搜索结果：Science translational medicine

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition characterized by persistent difficulties in social communication together with restricted, repetitive patterns of behaviour and sensory-processing differences. Growing evidence suggests that ASD is shaped by complex interactions among genetic susceptibility, epigenetic regulation, immune signalling, maternal and early-life exposures and gut microbiome-related pathways. However, many of these associations remain biologically plausible rather than definitively causal, particularly when findings from experimental models are considered alongside human clinical data. This narrative review examines recent advances across these interconnected domains, with particular emphasis on maternal immune activation, prenatal nutrition, gut microbial imbalance, epigenetic and molecular mechanisms, emerging therapeutic directions and developing biomarker platforms. We also discuss current diagnostic limitations and evaluate the potential of salivary microRNAs, perinatal metabolic and epigenetic markers, oxidative stress-related measures and microbiome-based profiles as early and biologically informative indicators of ASD risk. Special attention is given to the need for biologically informed stratification, although current subgrouping frameworks remain preliminary and not yet sufficiently validated for routine clinical use. Likewise, candidate biomarkers remain investigational and require stronger evidence for reproducibility, external validation, longitudinal performance and clinically meaningful sensitivity and specificity before they can be considered for screening or precision-guided care. Emerging therapeutic strategies targeting immune, epigenetic and microbiome-related pathways are also reviewed, but most remain preclinical or early-stage and face substantial translational barriers. The convergence of epigenomics, microbiome research and early diagnostic science may help advance a more personalized medicine framework for ASD, provided that future studies improve cross-cohort reproducibility, clarify brain relevance of peripheral signals and develop practical multiomics models that can support clinically meaningful integration.

Hepatocyte-based therapies represent a promising alternative to liver transplantation, yet their clinical translation is constrained by the limited availability of functional cells and inefficient engraftment. Here, we review progress in the field from a translational perspective, focusing on strategies to overcome these core challenges. We analyze emerging cell sources derived from stem cell technologies and assess their therapeutic potential. These translational efforts are organized around two clinical paradigms: hepatocyte replacement for long-term functional correction and temporary hepatocyte support for liver failure. Beyond hepatocytes, we also discuss preclinical and translational advances involving other liver cell types. To conclude, we outline critical gaps that need to be addressed for clinical translation, including scalable good manufacturing practice (GMP)-compliant manufacturing, efficient preconditioning regimens, long-term immune compatibility with non-invasive graft monitoring, and patient stratification for optimal clinical outcomes. We also discuss how hepatocyte-based therapies can complement gene/RNA therapies and xenotransplantation to broaden treatment options for liver diseases.

This scoping review examines current evidence supporting multimodal artificial intelligence, continuous monitoring, and digital twin concepts in spine care. Our primary aims were to (1) characterize the state of digital twin development in spine care, (2) identify key technological and conceptual gaps, and (3) evaluate translational barriers to clinical implementation. A scoping review was conducted following PRISMA-ScR guidelines. PubMed/MEDLINE, Scopus, and Web of Science were searched for studies published between January 2010 and March 2025. Findings were synthesized qualitatively. Twenty-six studies met inclusion criteria. Existing spine prediction models demonstrate modest discrimination and are predominantly static. Imaging-based AI shows weak associations with pain and disability. Wearable sensor monitoring is feasible but lacks consistent evidence for improved outcomes. Spine-specific digital twins remain conceptual, with no prospective validation demonstrating improved decision-making. Multimodal AI-enabled digital twins represent a compelling conceptual framework for personalized spine care, but current evidence does not support clinical superiority or readiness for implementation. Progress will require prospective validation, standardized data integration, and regulatory clarity.

