Combination therapies with immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) have revolutionized the landscape of cancer treatment, improving the quality of life and overall survival of patients. A deep knowledge of the side effects of ICIs and TKIs combination therapy is mandatory to ensure patient compliance and improve clinical outcomes. Both ICIs and TKIs may cause endocrinopathies such as thyroid dysfunction, adrenal insufficiency, hypophysitis, and diabetes mellitus. To avoid life-threatening conditions and improve patient’s compliance and outcomes, an early diagnosis of endocrine toxicity should be achieved and a multidisciplinary approach involving both endocrinologists and oncologists may be beneficial. This review specifically examines the endocrine adverse events reported in the clinical trials of ICI plus TKI combined treatment, their underlying mechanisms, and practical management guidelines. [Image: see text]
Endocrine disorders in pediatric patients often involve a variety of imaging modalities as part of a diagnostic workup or disease surveillance. This pictorial essay and review of the literature highlights adrenal and reproductive system imaging findings related to endocrine-related diseases. This review includes descriptions of normal adrenal gland anatomy and imaging characteristics, as well as the clinical presentations and diagnostic imaging of congenital adrenal hyperplasia and of benign and malignant adrenal masses. Additionally, normal reproductive tract development and puberty will be covered, followed by an overview of Müllerian anomalies, 46,XY gonadal dysgenesis, and polycystic ovarian syndrome. Differential diagnostic considerations, appropriate imaging protocols, and clinical management strategies will be discussed.
The 17β-hydroxysteroid dehydrogenase (hsd17b) gene family plays a pivotal role in sex steroid metabolism and gonadal differentiation in teleosts; however, their evolutionary dynamics and regulatory mechanisms during sex reversal in the mandarin fish (Siniperca chuatsi) remain poorly understood. In this study, we identified ten hsd17b family members in the S. chuatsi genome. Structural and phylogenetic analyses revealed the conservation of the core SDR domain across all members, alongside significant structural divergence in hsd17b4, which uniquely fused with SCP2 and PLN domains, indicating a pleiotropic role in both steroidogenesis and peroxisomal lipid metabolism. Spatiotemporal expression profiling demonstrated pronounced subfunctionalization: hsd17b4 exhibited robust testis-biased expression during spermatogenesis, whereas hsd17b1 was transiently upregulated during critical windows of ovarian differentiation. Furthermore, exogenous hormone treatments (MT, ETO, and E1) successfully induced functional sex reversal, accompanied by profound transcriptional reprogramming. Notably, ETO- and MT-induced masculinization was driven by a synergistic metabolic shift within the gonads. This process involved the significant up-regulation of the core testis-associated gene (hsd17b4), coordinated with genes facilitating cholesterol biosynthesis (hsd17b7) and estrogen inactivation (hsd17b8), effectively suppressing the female steroidogenic network (hsd17b1, hsd17b12a). Conversely, E1-induced feminization repressed male-pathway genes and promoted hsd17b1 transcription. Taken together, our findings demonstrate that the transcriptional antagonism and synergistic metabolic coordination among hsd17b members constitute the core molecular underpinning of endocrine-induced sexual plasticity. This study provides crucial molecular insights and viable targets for sex control breeding in teleost aquaculture.
Extrahepatic islet transplantation offers a clinically attractive alternative to intrahepatic delivery, but its success has been constrained by inadequate vascularization and lack of a supportive microenvironment. To address this, we engineered vascularized endocrine constructs (VECs) by coencapsulating pancreatic islets with human blood outgrowth endothelial cells in a good manufacturing practice-compliant amniotic membrane hydrogel (Amniogel). Amniogel provides extracellular matrix-bound prosurvival cues that enhance islet viability and function and promote endothelial self-assembly into vascular networks-improving β-cell gap junction coupling and restoring dynamic glucose-responsive insulin secretion. After subcutaneous implantation in diabetic mice, VECs anastomosed with host vessels and reestablished normoglycemia, outperforming nonvascularized controls. Furthermore, Amniogel impeded chemokine-driven cytotoxic T cell migration and delayed β-cell killing in vitro in a concentration-dependent manner. This integrative strategy, combining a scalable biological scaffold with vascularization and intrinsic barrier properties that may limit early immune cell infiltration, offers a clinically relevant path toward durable β-cell replacement therapies in type 1 diabetes.
