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Immune checkpoint B7-H3 is an emerging target for immunotherapy. DS-7300a is an advanced B7-H3-targeting antibody-drug conjugate (ADC) warheaded with the topoisomerase I inhibitor DXd. DS-7300a has demonstrated clinical activity, but molecular biomarkers to predict its therapeutic response remain elusive. TP53 is one of the most mutated tumor suppressor genes across cancers, and effective therapies are urgently needed for TP53-deficient cancers. Using prostate cancer (PCa) as a model system, we reported that DS-7300a's anti-tumor efficacy is highly dependent on functional p53 in cancer cells, and TP53 defects confer resistance to DS-7300a. Mechanistically, we found that DS-7300a and its payload, DXd, induce DNA damage and activate the ATM/ATR/CHK signaling cascade, thereby stabilizing p53 and inducing a pro-apoptotic and senescence-associated transcriptome. In contrast, TP53-deficient cells fail to sense DXd-induced DNA damage, maintain a high proliferation rate, and exhibit low levels of apoptosis and senescence, thereby conferring resistance to DS-7300a. Ferroptosis is an iron-dependent form of regulated cell death triggered by lipid peroxidation, which is mechanistically and morphologically distinct from apoptosis. Interestingly, DS-7300a treatment elevates lipid peroxidation in TP53-deficient cancer cells and upregulates glutathione peroxidase 4 (GPX4), an antioxidant enzyme that mitigates lipid peroxidation. Using isogeneic xenograft models and a newly developed humanized B7-H3 PCa model, we demonstrated that inducing ferroptosis by pharmacological inhibition of GPX4 enhances DS-7300a's efficacy in TP53-deficient tumors. Our studies demonstrate that TP53 status dictates anti-tumor responses to DS-7300a, and ferroptosis induction represents a promising therapeutic approach to overcome resistance to DS-7300a in malignancies harboring TP53 defects.

Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by chronic hyperglycemia and represents a growing global health burden. One of its major complications is diabetic kidney disease (DKD), a progressive condition characterized by declining kidney function accompanied by structural alterations in tissue. Among the multiple pathways involved in DKD progression, inflammation has emerged as a key contributor. In parallel, increasing evidence suggests that biological sex influences disease progression; however, whether and how sex modulates inflammatory mechanisms driving DKD progression remains incompletely understood. In this study, we investigated the interplay between inflammation and biological sex in DKD using the BTBR ob/ob model, which closely recapitulates the human disease. Obese diabetic mice exhibited significant albuminuria regardless of sex; however, podocyte-associated proteins displayed sex-dependent molecular regulation. At the inflammatory level, no changes were detected in whole-kidney analyses based on the selected markers, but a compartment-specific response was observed, characterized by increased macrophage infiltration and upregulation of Ccl2 (MCP-1) gene expression in the glomerular compartment, especially in males. Additionally, the tubular compartment exhibited distinct sex- and metabolism-dependent inflammatory gene expression patterns. Together, these findings indicate that inflammation in this model is spatially compartmentalized and also differentially regulated according to sex. This integrated perspective may contribute to a better understanding of DKD progression and support the development of more precise and targeted therapeutic strategies.