The essentiality of protein in the human diet is unequivocal. Yet researchers, clinicians, and lay people often believe numerous propositions about dietary protein despite insufficient supporting or refuting data in some instances. To address this disconnect, and to "pressure-test" current beliefs about dietary protein, the Indiana University School of Public Health-Bloomington convened a workshop in February 2025 titled "Human Dietary Protein Needs and Benefits: A Critical Assessment of Postulated Propositions." More than 20 international experts discussed (1) methodologic issues affecting data acquisition and interpretation; (2) "optimal" dietary protein intakes and effects on muscle protein synthesis rates, muscle protein accretion, muscle growth, and muscle repair; (3) protein needs during weight loss; (4) acute protein intake thresholds above and below which protein is no longer related to anabolism; and (5) dietary protein intakes above which protein may be detrimental to health. The experts rated each proposition on a scale from "existing evidence strongly supports the proposition" to "existing evidence seems sufficient to rule out the viability of the proposition." In most instances, the experts believed additional research was warranted. For many propositions the research base was insufficient in terms of quality (rigor), quantity (sample size, study duration), or pertinence (e.g., use of surrogate markers).

Hepatitis and cirrhosis constitute a substantial global health burden, with therapeutic options remaining largely confined to antiviral agents and liver transplantation. Traditional Chinese medicine has long employed Epimedium species (Berberidaceae) for hepatoprotective indications, with contemporary investigations identifying prenylated flavonoids-principally icariin and its active metabolite icaritin-as the principal bioactive constituents. This integrative review systematically examined 33 high-impact studies published up to March 2026, selected based on a comprehensive search of PubMed, Web of Science, Scopus, Embase, Cochrane Library, CNKI, Wanfang, and Google Scholar. Included investigations were critically evaluated for mechanistic sophistication, translational validity, methodological rigor, and pharmacokinetic relevance. Preclinical evidence, derived predominantly from toxin-induced (e.g., CCl4, TAA), metabolic, and acute injury models, demonstrates that icaritin exerts consistent anti-fibrotic activity through dual inhibition of HIF-1α and TGF-β/Smad signaling, selective induction of hepatic stellate cell apoptosis, and suppression of angiogenesis via VEGF/VEGFR2 blockade. Immunomodulatory properties observed in preclinical tumor models and early-phase clinical trials in advanced HBV-related hepatocellular carcinoma, encompass reduction of myeloid-derived suppressor cells (-43%), regulatory T cells (-31%), and enhancement of CD8+ T-cell function (+2.8-fold) providing proof-of-concept for immune modulation in an HBV-endemic population. Clinical data in liver disease remain limited to small, non-randomized studies (primarily in HCC), with no phase III trials specifically targeting fibrosis or cirrhosis endpoints. Critical evidence gaps-including the absence of validation in viral hepatitis models, undefined pharmacokinetics in cirrhosis, and lack of drug-drug interaction data with antivirals-currently preclude routine clinical application in hepatitis and cirrhosis. Safety analyses reveal dose-dependent hepatotoxicity at concentrations exceeding 50 μM icaritin and substantial inter-individual variability in gut microbiota-mediated bioactivation. Epimedium flavonoids exhibit multi-target therapeutic potential that bridges traditional botanical medicine and modern pharmacology, though critical translational gaps persist. Future investigations must prioritize phase III fibrosis trials, pharmacokinetic optimization in cirrhotic populations, and comprehensive drug-drug interaction studies with direct-acting antivirals to establish evidence-based clinical protocols.

