Pharmacogenetics is pivotal in modern HIV management, facilitating the transition from the traditional "one-size-fits-all" model toward personalized precision medicine. By analyzing how unique genetic profiles influence pharmacological responses, clinicians can maximize therapeutic efficacy while minimizing toxicities and adverse drug reactions. Given the high interindividual variability in antiretroviral drug exposure and the necessity for lifelong treatment, identifying key genetic biomarkers is essential to optimize patient safety, treatment adherence, and overall quality of life.

In situ glia-to-neuron conversion induced by a single transcription factor is a promising regenerative strategy for treating central nervous system injuries and neurodegenerative diseases. Previous studies reported that NeuroD1 can induce microglia-to-neuron cross-lineage conversion and improve recovery after brain injury. However, these findings remain controversial. To examine the ability of NeuroD1 in inducing microglia-to-neuron conversion, we employed virus-free genetic lineage-tracing systems in mice to specifically induce NeuroD1 expression in microglia and track the cell fate of NeuroD1-expressing cells at multiple timepoints. Meanwhile, we longitudinally monitored NeuroD1-expressing microglia via two-photon imaging and characterized their transcriptional profile by single-cell RNA sequencing. All observations across these methods revealed that NeuroD1-expressing cells retained their microglia identity and cannot convert into neurons, no matter under physiological and injury conditions. Instead, sustained expression of NeuroD1 facilitated microglia apoptosis in vivo. Collectively, our findings provide strong evidence that NeuroD1 alone is not sufficient to induce microglia-to-neuron conversion. This study further highlights the importance of rigorous lineage-tracing and cell fate-mapping strategies for validating in situ glia-to-neuron conversion.

Understanding how stromal and immune cells regulate tumor mechanics is essential for deciphering cancer progression and therapy resistance. This study presents a microparticle-based traction force microscopy strategy for in situ quantification of compressive forces within 3D tumor spheroids. Multicellular spheroids composed of tumor cells (T), fibroblasts (F), and macrophages (M) were generated to mimic the tumor microenvironment and to understand the contribution of fibroblast-macrophage crosstalk in tumor mechanobiology. Tri-culture spheroids exhibited the highest proliferative capacity compared to mono- and bi-cultured tumor spheroids. Gene expression profiling indicated strong fibroblast activation, extracellular matrix remodeling, and M2-like macrophage polarization, highlighting a pro-tumoral phenotype. Incorporation of deformable hydrogel microparticles allowed direct mapping of local compressive and indirect quantification of anisotropic stresses. This mapping revealed fibroblasts are the principal source of force generation with the spheroids. Notably, macrophages amplified bulk and anisotropic stresses over two-fold through paracrine activation of fibroblasts. Spatial mapping showed pressure gradients from the core to the periphery, while temporal analyses demonstrated a progressive increase in mechanical stresses with spheroid growth. Together, these findings reveal a surprising governing of intratumoral mechanics by macrophage-fibroblast interactions and demonstrate the potential of microparticle-based 3D force mapping within complex tumor environments.

We determine how innate immunity adapts to transitions between fasting and feeding. Feeding rapidly induced periprandial neutrophilia. HFD accelerated this reponse. We therefore sought to examine whether periprandial states regulate neutrophil dynamics. We identified that the glucagon-like peptide 1 and insulin axis modulates the neutrophil surge, which is critical during endotoxin challenges. The periprandial state prepares the host for endotoxemia. We bridge nutrient intake and incretin-sensitive immunity to inflammatory tone, redefining postprandial inflammation, insulin resistance, and cardiometabolic risk in diabetes.

