Journal of Neuroendocrinology最新文献

Colonic neuroendocrine tumors (NETs), excluding rectal NETs, are often described as relatively common and aggressive, with inferior median survival compared with other gastrointestinal (GI) primary sites. However, epidemiological databases may conflate well-differentiated NETs with poorly differentiated neuroendocrine carcinomas (NECs), leading to a lack of precise data on the prevalence, clinical behavior, and prognosis of well-differentiated colonic NETs. We analyzed a large institutional database to identify patients with well-differentiated NETs originating in the colon, excluding rectal NETs. Cecal NETs were included; however, ileocecal NETs (overlapping the ileocecal valve) were not. We assessed their prevalence compared with other primary sites, grade, stage, and prognosis. Among 3639 patients with gastroenteropancreatic (GEP) NETs, only 19 (0.5%) had well-differentiated colonic NETs. This included 11 cecal and eight sigmoid colon primaries (two described as "rectosigmoid"). No tumors originated in the ascending, transverse, or descending colon. Sigmoid NETs were typically early-stage polyps discovered incidentally during colonoscopy. In contrast, eight of the 11 cecal NETs metastasized (p = .04). Six of the cecal primary patients (55%) exhibited carcinoid syndrome versus none of the sigmoid primary cases (p = .01). Well-differentiated colon NETs are exceptionally rare, comprising approximately 0.5% of GEP-NETs. These tumors fall into two distinct categories: cecal NETs, which resemble ileal NETs in behavior, and sigmoid NETs, which appear similar to rectal NETs. The broad categorization of colonic "NETs" in epidemiologic databases likely includes NECs, obscuring the true clinical picture.

Gonadotroph neuroendocrine pituitary tumors are among the most common intracranial neoplasms. A notable proportion of these tumors is characterized by invasive growth which hampers the treatment results and worsens prognoses of patients. Increased hsa-miR-184 expression was observed in invasive as compared to non-invasive gonadotroph tumors. This study aimed to determine the role of hsa-miR-184 expression in invasive growth of gonadotroph tumors. QRT-PCR and bisulfite pyrosequencing were used for evaluating hsa-miR-184 expression and MIR184 DNA methylation levels, respectively, in tumors and normal pituitary samples. LβT2 and αT3-1 gonadotroph cells were used to test the effect of miR-184 on cell viability (MTT test), proliferation (BrdU incorporation), and migration (scratch assay). RNA sequencing was applied for transcriptome profiling in miR-184-treated and untreated LβT2 cells. Differential genes expression analysis combined with target prediction served for identification of miR-184 targets. MiRNA-mRNA interaction was subsequently validated with Luciferase reporter assay. Analysis of tissue samples showed that hsa-miR-184 is upregulated in gonadotroph tumors and its expression is higher in invasive than in noninvasive ones. Promoter of MIR184 is demethylated in tumors, and the methylation level is negatively correlated with hsa-miR-184 expression. Transfecting LβT2 and αT3-1 with miR-184 mimic resulted in increased cellular proliferation and viability. Differentially expressed genes were identified when comparing miR-184-treated and untreated cells, including Nus1 as the only predicted miR-184 target. The interaction between miR-184 and 3'UTR of Nus1 was confirmed in vitro in both LβT2 and αT3-1. Overexpression of Nus1 resulted in lowering cell viability in both cell lines and proliferation in LβT2. The expression level of NUS1 was lower in invasive than in noninvasive tumors. Our results indicate that DNA hypomethylation-related increase of hsa-mir-184 expression contributes to invasive growth of gonadotroph pituitary tumors through targeting NUS1, being one of the various molecular mechanisms involved in conferring aggressive growth potential.

Alzheimer's disease (AD) is associated with early metabolic dysfunction and adiponectin, which may play a pathophysiological role. Adiponectin is implicated in the regulation of energy homeostasis, carbohydrate, and lipid metabolism, as well as in inflammation modulation. The aim of this study was to study whether plasma adiponectin levels were different between patients with AD confirmed by biomarkers and neurological control subjects. We performed a monocentric, retrospective, cross-sectional, observational study in AD patients and neurological controls recruited from daily clinical practice in a tertiary memory clinic. Plasma adiponectin levels were measured using a chemiluminescent enzyme immunoassay. We analyzed the relationship between adiponectin and AD using linear regression models including age, gender, and BMI. We also described the distribution of adiponectin concentrations, across age, and gender categories. Two hundred and six patients (142 AD patients and 64 neurological controls) were included, with mean age = 68.8 ± 10.0 years, and 56% were women. Higher adiponectin concentrations were observed in females and in older adults. Plasma adiponectin levels were significantly higher in AD patients (mean = 6.45 ± 3.42 μg/mL) than neurological controls (4.85 ± 3.54 μg/mL) (p < .001). This association was mediated by age, gender, and BMI, which were significantly and independently associated with plasma adiponectin levels (p < .01 for each), while adiponectin was no longer associated with AD in multivariate models. Patients with AD showed higher adiponectin levels, but this association was driven by older age, female gender, and lower BMI in the AD group. Further studies are needed to better characterize the hormonal signature of AD.