Iron overload (IO) disorders, including thalassaemias, hereditary haemochromatosis, and transfusion-dependent anaemias, represent a growing clinical challenge with widespread systemic implications. Reproductive dysfunction remains severely underappreciated despite its high prevalence. Hormonal changes due to iron toxicity are frequently reported, yet are seldom the focus of reproductive medicine, causing fragmented knowledge, inconsistent clinical approaches, and a lack of consensus guidelines. This review synthesizes evidence on the impact of IO on male and female reproductive function, including gonadal dysfunction, impaired fertility, sexual dysfunction, and endocrine-metabolic complications. By addressing gaps in study design, diagnostic criteria, and management, we aim to provide the first comprehensive, expert-driven synthesis on the topic, integrating clinical, translational, and mechanistic insights to establish a structured framework for future research and patient care. A systematic literature search was conducted across PubMed, Scopus, and Web of Science, including studies up to May 2025. Search terms included 'iron overload', 'thalassemia', 'hemochromatosis', 'hypogonadism', 'fertility', 'spermatogenesis', 'ovarian insufficiency', and 'pregnancy'. Quantitative synthesis involved pooling data on prevalence rates of hypogonadism, semen abnormalities, primary and secondary amenorrhoea, age at menarche, and pregnancy outcomes. Gonadal dysfunction primarily arises from iron deposition within the hypothalamic-pituitary-gonadal axis, coupled with oxidative damage to Leydig and Sertoli cells in males, disrupting testosterone synthesis and spermatogenesis, and to ovarian follicles and granulosa cells in females, causing reduced ovarian reserve and altered hormonal signalling. Iron-induced hypogonadism is the most frequent endocrine complication, significantly impacting reproductive health and quality of life. Our analysis of 1201 men and 2134 women indicated hypogonadism, reflecting impaired testicular endocrine function, in 47.0% of men; among those specifically assessed for spermatogenesis, over half presented azoospermia (17.6%) or other sperm abnormalities (37.5%). In women, primary amenorrhoea was reported in 45.7%, secondary amenorrhoea in 20.0%, and the weighted mean age at menarche was delayed (14.4 ± 2.1 years). Sexual dysfunction, notably erectile dysfunction, commonly accompanies hypogonadism, further impairing quality of life. Female sexual health has not been investigated at all. Pregnancy is increasingly achievable, but remains clinically challenging. Across 3536 reviewed pregnancies, ART was required in ∼20%, miscarriage occurred in 11.2%, and caesarean section was used in ∼80%. Mean gestational age at delivery was 37.1 ± 3.1 weeks, and mean birth weight was 2.64 ± 0.68 kg. Besides gonadal damage (direct or pituitary-related), systemic iron-related endocrine and metabolic disturbances, including hypothyroidism, growth hormone deficiency, diabetes mellitus, and cardiovascular disease, further aggravate reproductive impairments. Although effective iron chelation therapy reduces the systemic iron burden and is effective in preventing endocrine complications when initiated early, evidence supporting the reversal of established reproductive dysfunction remains limited, highlighting the need to optimize iron control from a young age to preserve reproductive health. This review underscores the critical need for standardized gonadal screening to facilitate personalized reproductive care and early intervention in subjects with IO disorders. We propose an integrated clinical framework, combining early endocrine monitoring, fertility preservation protocols, and reproductive counselling. Future multidisciplinary research should prioritize prospective studies with clearly defined reproductive endpoints and explore optimized chelation strategies to safeguard reproductive potential. Addressing these gaps will fundamentally reshape clinical management, bridging haematology, endocrinology, and reproductive medicine.

Angiogenesis is essential for breast cancer progression and metastasis; however, the clinical impact of vascular endothelial growth factor (VEGF)-targeted therapies remains limited due to adaptive resistance and activation of compensatory angiogenic pathways. Angiogenesis-regulating microRNAs (angiomiRs) act as upstream modulators of both VEGF-dependent and VEGF-independent signaling networks contributing to vascular plasticity, immune evasion, and therapeutic escape. Dietary flavonols such as kaempferol, myricetin, and quercetin have demonstrated anti-angiogenic activity in preclinical models, yet their mechanistic interaction with angiomiR-mediated regulation in breast cancer remains poorly characterized. This narrative review critically evaluates evidence identified through structured searches of Google Scholar, PubMed, Scopus, and Web of Science (2010-2026). We synthesize mechanistic and translational findings linking flavonols to microRNA-associated regulation of hypoxia signaling, endothelial activation, extracellular vesicle communication, and vascular normalization. Available evidence indicates that flavonols may influence angiogenic pathways both directly, by inhibiting key signaling cascades, and indirectly, through modulation of non-coding RNA networks. Despite these insights, experimental validation of specific flavonol-angiomiR interactions in breast cancer remains limited. AngiomiR modulation by flavonols, therefore, represents a mechanistically grounded but predominantly preclinical concept that warrants further translational investigation to clarify its therapeutic relevance and potential applications within precision oncology in breast cancer. Blood vessels are essential for supplying breast cancer tumors with nutrients and oxygen. Tumors often rely on a molecule called vascular endothelial growth factor (VEGF) to form new blood vessels. For this reason, treatments that block VEGF have been developed to slow tumor growth. However, these treatments can lose effectiveness over time because cancer cells can find alternative ways to keep their blood supply. Blood vessel formation is controlled by signals within cells. MicroRNAs (miRNAs) are very small molecules that help turn genes on or off, influencing how blood vessels develop and how tumors respond to treatment. Flavonols are naturally occurring compounds found in certain fruits and vegetables. Some studies suggest that flavonols can affect blood vessel growth, possibly by influencing miRNAs involved in this process. Although early findings are promising, most evidence comes from laboratory and preclinical studies. Further research is needed to determine whether targeting these pathways could lead to safe and effective treatment strategies for patients with breast cancer.

