Neuroendocrinology最新文献

Background: Bipolar disorder (BPD) represents a frequent and disabling disease, characterized by the occurrence of extreme mood swings leading to episodes of depression or mania. Although dysfunctions in dopamine (DA) neurotransmission are increasingly recognized as key determinants of BPD, little attention has been given to the biological factors which may shape such a cyclicity of mania and depression.

Summary: We propose that BPD may result, at least in part, from skewed connections between the neuroendocrine system, the DA system, and the hypothalamic clock center. First, we provide a brief description of the hypothalamic-pituitary complex, i.e., the core anatomical structure of the neuroendocrine system. We then review clinical data demonstrating the frequent onset of BPD at menopause, during postpartum or in peri-pubertal periods, suggesting that hormonal changes, under neuroendocrine regulation, may favor the clinical expression of BPD. Finally, we revisit the DA hypothesis of BPD and propose that both the hypothalamic clock center and the hypothalamic-pituitary axis exert rheostat effects on the regulation of mood by DA. Thus, in individuals with a genetically determined predisposition to BPD, an alteration of such rheostat functions may translate into a hyper- or hypo-activity of the DA system. Potential therapeutic implications and future research directions are discussed.

Key messages: BPD may be related to altered connections between the DA system, the neuroendocrine system and the hypothalamic clock center. We hope this article will provide a basis for future interactions between endocrinologists, neurobiologists, and psychiatrists.

Introduction: Exposure to social trauma may alter engagement with both fear-related and unrelated social stimuli long after. Intriguingly, how simultaneous discrimination of social fear and safety is affected in neurodevelopmental conditions remains underexplored. The role of the neuropeptide oxytocin is established in social behaviors and yet unexplored during such a challenge post-social trauma.

Methods: Using Magel2 knockout mice, an animal model of Prader-Willi syndrome (PWS) and Schaaf-Yang syndrome (SYS), we tested memory of social fear and safety after a modified social fear conditioning task. Additionally, we tracked the activity of oxytocin neurons in the supraoptic (SON) and paraventricular (PVN) nuclei of the hypothalamus by fiber photometry, as animals were simultaneously presented with a choice between fear and safe social cue during recall.

Results: Male Magel2 KO mice trained to fear females with electrical footshocks avoided both unfamiliar females and males during recalls, lasting even a week post-conditioning. On the contrary, trained Magel2 WT avoided only females during recalls, lasting days rather than a week post-conditioning. Inability to overcome social fear and avoidance of social safety in Magel2 KO mice were associated with the reduced engagement of oxytocin neurons in the SON but not the PVN.

Conclusion: In a preclinical model of PWS/SYS, we demonstrated region-specific deficit in oxytocin neuron activity associated with behavioral generalization of social fear to social safety. Insights from this study add to our understanding of oxytocin action in the brain at the intersection of social trauma and PWS/SYS.

Introduction: Clinical presentation and genetic profile of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are highly variable, hampering their management. Sequencing of circulating tumor DNA from liquid biopsy (LB) has been proposed as a less invasive alternative to solid biopsy (SB). Our aim was to compare the mutational profile (MP) provided by LB with that deriving from SB in GEP-NETs.

Methods: SB and LB were derived simultaneously from 6 GEP-NET patients. A comparative targeted next-generation sequencing (NGS) analysis was performed on DNA from SB and LB to evaluate the mutational status of 11 genes (MEN1, DAXX, ATRX, MUTYH, SETD2, DEPDC5, TSC2, ARID1A, CHECK2, MTOR, and PTEN).

Results: Patients (M:F = 2:1; median age 64 years) included 3 with pancreatic and 3 with ileal NETs. NGS detected a median number of 55 variants/sample in SB and 66.5 variants/sample in LB specimens (mutational burden: 0.2-1.9 and 0.3-1.8 mut/Mb, respectively). Missense and nonsense mutations were prevalent in both, mainly represented by C>T transitions. ARID1A, MTOR, and ATRX were consistently mutated in SB, and ARID1A, TSC2, MEN1, PTEN, SETD2, and MUTYH were consistently mutated in LB. DAXX mutations were absent in LB. Seventeen recurrent mutations were shared between SB and LB; in particular, MTOR single-nucleotide variants c.G4731A and c.C2997T were shared by 5 out of 6 patients. Hierarchical clustering supported genetic similarity between SB and LB.