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Dynein axonemal assembly factors (DNAAF) are essential for the assembly and transport of dynein motor complexes, which are crucial for the movement of cilia. Mutations in genes encoding these proteins often lead to motile ciliopathies called primary ciliary dyskinesia (PCD). In humans, loss-of-function mutations of Cilia and flagella-associated protein 300 (CFAP300, also known as DNAAF17) have been reported to cause PCD. The function of CFAP300 during embryogenesis, however, has not been reported. We carried out functional studies using zebrafish to understand its function during vertebrate development. The expression of cfap300 mRNA during zebrafish embryogenesis was identified using whole-mount in situ hybridization (WISH). A knockout zebrafish line was created using TALEN and the function of cfap300 during embryogenesis was studied. cfap300 mRNA is highly expressed in the zebrafish pronephros. Hence, the effect of cfap300 knock-out on zebrafish pronephros segmentation, multiciliated cell (MCC) and Corpuscle of Stannius (CS) development was studied by analysing the expression of marker genes in these segments and cells using WISH. The gene expression during CS gland development was analysed using RT-qPCR and digital PCR. In zebrafish embryos, cfap300 is expressed in multiple ciliated organs, beginning at 10 hpf in Kupffer's vesicle and later in the notochord, pronephros, otic placode, floor plate, brain, and tail bud. cfap300 mutants develop normally and show no nephron segmentation defects, but exhibit impaired CS development. The CS gland is an endocrine gland in teleost fish, including zebrafish, that secretes Stanniocalcin 1 (Stc1) hormone and regulates calcium homeostasis. The CS gland originates by transdifferentiation of pronephric tubule epithelial cells at the distal early (DE) and distal late (DL) boundary. Mechanistically, hnf1ba expression is increased in the cfap300 mutants, which in turn drives transcription of cdh17 and leads to impaired CS precursor transdifferentiation. In cfap300 mutants, knockdown of hnf1ba or knockout of cdh17 restores CS gland formation. These results uncover a Cfap300-Hnf1ba-Cdh17 pathway that regulates epithelial-to-endocrine transdifferentiation, revealing a novel, lineage-specific role for a DNAAF protein in endocrine organogenesis.
Long-term estrogen-deprived (LTED) cells were obtained from parental MCF-7 breast cancer (BC) cells cultured under conditions of prolonged estrogen deprivation. In LTED cells, which mimic estrogen receptor α (ERα)-positive BC that has relapsed after endocrine therapy, βIII-tubulin (TUBB3) expression is downregulated. However, the biological significance of TUBB3 downregulation is unclear. To address this, we assessed the effects of siRNAs targeting individual TUBB isotypes. Among of them, only TUBB3-targeting siRNA stimulated the proliferation of MCF-7 cells, but it did not affect LTED cells. After treating LTED cells with 17β-estradiol (E2), the upregulation of TUBB3 expression and antiproliferative effects were detected, suggesting that TUBB3 mediates the antiproliferative effects of E2. Furthermore, the attenuated TUBB3 expression was related to poor prognosis in patients with ERα-positive BC receiving endocrine therapy. These findings identify TUBB3 as an E2-sensitive antiproliferative molecule in ERα-positive BC cells, suggesting that it could be targeted for endocrine therapy-resistant BC.
Down syndrome (DS) is associated with immune dysregulation and a broad spectrum of autoimmune diseases; however, autoimmune involvement of the pituitary gland remains poorly characterized. Isolated adrenocorticotropic hormone deficiency (IAD) is a rare cause of secondary adrenal insufficiency, and its relationship to DS-related autoimmunity has not yet been elucidated. We encountered a single case of DS that was complicated by IAD. We describe the clinical course in detail and present immunological findings suggestive of an autoimmune basis for IAD in the context of DS. To experimentally evaluate pituitary-directed autoimmunity, circulating antibodies were analyzed using immunofluorescence staining of mouse pituitary tissue. Immunoglobulin G derived from an individual with DS and IAD specifically showed reactivity toward corticotrophs, as demonstrated by colocalization with ACTH immunostaining. HLA genotyping did not identify alleles previously associated with idiopathic IAD, suggesting a disease mechanism distinct from established genetic susceptibility. The identification of anti-corticotroph antibodies in DS provides the first immunological evidence linking IAD to DS-related autoimmunity. These findings suggest that autoimmune IAD may represent a previously unrecognized component of endocrine polyautoimmunity in DS and underscore the importance of considering pituitary autoimmunity in the endocrine assessment of this population. However, considering that the present findings are derived from a single case, further studies are warranted to confirm their broader applicability.