The placenta is a fetal endocrine organ that secretes many neuroactive factors, including steroids, that play critical roles in brain development. The study of the placenta-brain axis and the links between placental function and brain development represents an emerging research area dubbed "neuroplacentology." The placenta drives many circulating fetal steroids to very high levels during gestation. Recent studies have highlighted the critical role of placental steroids in shaping specific brain structures and behaviors. This review uses a cross-species framework to discuss the genomic factors, in-utero environmental changes, and placental conditions that alter placental steroidogenesis, leading to changes in early developmental trajectories relevant for psychiatric conditions such as autism, in a sex-linked manner.

Kisspeptin (KISS1) and its cognate receptor (KISS1R) are implicated in the progression of various cancers. A gallium-68 labelled kisspeptin-10 (KP10), the minimal biologically active structure, has potential as a pan-tumour radiopharmaceutical for the detection of cancers. Furthermore, a lutetium-177 labelled KP10 could find therapeutic application in treating oncological diseases. DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) was attached to the NH2-terminus of KP10 as we posited from our previous publications that this modification would not impair biological activity. Here, we showed that the biological activity, as monitored by stimulation of inositol phosphate accumulation in HEK293 transfected with the KISS1R gene, was indeed similar for KP10 and DOTA-KP10. The optimisation of radiolabelling with gallium-68 and lutetium-177 is described. Stability in serum, plasma and whole blood was also investigated. Pharmacokinetics and biodistribution were established with micro-PET/CT (positron emission tomography/computerised tomography) and ex vivo measurements. Dynamic studies with micro-PET/CT demonstrated that background clearance for the radiopharmaceutical was rapid with a blood half-life of 18 ± 3 min. DOTA-KP10 demonstrated preserved functionality at KISS1R and good blood clearance. These results lay the foundation for the further development of DOTA-KP10 analogues that have high binding affinity along with proteolytic resistance.

Among contributors to diffusible signaling are portal systems which join two capillary beds through connecting veins. Portal systems allow diffusible signals to be transported in high concentrations directly from one capillary bed to the other without dilution in the systemic circulation. Two portal systems have been identified in the brain. The first was discovered almost a century ago and connects the median eminence to the anterior pituitary gland. The second was discovered a few years ago and links the suprachiasmatic nucleus to the organum vasculosum of the lamina terminalis, a sensory circumventricular organ (CVO). Sensory CVOs bear neuronal receptors for sensing signals in the fluid milieu. They line the surface of brain ventricles and bear fenestrated capillaries thereby lacking blood-brain barriers. It is not known whether the other sensory CVOs, namely the subfornical organ (SFO), and area postrema (AP) form portal neurovascular connections with nearby parenchymal tissue. To preserve the integrity of the vasculature of CVOs and their adjacent neuropil, we combined iDISCO clearing and light-sheet microscopy to acquire volumetric images of blood vessels and traced the vasculature in two experiments. In the first, the whole brain vasculature was registered to the Allen Brain Atlas in order to identify the nuclei to which the SFO and AP are attached. In the second study, regionally specified immunolabeling was used to identify the attachment sites and vascular connections between the AP, and the SFO to their respective parenchymal attachment sites. There are venous portal pathways linking the capillary vessels of the SFO and the posterior septal nuclei, namely the septofimbrial nucleus and the triangular nucleus of the septum. Unlike the arrangement of portal vessels, the AP and the nucleus of the solitary tract share a common capillary bed. Taken together, the results reveal that all three sensory CVOs bear direct capillary connections to adjacent neuropil, providing a direct route for diffusible signals to travel from their source to their targets.

Traumatic brain injury (TBI) is a major global cause of disability and mortality. TBI results in a spectrum of primary and secondary injuries that impact neural function and overall survival. Insulin, beyond its well-known role in regulating blood glucose levels, plays critical roles in the central nervous system (CNS). These roles include the modulation of synaptic plasticity, neurotransmitter levels, neurogenesis, and neuroprotection. Central insulin resistance, a reduced sensitivity to insulin in the brain, has been observed in TBI patients. This insulin resistance impairs insulin function in the brain and increases the risk of neurodegenerative processes. This review will delve into the central role of insulin resistance in the pathological changes observed after TBI and explore the potential benefits of insulin therapy as a treatment approach for TBI.