Autoimmune encephalitis (AE) encompasses a highly heterogeneous spectrum of severe immune-mediated neurological disorders. Over the past 50 years, research has expanded rapidly, yet a quantitative synthesis of its evolution, key contributors, and thematic trends is lacking. Here, we provide a comprehensive 50-year, multi-database bibliometric study that systematically maps the full trajectory of AE research-from early descriptions to the current era of mechanism-driven therapeutics-using advanced analytical tools. We systematically retrieved AE-related publications from 1971 to May 24, 2025 from PubMed, Web of Science, and Scopus. After deduplication, records were analyzed using bibliometric tools (CiteSpace, VOSviewer, Bibliometrix). Analyses included publication trends, national/institutional contributions, author networks, journal distributions, co-citation patterns, keyword co-occurrence, and thematic evolution. Annual publications surged after 2007, coinciding with the discovery of anti-NMDA receptor encephalitis (anti-NMDAR AE), reaching a peak in 2022. The USA and China were the leading contributors by volume, while Spain had the highest average citation impact. The University of Pennsylvania and the University of Oxford emerged as the most productive institutions. Dr. Josep Dalmau is the most prolific author in the field, leading a major collaborative cluster. Frontiers in Neurology published the most papers, while Neurology had the highest H-index. Keyword and thematic analyses confirmed anti-NMDAR AE as the dominant research focus, with intense scholarly interest in its pathogenesis, diagnosis, and immunotherapy. Recent trends highlight emerging topics like COVID-19-associated AE, anti-IGLON5 disease. This study outlines the development, collaboration patterns, and research hotspots in AE. Research continues to center on anti-NMDAR encephalitis, with a growing focus on clinical and therapeutic applications. Future directions include mechanistic studies, biomarker discovery, and advanced immunotherapies.

The ability to cryopreserve and rewarm whole organs without damage has the potential to transform transplantation by enabling long-term banking and global organ sharing. Successful transplantation of rat kidneys cryopreserved and rewarmed using nanowarming, a technique in which silica coated iron oxide nanoparticles (sIONP) are perfused throughout the organ's vasculature along with cryoprotective agents (CPAs), which are then both washed out of the organ after rewarming prior to transplant has recently been reported. To support development towards clinical organ scale translation, the potential toxicity of sIONP in male Sprague-Dawley rats was evaluated, administering doses six to seven orders of magnitude higher than the estimated systemic exposure corresponding to the highest reported residual iron levels in organs following nanowarming and cryopreservation (3.36 ng Fe/kg). These doses are effectively within the range of a theoretical worst-case scenario, where a fully loaded kidney is transplanted (10.5-14 mg Fe/kg) without washout. Toxicity was assessed at 24 h for (5, 12, and 20 mg Fe/kg) and over 28 days for 12 mg Fe/kg dose. Furthermore, plasma pharmacokinetics, hematology, clinical chemistry, biodistribution and histopathology were evaluated. No overt toxicity was observed at the lower doses, while some adverse effects emerged at the highest dose of 20 mg Fe/kg. These findings suggest minimal toxicity associated with sIONP injections of a dose equivalent to a fully loaded organ, supporting the translational potential of sIONP for organ nanowarming.