Aortic dissection (AD) is a catastrophic cardiovascular syndrome with an in-hospital mortality of more than 90%. We previously identified oxidative inactivation of sarcoplasmic/endoplasmic reticulum Ca2+-ATPase 2 (SERCA2) at cysteine 674 (C674) as a driver of aortic smooth muscle cell (ASMC) phenotypic switching. However, its causal impact on autophagic flux and AD remains unresolved. SERCA2 C674S mutant knock-in (SKI) mice, human AD specimens, and primary ASMCs were subjected to quantitative proteomics, histopathology, and autophagy flux assays. Interventions included Ca2+ chelation (BAPTA-AM), endoplasmic reticulum (ER) stress inhibitor 4-phenylbutyrate, mammalian target of rapamycin (mTOR) inhibitor rapamycin, redox modulator Tempol, calcineurin inhibitor cyclosporine A, peroxisome-proliferator-activated receptor γ (PPARγ) agonist pioglitazone, and SERCA2 agonist [6]-gingerol. Therapeutic efficacy was evaluated in β-aminopropionitrile (BAPN)-induced AD. Human AD specimens and SKI aortas displayed suppressed autophagy within the tunica media. SERCA2 dysfunction activated PI3K-AKT-mTOR signaling pathway, reduced TFEB and Rab7, and impaired autophagosome-lysosome fusion in ASMCs. These defects were rescued by BAPTA-AM, 4-phenylbutyrate, rapamycin, Tempol, or [6]-gingerol, but not by calcineurin or pioglitazone. In vivo, rapamycin and [6]-gingerol restored medial autophagy, suppressed ASMC synthetic phenotype, lowered AD incidence and severity, and preserved medial integrity in BAPN-treated SKI mice. In conclusion, oxidative SERCA2 inactivation evokes cytosolic Ca2+ overload, couples ER/oxidative stress to mTOR hyper-activation, and blunts autophagic flux, thereby establishing a self-amplifying loop that precipitates AD. We define a previously unrecognized SERCA2-Ca2+-mTOR-autophagy axis as a guardian of aortic wall homeostasis and establish autophagy rebalancing and SERCA2 activation as mechanistically grounded therapeutic strategies against AD.

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RNA velocity provides a powerful framework for inferring cellular dynamics from single-cell RNA sequencing data. The rapid proliferation of computational methods within this field has prompted a need for systematic evaluation. However, existing comparisons often suffer from limited scope or incomplete task design, leaving users without clear guidance. Consequently, there is a lack of a comprehensive and standardized benchmark that evaluates methods across diverse biological and technical scenarios using appropriate, context-specific metrics. In this study, we present a comprehensive benchmark of 19 computational RNA velocity tools covering 30 distinct methods. We systematically evaluate 25 RNA-only methods across eight evaluation tasks, designating directional consistency, temporal precision, negative control robustness, and sequencing depth stability as core tasks, while assessing five multimodal-enhanced methods specifically on the multimodal integration task. These assessments utilize 34 datasets spanning 26 real-world and eight simulated scenarios. Our results reveal a clear trade-off between directional consistency and negative control robustness, distinct group-wise behaviors across temporal modeling strategies, and variability driven by sequencing depth and quantification choices. This study also identifies several methodological gaps, including the need for improved modeling of gene dependence, more accurate temporal inference strategies, and better-designed multimodal architectures. This benchmark establishes a unified framework for evaluating RNA velocity methods. Crucially, we provide task-aware guidance to facilitate method selection based on specific biological contexts and technical constraints, rather than relying on a single overall ranking.

Ischemic stroke represents a dynamic metabolic disorder of the neurovascular unit (NVU) rather than a static vascular occlusion followed by neuronal demise. Immediate oxygen and glucose deprivation rapidly deplete ATP, disrupt the transmembrane ionic gradients, increase glutamate excitotoxicity, and overload mitochondrial with calcium. These events alter glycolytic, lipid, amino acid, and redox pathways. During the subacute and chronic phases, astrocytes, microglia, macrophages, endothelial cells, pericytes, oligodendrocytes, and surviving neurons continue to remodel substrate utilization. These phase-specific metabolic programs either accelerate infarct expansion and blood-brain barrier disruption or facilitate angiogenesis, synaptic plasticity, and tissue repair. Consequently, cell-based therapeutic paradigms have shifted from direct neuronal replacement toward metabolic rescue. Transplanted cells and cell-free derivatives deliver trophic factors, extracellular vesicles, microRNAs, antioxidant signals, mitochondrial cues, and immunoregulatory factors. These signals enhance mitochondrial fitness, restore redox homeostasis, attenuate pro-inflammatory glycolysis, and stabilize endothelial-pericyte coupling to stabilize a permissive neurorehabilitation microenvironment. This review synthesizes post-stroke metabolic landscapes and evaluates how mesenchymal stromal, neural stem/progenitor, endothelial progenitor, cord blood-derived, and mononuclear cells, and extracellular vesicles, may be incorporated into a phase-specific translational framework supported by target-engagement biomarkers and standardized potency assays.