Conclusions: This pilot study explores the applicability of LB in GEP-NET MP evaluation. Further studies with larger cohorts are needed to validate LB and to define the clinical impact.

Background: One-carbon metabolism (OCM) and steroid metabolism are fundamental biochemical pathways that regulate essential cellular processes and physiological functions. OCM is involved in DNA synthesis, methylation, and redox balance, while steroid metabolism governs the production and degradation of steroid hormones, which notably influence growth, reproduction, and stress responses. Despite their distinct roles, emerging evidence suggests a strong interplay between these two pathways. Summary: This review examines the bidirectional relationship between OCM and steroid metabolism, emphasizing their shared intermediates and cofactors. Folates and methionine, key intermediates of OCM, influence steroid biosynthesis, while the methylation status regulated by OCM affects the expression of steroidogenic enzymes. Conversely, steroid hormones modulate OCM by altering the activity of enzymes in folates and methionine cycles. Disruptions in either pathway are linked to diseases such as cancer, cardiovascular disorders, and neurodegenerative conditions. This narrative review examines the clinical and preclinical data on the interactions between OCM and sex steroids, in both women and men, adrenal steroids and vitamin D metabolism. Key Messages: The interdependence between OCM and steroid metabolism highlights the need to consider both pathways in disease pathogenesis and therapeutic strategies. Their crosstalk plays a crucial role in maintaining cellular homeostasis and responding to metabolic stress. Targeting this metabolic interplay offers new opportunities for treating metabolic disorders, with potential clinical applications in modulating one pathway to influence the other for more integrated disease management.

Introduction: Pancreatic neuroendocrine neoplasms (PanNENs) are characterized by significant clinical heterogeneity and limited therapeutic options, particularly in metastatic or recurrent cases. Identifying actionable molecular targets and biomarkers is essential for improving patient outcomes.

Methods: We employed a multi-omics approach to identify biomarkers and therapeutic targets for PanNENs. Two-sample Mendelian randomization (TSMR) was conducted using plasma proteome data from [Nat Genet. 2020;52(10):1122-31] and deCODE. Differential expression and weighted gene co-expression network analyses (WGCNA) were performed on the GSE73338 dataset to prioritize biomarkers. Validation included cis-expression quantitative trait loci (cis-eQTL) data from eQTLGen and summary data-based MR (SMR) with heterogeneity in dependent instrument (HEIDI) tests. Immune mediation analysis was performed, followed by transcriptomic validation using gene expression microarrays (GSE43795) and single-cell RNA sequencing (GSE256136) data. Immune infiltration was assessed using CIBERSORT, and protein expression was validated using immunohistochemistry. Pan-cancer analysis was conducted using TCGA and GTEx data, and diagnostic performance was evaluated using ROC curves and nomograms.

Results: PDIA5 and ARFIP1 were identified as potential biomarkers and therapeutic targets for PanNENs. Both proteins were upregulated in PanNEN tissues and showed consistent associations with PanNEN risk through TSMR and SMR analyses. Immune mediation analysis suggested their involvement in immune modulation. Pan-cancer analysis revealed their overexpression in multiple cancer types. Diagnostic performance, evaluated using ROC curves, demonstrated the strong potential of PDIA5 and ARFIP1 in PanNEN diagnosis.

Conclusion: PDIA5 and ARFIP1 are promising biomarkers and therapeutic targets for PanNEN. Further validation and clinical exploration are required.

Introduction: Incidence of neuroendocrine neoplasms (NENs) is rising globally, yet clinical and genetic factors remain poorly understood. Evidence for the role of obesity is conflicted, and studies on prospectively collected data are sparse. We aimed to identify clinical and germline genetic risk factors associated with NEN in the UK Biobank.