Sleep plays a critical role in animal physiology, primarily governed by the brain, and its disruption is prevalent in various brain disorders. Mettl5 is associated with intellectual disability (ID), which often includes sleep disturbances. However, the mechanism underlying these sleep disruptions in ID remains poorly understood. In this study, we investigated the sleep phenotypes resulting from Drosophila Mettl5 mutations. Rescue experiments revealed that Mettl5 functions predominantly within neurons and glia marked by Mettl5-Gal4 to regulate sleep. Previous work established that Mettl5 forms a complex with Trmt112 to influence rRNA methylation. Notably, a mutation in Trmt112 recapitulated these sleep disturbances, implicating translational regulation by the Mettl5/Trmt112 complex. Subsequent RNA-seq and Ribo-seq analyses of Mettl51bp mutants uncovered downstream effects, including altered expression of proteasome components and clock genes. Rescue experiments confirmed that the net increase in PERIOD protein underlies the sleep phenotype. This study illuminates the interplay between ribosome function, clock genes, and the proteasome in sleep regulation, highlighting the integrated roles of protein synthesis and degradation. These findings could potentially provide an example for in vivo study of rRNA methylation function, expand our understanding of protein homeostasis in sleep, and offer insights into the sleep phenotypes associated with ID.

Early-life disruption of microbiome development is known to impair health; however, the long-term effects of pregnancy-related pharmacological alterations to the maternal gut microbiota on offspring health remain unclear. This meta-analysis aimed to evaluate the impact of maternal antibiotic use (either prenatal or intrapartum) on the risk of childhood atopic dermatitis, based on cohort and case-control studies. Literature searches were conducted in EMBASE, PubMed, Cochrane, and Web of Science databases using predefined PICO (patients, intervention, comparison, outcome) criteria. Overall, our meta-analysis included 30 studies with a total of 4,125,143 mothers and 4,346,050 children. Using the random effects model, our study found that prenatal antibiotic use was associated with higher odds of atopic dermatitis in childhood (aOR: 1.32; 95% CI: 1.12; 1.56). This result remained significant after adjusting publication bias by the trim-and-fill method (aOR: 1.22; 95% CI: 1.03; 1.44), highlighting the potential relevance of antibiotic prescribing practices during pregnancy in relation to childhood atopic disease risk. Intrapartum antibiotic use was not associated with elevated risk for atopic dermatitis in the children (OR: 1.64; 95% CI: 0.84; 3.17). Prenatal antibiotic use appears to have a modest effect on atopic dermatitis in offspring.

Although COVID-19 in children is benign, it has revealed a critical vulnerability in the neonatal population. This study aimed to identify the mortality predictors and determinants of survival in children affected by COVID-19 in the Marrakech-Safi (RMS) region of Morocco. This was a retrospective, multicenter cohort study conducted among children hospitalized with COVID-19 between March 2020 and December 2021 in two RMS hospitals. All patients aged under 15 years with confirmed SARS-CoV-2 infection were included; incomplete files, misdiagnoses, and transferred patients were excluded. Overall survival was assessed using the Kaplan-Meier curve, associations were examined with the log-rank test, and predictors were identified using Cox proportional hazards regression models. A total of 167 children were identified, including 52.7% females and 20.4% (n = 34) neonates. The death rate was 4.79%, with a mean overall survival of 40.9 days. The analysis identified thrombocytopenia (adjusted hazard ratio [aHR] = 87.07, 95% confidence interval [CI]: 59.85-126.77, P <0.001), cardiopathy (aHR = 34.95, 95% CI: 3.41-358.23, P = 0.003), maternal-fetal infection (aHR = 57.65, 95% CI : 4.00-831.62, P = 0.003), and the presence of respiratory distress (aHR = 48.37, 95% CI: 3.30-709.01, P = 0.005) as major mortality predictors. Implementing rapid intervention and preventive medicine strategies is essential to reducing morbidity and mortality in pediatric populations during future public health emergencies.

Thyroblastoma is a rare and highly aggressive embryonal thyroid malignancy typically associated with DICER1 alterations. However, DICER1-wildtype cases remain poorly characterized at the molecular level. We report a case of aggressive thyroblastoma in a 62-year-old male, negative for canonical DICER1 RNase IIIb mutations. Comprehensive genomic profiling was performed using Oxford Nanopore long-read sequencing, followed by integrative bioinformatic and pathway-level analyses. Molecular analysis revealed an alternative oncogenic signature characterized by an EIF1AX p.Lys3_Lys5dup duplication, TERT alterations (promoter C228T and coding p.C42R), and an AGK-BRAF fusion predicted to drive constitutive MAPK/ERK signaling. Functional enrichment analyses highlighted dysregulation of translational initiation, telomere maintenance, and mitogenic pathways, alongside potential immune-escape mechanisms linked to DUX4 activation. Clinically, the tumor exhibited a triphasic morphology, extensive locoregional infiltration, pulmonary metastases, and only transient response to chemotherapy. These findings expand the molecular spectrum of thyroblastoma beyond the canonical DICER1-driven paradigm and suggest that DICER1-wildtype cases may represent a distinct biological subgroup. The identification of alterations affecting TERT and MAPK pathways highlights potential therapeutic vulnerabilities and supports the clinical value of comprehensive genomic profiling in ultra-rare thyroid malignancies.