Non-small cell lung cancer (NSCLC) constitutes the predominant lung cancer subtype and remains a leading cause of cancer-related mortality worldwide, underscoring an imperative need for mechanistically informed therapeutic strategies. Salvianolic acid B (SalB), a bioactive polyphenolic compound isolated from Salvia miltiorrhiza, has demonstrated antitumor potential across several malignancies; however, the precise molecular mechanisms governing its activity in NSCLC remain largely undefined. The anticancer activity of SalB was evaluated in human NSCLC cell lines (A549, H460 and PC-9) and in an A549 xenograft mouse model. Apoptosis, proliferation, autophagy, oxidative stress, ferroptosis-associated phenotypes, and mitochondrial function were assessed using flow cytometry, clonogenic assays, immunofluorescence, transmission electron microscopy, and Western blotting. Nuclear factor erythroid 2-related factor 2 (Nrf2) protein stability and ubiquitination were examined using proteasome inhibition and immunoprecipitation assays. The functional relevance of Nrf2 was further validated by gain-of-function approaches both in vitro and in vivo. SalB potently induced apoptosis and abrogated the proliferative capacity of NSCLC cells. Mechanistically, SalB engaged autophagic machinery and elicited hallmark features of ferroptosis, including excessive reactive oxygen species generation, labile iron accumulation, glutathione depletion, elevated malondialdehyde (MDA) accumulation, mitochondrial depolarization, and coordinate downregulation of critical ferroptosis defense proteins-glutathione peroxidase 4 (GPX4), ferritin heavy chain 1 (FTH1), and the cystine/glutamate antiporter xCT (solute carrier family 7 member 11, SLC7A11). Pharmacological blockade of autophagic flux partially attenuated SalB-induced oxidative stress and iron dysregulation, indicating that autophagy contributes to SalB-induced ferroptosis-associated phenotypes. At the molecular level, SalB accelerated proteasome-dependent degradation of Nrf2 by selectively potentiating K48-linked polyubiquitination. Enforced Nrf2 overexpression partially attenuated SalB-induced autophagy activation, ferroptosis-associated molecular alterations, apoptotic cell death, and proliferative suppression. Concordantly, Nrf2 overexpression substantially abrogated the antitumor efficacy of SalB in vivo. These findings establish that SalB suppresses NSCLC progression by promoting Nrf2 proteasomal degradation, thereby enhancing autophagy-associated ferroptotic vulnerability. Pharmacological targeting of the Nrf2-autophagy-ferroptosis regulatory axis may provide a potential therapeutic avenue for NSCLC.

Anti-Yo paraneoplastic cerebellar degeneration (PCD) is a rare autoimmune disorder linked to ovarian and breast cancers. Neurological symptoms often precede cancer diagnosis, yet conventional imaging techniques may fail to detect early cerebellar changes. This study quantitatively assessed cerebellar atrophy and network alterations in anti-Yo PCD patients compared to healthy controls and patients with spinocerebellar ataxia type 1 (SCA1). We analyzed structural MRI data from 11 antiYo PCD patients, 17 healthy controls, and 17 SCA1 patients. Cerebellar lobular segmentation and cortical thickness measurements were conducted. Structural covariance networks were built using inter-lobular Pearson correlation coefficients (threshold |r| > 0.5), with graph theory metrics assessing connectivity. Univariate and age-adjusted multivariate analyses evaluated group differences, and machine learning assessed the discriminative power of regional morphometric measures. AntiYo PCD patients showed pronounced anterior cortical thinning, while SCA1 atrophy was milder and more posterior. Two PCD subtypes emerged: one with severe atrophy, another with nearnormal thickness. Network analysis revealed increased node strength and clustering coefficients, but reduced betweenness centrality in PCD, suggesting altered network hierarchy and widespread clustering that may reflect pathological reorganization. In cross-validated analysis, regional cerebellar features distinguished PCD, SCA1, and controls with promising AUC values. Anti-Yo PCD is characterized by anterior cerebellar vulnerability and network reorganization distinct from SCA1. These morphometric and connectivity markers are candidate imaging biomarkers for early diagnosis and subgroup stratification in paraneoplastic cerebellar degeneration.

