factor (TNF)-α and IL-17 were lower in pregnant dams exposed to RQ. Fetal cytokines (E15) were altered at the same timepoint with fetal plasma IL-6 and IL-17 greater after RQ compared to vehicle, while IL-10 and TNF-α were higher in male fetuses but not female. Other timed-pregnant dams were allowed to give birth. MIA with RQ did not alter the female to male ratio of offspring born per litter. Body weights were reduced significantly in both sexes at birth, and over the next 5 weeks. Offspring from RQ-injected mothers opened their eyes 5 days later than controls. Similarly, female offspring from RQ-injected mothers exhibited pubertal delay based on vaginal opening 2–3 days later than control females. On the behavioral side, juvenile and adult male and female MIA offspring exhibited less social-like behavior in a social interaction test. Anhedonia-like behavior was greater in MIA adult female mice. This study provides support for sex-dependent influences of fetal antecedents for altered brain development and behavioral outputs that could be indicative of increased susceptibility for adult disorders through immune mechanisms. Future studies are needed to determine neural cellular and molecular mechanisms for such programming effects.

孕期感染与成年后患神经精神疾病(如重度抑郁症、精神分裂症和自闭症谱系障碍)的风险增加有关。在母体免疫激活(MIA)的小鼠模型中,不同的收费样受体(TLR)受到刺激,从而引发母亲和胎儿的炎症反应。本研究的目的是利用 TLR7/8 激动剂 Resiquimod(RQ)确定母体免疫激活对神经发育的性别依赖性。在胚胎 12.5 天对定时怀孕的小鼠施用 RQ。在胚胎发育到第 15 天时,用酶联免疫吸附试验(ELISA)测定母体/胎儿血浆细胞因子。暴露于 RQ 的母体细胞因子白细胞介素 (IL)-6 和 IL-10 较高,而肿瘤坏死因子 (TNF)-α 和 IL-17 较低。胎儿细胞因子(E15)在相同的时间点也发生了变化,与暴露于 RQ 的车辆相比,暴露于 RQ 的胎儿血浆 IL-6 和 IL-17 较高,而雄性胎儿的 IL-10 和 TNF-α 较高,雌性胎儿则不高。其他定时怀孕的母体可以分娩。使用 RQ 的 MIA 并未改变每胎所生后代的雌雄比例。雌雄胎儿的体重在出生时和随后的 5 周内都明显下降。注射 RQ 的母亲所生后代的睁眼时间比对照组晚 5 天。同样,注射 RQ 的母亲所生的雌性后代的青春期延迟表现为阴道张开时间比对照组雌性后代晚 2-3 天。在行为方面,MIA 的幼年和成年雄性和雌性后代在社会互动测试中表现出较少的类社会行为。MIA成年雌性小鼠的失神行为更多。这项研究支持胎儿前因对大脑发育和行为输出改变的性别依赖性影响,这可能表明通过免疫机制增加了成年疾病的易感性。未来的研究需要确定这种编程效应的神经细胞和分子机制。
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引用次数: 0
In memoriam: Roger Guillemin, neuroendocrinologist, Nobel Prize in physiology or medicine 悼念诺贝尔生理学或医学奖获得者、神经内分泌学家罗杰-吉勒明。
IF 3.3 4区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-05-31 DOI: 10.1111/jne.13419
Sebastien G. Bouret, Hubert Vaudry, Vincent Prevot
<p>Roger Guillemin was born in Dijon, Burgundy (France) on January 11, 1924. In 1942, he began studying Medicine at the University of Burgundy. After a mandatory break during World War I, he obtained his medical degree from the Faculty of Medicine of Lyon in 1949.</p><p>He began to practice as a family doctor, during which he acquired many excellent memories. However, he also quickly realized the limitations of medicine at that time. He recalled that he “could only prescribe three types of medicine, one of which being aspirin.” His scientific curiosity made him read specialized journals, which made him aware of Hans Selye's research in Montreal on the “General Adaptation Syndrome,” now known as the endocrine reaction of the organism to stress. He heard that the Canadian professor was invited to give a series of lectures at the Pitié Hospital and decided to attend his talks. Fortunately, Hans Selye presented his lectures in French, as Roger Guillemin did not speak English at that time. At the end of the third lecture, he introduced himself to Pr. Selye and asked him if he could join his lab for a year to prepare for his medical doctorate. Roger Guillemin left his native Burgundy and flew to Montreal. During his stay in Pr. Selye's laboratory, he first prepared a medical thesis, followed by a PhD in Physiology, specializing in Experimental Endocrinology, which he obtained in 1953.