Search Results (19,676)

Background: Dedicator of cytokinesis 8 (DOCK8) deficiency is an autosomal-recessive combined immunodeficiency marked by severe cutaneous viral infections, atopy with elevated IgE, malignancy, and early mortality without hematopoietic stem-cell transplantation (HSCT). Foundational syntheses predate the current transplant era and biologic therapy. Objective: It aims to provide an updated individual-patient-data (IPD) synthesis of DOCK8 deficiency cases reported from 2017 to 2026. Methods: Following PRISMA 2020 and PRISMA-IPD guidance, we searched PubMed/MEDLINE (with full Boolean strings provided for Embase, Scopus, Web of Science and Cochrane CENTRAL) for reports with extractable individual data on confirmed DOCK8 deficiency. Two-stage screening, Murad-2018 risk-of-bias assessment, random-effects Freeman–Tukey pooled proportions (with a random-intercept logistic model as a sensitivity analysis), and reconstructed Kaplan–Meier analyses were performed. Results: Of 360 records, 56 full texts were assessed, and 41 studies were included; 29 provided individual data for 64 patients from 22 countries, and 12 contributed aggregate data. Sixty-three potentially eligible reports were paywalled and could not be retrieved, and non-English reports were excluded, introducing possible retrieval and language bias. Consanguinity was reported in 40/43 (93%); the genotype spectrum was dominated by large deletions and splice/intronic variants. Eczema (72%), cutaneous viral infection (80%) and bacterial infection (64%) predominated. The pooled proportion alive at last reported follow-up was 87.3% (95% CI 81.1–92.6); this is a cross-sectional proportion over variable follow-up and is not a long-term survival estimate, as reconstructed age-specific Kaplan–Meier survival fell to approximately 53% by age 20 (exploratory analysis). Pooled malignancy prevalence was 10.6% (95% CI 3.4–20.7; I² = 66%), and pooled post-HSCT survival was 86.3% (95% CI 79.0–92.5). Conclusions: Contemporary reports reaffirm the severe infectious and malignant burden of DOCK8 deficiency and support HSCT as definitive therapy, alongside emerging biologic (dupilumab, siltuximab) and gene-directed strategies. Findings are constrained by reporting, retrieval and language bias and by reconstructed IPD; completion of the planned multi-database searches and independent second-reviewer verification are ongoing to finalise the evidence base. Full article

Background: Endometriosis-associated ovarian cancers (EAOCs), encompassing clear cell (CC) and endometrioid carcinomas (EC), constitute distinct biological entities yet lack robust biomarkers for precise classification, prognostication, and therapeutic decision-making in women. Therefore, we aimed to describe novel biomarkers. Methods: In this study, we conducted an integrated transcriptomic analysis, powered by machine learning, to discover novel consensus biomarkers and delineate cancer hallmark signatures specific to EC and CC. Drawing on gene expression profiles from EAOC specimens, we merged differential expression analysis with LASSO regression and Random Forest classification to generate a reliable biomarker panel that effectively distinguishes EC from CC. Kaplan–Meier survival analyses and mutation analyses have been performed for selected biomarker genes. Results: Novel biomarkers, among others, the genes RPS28, EPAS1, ALKBH2, and DCLRE1A, uncover extensive transcriptional alterations tied to hypoxia signaling, oxidative stress, DNA repair, and metabolic reprogramming. Gene Ontology and pathway enrichment analyses revealed synchronized upregulation of epithelial–mesenchymal transition, TNF-α/NF-κB signaling, oxidative stress, hypoxia, and KRAS signaling pathways. Conclusions: Our work establishes novel exploratory transcriptomic candidates for innovative consensus biomarkers, yielding novel diagnostic and prognostic insights into EAOC and supporting further study of subtype-associated expression programs. The current study was designed primarily as an integrative computational investigation aimed at identifying candidate genes and molecular pathways distinguishing CC from EC. Full article