To compare the erythropoietin adsorption characteristics of two adsorption devices, Lixelle&#xae; and FILTOR&#xae;, used for the treatment of dialysis-related amyloidosis, using bovine serum. Three recirculating perfusion studies were performed using bovine serum containing recombinant human erythropoietin (epoetin beta; EPO), darbepoetin alfa (DA), or epoetin beta pegol (C.E.R.A.). Because direct quantitative assays for DA and C.E.R.A. were unavailable, and it was difficult to obtain suitable measurement systems for these agents, they were evaluated using an erythropoietin immunoassay based on assay cross-reactivity. In the EPO perfusion test (n&#x2009;=&#x2009;3), the 4-h EPO removal rate was 18.7&#x2009;&#xb1;&#x2009;3.2% in the Lixelle&#xae; group and 53.0&#x2009;&#xb1;&#x2009;3.1% in the FILTOR&#xae; group (p&#x2009;<&#x2009;0.05). In the DA perfusion test (n&#x2009;=&#x2009;3), the 4-h removal rate based on erythropoietin immunoassay measurements was 3.3&#x2009;&#xb1;&#x2009;1.5% in the Lixelle&#xae; group and 31.0&#x2009;&#xb1;&#x2009;6.1% in the FILTOR&#xae; group (p&#x2009;<&#x2009;0.05). In the C.E.R.A. perfusion test (n&#x2009;=&#x2009;3), the corresponding removal rates were 0.3&#x2009;&#xb1;&#x2009;0.6% and 1.3&#x2009;&#xb1;&#x2009;2.3%, respectively, with no significant difference (p&#x2009;=&#x2009;0.5351). The FILTOR&#xae; adsorption device showed greater reductions in erythropoietin concentration than the Lixelle&#xae; device in experiments using EPO. A similar trend was observed for DA, whereas no apparent difference was observed for C.E.R.A. Because DA and C.E.R.A. were evaluated using assay cross-reactivity, and quantitative assessment was limited by the sampling strategy, these findings should be interpreted with caution.

Schistosomiasis is an acute and chronic illness caused by parasites of the genus Schistosoma. It is present in 79 countries worldwide and primarily affects socioeconomically vulnerable populations due to exposure to infested water during daily activities. Praziquantel is the primary drug used in international schistosomiasis treatment. However, adverse effects and parasite resistance mechanisms have been reported, ranging from experimentally induced resistance to naturally occurring resistance in real-world populations. New therapeutic targets have been identified to address these issues. Consequently, drug repurposing is often considered a faster alternative that may offer lower development risks and potentially fewer adverse outcomes than newly synthesized drugs.&#xa0;Building on this potential, this study aimed to identify drug repurposing candidates as alternatives for schistosomiasis treatment through a systematic review. Two databases (ScienceDirect and PubMed) were searched. The selection of studies and writing of this systematic review followed the PRISMA guidelines.&#xa0;Of the 313 articles identified, 28 were selected after applying the exclusion criteria. The best results observed were celecoxib (over 90% for egg burden and parasite load), mefenamic acid (92% for parasite load and 82% for egg burden), and chlorambucil (75% parasite load and 85% egg burden).&#xa0;This review highlights the data supporting this strategy as a viable alternative for developing new therapies for schistosomiasis. As these compounds have been used clinically for a long time, substantial preclinical, biosafety, and pharmacovigilance data are already available. Their adverse effects and toxicities are well characterized, which may contribute to a reduction in overall costs and development timelines, although robust clinical validation remains a prerequisite for their use.