</p><p>Pr. Selye was the head of the Institute of Experimental Medicine and Surgery, where he established a series of lectures called “The Claude Bernard Lectures” inviting internationally renowned researchers. This is how Roger Guillemin met Geoffrey Harris, who is nowadays considered the father of Neuroendocrinology. Through various approaches of electrical stimulation, ligation or section of the pituitary stalk, and pituitary transplantation, Pr. Harris demonstrated a key role of the portal system in the relationship between the hypothalamus and the adenohypophysis.<span><sup>1</sup></span> Harris's work made it possible to understand how the “first mediators” (according to Selye's terminology), which will later be called “releasing factors,” reached the pituitary cells. The objective of Roger Guillemin was now clear: to chemically identify hypothalamic factors that govern the anterior pituitary's function, starting with the neural mediator suspected by Hans Selye controlling the hypothalamic–pituitary–adrenal axis.</p><p>Hans Selye's laboratory did not have the equipment and expertise to identify chemical factors governing the anterior pituitary function. Roger Guillemin decided to move to the Department of Physiology of Baylor College in Houston, Texas, which was headed by Hebbel Hoff. However, Roger Guillemin did not have the expertise to purify the hypothalamic factors he was looking for. Therefore, he teamed up with talented (bio)chemists, including Walter Hearn, with whom he used paper chromatography on a few dozen sheep hypothalami with the hope of isolating the
Roger Guillemin 于 1924 年 1 月 11 日出生于法国勃艮第的第戎。1942 年,他开始在勃艮第大学学习医学。第一次世界大战期间,他不得不中断学业,之后于 1949 年获得里昂医学院医学学位。然而,他也很快意识到当时医学的局限性。他回忆说,他 "只能开三种药,其中一种是阿司匹林"。他对科学的好奇心让他阅读专业期刊,这让他了解到汉斯-塞利(Hans Selye)在蒙特利尔进行的 "一般适应综合征 "研究,也就是现在所说的机体对压力的内分泌反应。他听说这位加拿大教授受邀在皮蒂埃医院举办系列讲座,于是决定参加他的讲座。幸运的是,汉斯-塞利的讲座是用法语进行的,因为罗杰-吉列明当时还不会说英语。在第三场讲座结束时,他向汉斯-塞利教授做了自我介绍,并问他是否会说英语。在第三次讲座结束时,他向塞利教授做了自我介绍,并询问他是否可以加入他的实验室一年,为获得医学博士学位做准备。罗杰-吉耶明离开家乡勃艮第,飞往蒙特利尔。在塞利教授的实验室逗留期间在塞利教授的实验室工作期间,他首先撰写了医学论文,随后于1953年获得了生理学博士学位,专攻实验内分泌学。塞利教授当时是实验医学和外科研究所的所长,他在那里开设了一个名为 "克劳德-贝尔纳讲座 "的系列讲座,邀请国际知名研究人员参加。罗杰-吉列明也因此结识了如今被誉为神经内分泌学之父的杰弗里-哈里斯。通过电刺激、结扎或切除垂体柄以及垂体移植等各种方法,哈里斯教授证明了垂体门静脉的关键作用。1 哈里斯的工作使人们得以了解 "第一介质"(按照塞利的术语),即后来被称为 "释放因子",是如何到达垂体细胞的。现在,罗杰-吉列明的目标很明确:从汉斯-塞利怀疑的控制下丘脑-垂体-肾上腺轴的神经介质开始,用化学方法鉴定支配垂体前叶功能的下丘脑因子。汉斯-塞利的实验室不具备鉴定支配垂体前叶功能的化学因子的设备和专业知识。罗杰-吉列明决定转到得克萨斯州休斯顿贝勒学院的生理学系,该系由赫伯尔-霍夫领导。然而,Roger Guillemin 并不具备纯化他所寻找的下丘脑因子的专业知识。因此,他与沃尔特-赫恩(Walter Hearn)等才华横溢的(生物)化学家合作,在几十只绵羊下丘脑上使用纸层析法,希望分离出汉斯-塞利(Hans Selye)著名的 "第一介质"。遗憾的是,这种方法在检测垂体激素方面不够灵敏。罗杰-吉列明发现,他必须收集更大量的组织样本,并进行相应的组织处理。他还改用了液态凝胶色谱法,这是一种更灵敏的方法,维克多-穆特(Viktor Mutt)在卡罗林斯卡学院成功地使用这种方法从猪消化道中提纯多肽。因此,他带着妻子露西安娜-比拉尔(Lucienne Billard)搬到了巴黎,这是他在汉斯-塞利(Hans Selye)实验室任职期间认识的。不过,赫伯尔-霍夫坚持让罗杰继续留在贝勒的实验室工作,在那里他可以依靠安德鲁-沙利(Andrew Schally)完成分析步骤,依靠哈里-利普斯科姆(Harry Lipscomb)进行生物测试。在法兰西学院,他与波兰化学家玛丽安-尤蒂斯(Marian Jutisz)和爱德华-萨基兹(Edouard Sakiz)合作,前者后来在法国神经内分泌学会(SNE)中发挥了重要作用,后者则是未来的罗塞尔-乌克拉夫制药公司首席执行官。罗杰-吉列明将几十万只绵羊下丘脑的采集工作外包给了一家巴黎私人公司。他还决定暂时停止寻找促肾上腺皮质激素释放因子(CRF),转而关注促甲状腺激素释放因子(TRF),并为此开发了一种更简单的生物检测方法,即在垂体和甲状腺的共培养物中加入放射性碘。在巴黎度过 3 年后,吉列明带着行李中约 50 万个下丘脑的冻干提取物,举家返回德克萨斯州休斯顿。威利-维尔加入了实验室,最初的任务是在圣安东尼奥屠宰场再收集数千个下丘脑。
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Journal of Neuroendocrinology
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