Vitiligo is an autoimmune depigmenting disorder characterized by marked heterogeneity in therapeutic response, both between patients and among lesions within the same individual. While current therapies primarily target interferon-γ (IFN-γ)-driven inflammation, clinical outcomes remain variable and frequently incomplete, suggesting that additional lesion-specific biological factors contribute to repigmentation potential. In this narrative review, we propose the concept of repigmentation competence to describe the capacity of an individual lesion to achieve clinically meaningful repigmentation under therapy. We hypothesize that this competence emerges from the interaction of four interconnected biological axes: (i) cytokine network and immune memory, (ii) local immune regulation, (iii) regenerative capacity, and (iv) microenvironmental permissiveness. A targeted search of PubMed/MEDLINE and ClinicalTrials.gov up to March 2026 was conducted to identify translational studies, mechanistic models, and clinical trials relevant to these pathways. Evidence was synthesized thematically with emphasis on cytokine-mediated mechanisms and their interaction with regenerative and tissue-context processes. The IFN-γ/CXCL9/CXCL10 axis and tissue-resident memory T cells (TRM) represent the most clinically validated drivers of disease persistence, as demonstrated by the therapeutic efficacy of JAK inhibitors, although immune suppression alone often fails to achieve complete or durable repigmentation. In contrast, regulatory pathways involving PD-1/PD-L1 signaling, regulatory T cells (Tregs), IL-10, TGF-β, and IL-2–based strategies remain biologically compelling but only partially translated into effective therapies. Regenerative capacity has also emerged as an important determinant of treatment response, with growing evidence supporting the role of melanocyte stem cell niches, follicular regeneration, and Wnt/β-catenin signaling. Accordingly, regenerative approaches such as non-cultured epidermal cell suspension (NCES) are increasingly being integrated into combination therapeutic strategies. The lesional microenvironment remains the least therapeutically developed axis despite growing experimental evidence supporting its importance in melanocyte survival and migration. Collectively, these observations suggest that the variable efficacy of current therapies may reflect different combinations of lesion-specific biological constraints. The emerging benefit of combination strategies may therefore derive not simply from additive effects, but from the simultaneous engagement of multiple axes involved in repigmentation competence. Our review supports a shift from a predominantly drug-centered model toward a lesion-oriented framework integrating immune, regenerative, regulatory, and microenvironmental determinants of response. Full article

Glioblastoma remains the most lethal primary malignancy of the central nervous system, and the modest gains achieved with maximal surgery, radiotherapy and temozolomide have not been matched by the immune checkpoint inhibitors and antigen-specific vaccines that reshaped the treatment of many extracranial cancers. The recurrent disappointment of these approaches has been attributed less to a single molecular lesion than to a confluence of obstacles: profound intratumoural heterogeneity, a densely immunosuppressive and myeloid-rich microenvironment, sequestration and exhaustion of conventional T cells, and the practical difficulty of delivering effectors across the blood–brain barrier. Against this background, γδ T cells have attracted interest as an unconventional effector population that recognises transformed cells through stress-associated and metabolic cues rather than peptide–major histocompatibility complex (MHC) complexes, that kills in an MHC-unrestricted manner, and that can be expanded from healthy donors for allogeneic, off-the-shelf use with little expectation of graft-versus-host disease. This narrative review examines, with a deliberately critical lens, the biological rationale and the experimental evidence for γδ T cell-based immunotherapy of glioblastoma. We summarise the developmental biology and functional subsets of human γδ T cells, the natural killer group 2 member D (NKG2D)-, DNAX accessory molecule 1 (DNAM-1)- and T-cell-receptor-dependent mechanisms through which they engage glioblastoma cells and glioma stem-like cells, and the in vitro and animal-model studies that underpin the field, taking care not to overstate efficacy that has so far been demonstrated only in preclinical or early-phase settings. We then weigh the principal opportunities—locoregional and repeated dosing, combination with chemoradiotherapy, checkpoint blockade and antibody-based redirection—against barriers that include limited persistence, uncertain intratumoural trafficking, donor and manufacturing variability, and the unsettled requirements of potency testing and trial design. We give particular weight to what becomes of γδ T cells inside a hostile tumour—the exhaustion-like dysfunction that follows chronic stimulation, the oxygen and glucose dependence of their effector programme, the interleukin-17-polarising signals generated by activated microglia and by genotoxic therapy, and the confounding effect of corticosteroids—together with the engineering and pharmacological strategies proposed to counter them. The first peer-reviewed phase 1 report of intracranially delivered, drug-resistant γδ T cells has now appeared and documents tolerability in a small, single-arm cohort without establishing survival benefit. Throughout, γδ T cells are presented as a biologically plausible but still investigational strategy whose clinical value will be determined by adequately powered trials rather than by mechanistic appeal alone. Full article

