Abstract Despite innovative progress, cellular therapies have not produced durable, population-level survival gains in glioblastoma. Across 3 major modalities, engineered effectors such as chimeric antigen receptor T cell (CAR-T) and natural killer (NK) cells, immune-education platforms such as dendritic and whole-cell vaccines, and carrier cells delivering oncolytic or drug payloads, trials have shown measurable bioactivity, but durability has varied. This likely reflects systemic barriers, including therapy-induced lymphopenia, myeloid dominance, and T-cell sequestration, as well as local barriers such as antigen heterogeneity and immune suppression. To understand why some studies nevertheless showed more favorable efficacy signals, we reviewed clinical outcomes across these modalities and identified 4 recurring design features that appeared repeatedly among studies reporting more favorable survival signals: treatment in the minimal residual disease setting, a T-helper type 1 supportive context, broadened antigenic coverage, and effective immune hand-off from the initiating therapy to endogenous or adoptively transferred effectors. Across heterogeneous early-phase studies, greater feature alignment sometimes co-occurred with more favorable signals, although this retrospective pattern is descriptive and does not establish association or causality. These observations may help guide future biomarker-informed strategies and provide a practical framework for organizing multimodal trials aimed at converting transient bioactivity into more durable, polyclonal control.
Early cortical differentiation in human brain organoids is a critical step of corticogenesis, but remains poorly coordinated under conventional culture conditions. In a standard orbital shaker system, mechanical shear and variability in extracellular matrix support, can disrupt neuroepithelial organisation, leading to inconsistent early cortical differentiation. Here, we investigated how ClinoStar-associated low-shear culture conditions affect early corticogenic marker expression in brain organoids and examined GFRA1/RET-related signaling as a candidate pathway associated with these culture-related effects. Using a low-shear ClinoStar bioreactor, we observed improved neuroepithelial-like expansion, enhanced tissue organisation, and promoted early cortical differentiation during the neuroepithelial expansion stage. Compared with conventional conditions, low-mechanical shear in ClinoStar was associated with increased proliferation capacity and supported the number of TBR2+ intermediate progenitors and TBR1+ early cortical neurons. Transcriptomic analysis revealed enrichment of neuronal differentiation and neuroactive ligand-receptor interaction pathways, with increased upregulation of GDNF signalling components under reduced mechanical shear. Functional experiments showed that GDNF supplementation increased TBR2+ intermediate progenitor-associated and TBR1+ early neuronal marker-related populations in brain organoids, suggesting a positive effect on early corticogenic marker expression. Consistent with this, GFRA1/RET levels were elevated in organoids in the ClinoStar culture with low-mechanical shear stress, and manipulation of GFRA1 affected early cortical differentiation outcomes. These findings suggest that ClinoStar low-shear culture promoted early corticogenic marker expression, potentially associated with GDNF-GFRA1/RET signalling. Collectively, this study provides a refined culture framework for improving the reproducibility and structural organisation of human brain organoid models of early cortical differentiation.
Retractions of published journal articles are an increasingly common means by which the research community ensures the quality and integrity of publications and addresses research misconduct missed during pre-publication peer review. Retractions are intended to notify the public of issues that undermine the integrity of these publications so that readers will not rely on their findings and conclusions. Continued citation and other uses of these publications without acknowledging their retracted status are therefore problematic and suggest shortcomings in retraction processes. In this commentary, we use the examples of retracted articles published in this journal to outline ways in which retracted articles can maintain an influential afterlife in the academic literature, online materials from non-profit organizations and private businesses, and responses from generative artificial intelligence. Given that this ongoing influence compounds the harms of these publications, we recommend changes in how publishers manage article retractions. These changes include ensuring that article retraction notices are maintained when journal publishing agreements change, increasing the visibility of retractions, and notifying scholars and members of the public when an article they reference is retracted. While these changes will make article retractions more effective, there is a continued need to limit the publication of studies that violate the requirements of research integrity.
Epilepsy represents as one of the most prevalent and serious neurological disorders, with approximately one-third of patients resistant to conventional treatments. Current pharmacologic therapies primarily suppress seizures without targeting the underlying epileptogenesis, resulting in unchanged long-term prognosis. At the same time, epilepsy surgery remains underutilized due to the requirement for extensive evaluations and specialized expertise. Stem cell-based therapy has emerged as a promising avenue, offering the potential to address both the neurological and neuropsychiatric aspects. This review summarizes recent preclinical and clinical studies on stem cell therapy in epilepsy, with a focus on their mechanisms of action, including direct engraftment, restoration of normal neurogenesis, and immunomodulation via bystander effect. Advances in genetic engineering, extracellular vesicle-based therapy, and patient-derived brain organoids offer more personalized treatment strategies. Although stem cell therapy holds significant promise as a treatment for epilepsy, further extensive research is required to establish its clinical safety and efficacy.
INTRODUCTION:Human corneal stromal stem cells (hCSSCs), which exhibit mesenchymal stem cell (MSC) features, prevent fibrotic scarring and promote regeneration of injured stromal tissue, thereby restoring corneal clarity in mice. These therapeutic effects rely on hCSSCs' ability to respond to early inflammatory cues, suppress chronic neutrophil infiltration, and inhibit fibrosis. In this study, we examined the responses of hCSSCs to transient pro-inflammatory M1 stimulation and characterized the exosomes (Exo) they secreted. METHODS:We evaluated the expression of full-length protein-coding human TGFB3 mRNA molecules in purified Exo, and investigated Exo uptake, induction of human transforming growth factor β3 (hTGFβ3) protein expression, and the effects of different hTGFβ3/β1 ratios on myofibroblast generation from human corneal stromal keratocytes (CSKs) and stromal fibroblasts (SFs). The anti-scarring effect of hCSSC-Exo enriched in TGFB3 mRNA was assessed in a mouse model of acute corneal stromal injury. RESULTS:Our results showed that hCSSC-Exo contained TGFB3 mRNA transcripts, and their abundance increased following pro-inflammatory M1 stimulation. Exo uptake enhanced hTGFβ3 protein expression in hCSKs, and a higher hTGFβ3/β1 ratio in hCSKs and hSFs suppressed expression of α-smooth muscle actin and TGFβ1-induced myofibroblast differentiation. In vivo, topical treatment with M1-primed hCSSC-Exo reduced corneal opacity compared with sham-treated controls. Notably, hCSSC-Exo enriched with TGFB3 mRNA demonstrated greater scar-reducing and wound-healing efficacy. CONCLUSIONS:M1-primed hCSSC-Exo containing protein-coding TGFB3 mRNA significantly inhibited corneal opacity and promoted scar-free healing in injured mouse corneas. These findings support the anti-fibrotic and regenerative potential of hCSSC-Exo, which can be developed as a cell-free therapeutic strategy for corneal fibrosis and scarring.