Copyright: © 2026 El-Deiry et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The WIN Consortium International Molecular Tumor Board brings together precision oncology experts from 18 organizations in 13 countries across four continents and provides discussion for patients with cancer across the world. This case report details the medical journey of a 55-year-old man diagnosed with high-grade glioblastoma (GBM), characterized by amplifications of MDM2 and EGFR, alongside other critical genomic alterations, including a CDKN2A frameshift mutation. Despite the aggressive nature of GBM, the patient was in remission following a combination of radiotherapy and chemotherapy, surgery and participation in a phase II clinical trial (PI3K/mTOR inhibitor) combined with ketogenic diet and metformin. However, the patient was also considering personalized neoantigen vaccine therapy targeting tumor-specific mutated peptides as part of his treatment strategy. This case underscores the immense complexity of treating GBM. Next generation sequencing showed MDM2 amplification, which hinders the tumor-suppressive functions of p53, and EGFR amplification, which promotes oncogenic signaling. The experts highlighted various therapeutic options discussed in the event of relapse: EGFR inhibitors, various MDM2 inhibitors, and personalized combination therapies targeting both EGFR and CDK4/6. Additionally, the Molecular Tumor Board discussed the reported risk of resistance or hyper-progression with immune checkpoint blockade in the presence of EGFR and MDM2 alterations. Innovative approaches such as combining MDM2 and EGFR inhibitors with immunotherapy, as well as the use of teserpaturev, a genetically engineered herpes simplex virus were addressed. This case emphasizes the importance of personalized treatment strategies for GBM and the need for ongoing clinical research to explore novel therapeutic options.

Lecanemab is a humanized IgG1 monoclonal antibody that targets amyloid-β (Aβ) aggregates, a pathological hallmark of Alzheimer's disease (AD). In the largest clinical trial of its kind to date, lecanemab slowed cognitive decline by 27% in patients with early-stage AD. Lecanemab has also been shown to reduce cerebral Aβ deposition. Lecanemab expresses the immunoglobulin GM 3 allotype, which is defined by an arginine residue in the CH1 region of the γ1 chain and is potentially immunogenic in individuals who lack this allotype. I hypothesize that anti-GM 3 antibodies, generated either following lecanemab administration or acquired previously through maternal-fetal incompatibility or transfusion of allotype-incompatible blood products, may form immune complexes with the therapeutic antibody. These immune complexes could be cleared by phagocytic cells, including microglia, thereby reducing the availability and efficacy of lecanemab and contributing to therapeutic nonresponsiveness. If validated, GM allotypes could serve as genetic markers for predicting response to lecanemab therapy and may help guide personalized treatment strategies in AD.

Branch retinal artery occlusion (BRAO) is an extremely rare vascular event in the pediatric population. Unlike elderly patients, in whom atherosclerosis is the primary cause, BRAO in children and adolescents is often associated with systemic conditions, including hypercoagulation and genetic predisposition to thrombosis. Ophthalmoscopy and OCT revealed local ischemic retinal edema along the inferior temporal branch of the central retinal artery. Systemic examination and molecular genetic testing revealed combined genetic thrombophilia: heterozygous mutation of the MTHFR gene (A1298C) and homozygous PAI-1 polymorphism (4G/4G). There was also an increase in the level of D-dimer (0.65 µg/ml). The patient received comprehensive conservative therapy aimed at improving microcirculation in the retinal vessels, dilating capillaries, lowering intraocular pressure, stabilizing the rheological properties of blood, and enhancing neuroprotection. Despite the fact that the best-corrected visual acuity (BCVA) was restored to 1.0, there was a persistent absolute scotoma in the upper nasal quadrant, corresponding to the area of secondary atrophy of the inner retinal layers in the affected zone recorded on follow-up OCT. This case highlights the clinical importance of a multidisciplinary approach in the treatment of retinal vascular occlusions in children. BRAO in a child should be considered as a potential marker of serious systemic disease, in particular hereditary thrombophilia, which requires early intervention to prevent further complications.

