Introduction: The purpose of this study was to evaluate longitudinal changes in Ki-67 indices of SI-NETs and assess the impact of these in overall survival (OS).
Methods: We screened 551 patients with SI-NETs diagnosed from 1993, through 2021, identified using the SI-NET databases from five European referral centres. Only patients with well-differentiated tumours and available baseline tumour samples, and follow-up re-biopsies were included. For tumour grading, apart from 2017 WHO classification system, we applied a recently proposed SI-NET site-specific modified histopathological grading system with Ki-67 cut-offs of 5 and 10%.
Results: We included 45 patients. Median Ki-67 index at SI-NET diagnosis was 2% (range 0.5-15%). Thirty-three patients had Ki67 indices <5% (70.2%), 6 had Ki67: 5-10% (12.8%) and 8 had Ki67 ≥10% (17%). Mean time to re-biopsy was 48.8 months (SD: +/-162.5). At re-biopsy, the median change in Ki-67 index (absolute value; follow-up minus time of diagnosis) was 1% (range -10 to +38%). An increase in Ki-67 occurred in 20 patients (42.6%); in 14 patients the change in Ki-67 resulted in progression to higher tumour grade following the modified grading system. Patients with an increment in Ki-67≥1% had a median OS of 32.9 months vs. 80.5 months in patients without (HR 5.6, 95% CI: 1.42-22.02, p=0.014). When applying the novel modified histopathological grading system for SI-NETs, patients with grade progression had a median OS of 32.9 months vs. 53.7 months in those without (HR=4.61, 95%CI: 1.22-13.54; p=0.022). At multivariable analysis, grade progression was confirmed as an independent predictor for death (HR=7.2, 95%CI: 1.58-32.82; p=0.011).
Conclusions: Metachronous increment in Ki-67 indices and related grade progression over time following a site-specific modified histopathological grading system with Ki-67 cut-offs of 5 and 10% is observed in approximately 1/3 of SI-NETs included in this study and it is associated with worse survival outcomes.
Introduction In perinatal female rats, the glutamine (Gln)-glutamate cycle (GGC) constitutively supplies Gln to neurons of the ventral lateral ventromedial nucleus of the hypothalamus (vlVMH) to sustain glutamatergic synaptic transmission (GST). In contrast, male pups may use Gln only during periods of elevated neuronal activity. Perinatal disruption of the GGC has sex-specific effects on the GST and morphology of vlVMH neurons during adulthood. Since (vl)VMH neuronal activities regulate mating behavior expression, we hypothesize that maintaining a perinatal intact GGC may be essential for the sexual differentiation of reproductive behaviors. Methods Using perinatal rats of both sexes, we pharmacologically killed astrocytes or blocked the GGC and supplemented them with exogenous Gln. Mating behavior, an open-field test and protein levels of GGC enzymes were examined during adulthood. Results Killing astrocytes reduced mating behavior expression by 38-48% and 71-72% in male and female rats, respectively. Any blocker targeting the GGC consistently reduced female lordosis behavior by 52-73% and increased glutaminase protein levels in the hypothalamus, but blockers had no effect on the expression of or motivation for copulatory behavior in males. Exogenous Gln supplementation partly rescued the decline in Gln synthetase inhibitor-mediated sex behavior in females. Perinatal interruption of the GGC did not increase induced expression of female sexual behavior in hormone-primed castrated male rats or affect locomotion or anxiety-like behavior in either sex. Conclusion The intact GGC is necessary for behavioral feminization in female rats and may play little or no role in behavioral masculinization or defeminization in males.
Introduction: Nonfunctioning pancreatic neuroendocrine tumor (NF-PanNET) ≤2 cm can be observed or resected. Surgery remains recommended for NF-PanNET >2 cm but its extent, enucleation (EN) versus formal resection, remains controversial.
Methods: Multicentric retrospective cohort of sporadic NF-PanNET patients treated with EN. Short- and long-term outcomes were compared according to tumor size on imaging ≤2 cm versus >2 cm.
Results: 131 patients underwent EN for NF-PanNET, including 103 (79.0%) ≤2 cm and 28 (21.0%) >2 cm (extremes, 4-55 mm). Patients' characteristics were comparable, and tumor characteristics only differed in their diameter. Clavien III-IV complications were similar (18.4% vs. 17.9%, p = 1.00) with one death in NF-PanNET ≤2 cm. Grade B/C pancreatic fistula were comparable (16.5% vs. 10.7%, p = 0.850). In NF-PanNET >2 cm there were more pT2/3 stage tumors (85.7% vs. 21.4%, p < 0.001), similar rates of grade G2/3 tumors (25% vs. 16.5%, p = 0.408) with a median Ki67 of 2 (interquartile range: 1-3), and of lymphovascular and perineural invasions. Lymph node picking was done in 46 (35.1%) patients, with a higher median number of harvested lymph nodes in NF-PanNET >2 cm (4 vs. 3, p = 0.01). All were pN0. R0 resection rate (78.6% vs. 82.5%, respectively; p = 0.670) was equivalent. Five-year overall (100% vs. 99%, p = 0.602) and 10-year disease-free (96% vs. 92%, respectively; p = 0.532) survivals were comparable.
Conclusions: EN for selected NF-PanNET >2 cm carries equivalent morbidity, overall and disease-free survivals compared to those observed with NF-PanNET ≤2 cm.
Introduction: Empathy is the ability of an individual to present and respond to the emotions of others and is thought to originate from parental behavior. Testosterone could promote aggression and inhibit biparental behavior and vasopressin (AVP) could promote aggression. Given levels of aggression and parental care are closely associated with levels of empathy, we hypothesized that testosterone may influence empathetic behavior via the AVP system.