Background: Dental follicle cells (DFCs) are promising candidates for regenerative medicine due to their osteogenic potential. While the protein kinase C (PKC) inhibitor Gö6976 is known to enhance DFC differentiation, the underlying molecular mechanisms remain partially understood. Methods: A phosphoproteomic analysis of DFCs after 14 days of osteogenic induction was performed. Cells treated with osteogenic differentiation medium (ODM) were compared to those in control medium and ODM supplemented with Gö6976. Reactome pathway analysis identified the RhoGTPase signaling pathway as significantly regulated. This pathway was further validated using PCR arrays, Western blotting, and functional assays (ALP activity, Alizarin Red staining). The impact of RhoGTPase signaling was tested using inhibitors (NSC23766, Y27632, Rhosin) and the activator Geranylgeranyl pyrophosphate (GGPP). Results: Phosphoproteomic data highlighted RhoGTPase signaling as a regulatory node. While protein expression of RhoGTPases remained relatively stable, RhoA PCR arrays revealed significant transcriptional regulation after induction of osteogenic differentiation. However, functional inhibition via NSC, Y27632, or Rhosin did not significantly impair basal ODM-induced differentiation; however, Y27632 notably induced SOST expression. Conversely, activation of RhoGTPases via GGPP increased ALP activity and downregulated SOST, suggesting a supportive role of active Rho signaling during differentiation. Crucially, we demonstrated that Gö6976-enhanced mineralization is linked to the activation of RhoA and RhoB. This was confirmed by simvastatin-mediated regulation of Rho expression, which was fully reversed by simultaneous treatment with Gö6976. Furthermore, Rhosin effectively counteracted the pro-osteogenic effects of Gö6976 by inhibiting ALP activity and mineralization while inducing SOST, which is normally suppressed by Gö6976. Conclusions: These findings indicate that RhoGTPase signaling, particularly RhoA, is a critical downstream mediator required specifically for the Gö6976-enhanced osteogenic effect in DFCs. We conclude that Gö6976 exerts its stimulatory effect on mineralization by activating RhoGTPases and suppressing the osteogenesis inhibitor SOST, providing a context-dependent mechanism for accelerated differentiation rather than driving basal osteogenesis. Full article

Background and Objectives: Melissa officinalis (lemon balm) contains phenolic constituents with antioxidant and cytotoxic activities; however, evidence regarding aqueous leaf extracts in lung adenocarcinoma models and reconstructed human airway tissues remains limited. The novelty of the present study lies in the integrated evaluation of the same aqueous extract through phytochemical and antioxidant characterization, a three-dimensional reconstructed tracheobronchial tissue model, and complementary short- and long-term biological endpoints in A549 lung adenocarcinoma cells. Materials and Methods: Antioxidant activity was evaluated using the DPPH assay, total phenolic content (TPC) using the Folin–Ciocalteu method, and the targeted phenolic profile using UHPLC–MS/MS. EpiAirway^TM tissues were exposed to 1000 µg/mL extract for 24 h, and tissue metabolic viability was assessed using the MTT assay. A549 cells were treated with 20–1000 µg/mL extract for 24 h and evaluated using complementary metabolic, lysosomal, mitochondrial, morphological, membrane-integrity, and clonogenic endpoints. Results: The extract exhibited concentration-dependent DPPH radical-scavenging activity, with an estimated IC₅₀ of 1.37 mg/mL (95% CI: 1.00–1.88 mg/mL), and a TPC of 10.84 ± 0.03 mg GAE/g dry extract. The most abundant targeted analytes were the unresolved 3,5-dihydroxybenzoic acid/3,4-dihydroxybenzoic acid group (2.09 ± 0.60 µg/mL) and the p-coumaric acid/trans-p-coumaric acid group (1.31 ± 0.04 µg/mL). EpiAirway^TM tissue viability was 85.87% following exposure to 1000 µg/mL. In A549 cells, metabolic viability decreased to approximately 59% and 53% at 500 and 1000 µg/mL, respectively, whereas neutral red uptake declined to approximately 50% at 1000 µg/mL. Treatment was also associated with mitochondrial membrane depolarization, concentration-dependent cellular and nuclear alterations, apoptotic-like and necrotic staining patterns, and a reduction in clonogenic capacity to approximately 21% at 1000 µg/mL. Conclusions: The aqueous M. officinalis leaf extract exhibited measurable antioxidant activity, did not cause a marked acute reduction in EpiAirway^TM tissue metabolic viability under the single exposure condition tested, and produced concentration-dependent cytotoxic and sustained antiproliferative effects in A549 cells. These exploratory findings do not establish comprehensive respiratory safety, a specific cell-death mechanism, or tumor selectivity. Nevertheless, the integrated experimental approach supports further investigation using standardized multiple extract batches, matched malignant and non-malignant lung epithelial models, and quantitative molecular endpoints. Full article