We anatomically investigated whether the superior fasciculus (SF) of the external obturator muscle (EOM) influences the spread of dye into the obturator canal, in a cadaveric model simulating a proximal ultrasound-guided obturator nerve block. Thirteen sides from seven Thiel-embalmed cadavers (five male cadavers, nine sides; two female cadavers, four sides) were studied. Blue dye was injected either between the pectineus muscle and the EOM, the pectineus muscle and the SF, or the SF and the main belly of the EOM. After injection, gross dissection was performed to evaluate dye spread along the obturator nerve and into the obturator canal. In the SF-absent sides (four of thirteen), the dye injected between the pectineus muscle and the EOM broadly stained both the anterior and posterior branches and spread into the obturator canal, with staining of the obturator nerve trunk in all cases. In the SF-present sides (nine of thirteen), dye injection between the pectineus muscle and the SF (five sides) failed to produce canal spread, and neither the posterior branch nor the trunk was stained. In contrast, dye injection between the SF and the main belly of the EOM (four sides) stained both branches in all cases and achieved canal spread with obturator nerve trunk staining on three sides. Because the SF may restrict obturator-canal spread during the proximal approach, the injection site may need to be adjusted according to the presence of the SF.

The genetic status of embryos obtained during in vitro fertilization (IVF) programs using spermatozoa selected by microfluidic sorting was evaluated. Genetic testing was conducted on 127 embryos in the main group and 194 in the control group. The embryos were cultured under standard conditions; blastocyst biopsy was performed on day 5 for subsequent preimplantation genetic testing for aneuploidies using high-throughput sequencing. The use of microfluidic chips significantly increased the yield of blastocysts (p = 0.03) without affecting fertilization rates or embryo quality. However, when assessing the genetic status of embryos, no significant differences were found: the frequency of embryos with a normal karyotype was 29.9% in the main group and 32.4% in the control group (odds ratio, OR = 0.88). Microfluidic sperm sorting improves embryological parameters, particularly blastulation rates, but has no statistically significant effect on the genetic status of preimplantation human embryos, leaving this topic open for further investigation.

Despite advances in tuberculosis treatment and prevention, tuberculosis remains a global health threat, responsible for an estimated 1.23 million deaths in 2024 [46], with continued concern over drug-resistant strains. In the Western Cape, South Africa, co-infection of tuberculosis and HIV is a significant public health concern contributing to a higher burden of disease.&#xa0;We compared the transcriptomes of two genetically similar Beijing family strains of Mycobacterium tuberculosis under four different growth conditions, including oxidative stress, using three biological replicates for each isolate.&#xa0;We identified an operon containing genes involved in the biosynthesis of molybdenum cofactor that showed consistently lower levels of expression in the hypervirulent isolate. This pathway is known to play a critical role in numerous metabolic and redox processes, and its dysregulation could contribute to the observed differences in disease severity between the two isolates. The moa genes, which are involved in the biosynthesis of the molybdenum cofactor, have been previously linked to M. tuberculosis virulence through their essential role in redox metabolism and oxidative stress response.&#xa0;Our results support this hypothesis by identifying differential expression of the moa operon as a potential mechanism underlying the differences in disease severity between the two isolates. Furthermore, the minimal genetic differences between these isolates make them an ideal system for further study of this pathway and its contributions to tuberculosis pathogenesis.