Multiple Endocrine Neoplasia type 1 (MEN1) Clinical Practice Guidelines (2012) are predominantly based on expert opinion due to limited available evidence at the time, leaving room for interpretation and variation in practices. Evidence on the natural course of MEN1-related neuroendocrine tumours (NET) and the value of screening programs has increased and new imaging techniques have emerged. The aim of this study is to provide insight in the current practices of screening and surveillance for MEN1-related NETs in ENETS Centers of Excellence (CoEs). A clinical practice questionnaire was distributed among all 65 ENETS CoEs. Response rate was 91% (59/65). In 14% of CoEs <10 patients, in 50% 10-49, in 31% 50-100 and in 3 centres (5%) >100 patients with MEN1 are seen. Practices with regard to screening and surveillance of NETs were markedly heterogeneous. Differences between countries were noted in the use of gut hormones for biochemical screening and the choice for imaging modality for screening/surveillance of pancreatic NETs (PanNETs). Magnetic resonance imaging (MRI) is the preferred modality for screening and surveillance of PanNETs, whereas this is computed tomography (CT) for thoracic NETs. Practices regarding screening for thoracic NETs were more homogeneous among larger volume CoEs, with longer screening intervals. The majority of CoEs tailored the surveillance of small pancreatic and lung NETs to observed growth rate. 68% of CoEs advise patients with clinical MEN1 with negative genetic testing to undergo periodic screening like mutation-positive patients. In conclusion, there is still marked heterogeneity in practice, although there are also common trends. Differences were sometimes associated with volume or country, but often no association was found. This underscores the need for clear and evidence-based practice recommendations.

Different populations of hypothalamic kisspeptin (KISS1) neurons located in the rostral periventricular area of the third ventricle (RP3V) and arcuate nucleus (ARC) are thought to generate the sex-specific patterns of gonadotropin secretion. These neuronal populations integrate gonadal sex steroid feedback with internal and external cues relayed via the actions of neurotransmitters and neuropeptides. The excitatory amino acid neurotransmitter glutamate, the main excitatory neurotransmitter in the brain, plays a role in regulating gonadotropin secretion, at least partially through engaging KISS1 signaling. The expression and function of individual glutamate receptor subtypes in KISS1 neurons, however, are not well characterized. Here, we used GCaMP-based calcium imaging and patch-clamp electrophysiology to assess the impact of activating individual ionotropic (iGluR) and group I metabotropic (mGluR) glutamate receptors on KISS1 neuron activity in the mouse RP3V and ARC. Our results indicate that activation of all iGluR subtypes and of group I mGluRs, likely mGluR1, consistently drives activity in the majority of KISS1 neurons within the RP3V and ARC of males and females. Our results also revealed, somewhat unexpectedly, sex- and region-specific differences. Indeed, activating (S)-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) type iGluRs evoked larger responses in female ARC^KISS1 neurons than in their male counterparts whereas activating group I mGluRs induced larger responses in RP3V^KISS1 neurons than in ARC^KISS1 neurons in females. Together, our findings suggest that glutamatergic neurotransmission in KISS1 neurons, and its impact on the activity of these cells, might be sex- and region-dependent in mice.

To evaluate a radiomic strategy for predicting progression in advanced gastroenteropancreatic neuroendocrine tumor (GEP-NET) patients treated with somatostatin analogs (SSAs). Fifty-eight patients with GEP-NETs and liver metastases, with baseline computerized tomography (CT) scans from June 2013 to November 2020, were studied retrospectively. Data collected included progression-free survival (PFS), overall survival (OS), tumor grading, death, and Ki67 index. Patients were categorized into progressive and non-progressive groups. Two radiologists performed 3D liver segmentation on baseline CT scans using 3DSlicer v4.10.2. One hundred six radiomic features were extracted and analyzed (T-test or Mann-Whitney). Radiomic feature efficacy was evaluated via receiver operating characteristic curves, and both univariate and multivariate logistic regression were used to develop predictive models. A significance level of p < .05 was maintained. Of 55 patients, 38 were progressive (median PFS and OS: 14 and 34 months, respectively), and 17 were non-progressive (median PFS and OS: 58 months each). Six radiomic features significantly differed between groups (p < .05), with an area under the curve (AUC) range of 0.64-0.74. Ki67 was the only clinical parameter significantly associated with progression risk (odds ratio (OR) = 1.14, p < .05). The combined radiomic features and Ki67 model proved most effective, showing an AUC of 0.814 (p = .008). The radiomic model alone did not reach statistical significance (p = .07). A combined model incorporating radiomic features and the Ki67 index effectively predicts disease progression in GEP-NET patients eligible for SSA treatment.