Circadian misalignment caused by altered feeding behaviors disrupts metabolic homeostasis and endocrine rhythms. Asprosin, a fasting-induced adipokine derived from the cleavage of profibrillin-1 (FBN1), stimulates hepatic glucose release and activates hypothalamic pathways that regulate appetite. Although asprosin's metabolic functions are increasingly recognized, its temporal expression patterns and interactions with peripheral and central tissues remain insufficiently explored. This study aimed to investigate the circadian expression patterns of the orexigenic hormone asprosin and its receptor OLFR734 in metabolically relevant tissues and the olfactory bulb of male Balb/c mice. Male Balb/c mice (n = 28) were evaluated at defined circadian time points. Quantitative real-time PCR, immunohistochemistry, and ELISA were used to assess the gene and protein expressions of asprosin and OLFR734, together with circulating levels of asprosin, glucose, and melatonin. Asprosin and OLFR734 showed significant diurnal oscillations (p <0.05-p <0.0001). Peak serum asprosin levels coincided with nocturnal melatonin elevation and reduced glucose concentrations. Tissue-specific variations were observed in both central and peripheral expression patterns. These results demonstrate that the asprosin-OLFR734 axis manifests a pronounced circadian rhythmicity, underscoring its pivotal role in the temporally coordinated regulation of appetite and glucose homeostasis. Such rhythmicity offers critical insight into the intricate endocrine mechanisms that govern nocturnal metabolic adaptations and provides a conceptual framework for future research on the temporal orchestration of energy balance and metabolic function.
Post-traumatic stress disorder (PTSD) frequently emerges following early-life trauma, yet the temporal dynamics of PTSD-like phenotypes and their pharmacological modulation during development remain poorly understood. In the present study, we investigated time-dependent behavioral and endocrine alterations in a peripubertal rat stress-restress model and assessed the effects of fluoxetine across early and delayed post-treatment stages. Male peripubertal rats were exposed to a combined stress-restress paradigm and treated with fluoxetine for 21 days. Anxiety-like behavior, social behavior, stress-coping behavior, and spontaneous locomotor activity were assessed immediately after treatment completion and again after a drug-free washout period, the duration of which (3-4 weeks) depended on the behavioral parameter evaluated. Serum corticosterone levels were measured as an index of hypothalamic-pituitary-adrenal axis activity. PTSD-like stress induced robust but domain-specific behavioral alterations that evolved over time. Anxiety-like behavior persisted across both observation phases but was expressed through different behavioral components at early versus delayed stages. Basal sociability was markedly reduced following stress exposure and was largely normalized by fluoxetine, whereas social novelty-related alterations were more selective and resistant to pharmacological modulation. Stress-exposed animals exhibited increased activity and reduced immobility in the forced swim test, reflecting altered stress-coping strategies rather than reduced depressive-like behavior. Consistently, spontaneous locomotor activity was elevated at early stages, indicating hyperarousal, which attenuated over time but was not robustly normalized by fluoxetine. Endocrine assessment revealed a biphasic corticosterone profile, with elevated levels in the early phase and reduced levels at the delayed stage; fluoxetine did not normalize corticosterone concentrations. These findings demonstrate that PTSD-like phenotypes induced during the peripubertal period are dynamic and strongly time-dependent, and that fluoxetine exerts selective, domain-specific effects rather than uniform normalization. The study highlights the importance of developmental stage and timing of assessment when evaluating behavioral outcomes and pharmacological efficacy in preclinical models of PTSD.
To investigate the compensatory role of α-cell-derived paracrine signaling through glucagon and GLP-1 receptors in maintaining β-cell function when insulin secretion is compromised. A β-cell-specific Nox4 knockout mouse (Nox4βKO) displays defective glucose-stimulated insulin secretion and develops a prediabetic phenotype. To uncover the adaptive changes, we ran a detailed analysis of Nox4βKO pancreatic islets. We analyzed their composition, hormone secretion dynamics, receptor expression profiles, and downstream signaling pathways by immunocytochemistry, flow cytometry, RNA sequencing, cAMP assays, and insulin or glucagon secretion assays using both isolated islets and pancreatic slices across different glucose levels and receptor-modulating conditions. Prediabetic Nox4βKO islets showed increased α-cell numbers, expansion of bihormonal cells, and elevated production of glucagon and GLP-1. Receptor profiling revealed a shift in receptor engagement: whereas GLP-1R dominated in wild-type islets, GCGR signaling gained prominence in Nox4βKO islets. This functional rebalancing is consistent with an adaptive response to emerging β-cell dysfunction. Functional assays demonstrated that insulin secretion in prediabetic islets became increasingly reliant on glucagon-driven potentiation of GLP-1R and cAMP-dependent pathways. Transcriptomic and signaling data confirmed enhanced expression of cAMP-related intermediates and calcium-handling components, indicating partial preservation of insulin secretory capacity despite underlying defects. α-cell remodeling and flexible engagement of glucagon and GLP-1 receptors act as key compensatory mechanisms that may help to sustain insulin secretion during early β-cell stress. The context-dependent plasticity of intra-islet receptor activation highlights a coordinated multicellular adaptation in prediabetes and suggests that targeting intra-islet endocrine crosstalk may help preserve β-cell function in prediabetes.