Radiotherapy efficacy is constrained by tumor radioresistance, which arises in part from the interplay between reactive oxygen species (ROS) and epigenetic regulation. This review systematically synthesizes the bidirectional "epigenetics-ROS interactive network" that governs tumor radiosensitivity. We propose that this network operates through three core principles: stress adaptation (acute ROS triggers transient epigenetic adjustments for redox recovery), malignant reinforcement (chronic ROS drives stable epigenetic reprogramming toward therapy resistance), and contextual determinacy (cellular outcomes depend on integrated ROS-epigenetic patterns rather than individual signals). Mechanistically, we delineate four regulatory layers including DNA methylation, histone modifications, non-coding RNAs, and chromatin remodeling, through which the epigenetic machinery controls ROS homeostasis, and conversely, how radiation-induced ROS reshape the epigenetic landscape via oxidative modification of epigenetic enzymes and signaling pathways. These bidirectional interactions form feedback circuits that ultimately dictate whether cells undergo repair, senescence, apoptosis, or ferroptosis. Based on this mechanism, we propose a context-dependent decision framework that matches four distinct combination strategies (ROS amplification, epigenetic priming, hypoxia relief, and multi-pathway cell death induction) with four tumor subtypes defined by their oxidative and epigenetic profiles. We also identify five translational roadblocks including toxicity, delivery inefficiency, manufacturing scalability, regulatory uncertainty, and preclinical-clinical discordance. Resolving these barriers is essential for unlocking the therapeutic potential of this regulatory axis. Strategically targeting the epigenetics-ROS network offers a transformative paradigm for overcoming radioresistance and personalizing cancer radiotherapy.

Pancreatic ductal adenocarcinoma (PDAC) remains a lethal malignancy with limited targeted therapeutic options. Mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) has been implicated in PDAC progression, but the development of effective MAP4K4 inhibitors requires further improvement in potency, selectivity, and mechanistic characterisation. We previously identified F389-0746 as a selective benzoxazine-based MAP4K4 inhibitor with anti-cancer activity in pancreatic cancer. Here, we used the F389-0746 scaffold to guide the selection and evaluation of benzoxazine-based analogs, followed by biochemical, structural, selectivity, and cellular characterisation of the most potent analogue. Among the identified analogs, F389-0736 showed the strongest MAP4K4 inhibitory activity, with an IC50 value of 44.0 nM, representing an approximately threefold improvement over F389-0746. Docking and structure-activity relationship analyses identified key binding interactions that support the enhanced potency of F389-0736 within the MAP4K4 binding pocket. Kinase profiling further demonstrated the selectivity of F389-0736 for MAP4K4 across the tested kinase panel. CETSA further demonstrated F389-0736-induced thermal stabilisation of MAP4K4, supporting intracellular target engagement. In pancreatic cancer cells, F389-0736 suppressed TAK1, JNK, and p38 phosphorylation and significantly reduced cell viability and proliferation, with IC50 and GI50 values of 4.41-4.65 μM and 4.03-5.12 μM, respectively. F389-0736 also inhibited clonogenic growth and induced sub-G1 accumulation with activation of apoptotic signalling. RNA sequencing identified 398 differentially expressed genes and revealed enrichment of inflammatory and stress response pathways, programmed cell death programs, oncogenic signalling perturbation, and metabolic reprogramming. These findings identify F389-0736 as a potent and selective benzoxazine-based MAP4K4 inhibitor and support its use as a chemical probe and lead scaffold for investigating MAP4K4-dependent signalling and therapeutic vulnerability in pancreatic cancer.

The eye is well suited to gene therapy because of its compartmentalized anatomy, accessibility for local delivery, and capacity for longitudinal assessment. In China, ocular gene therapy is undergoing rapid clinical translation, with expanding innovation in vector engineering, delivery technologies, genome editing, and therapeutic modalities. Clinical development has progressed from inherited optic neuropathies and retinal diseases to complex acquired ocular disorders, anterior-segment genome editing, and optogenetic vision restoration. This review summarizes the technological landscape and representative clinical advances of ocular gene therapy in China, highlighting the evolution from established gene-replacement approaches toward increasingly differentiated therapeutic strategies. We further discuss key challenges in interpreting clinical benefit and translating early clinical signals into durable, reproducible outcomes. Future progress will depend on clinically driven innovation, rigorous evidence of meaningful patient benefit, and standardized pathways for sustainable clinical translation.