Methods: Cases of NEN were identified in the UK Biobank's cancer registry data (N∼500,000). Using a combination of ICD-O3 codes for cancer site and histology, NEN cases were stratified into neuroendocrine tumour (NET), neuroendocrine carcinoma (NEC), and small/large cell lung cancer (SLCLC). A Cox proportional hazards model was used to test for an association between clinical phenotypes and increased NEN risk, and a gene burden test in Regenie was used to test for causal variants in the exome sequencing data.

Results: We identified 704 NET, 340 NEC, and 550 SLCLC cases. Obesity (BMI or waist-hip ratio) and lower cholesterol (LDL, HDL, or total) had a significantly significant association with NEN risk; however, the effect size was marginal. Smoking and HbA1c were associated only with SLCLC. Air pollution was not significantly associated when adjustment was made for socio-economic status. We replicated a known germline association between loss of function variants in MEN-1 and NEC, but did not detect any novel association in exome variants.

Conclusion: This is the first large prospective population-based study to identify potential clinical and genetic risk factors for NEN and define a novel phenotype in the UK Biobank. More research is needed to establish whether these relationships are causal. The exome study was underpowered, and future work in this area should focus on meta-analysing multiple large datasets.

Neuroendocrine tumours (NETs) are uncommon tumours, initially described as "Carzinoides" over hundred years ago and had since then multiple changes in terminology and difference in consideration of benign or malignant tumours. There have been multiple subclassifications and definitions made by the World Health Organisation (WHO). Multiple studies suggest an increase in incidence and prevalence. There are three types of sources of information for these studies; national databases, regional databases or single-centre studies. These different sources of data describe small or larger cohorts of patients with NETs, including risks of bias and concerns regarding accuracy of data. The studies aim to describe the prognosis of patients with NETs, using outcomes as overall survival (OS), progression-free survival and relative survival rate. There is a heterogeneity of studies including different patient populations, different study periods, different definitions, and different outcomes of prognosis it is difficult to compare studies.This review aims to describe how the prognosis changed in the past 30 years for patients with NETs taken into account changes in treatment. During the past 3 decades, new treatments including targeting somatostatin receptors with somatostatin analogues or peptide receptor radionucleide therapy, systemic anti-cancer treatments with Sunitinib, Everolimus, and Cabozantinib were developed. In this review, the treatments and prognosis between 1990 and 2000 are described. Subsequently per decade 2000-2010, 2010-2020, and 2020-currently, new treatments and up to date studies regarding the prognosis are reviewed. The aim of this study was to explain changes in prognosis of patients with NETs.

Background: The incidence of neuroendocrine neoplasms (NENs) has been rising globally. However, epidemiological studies on NENs often lack comprehensive geographical comparisons, with limited reporting on demographic variations, risk factors, and tumour site-specific trends.

Summary: This review examines the global epidemiological trends in NENs, focussing on incidence, demographic variations, risk factors, and survival outcomes across tumour sites. A literature search was conducted using PubMed, MEDLINE, and Embase, identifying 74 eligible epidemiology-focused studies on adult NEN populations published between 2012 and October 13, 2022. Results indicate a rising incidence of NENs across multiple sites, with significant regional and demographic variations. Gastrointestinal NENs are the most prevalent, with rectal NENs experiencing the highest increase. Gastric NENs are more common in Asian countries, while appendiceal NENs are predominantly found in younger Caucasian females. Pancreatic NENs exhibit racial disparities, with black patients diagnosed at younger ages and facing socioeconomic barriers to care. Lung NEN incidence is rising, except for small-cell lung cancer, which is declining due to reduced smoking rates. Survival outcomes vary by site, with rectal and appendiceal NENs having better prognoses and gastric and colonic NENs having worse survival rates. Across all sites, advancing age is linked to poorer survival, while females generally have better outcomes. Common modifiable risk factors include obesity, type 2 diabetes, smoking, alcohol consumption, and metabolic syndrome.

Key messages: This review provides a comprehensive global perspective on NEN epidemiology, allowing healthcare providers to identify high-risk populations to inform screening strategies and address modifiable risk factors to help mitigate the increasing incidence and improve patient outcomes worldwide.