Journal of Neuroendocrinology最新文献

Poorly differentiated neuroendocrine carcinomas (NECs) are rare malignancies with a dismal prognosis, few therapeutic options, and a lack of predictive factors. We describe a large series of extra-pulmonary (EP) NEC patients from a neuroendocrine neoplasm (NEN) referral center, aiming to improve the clinical management of these diseases. Medical records of patients with histological diagnosis of pure histology EP-NEC, discussed at the NEN-dedicated multidisciplinary team (MDT) between October 2018 and August 2022, were included. Demographic features, tumor characteristics, molecular profile, treatments, and responses to treatments were collected. Among 1594 NEN diagnoses discussed at the MDT during the study period, 377 were NECs; the final population consisted of 173 patients, mostly presenting with advanced disease and often with a gastroenteropancreatic tract primary tumor. Molecular profiling was available for 52 patients (30%). The most frequent alterations occurred in TP53 and KRAS. One of 25 patients tested for microsatellite instability was confirmed MSI-h; one of 52 patients tested had a high tumor mutational burden (TMB = 19). Median overall survival (OS) was 15.4 months (95% confidence interval [CI]: 13.2–18.5). Most patients with advanced disease received a first-line chemotherapy (136/153 [88.9%]), often platinum plus etoposide (111/136 patients [82%]). The overall response rate (ORR) to first-line was 40%. Median progression-free survival (PFS) was 5.7 months (95% CI: 4.4–6.4). Forty-two percent and 18% of patients received second- and third-line therapy, respectively. No significant difference was seen when stratifying OS and PFS by Ki-67 groups and tumor cell morphology, whereas performance status and presence of metastases were significantly related to OS. In this single-center retrospective large series of EP-NECs, almost half of the patients showed a tumor response to first-line chemotherapy. No relevant correlation was found with primary site, tumor cell morphology, or Ki-67. The proportion of patients receiving subsequent lines, along with the mOS, confirms the aggressiveness of this disease. Molecular profiling was performed only fragmentarily, with limited practical applicability. Efforts shall be made in the future to implement these investigations.

The 20 kDa isoform of human growth hormone variant (20K hGH-V) (derived from the GH2 gene) has previously been shown to promote growth but lacks the diabetogenic and lactogenic activities of human GH (derived from the GH1 gene). That is, 20K hGH-V-treated mice have similar body size and composition to hGH-treated mice, as well as improved insulin sensitivity despite having similar adipose tissue mass. Furthermore, 20K hGH-V-treated prolactin receptor-positive cancer cells exhibited significantly less growth compared to hGH treatment. The aim of this study was to use transcriptomics to compare the effects of 20K hGH-V injection to that of hGH injection on adipose and muscle tissue. GH knockout (GHKO) mice, which do not produce endogenous GH, were injected with hGH or 20K hGH-V daily for 5 days and dissected 4 h after the final injection. RNA was extracted from inguinal subcutaneous adipose tissue and quadriceps muscle and subjected to RNA sequencing. When comparing hGH to 20K hGH-V, there were 73 genes that were significantly altered (q value <.05 and log₂ fold change >1 or < −1) in adipose and 32 in muscle, with two genes (Cish and Sv2b) common to both tissues. Gene set enrichment analysis (GSEA) indicated that the adipose tissue of the 20K hGH-V-treated mice had decreased enrichment of genes associated with T and B lymphocytes compared to hGH-treated adipose tissue. Furthermore, 20K hGH-V treatment resulted in increased enrichment of genes associated with adipogenesis and carbon metabolism compared to hGH treatment. In muscle tissue, the electron transport chain and muscle contraction pathways were upregulated in 20K hGH-V-treatment, while cell cycle, extracellular matrix organization, and xenobiotic metabolism pathways were negatively enriched. While most genes and signalling pathways were similar between the two hormone treatments, the differentially expressed genes identified may help explain some of the phenotypic differences between 20K hGH-V and hGH treatment and also suggest additional novel differences, notably muscle fibre type, immune cell infiltration, and fibrosis.

Gastric, duodenal and rectal neuroendocrine tumours (NETs) are increasingly detected due to advances in endoscopic imaging. While international guidelines provide criteria for endoscopic management, several aspects remain controversial due to limited high-quality evidence. This position paper, developed by an expert panel, aims to clarify these unresolved issues and provide consensus-based recommendations. The primary objective of this position paper is to critically analyse and address key controversies in the endoscopic management of gastro-duodenal-rectal NETs. These include the optimal selection of endoscopic resection techniques, the significance of R1 resections, pathological assessment and surveillance strategies. Special attention is given to site-specific challenges, including the role of Ki-67 in type 1 gastric NETs, the management of multiple gastric lesions, the feasibility of endoscopic resection for type 3 gastric NETs and the limitations of advanced endoscopic techniques in the duodenum. This position paper was developed using an Expert Panel Consensus methodology. Topics were identified during the 2024 ENETS Advisory Board meeting and addressed through a structured literature review. Evidence was critically appraised, and expert discussions were conducted to identify key points. By reviewing controversial aspects of endoscopic management, this position paper will provide practical guidance to optimise decision-making and improve outcomes for patients with gastro-duodenal-rectal NETs. Multidisciplinary evaluation remains crucial to tailoring treatment strategies based on tumour characteristics, patient factors and procedural risks.