Serous cystadenoma (SCA) of the pancreas is typically a benign neoplasm, and variants are exceptionally rare. While tumors in the pancreatic head often cause upstream ductal dilatation and parenchymal atrophy due to obstruction, the concurrent presentation of SCA with congenital distal pancreatic duct atresia and complete acinar cell loss is unique. We report this case to highlight a potential congenital pathogenesis linking ductal developmental defects to the formation of these lesions. A 56-year-old woman presented with persistent right upper abdominal distension and discomfort lasting over one year. She had a 20-year history of an abdominal mass and had undergone two previous unsuccessful surgical interventions, including a palliative bypass and an aborted resection. Preoperative imaging revealed a large cystic-solid mass in the pancreatic head. Intraoperative exploration identified a 12-cm lesion replacing the pancreatic head and neck, accompanied by complete fatty replacement of the pancreatic body and tail. The patient underwent en bloc pancreaticoduodenectomy with partial portal vein resection and synthetic vascular graft reconstruction. Histopathological examination confirmed the diagnosis of SCA. Notably, the distal pancreatic tissue exhibited a complete absence of acini and visible ductal structures, while islet cells were preserved. Postoperative recovery was uneventful, and at the 12-month follow-up, the patient remained disease-free with preserved endocrine function despite the loss of exocrine function. This case illustrates the rare coexistence of a SCA with congenital distal pancreatic duct atresia and acinar cell depletion. The preservation of islet function amidst complete exocrine loss supports a developmental anomaly rather than obstruction-induced atrophy. This association suggests that congenital ductal defects may predispose patients to SCA formation. Surgical resection remains the optimal strategy for the diagnosis and management of atypical cystic pancreatic lesions with uncertain biological behavior.
The residue of phthalates (PAEs) in edible products can cause endocrine disorders in the human body. In this study, a solid-phase microextraction (SPME) probe coated with fluoro-functionalized covalent organic frameworks (F-COFs) was developed for the extraction of PAEs. The synthesized F-COFs coating exhibited excellent hydrophobicity and high thermal stability, making it suitable for adsorbing PAEs. The established F-COF-SPME-GC method achieved a green analytical chemistry score of 0.63 in terms of environmental friendliness. It also exhibited satisfactory linear ranges of 0.02-100 μg L-1 for all PAEs (R²≥0.9901), and limits of detection (LODs) ranged from 0.010 to 0.019 μg L-1. The method was successfully applied to determine PAEs in six edible oils and six traditional medicinal crops, exhibiting relatively strong resistance to matrix interference. These results indicated that the F-COF-SPME probe provided significant promise for the efficient and robust adsorption and detection of PAEs in complex samples.
Diabetes mellitus (DM) is characterized by progressive β-cell dysfunction, and current therapies improve glycemic control without restoring endogenous β-cell mass. Induced pluripotent stem cell (iPSC)-based approaches offer a potential regenerative strategy. This systematic review and meta-analysis evaluates the efficacy and safety of iPSC-based interventions for diabetes in preclinical models. A comprehensive literature search was conducted in PubMed, ScienceDirect, and Web of Science for studies published up to November 2025. Studies assessing iPSC-based therapies in diabetic models were systematically reviewed and quantitatively synthesized. Thirty-one preclinical studies involving 424 animals were included. iPSC-based interventions were associated with reduced mortality (odds ratio [OR] 0.14) and reductions in blood glucose across 21 studies (mean difference [MD]  -267.36). Glucose-lowering effects were observed under fasting, non-fasting, and glucose-challenge conditions and were accompanied by increased insulin and C-peptide levels. Improvements were also reported in several diabetes-related complications, including cardiac dysfunction, impaired wound healing, neuropathy, and retinopathy. iPSC-based therapies show potential to improve glycemic control and diabetes-related complications in preclinical models, likely through a combination of endocrine replacement and paracrine-mediated regenerative mechanisms. However, substantial heterogeneity across outcome assessments, reliance on short- to mid-term follow-up, and limitations of experimental disease models constrain the interpretation and generalizability of these findings. Immune compatibility, long-term safety, and scalable manufacturing remain key challenges for clinical translation.