Alzheimer’s disease (AD) is characterized by the excessive production and aggregation of β-amyloid (Aβ), which serves as key pathological features of disease progression. Although Humulus japonicus Siebold & Zucc. is a traditional medicinal plant rich in flavonoids and phenolic compounds, its specific anti-amyloidogenic constituents remain to be fully elucidated. This study evaluated the effects of the aerial parts of H. japonicus on Aβ production and aggregation, and identified its active constituents through bioassay-guided isolation. The 80% ethanolic extract of H. japonicus aerial parts significantly reduced soluble amyloid precursor protein β (sAPPβ) levels and BACE1 protein expression in Chinese Hamster Ovary cells stably expressing amyloid precursor protein (APP-CHO cells). Furthermore, it inhibited Aβ aggregation and promoted fibril disaggregation in Thioflavin T assays. Among the solvent-partitioned fractions, the ethyl acetate fraction exhibited the most potent anti-amyloidogenic activity and was subjected to chromatographic isolation, leading to the characterization of fourteen compounds (7 flavonoids, 2 phenolic acids, 2 sesquiterpenoids, and 3 phenylpropanoids). Specifically, luteolin 7-O-β-d-glucopyranoside (2), orientin (3), vitexin (5), vomifoliol (8), abscisic acid (9), and p-hydroxyphenylethyl-p-coumarate (12) significantly decreased sAPPβ levels, as well as BACE1 and Presenilin-1 protein expression. Meanwhile, luteolin 7-O-β-d-glucopyranoside (2), orientin (3), vitexin (5), and quercetin 7-O-β-d-glucopyranoside trimer (7) effectively reduced Aβ aggregation and enhanced the disaggregation of pre-formed Aβ aggregates. Collectively, luteolin 7-O-β-d-glucopyranoside (2), orientin (3), and vitexin (5) exhibited the most consistent dual inhibitory effects on both Aβ production and aggregation, supporting their selection as key marker compounds. Among the extracts prepared with varying ethanol concentrations, the 100% ethanol extract yielded the highest levels of these flavonoid glycosides and exhibited the strongest anti-amyloidogenic activity. These findings suggest that the aerial parts of H. japonicus and its constituent flavonoid glycosides represent promising natural resources for modulating amyloidogenic APP processing and Aβ aggregation in AD. Full article