Methods: We examined testosterone levels and tested social, empathic, and anxiety-like behaviors after castration surgery to pubertal mice, and subsequently examined the molecular levels of AVP, V1aR in different brain regions. Finally, pharmacological experiments were used to test the effects on empathic behavior by injecting testosterone in combination with V1aR antagonist.
Results: Here, we show that pubertal castration reduced serum testosterone levels, increased empathetic behavior and sociality, and reduced anxiety-like behaviors in male C57 mice. The pubertal castration also reduced AVP and vasopressin receptor (V1aR) protein levels, and AVP mRNA levels in the PVN. It also reduced the number of AVP-positive neurons in the PVN. In addition, pubertal subcutaneous injection of testosterone reduced emotional contagion and consolation of castrated mice, while concomitant injection of V1aR antagonists into the anterior cingulate cortex (ACC) reversed the downregulation of emotional contagion and consolation induced by testosterone.
Conclusion: It is suggested that testosterone in puberty regulates empathetic behavior in C57 mice possibly via the AVP system in the ACC. These findings help us to understand the neuroendocrine mechanisms underlying empathetic behavior and provide potential targets for the treatment of psychiatric disorders associated with low empathy.
Introduction: Light is the primary source of energy and regulates seasonal changes in physiology and behavior. The role of photoperiod has been much investigated in several bird species, but the role of illumination in seasonal adaptations of passerine finches is less understood. We, therefore, investigated the effects of photoperiod and illuminance on migratory physiology in a Palearctic-Indian migratory finch, redheaded bunting (Emberiza bruncieps).
Methods: Photosensitive buntings maintained under short days (8L:16D) were divided into three groups receiving 5, 25, and 100 lux of white daytime illuminance, respectively. Thereafter, using photoperiodic manipulation three life history states, i.e., nonmigratory (NM), premigratory (PM), and migratory (MIG) states were induced in the buntings. The birds in the MIG state were consecutively perfused after seven nights of Zugunruhe (nighttime migratory restlessness) for neuropeptide Y (NPY)-immunohistochemistry, which is involved in a wide range of functions including energy homeostasis, vision, and fat deposition in birds.
Results: We found differential effects of illuminance on locomotor activity and physiology. Photostimulated birds showed intense nighttime activity in the MIG state. We observed premigratory hyperphagia in the birds, with increased food intake in the 100 lux group, which was reflected in the body mass gain in the MIG state. NPY expression on the periphery of the nucleus rotundus suggests its potential role in visual acuity, where the NPY-cell count significantly decreased under 25 lux illumination.
Conclusion: We demonstrate that migrating birds may also experience physiological effects from changes in daytime illumination. We observed illuminance-dependent variations in the quantity of food consumed by the birds. It indicates that the illuminance may also impact the encephalic centers that control food intake.
Introduction: In women of childbearing age with epilepsy, 30% experience the comorbidity of polycystic ovary syndrome (PCOS), which is marked by a higher prevalence of hyperandrogenism. Our recent clinical observations indicate the potential contribution of hyperandrogenism-induced PCOS to epilepsy susceptibility, and this study aimed to unravel the underlying factors that increase the susceptibility of females to epilepsy.
Methods: A letrozole-induced PCOS rat model was employed to simulate endogenous hyperandrogenism. The threshold of seizure was assessed through seizure kindling rates using pentetrazol and electroencephalogram recordings. Additionally, the role of androgens in epilepsy was verified through interventions using Diane-35.
Results: This study revealed that letrozole-induced elevated testosterone levels and PCOS-related changes in female rats. PCOS rats, through pentetrazol-kindling, exhibited a reduced seizure threshold compared with controls. Elevated testosterone levels were observed in both the hippocampal and frontal brain tissues, accompanied by changes in circulation. Two weeks of Diane-35 intervention showed a tendency to alleviate these changes, modifying testosterone levels in both the plasma and brain tissue. Western blotting and immunohistochemistry revealed increased expression of GABA-A receptor in the hippocampus and decreased AMPA receptor expression in the frontal cortex, correlating with antiepileptic status in PCOS rats.
Conclusion: This study delves into the impact of elevated androgen levels on seizure threshold, providing crucial insights into the underpinnings of the comorbidity between PCOS and epilepsy. These findings significantly contribute to the evolving field of epilepsy research, emphasizing the imperative consideration of hormonal influences for the development of targeted therapeutic interventions in individuals with epilepsy and PCOS.
Background: Mounting evidence underscores the significance of cellular diversity within the endocrine system and the intricate interplay between different cell types and tissues, essential for preserving physiological balance and influencing disease trajectories. The pituitary gland, a central player in the endocrine orchestra, exemplifies this complexity with its assortment of hormone-secreting and nonsecreting cells.
Summary: The pituitary gland houses several types of cells responsible for hormone production, alongside nonsecretory cells like fibroblasts and endothelial cells, each playing a crucial role in the gland's function and regulatory mechanisms. Despite the acknowledged importance of these cellular interactions, the detailed mechanisms by which they contribute to pituitary gland physiology and pathology remain largely uncharted. The last decade has seen the emergence of groundbreaking technologies such as single-cell RNA sequencing, offering unprecedented insights into cellular heterogeneity and interactions. However, the application of this advanced tool in exploring the pituitary gland's complexities has been scant. This review provides an overview of this methodology, highlighting its strengths and limitations, and discusses future possibilities for employing it to deepen our understanding of the pituitary gland and its dysfunction in disease states.
Key message: Single-cell RNA sequencing technology offers an unprecedented means to study the heterogeneity and interactions of pituitary cells, though its application has been limited thus far. Further utilization of this tool will help uncover the complex physiological and pathological mechanisms of the pituitary, advancing research and treatment of pituitary diseases.
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