Bovine tuberculosis&#xa0;(bTB), caused by Mycobacterium bovis, is a zoonosis that threatens public health and causes substantial economic losses in livestock. The suboptimal Escherichia coli-expressed recombinant proteins limit the diagnostic performance of current bTB&#xa0;serological tests. To overcome this limitation, we evaluated Mycolicibacterium smegmatis as an expression host capable of producing recombinant antigens with post-translational modifications comparable to those of M. bovis. Ten antigen candidates were individually expressed in E. coli using the pET-26b(&#x2009;+) vector and in M. smegmatis using the pSO&#x394;Bam vector. Their diagnostic performance was evaluated using an&#xa0;enzyme-linked immunosorbent assay&#xa0;(ELISA) with plasma samples from interferon-gamma release assay (IGRA)-negative (n&#x2009;=&#x2009;30) and -positive (n&#x2009;=&#x2009;46) cattle in South Korea, followed by receiver operating characteristic (ROC) curve analysis. Among the single antigens, LprA expressed in M. smegmatis demonstrated diagnostic performance comparable to that of&#xa0;the well-established antigen MPB70 (sensitivity: 50.0%, specificity: 96.6%, AUC: 0.791). In addition, several M. smegmatis-derived antigens showed higher concordance with the IGRA results, as assessed by Cohen's kappa and Fisher's exact tests, and a stronger association between age and antigen-specific antibody responses was observed among IGRA-positive cattle. Moreover, a multiple logistic regression model incorporating eight antigens, including those derived from both hosts, achieved high predictive accuracy for IGRA results (sensitivity: 87.0%, specificity: 100%, AUC: 0.991). These findings suggest that M. smegmatis is a promising host for identifying novel antigens and that a multi-host strategy may improve bTB serodiagnosis.

Central nervous system (CNS) development commences in third week of gestation with neural stem cells (NSCs), which, through symmetric division, expand the pool of stem cells and generate diverse types of neuronal and glia cells of CNS via asymmetric division. During neurodevelopment, spatiotemporal coordination is fundamental for appropriate morphogenesis and producing neuronal connections. Besides gene regulatory networks, external and internal factors guide NSCs during self-renewal, fate determination and differentiation. Recent studies indicate metabolism as one of the common converging integrators in NSCs to trigger modifications in response to external factors. One such external factor is micronutrients that profoundly affect different stages of neurodevelopment, including, differentiation, neural migration and maturation. This review aims to provide a summary of recent insights into how metabolism and micronutrients regulate different events of neurodevelopment including proliferation, fate determination and differentiation. Notably, we focus on illustrating the implications of mitochondria as key determinants of NSC fate and functionality. We also highlight the recent development on how metabolism orchestrates the epigenome of NSCs during proliferation and differentiation. We further explore the role of nutraceuticals in mitigating the risk of neurodevelopmental and adult neurological disorders, highlighting recent innovations in their therapeutic applications. An in-depth grasp of these molecular processes is fundamental to improving translational strategies for treating neurological disorders.

Based on DNA-gated stimuli-responsive nanoscale porous carbon, a smart phototheranostic nanovehicle, which can respond to targeted near-infrared laser irradiation, is assembled. Utilizing single-stranded DNA as a gating molecule through &#x3c0;-&#x3c0; interactions, the nanoscale porous carbon loaded with photothermal organic dyes was completely packaged. Under laser irradiation, synergistic photothermal conversion is initiated, and the temperature rises up to nearly 55&#xb0;C in the designated region, which provides an ideal local condition for photothermal therapy. In the meantime, heat drives single-stranded DNA (ssDNA) detaching from the surface of NCZIF, and organic dyes are leaked for in situ fluorescent imaging of tumor sites. As a proof of concept, two nanovehicles, ICG@NCZIF and MB@NCZIF, are separately prepared and systematically compared. The better-performed ICG@NCZIF is further used in in vivo phototheranostics of renal cell carcinoma (RCC) and exhibits satisfactory results of tumor inhibition and accurate tumor imaging. Thus, the as-designed phototheranostics nanovehicle ICG@NCZIF holds potential for (pre)clinical translational development.