Background: The treatment paradigm for relapsed/refractory (R/R) large B-cell lymphoma (LBCL) has undergone significant change with the advent of CD19-directed chimeric antigen receptor T-cell (CAR-T) therapies and CD20 × CD3 bispecific antibodies (BsAbs). Although both approaches have shown high response rates in single-arm studies, the absence of prospective randomized head-to-head comparisons has resulted in true clinical equipoise. Methods: A narrative synthesis was conducted, incorporating pivotal and updated phase 2 and 3 trial data, real-world evidence, and published meta-analyses. Results: In the second-line setting, CAR-T therapy demonstrates superior event-free survival, progression-free survival, and overall survival compared to standard-of-care chemo-transplant regimens. In the third-line setting, a pooled meta-analysis indicates significantly higher complete response rates for CAR-T compared with BsAbs, as well as superior 12-month progression-free survival. BsAbs provide immediate availability, greater accessibility, more favorable neurotoxicity profiles, and are feasible for frail or elderly patients. Real-world data show that BsAb complete response rates are consistently lower than those observed in clinical trials, whereas CAR-T real-world effectiveness closely aligns with pivotal trial outcomes. Emerging phase 3 data on fixed-duration and monotherapy bispecific regimens suggest that a genuine, if less mature, curative fraction may also be achievable among BsAb-treated complete responders. Conclusions: CAR-T therapy remains the standard of care for fit, eligible patients with R/R LBCL in second- and third-line settings with curative intent, providing superior depth and durability of response and a growing potential for long-term cure. BsAbs constitute a critical therapeutic alternative for patients ineligible for CAR-T, those with rapidly progressive disease, frail or elderly individuals, and as bridging strategies. A patient-centered, scenario-specific clinical decision framework is recommended. Full article

Prabchompoothaweep (PCT) is an anti-allergic remedy on the Thailand National List of Essential Medicines, traditionally used to relieve common colds and allergic reactions in Thai traditional medicine (TTM). However, the anti-allergic activity of PCT and its plant ingredients had not been characterized. We evaluated the acute and chronic oral toxicity of PCT ethanolic extract in rats and assessed its in vitro and in vivo anti-allergic activities. Activity in vitro was measured as inhibition of antigen-induced β-hexosaminidase release in RBL-2H3 cells and in vivo using an ovalbumin (OVA)-induced allergic rhinitis mouse model. The extract produced no mortality or signs of toxicity in either study. Several plant ingredients and the PCT extract inhibited β-hexosaminidase release more effectively than chlorpheniramine. In OVA-induced mice, PCT (75, 150, and 300 mg/kg) did not significantly lower OVA-specific serum IgE or IgG2a (OVA-specific IgG1 was likewise not reduced); however, it reduced inflammatory cell infiltration, goblet cell hyperplasia and mast cell numbers in the nasal mucosa and downregulated the T helper 2 (Th2) cytokines IL-5 and IL-13. These findings support the traditional anti-allergic use of the PCT remedy. Full article

Synthetic antioxidants are attracting more interest as research moves beyond their traditional use as preservatives in food and materials. Recent studies are exploring how these redox-active molecules might be used in medicine. This review looks at how synthetic antioxidants are made, what is known about their biological effects, and the challenges of using them for neuroprotection, cancer treatment, organ protection, and regenerative medicine. In this review, synthetic antioxidants are defined as synthetic or semisynthetic small molecules with redox activity. Other antioxidant systems, such as non-phenolic molecules, prodrugs, peptides, metal complexes, nanocarriers, nanozymes, and biomaterials, are mentioned as related but are not considered classic synthetic antioxidants. Some of these compounds and delivery systems have shown promising results in cell, tissue, and animal studies. They have been found to influence neuroinflammation, mitochondrial function, and tumor redox responses, and to protect tissues from ischemic or inflammatory damage. However, most of these candidates are still in preclinical development. Progress is slowed by issues such as inconsistent bioavailability, dose-dependent toxicity, unclear mechanisms of action, a lack of reliable biomarkers, and manufacturing or regulatory challenges, especially for advanced delivery systems. New research highlights the potential of hybrid molecules, organelle-targeted delivery, and systems that respond to specific triggers. Still, there is not enough strong clinical data to support these approaches. Moving forward, the field will need thorough pharmacological studies, careful safety checks, standardized ways to measure effectiveness, and well-designed clinical trials. Full article