A challenge of adeno-associated virus (AAV)-mediated gene therapy is the high prevalence of preexisting anticapsid antibodies, which can reduce vector efficacy and, after high-dose systemic administration, promote formation of antibody-vector complexes that activate complement. Complement-mediated toxicities reported after systemic AAV administration have generally been observed several days after dosing. However, observations in nonhuman primates (NHPs) suggested that complement activation may occur within minutes of vector exposure in the presence of anti-AAV antibodies. To characterize this response, we evaluated complement activation following repeat systemic administration of AAVrh.10 vectors in African Green monkeys and assessed early and delayed time points when NHPs were seronegative and seropositive for anti-AAV antibodies. Five NHPs received intravenous AAVrh.10 vectors (1 × 1013 gc/kg) administered 42 days apart. Three animals received AAVrh.10 expressing human C1 esterase inhibitor and two received a transgene-null vector. Serum samples were collected from 10 min to 42 days after the first administration and from 10 min to 21 days after the second. Complement activation was assessed by measuring serum terminal complement complex (TCC) levels and anti-AAVrh.10 immunoglobulin G (IgG) titers were used to monitor humoral immunity. Vector administrations were well tolerated, with no treatment-related abnormalities. Following the initial dose, all animals developed robust anti-AAVrh.10 IgG responses that increased after readministration. No significant complement activation was observed after the first administration. In contrast, in the presence of anti-AAVrh.10 antibodies, all animals demonstrated rapid increases in TCC within 10 min of the second administration, reaching 10-fold above baseline and returning to baseline by 1 day. Complement activation was observed in animals with antivector titers >1/104, whereas little or no response was detected at titers <1/103. These findings identify rapid, transient complement activation as an underrecognized response to systemic AAV administration in the presence of anti-AAV antibodies and support complement monitoring during the first hour after vector dosing in clinical gene therapy studies.

This study evaluated whether three-dimensional (3D) bioprinted spherical, porous poly-L-lactic acid (PLLA) drug- loaded implants, combined with bone marrow mesenchymal stem cells (BMSCs) overexpressing transforming growth factor-β1 (TGF-β1) and interleukin-10 (IL-10), can enhance the repair of osteoarthritis (OA)-related cartilage defects. Rat BMSCs were transduced with lentiviral vectors to achieve dual overexpression of TGF-β1 and IL-10, induced toward chondrogenic differentiation, and assessed for chondrogenic marker expression (COL2A1, SOX-9, and aggrecan). Spherical porous PLLA drug-loaded implants were fabricated by 3D bioprinting and characterized for drug loading, porosity, cytocompatibility, skin sensitization, biodegradation, and in vivo release behavior. Histology, micro-computed tomography (micro-CT), and molecular assays evaluated cartilage repair and subchondral bone remodeling. Dual-gene transduction markedly promoted BMSC chondrogenic differentiation with significant up-regulation of COL2A1, SOX-9, and aggrecan. The PLLA scaffolds exhibited high porosity (88.88 ± 2.87%), meeting biomaterial requirements, showed no evident cytotoxicity or skin sensitization, and achieved a 12-week mass-loss (biodegradation) of 42.65%. In vivo, the combined treatment group displayed superior cartilage regeneration and subchondral bone repair compared with controls, accompanied by increased BMP2 and type II collagen (COL-2) expression. 3D-bioprinted porous PLLA drug-loaded implants combined with TGF-β1/IL-10 dual-gene-transduced BMSCs effectively promote repair of OA cartilage defects, indicating satisfactory biocompatibility and potential for clinical translation.

Epithelioid inflammatory myofibroblastic sarcoma is an extremely rare and aggressive variant of inflammatory myofibroblastic tumor, characterized by high mitotic activity, epithelioid cell morphology, and the expression of muscle markers and ALK protein resulting from ALK gene fusions. For many years, inflammatory myofibroblastic tumors of the uterus remained poorly studied and were often misdiagnosed as leiomyoma, leiomyosarcoma, or endometrial stromal sarcoma. In the latest WHO Classification of Tumors of the Female Reproductive System (2020), this entity has been assigned to a separate category based on its distinct morphological and molecular-genetic features. Epithelioid inflammatory myofibroblastic sarcoma represents an exceptionally rare variant of inflammatory myofibroblastic tumor in the female genital tract. ALK gene rearrangements are characteristic for inflammatory myofibroblastic tumors and provide opportunities for targeted therapy with ALK inhibitors. This article presents a rare clinical case of uterine inflammatory myofibroblastic sarcoma. The case highlights the importance of accurate morphological and molecular verification of the diagnosis and demonstrates the effectiveness of second-generation ALK inhibitors in managing aggressive forms of inflammatory myofibroblastic tumors of uterine localization.