Endometrial injury-related disorders, including intrauterine adhesions, thin endometrium, and chronic endometritis, are a major cause of female infertility. Conventional therapeutic approaches, primarily hormone therapy and surgical interventions, show limited effectiveness in patients with moderate to severe endometrial damage. In this context, regenerative medicine has emerged as a promising direction to overcome current therapeutic limitations and promote functional reconstruction of the endometrium. A comprehensive literature search was conducted across PubMed, Web of Science, Embase, and Scopus to identify relevant studies on endometrial repair and regenerative medicine. The search covered publications from January 2000 to August 2025. The following keyword combinations and MeSH terms were used: ("endometrial repair" OR "endometrial regeneration" OR "intrauterine adhesion" OR "Asherman syndrome" OR "thin endometrium" OR "chronic endometritis") AND ("mesenchymal stem cells" OR "platelet-rich plasma" OR "exosomes" OR "extracellular vesicles" OR "biomaterials" OR "hydrogel" OR "scaffold" OR "regenerative medicine"). Both basic science investigations and clinical studies were included to provide a comprehensive overview of current developments in the field. To minimize the risk of omission, the reference lists of included articles and relevant reviews were manually screened, and potentially pertinent studies were further evaluated. Inclusion criteria: (1) Original research articles or meta-analyses; (2) Focus on therapeutic interventions for endometrial regeneration; (3) Human clinical studies or mammalian animal models. Exclusion criteria: (1) Non-English articles, letters, conference proceedings, etc.; (2) Purely descriptive studies of endometrial physiology without therapeutic intervention, articles lacking quantitative data or sufficient methodological details. The screening process followed the PRISMA 2020 guidelines (Fig.&#xa0;1). After removing duplicates, 1936 records were screened by title and abstract, and 605 full-text articles were assessed for eligibility. Finally, 102 studies were included in this qualitative synthesis. This review provides a systematic synthesis of recent advances in cell-based therapies, cell-free approaches, and bioengineering strategies for endometrial repair. Evidence derived from different sources of mesenchymal stem cells, including bone marrow, umbilical cord, and endometrium, is comparatively evaluated alongside platelet-rich plasma and extracellular vesicles, with an emphasis on hierarchical assessment of evidence levels. Several critical issues are further examined. Current stem cell-based interventions are largely characterized by a broad reparative profile, yet precise targeting of key molecular mechanisms remains insufficient. To date, no studies have demonstrated the capacity to directly reverse suppression of signaling pathways such as the GZMA-PARD3 axis or to restore depleted regenerative stromal subpopulations, including IGFBP3&#x207a; cells. Clinical investigations of platelet-rich plasma exhibit substantial heterogeneity, which appears to stem mainly from the absence of standardized preparation protocols and the frequent reliance on surrogate endpoints, particularly endometrial thickness. However, the predictive value of endometrial thickness for live birth is limited, and its use as a primary endpoint may overestimate clinical benefit. Therefore, emphasis should shift toward patient-centered outcomes such as live birth rate. Concerns also arise regarding the degradation kinetics of biomaterials, as mismatches between material resorption and the cyclical regenerative dynamics of the endometrium may increase the risk of secondary adhesions. In addition, the actual delivery efficiency of microneedle-based systems within the enclosed and humid uterine environment has not yet been fully clarified. Based on this critical appraisal, we propose a translational framework that links mechanistic discovery with precision intervention. The importance of long-term follow-up is emphasized, with live birth rate regarded as a more clinically meaningful primary endpoint for evaluating therapeutic efficacy in endometrial regenerative medicine. Endometrial regenerative medicine is transitioning from empirical repair toward mechanism-informed reconstruction. Current evidence is dominated by short-term (<&#x2009;12 months), small-sample (n&#x2009;<&#x2009;50) exploratory studies with high interventional heterogeneity. Clinical translation will require unified preparation standards, individualized treatment strategies, and well-designed multicenter randomized controlled trials with live birth rate as the primary endpoint and minimum 2-year follow-up.

Deciphering how DNA sequence encodes gene regulation remains a central challenge in biology. Advances in machine learning and functional genomics have enabled sequence-to-function (seq2func) models that predict molecular regulatory readouts directly from DNA sequence, supporting variant effect prediction, mechanistic interpretation and regulatory sequence design. Despite strong performance on held-out genomic regions, generalization across genetic variation and cellular contexts remains inconsistent. In this Review, we examine how model architectures, training data and prediction tasks shape model behavior. We also synthesize how interpretability methods and evaluation practices have elucidated cis-regulatory organization and highlighted systematic failure modes, clarifying why strong predictive accuracy can fail to translate into robust regulatory understanding. Thus, we suggest that progress requires reframing seq2func models as continually refined systems, in which targeted perturbation experiments, systematic evaluation and iterative model updates are tightly coupled through artificial intelligence-experiment feedback loops, enabling self-improving models that progressively deepen mechanistic understanding and more reliably support biological discovery.