Chronic variable stress (CVS) procedures are widely used to model depression in laboratory mice and rats. In order to explore how study design might impact experimental outcomes, we systematically documented characteristics of study design in a series of published rodent CVS studies and, in a subset of studies, measured effect sizes in the behavioural tests used to evaluate the effects of CVS. We hypothesised that CVS procedures that were longer or involved more stressors would be associated with larger effect sizes in five commonly used behavioural tests: the sucrose preference test (SPT), the tail suspension test (TST), the forced swim test (FST), the open field test (OFT) and the elevated plus maze (EPM). We also hypothesised that effect sizes would positively correlate between the behavioural tests that are believed to measure the same consequences of CVS. We searched PubMed for articles using CVS procedures with mice or rats and systematically documented the duration (the length of the CVS procedure), burden (the total number of stressors experienced by the animal) and diversity (the total number of different types of stressors used) of the CVS procedures used. We also systematically documented the design of the behavioural tests used to evaluate the effects of CVS in each study and calculated the effect sizes obtained in these tests. To ask whether effect sizes in these tests correlated with characteristics of the CVS procedure used, we used a linear model of the effect of duration, burden, and diversity on the effect size, then calculated the Euclidean distance between studies' characteristics and correlated those with the differences in effect size between studies. To explore whether effect sizes correlated between different behavioural tests, we calculated a pairwise Pearson correlation. We observed that most studies used a unique CVS procedure. In contrast to our hypothesis, the most evident impact of CVS procedure design was on FST effect sizes, where longer-duration CVS procedures with more diverse types of stressors were associated with a smaller effect size in behavioural tests. When exploring correlations between behavioural test effect sizes, we found a positive correlation between effect sizes in the TST and FST, and in the OFT and EPM, but the strongest positive correlations were between the EPM and TST, and between the EPM and FST. These data uncover complex relationships that are not necessarily in concordance with current understanding of what these tests measure. Accordingly, our data raise scientific questions around the design of CVS procedures used and the behavioural tests used to evaluate them.

The corticotropin-releasing factor (CRF) system is primarily known for its conserved role in regulating pituitary corticotrope activity, but it can also influence thyroid hormone (TH) production by stimulating thyroid-stimulating hormone (TSH) production in non-mammalian vertebrates. However, few studies have explored how THs regulate the CRF system in teleosts. Furthermore, while the CRF system regulates corticotrope activity via a CRF receptor 1 (CRFR1) mediated pathway, the signaling pathway by which CRF stimulates TSH production in teleost thyrotropes is unknown. To better understand interactions between THs and the CRF system, we performed a series of in vivo, in vitro, and in silico analyses using Atlantic salmon (Salmo salar). We found that chronic elevation of triiodothyronine (T3) levels elicited ligand- and paralog-specific effects on transcript levels of CRF peptides in the hypothalamic and preoptic regions of the brain. Additionally, elevated T3 increased transcription of pituitary CRF receptor 2 (crfr2b) but had no effect on CRFR1 transcription. Consistent with interactions between THs and CRFR2, we found that transcription of TSH (tshba) only increased in cultured pituitaries when CRFR2 was activated. In contrast, CRFR1 activation only increased the transcription of corticotrope-related genes. Lastly, we found that putative TH response elements were present in the promoter of most CRF system components, further supporting the relationship between THs and the CRF system in teleosts. Collectively, our data reveal several novel mechanisms underlying crosstalk between THs and the central CRF system in teleost fishes and provide insight into the evolution of interactions between these hormone systems.

Cocaine- and amphetamine-regulated transcript (CART) is produced in several brain regions including the hypothalamus where it is made in cells that also produce melanin-concentrating hormone (MCH). CART-expressing MCH cells densely innervate the lateral septum (LS), which integrates food- and mood-related behaviours. However, while MCH typically promotes feeding and anxiolysis, CART suppresses feeding and promotes anxiogenesis. The LS is a target site of orexigenic MCH actions, but it is not known if the actions of CART converge or oppose that of MCH in the LS. We implanted a bilateral cannula over the lateral or medial LS of male and female wildtype mice and infused vehicle, CART_55–102, MCH, or CART + MCH. We then assessed the intake of a standard chow diet or palatable high sugar diet over 4 h, as well as anxiety-like behaviour via the open-field test. In both male and female mice, intra-LS CART infusion alone did not produce anorexigenic effects. However, CART infusion diminished MCH-mediated feeding, especially via the lateral LS. By contrast, intra-LS CART infusion reduced time spent in the centre of an open field in male but not female mice. Our findings indicated that CART elicited anorectic effects in the presence of MCH, but CART independently produced anxiogenic effects. These outcomes suggested that putative CART and MCH co-release from MCH neurons may provide biphasic regulation of feeding and anxiety.