Background: Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal cancers, with a five-year survival rate of less than 12%. Oncolytic viruses are considered a promising immunotherapeutic approach, but their effectiveness is often limited by the innate interferon response, which is the main antiviral barrier in resistant tumors. A combination of an oncolytic virus with JAK/STAT pathway inhibitors has been proposed to overcome this resistance. Methods: In this study, we investigated the oncolytic and immunotherapeutic potential of the attenuated yellow fever vaccine strain YFV 17D in combination with the JAK1/JAK2 inhibitor ruxolitinib in a panel of six PDAC cell lines with diverse genetic profiles and JAK/STAT signaling activities and in a syngeneic immunocompetent PAN02 mouse model. Results: In vitro, we identified three distinct response patterns: synergistic enhancement of viral replication and cytopathic effect, lack of synergism due to absent interferon signaling, and increased viral replication without cytopathic effect. Despite different cell mutation profiles, the cell response patterns were determined by the basal JAK/STAT activity of each cell line rather than by specific KRAS or TP53 mutation. In vivo, the combination therapy significantly extended median survival compared to YFV 17D monotherapy and the control group and induced tumor regression in 62.5% of animals. Since no difference in intratumoral viral RNA was detected between the combination and monotherapy groups, we suggest that the antitumor effect in vivo was mediated not by enhanced viral replication, but by activation of adaptive immunity. This is indirectly suggested by increased intratumoral IL-12, a fourfold increase in CD8⁺ T cell infiltration, a reduction in CD4⁺ cells, and the generation of virus-neutralizing antibodies. No systemic cytokine surge, neurovirulence, or viral dissemination was observed, suggesting the safety of the proposed regimen. Conclusions: These findings clarify the immune mechanisms determining the efficacy of YFV 17D combined with ruxolitinib and establish the basis for personalized patient stratification by tumor interferon signaling status. Full article

Objectives: Renal ischemia–reperfusion (I/R) injury is one of the most important pathological triggers of acute kidney injury. This study aimed to investigate the protective effects of meloxicam, a selective cyclooxygenase-2 (COX-2) inhibitor, against renal I/R injury through specific cell death pathways including inflammation, apoptosis, necroptosis, and the MAPK/ERK pathway, which is potentially linked to regulated cell death mechanisms such as ferroptosis. Methods: Male Wistar Albino rats weighing 280–300 g were used in the study and were divided into four groups: Sham, IR (40 min ischemia + 120 min reperfusion), Meloxicam + IR, and Meloxicam + IR1. Bilateral renal ischemia was induced for 40 min via a retroperitoneal approach under anesthesia. Meloxicam was administered intravenously at a dose of 1 mg/kg at the initiation of reperfusion in the Meloxicam + IR group, whereas in the Meloxicam + IR1 group, the same dose was administered 1 h after the onset of reperfusion. Total reperfusion time was 120 min in both groups. Renal function parameters (BUN and creatinine) and oxidative stress markers (TAS and TOS) were measured. Inflammatory cytokines (IL-6, IL-1β, and IL-10), the glomerular filtration injury marker Cystatin C, the tubular injury marker KIM-1, the apoptotic marker Caspase 3, the necroptosis markers RIPK3 and MLKL, and MAPK signaling pathway alterations (ERK1/2 and pERK1/2 levels) associated with cellular survival and death signaling were evaluated. Results: Most notably, meloxicam markedly modulated apoptosis, the expression of necroptosis markers RIPK3 and MLKL, and the activation of pERK1/2, a key node in MAPK signaling that is regulatory in cell survival and cell death processes. The drug also suppressed pro-inflammatory cytokines (IL-6 and IL-1β) while preserving anti-inflammatory IL-10 levels. Furthermore, improvements were observed in the levels of KIM-1, a marker of tubular injury, and Cystatin C, a marker of glomerular filtration impairment. Consequently, meloxicam administration significantly reduced the elevated serum creatinine and TOS levels observed in the IR group, although serum BUN levels remained without notable alteration. Conclusions: The findings of this study suggest that meloxicam may extend beyond its role as a classical anti-inflammatory agent, potentially offering biochemical and functional protection against renal I/R injury in association with the modulation of specific cell death mechanisms, including necroptosis and apoptosis, as well as the MAPK signaling pathway. Full article