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Long non-coding RNAs (lncRNAs) regulate gene expression, chromatin organization, and cellular signaling. Although traditionally considered non-coding, 21% of the ~190,000 annotated lncRNA transcripts contain poorly characterized open reading frames with unknown function. We systematically identified lncRNAs encoding micropeptides (MPs) using integrated computational and experimental evidence. Expression profiles across 17 cancer types from The Cancer Genome Atlas (TCGA) were analyzed to identify cancer-associated and transitional lncRNAs (Tr-lncRNAs). Structural modeling using AlphaFold was further applied to predict folding. We identified 478 lncRNA genes encoding 1782 MPs (10-100 amino acids). These MPs exhibit distinct amino acid and dipeptide compositions and are enriched for specific 4-mer motifs compared with canonical proteins. A subset of lncRNAs, including TNN-AS1, PVT1, XIST, and SNHG family members, encode multiple MPs. Analysis across cancer stages identified 2399 Tr-lncRNAs, most of them were cancer type and stage specific. Among these, 314 highly confident MPs from 72 Tr-lncRNAs were further analyzed. Pan-cancer analysis suggested MP-like functions for Tr-lncRNAs such as LINC01234, HAND2-AS1, XIST, UCA1, and HOXA11-AS. While most MPs are predicted to be intrinsically disordered, 3D structural modeling revealed several MPs with stable folds, including ubiquitin-like and RNase H-like structures. Tr-lncRNA-derived MPs represent a previously underexplored class of potentially functional molecules associated with cancer clinical annotation and may serve as biomarkers for disease progression.

The lack of brain penetrant and biologically stable positron emission tomography reporter systems hampers the development of neurological disease models and the monitoring of gene delivery because existing approaches depend on endogenous receptors that vary unpredictably in pathology. HaloTag, a fully exogenous protein label that forms rapid and irreversible bonds with synthetic ligands, provides a modular platform for engineering reporter probes with defined chemical properties. Here we developed a fluorine-18-labelled small-molecule HaloTag ligand optimized for brain entry and covalent retention at the reporter. The tracer showed specific binding in human cells expressing HaloTag and enabled non-invasive imaging of viral gene transfer to striatal neurons in mice, with clear detection of reporter expressing tissue and rapid clearance from surrounding regions. Optical imaging confirmed viral distribution and reporter expression, and a transgenic model expressing HaloTag fused to a postsynaptic protein demonstrated detection of physiologically expressed intraneuronal targets. This system establishes a modular platform for validating preclinical models and quantifying gene expression in the living brain.

Characterising somatic mutation profiles in human breast cancer (HBC) is essential for understanding tumour progression and guiding therapeutic strategies. We performed genomic and transcriptomic analyses to profile the mutational landscape of HBC. In addition to our primary analysis of HBC, we conducted comparative genomic analyses to evaluate the extent to which these mutational processes are recapitulated in canine mammary tumour (CMT), a widely proposed translational model. APOBEC3 (A3)-associated mutations were extensive in HBC but largely absent in CMT, likely due to structural differences in A3 proteins and lower basal expression. Transcriptomic stratification of HBC by A3 activity uncovered that tumours with A3 activity showed a strong association with the PAM50-HER2-Enriched (HER2E) subtype, and FGFR4 was significantly correlated with the expression and enzymatic function of APOBEC3A/B. These findings demonstrate that CMT is an unsuitable model for A3-mediated mutagenesis, emphasising the need to consider the limitations of cross-species mutational modelling in comparative oncology. Moreover, this study identifies a potential regulatory association between FGFR4 and A3, offering insights into the underlying mechanisms of A3-driven mutagenesis and suggesting that the FGFR4-A3 activity could be considered alongside other molecular biomarkers for the classification of the HER2E subtype.