During the post-partum period, new mothers are vulnerable to mood disorders. In adults, impairments in neurogenesis commonly associate with anxiety and depressive behaviors. Insulin-like growth factor 2 (IGF2) is expressed in the choroid plexus (CP) within the subventricular zone (SVZ) neurogenic niche, and global loss of IGF2 leads to increased anxiety. Previously, we have shown that Igf2 expression in CP tissue increases 6-fold during lactation but returns to baseline on suppression of prolactin present in lactation, suggesting it is induced by high levels of prolactin. To gain more insight into the role of prolactin-induced Igf2 expression in the CP, we have measured IGF2 levels in cerebrospinal fluid across reproductive states and developed mice in which Igf2 is conditionally removed from the CP. Using CP-derived IGF2 knockout mouse models, we have measured Prlr expression in CP tissue, SVZ mitogenesis, olfaction, and anxiety-like behavior using an elevated plus maze (EPM) and light/dark transition test (LDTT). Interestingly, we observed a reduction in Prlr expression in CP tissue in one of our Igf2 knockout mouse models, suggesting Igf2 may also act upstream to regulate Prlr expression in CP tissue. No changes were detected in SVZ proliferation rates between Igf2 knockout and controls. Using a buried food test (BFT), however, we show mice with conditional loss of Igf2 in the CP take longer to find a buried fruit loop as compared to controls, indicating olfaction deficits. Overall anxiety levels, however, were comparable between knockout and controls in the EPM and LDTT. Together, our findings reveal loss of CP-derived IGF2 leads to hyposmia in the absence of detectable changes to SVZ mitogenesis. We propose that CP-derived IGF2 may be acting directly in the olfactory bulb to elicit changes to improve olfaction, which may become particularly important during the post-partum period to facilitate mother–pup interactions.

Patients with gastroenteropancreatic–neuroendocrine tumors (GEP-NETs) may present skeletal fragility that might be related to multiple factors, including bone metastases, vitamin D deficiency, hormone secretion, and disease treatments. This study examines the prevalence and determinants of fragility fractures in low grading (G1-G2) GEP-NETs. This retrospective study included 291 patients with G1-G2 GEP-NETs (154 men and 137 women). A longitudinal examination was available for 247 patients, with a median follow-up of 49 months (range 24–83). Information regarding disease course, osteo-metabolic profile, and clinical fractures were collected from electronic medical records. Opportunistic chest-abdomen computed tomography or magnetic resonance imaging scans were retrospectively examined to investigate morphometric vertebral fractures. Fracture prevalence in men over 50 and post-menopausal women (n = 200) was compared to an age-matched control sample of 1010 subjects (146 men and 864 women). Forty-five patients with GEP-NETs (15.5%) had fragility fractures at diagnosis of disease. Fractures were significantly associated with age, body mass index, comorbidities, and severe vitamin D deficiency (25(OH)vitamin D < 10 ng/mL) at univariate analysis, and to severe vitamin D deficiency (p = .03) and age (p = .01) at multivariate analysis. When compared to the control group, GEP-NETs patients were found to be independently associated with fractures (OR 2.0 IC95% [1.1–3.6], p = .02). At longitudinal evaluation, 10% of GEP-NETs experienced new fractures in relation to pre-existing fractures and surgical treatment of the tumor. This study provides first evidence that GEP-NETs may have a high risk of fragility fractures at the diagnosis of the disease. A proper and early assessment of bone health is therefore advisable in these patients.

In a rapidly changing world, food resources are becoming more limited, leading to unpredictable bouts and durations of nutritional stress. Many studies indicate that developmental nutritional stress can permanently alter a suite of physiological, morphological, or behavioral traits, yet the phenotypic effects of low food supply in the environment may vary depending on the mode and degree of parental care. For example, our previous work suggests that zebra finch (Taeniopygia guttata castanotis) parents can buffer offspring from food restriction, minimizing negative effects on offspring growth, at the cost of maintaining their own body mass. To evaluate the effects of whole nest food restriction on the offspring further, we investigated short- and long-term changes in physiological and morphological traits of zebra finch young exposed to either an ad libitum diet or a 40% restricted diet as nestlings and juveniles until 60 days post-hatch. Specifically, we measured furculum fat, the adrenocortical response, and glucose levels throughout development and into adulthood as well as body mass in adulthood to examine any latent or persistent effect. Young from the food-restricted nests overall had significantly higher baseline corticosterone and glucose compared to controls, suggesting that the previously observed parental buffering may not have been sufficient to mitigate the deleterious effects of food restriction. Furthermore, food-restricted birds had lower body mass compared to controls in adulthood, suggesting that there was a latent effect that manifested in adulthood, potentially due to the physiological costs observed during treatment and the later release of treatment. Furculum fat, the glucose response, and the adrenocortical response did not differ between experimental groups. There was also no difference in brood body size variance between treatment groups, and previously observed parental compensation in food-restricted nests did not correlate with offspring body mass in adulthood. Lastly, there was a significant negative relationship between body mass and baseline corticosterone in adulthood, suggesting that although growth and body mass were maintained during treatment, energy may have been redirected from growth and body mass maintenance to different processes in adulthood. This study further supports the need for measuring traits after treatment ends to determine persistent effects of stressors and highlights that parents cannot fully buffer their offspring from adverse environmental conditions.