Introduction Thyroid cancer is the most common endocrine malignancy, and its diagnosis relies on thyroid ultrasound and fine needle aspiration (FNA). To ensure uniform and complete communication between radiologist and clinician, a standardized thyroid ultrasound reporting protocol was implemented in December 2019 across a regional thyroid network in the Netherlands. This study aims to quantitatively assess the adherence to the protocol and qualitatively assess the reflection of the stakeholders on this protocol in its current form. Methods A sample was collected of ultrasound reports (n = 100) from three hospitals three years before and after implementation, and analyzed focusing on the description of key points in the standardized report. Additionally, semi-structured interviews were conducted. The interview structure is based on the grounded-theory approach using the Capability, Opportunity, Motivation - Behavior (COM-B) model for instituting change. Results The quantitative analysis showed that Thyroid Imaging Reporting and Data System (TI-RADS) classification pre-implementation was described in 0.0% of reports, and only in 37.5% of reports post-implementation. Lymph nodes were described pre-implementation in 80.0% of reports and 95.0% of reports post-implementation. Qualitative analysis revealed that the primary issue with using the standardized ultrasound report revolves around time constraints. Collaboration among endocrinologists, surgeons, and radiologists was mentioned to be essential for developing a comprehensive protocol with widespread acceptance. Encouraging the involvement of new radiologists is crucial. To maintain protocol quality and utilization, it is recommended that there is a culture of open communication for feedback within the thyroid network. Conclusion The findings underscore the importance of continuous improvement efforts and clear communication channels to enhance reporting practices and ensure quality assurance for thyroid ultrasounds between, and within health care institutions. Clinical Relevance: Effective implementation of a standardized thyroid ultrasound reporting protocol within a regional network in the Netherlands enhances diagnostic accuracy and treatment planning for thyroid nodules and cancer, optimizing patient care across multiple healthcare institutions and maximizing healthcare resources.
Theranostics in nuclear medicine has traditionally referred to pairing a diagnostic scan with a matched radiopharmaceutical therapy. This review argues for a broader, target-centric framework. In this model, molecular imaging serves as an in vivo companion diagnostic that verifies target expression across the whole body and guides selection, initiation, and monitoring of targeted therapies. This paradigm extends beyond radiopharmaceutical therapy to include antibody-drug conjugates, immunotherapy, and endocrine therapy. As precision medicine evolves, theranostics is best understood as a clinical pathway linking target biology to treatment decisions through imaging.
The sodium leak channel non-selective (NALCN) is a key regulator of resting membrane potential and cellular excitability in neurons and endocrine cells. Gain-of-function de novo pathogenic variants in NALCN cause severe neurodevelopmental disorders with a broad and heterogeneous clinical spectrum. Partial inhibition of NALCN has been proposed as a therapeutic strategy; however, progress has been limited by the absence of selective pharmacological modulators. This gap largely reflects the lack of a robust heterologous expression system suitable for high-throughput screening, as functional NALCN requires multiple ancillary subunits and its constitutive expression is toxic in commonly used cell lines such as HEK293. To address these challenges, we developed a multitransposon-based approach to generate inducible HEK293 cell lines that stably express the complete NALCN channelosome, including wild-type and disease-associated variants. We further demonstrate that NALCN current expression is cell cycle-dependent, enabling the definition of optimized conditions for consistent and reproducible electrophysiological recordings. Using these cell lines, we conducted a systematic pharmacological characterization of the NALCN channelosome by patch-clamp electrophysiology and identified several candidate modulators that are currently under evaluation. Notably, we revisited NALCN modulation by N-benzhydryl quinuclidine compounds and found that these compounds can restore locomotor phenotypes in an animal model of NALCN gain-of-function. Together, this work establishes a foundational platform for the discovery of NALCN-targeting compounds and opens new therapeutic avenues not only for NALCN-associated neurodevelopmental diseases, but also potentially for psychiatric disorders, chronic pain, and cancer.
This article summarizes hereditary conditions associated with adrenal tumors, emphasizing the importance of germline genetic testing in patients with adrenocortical carcinoma (ACC) and pheochromocytoma/paraganglioma (PPGL). ACC is strongly linked to syndromes such as Li-Fraumeni, Lynch, and Beckwith-Wiedemann, while PPGL has one of the highest hereditary rates among endocrine tumors, often involving SDHx genes and other susceptibility genes, including VHL, RET, NF1, MAX, and TMEM127. The article outlines clinical features, gene-specific risks, management considerations, and evolving surveillance guidelines. Identifying hereditary predispositions improves patient care, guides targeted surveillance, and allows cascade testing for at-risk family members.