Bone metastases cause significant morbidity and ultimately death in some human cancer patients. Although experimental animal models of skeletal metastases have been invaluable for investigating the molecular mechanisms of cancer progression and growth in bones, few of these models recapitulate the heterogeneous nature of bone metastases observed in humans. Animals with naturally occurring cancers have been proposed as ideal and unique models for human cancer research. From this, understanding the incidence, histologic features, clinical presentation, and response to therapy of spontaneous bone metastases in animals with different cancers will help with animal model selection and translational experiments on bone metastasis. This review provides an overview of the natural history of spontaneous bone metastases that occur in animals with spontaneous cancer. The review focuses on companion animals (dogs and cats) and includes rodents and other animal species. The similarities and differences compared to human bone metastases are highlighted, permitting a valuable resource for future skeletal metastasis modeling and therapeutic discovery.

The CUG-BP and Elav-like (CELF) family of RNA-binding proteins are key regulators of post-transcriptional gene expression, coordinating alternative splicing, mRNA stability, and translation. Although individual members, particularly CELF1 and CELF2, have been extensively characterized, a systematic, paralog-resolved integration of structural determinants, regulatory mechanisms, and disease relevance across all six CELF proteins remains limited. Here, we establish an integrative framework linking conserved RNA recognition motifs and divergent linker domains to context-dependent regulatory outputs, mediated by phosphorylation, nucleocytoplasmic dynamics, and RNA network interactions. We further highlight the neuron-enriched CELF3-CELF6 subfamily, consolidating emerging evidence that extends their roles beyond neural splicing into cancer-associated regulatory programs. Notably, we delineate functional divergence within the family, with CELF1 frequently acting as an oncogenic driver in contrast to the tumor-suppressive role of CELF2, while positioning less-characterized paralogs within this regulatory spectrum. Together, this work defines a unified structure-function-disease axis for CELF proteins and provides a conceptual framework for their prognostic and therapeutic exploitation. However, current CELF-targeted strategies remain largely preclinical and face key translational challenges, including paralog selectivity, off-target effects, and delivery barriers such as limited blood-brain barrier penetration. Accordingly, the most immediate clinical utility of CELF biology is likely to lie in biomarker development and patient stratification, rather than direct therapeutic intervention.

Undifferentiated/dedifferentiated endometrial carcinoma (UEC/DEC, collectively referred to as UDEC) is a rare but highly aggressive subtype of endometrial cancer, characterized by strong metastatic potential, frequent recurrence, and resistance to conventional chemotherapy. Currently, there is no standardized treatment strategy for UDEC. Genomic profiling has revealed a high frequency of PTEN mutations, resulting in dysregulation of the PI3K/AKT/mTOR and cell cycle pathways. To investigate therapeutic options, we utilized patient-derived xenograft (PDX) and tumoroid models established from PDX tumors derived from UDEC patient samples to evaluate everolimus (an mTOR inhibitor) and palbociclib (a CDK4/6 inhibitor), alone and in combination. Combination therapy exhibited antitumor effects in UDEC cell lines and tumoroids and significantly suppressed tumor growth in PDX models without inducing weight loss in mice. RNA sequencing of treated PDX tumors identified survivin as a consistently downregulated target. Mechanistically, the combination reduced Sp1-mediated transcription of survivin. In a clinical cohort of 29 UDEC patients, higher survivin expression showed a trend toward shorter overall and progression-free survival, supporting its role as a prognostic biomarker. These findings highlight dual PI3K/AKT/mTOR and CDK4/6 inhibition as a promising strategy for UDEC and demonstrate the translational value of PDX and tumoroid models in aggressive gynecologic cancers.