Background: Peripheral neuropathy (PN) is one of the most common disorders of the peripheral nervous system, affecting around 10% of the general adult population. PN results in pain, paraesthesia, and sensory loss, negatively impacting patients’ quality of life. The condition is characterised by damage to peripheral nerves and is often linked to risk factors, among which diabetes is the most common cause. The incidence rate of patients suffering from PN has significantly increased in the last three decades, yet there are currently no pharmacological treatments to reverse or prevent the development of PN. Therefore, neurotropic B vitamins, specifically vitamins B1, B6, and B12, which are essential for protecting nerves from damage, nerve regeneration, and maintaining nerve health, are promising treatment options. Other biofactors with therapeutic potential are vitamin D3, which has been described as a regulator of neuroplasticity and neuroinflammation with indications to promote neuronal regeneration following injury, as well as alpha-lipoic acid (ALA), a well-described treatment option in PN. Methods: The regenerative capacity of vitamins B1, B6, B12, and D3 and ALA was determined following neurite degeneration in vitro induced by either hydrogen peroxide (H₂O₂) or homocysteine. Results: In line with previous studies, the results show that a combination of vitamins B1, B6, and B12 has a significantly better effect on neurite extension following homocysteine-induced degeneration. In H₂O₂-insulted neural cells, the combination of all three neurotropic B vitamins was also shown to be superior to that of individual B vitamin treatment, demonstrated by longer neurite length after insult. Vitamin D3 also demonstrated a neuro-regenerative effect on neurites in healthy and insulted neural cells, whereas ALA only appears to provide a protective effect, preventing ongoing damage and supporting neurite outgrowth in healthy cells. No synergistic effects were seen with any treatment combinations. Conclusions: We have established an in vitro model of homocysteine-induced degeneration, and using this model alongside H₂O₂-induced degeneration, we provide evidence of the neurite regenerative capacity of vitamins B1, B6, B12, and D3. Full article

Electrochemical reactions in proton exchange membrane fuel cells (PEMFCs) predominantly occur within the membrane electrode assembly (MEA), dictating power output and lifetime. As a key functional component of the catalyst layer (CL), ionomer plays a decisive role in establishing effective three-phase boundaries, maintaining proton-conducting networks. While the impact of ionomer-to-carbon (I/C) ratio on MEA performance has been recognized, its coupled effect on durability remains underexplored. Herein, MEAs with I/C ratios ranging from 0.4 to 1.2 were fabricated, and the influence of ionomer content on performance and durability was systematically investigated through microstructural characterization, electrochemical measurement, and accelerated stress testing. Results reveal distinct trade-offs: insufficient ionomer impairs proton transport and durability, while excess ionomer hinders mass transport and electrochemical performance but helps maintain CL stability. Specifically, an I/C ratio of 1.2 exhibits the highest durability but the lowest performance. An I/C ratio of 0.8 achieves the optimal peak power density (1156 mW cm^–2) while maintaining good durability, superior to lower I/C ratios. Balancing performance and durability, an I/C ratio of 0.8 emerges as the optimal choice. This work provides both experimental evidence and mechanistic insights into the influence of ionomer content in CL, offering guidance for the design of high-performance and durable PEMFCs. Full article

Background: Cellular senescence exerts a complex influence on BRCA progression and TME remodeling. However, the specific roles of ASIGs in regulating the TME and determining patient outcomes remain unclear. Methods: Using TCGA (training), METABRIC (validation), and single-cell RNA-seq datasets, we systematically characterized ASIGs in BRCA. Prognostic ASIGs were identified to define molecular subtypes and construct a 17-gene LASSO-Cox risk model, which was integrated with clinical factors to develop a prognostic nomogram. Microenvironmental features and cell–cell communication networks were deconstructed using computational deconvolution and single-cell algorithms (SCISSOR and CellChat). Results: We established a robust 17-gene ASIG-based prognostic signature that effectively stratified BRCA patients into high- and low-risk groups and served as an independent prognostic predictor (HR = 3.94, p < 0.001). The nomogram accurately predicted 1-, 3-, and 5-year overall survival. Notably, the two risk groups exhibited strikingly distinct TME landscapes. The low-risk group was characterized by a coordinated, B cell-centric immune network, whereas the high-risk group displayed T cell exhaustion and immunosuppressive myeloid infiltration. Conclusions: The ASIG-based prognostic risk model is independent of traditional clinicopathological factors, providing a robust tool for patient risk stratification and offering biological insights into senescence-driven microenvironmental remodeling. Full article