Search Results (43,268)

Background/Objectives: Allergic rhinitis (AR) is a complex immune-mediated disorder characterized by defective regulatory mechanisms. Emerging evidence suggests that impaired immune tolerance mediated by regulatory B cell (Breg) plays a pivotal role in AR pathogenesis. This study investigates the therapeutic potential of Der p1 allergen-modified dendritic cells (DC) in enhancing Breg-mediated immunotherapy and explores novel mechanisms underlying AR immunomodulation. Methods: Breg and the inflammatory cytokines were detected before and after allergen immunotherapy (AIT) in AR patients. Dust mite gene-derived dendritic cells were used to induce Breg. AR mice were treated with Der p1-DCs, and changes in Breg and related inflammatory indicators, as well as the impact of the IL-10/STAT pathway on DC vaccine treatment, were observed. Results: Following 6-month AIT, AR patients exhibited significant alleviation of nasal symptoms alongside restored peripheral Breg and Treg. In vitro co-culture of Der p1-DC-induced Bregs with CD4⁺CD25⁻T cells revealed that IL-10 blockade markedly increased Th cell. In AR murine models, intraperitoneal Der p1-DC administration suppressed allergic symptoms, upregulated nasal mucosal IL-10 expression, and attenuated STAT3 phosphorylation via IL-10 overexpression. Conclusions: AIT establishes immune tolerance through Breg-mediated regulatory mechanisms, while Der p1-DCs potently induce Breg differentiation and drive tolerance induction via the IL-10/STAT3 signaling axis. Full article

Background/Objectives: Patients with eosinophilic chronic obstructive pulmonary disease (COPD) often remain symptomatic despite optimized triple inhaled therapy. Dupilumab is a fully human monoclonal antibody that blocks the IL-4 receptor alpha subunit, thereby inhibiting IL-4 and IL-13 signaling. Evidence from randomized trials supports dupilumab for add-on treatment of type 2-high COPD, but data referring to short-term effectiveness in clinical practice are quite limited. Methods: We conducted an observational, compassionate-use study enrolling 13 consecutive outpatients with eosinophilic COPD (blood eosinophils ≥ 300 cells/µL) receiving add-on biologic therapy with dupilumab 300 mg every two weeks. Clinical (CAT, mMRC), functional (spirometry and body plethysmography), and inflammatory parameters (blood eosinophils/basophils, fibrinogen, FeNO) were evaluated at baseline and after four weeks of treatment. Safety was monitored after injection in a clinical setting, as well as via weekly phone follow-up. Results: Participants (84.6% male; mean age 67.08 ± 11.42 years) experienced rapid and clinically meaningful improvements at four weeks. CAT score decreased from baseline 21.40 ± 6.22 to 14.00 ± 5.58 (p < 0.001) and mMRC scale from 2.90 ± 0.73 to 1.80 ± 0.63 (p < 0.0001), respectively. Pre-bronchodilator FEV₁ increased from baseline 1.35 ± 0.65 L to 1.59 ± 0.84 L (p < 0.05), and FVC from 2.36 ± 0.92 L to 2.83 ± 1.11 L (p < 0.01). A marked lung deflation was observed: indeed, residual volume declined from baseline 4.17 ± 1.98 L to 3.47 ± 2.07 L (p < 0.05), with a concomitant reduction in specific effective airway resistance (from baseline 3.15 ± 1.77 to 2.43 ± 1.44 kPa·s; p < 0.05) associated with significant increases in mid-expiratory flow (FEF₂₅₋₇₅: from baseline 0.62 ± 0.38 to 0.86 ± 0.71 L/s; p < 0.05) and peak expiratory flow (3.80 ± 1.40 to 4.48 ± 1.79 L/s; p < 0.01). Type 2 inflammatory biomarkers changed as follows: blood eosinophil count fell from baseline 390.0 ± 43.75 to 190.0 ± 65.47 cells/µL (p < 0.001); blood basophil number decreased from baseline 37.50 ± 13.89 to 26.25 ± 13.02 cells/µL (p < 0.001); plasma fibrinogen lowered from baseline 388.4 ± 54.81 to 334.9 ± 72.36 mg/dL (p < 0.01); FeNO levels dropped from baseline 23.95 ± 18.10 to 14.00 ± 2.04 ppb (p < 0.0001). Dupilumab was well tolerated, and no treatment-related serious adverse events or discontinuations were detected. Conclusions: Within an exploratory context of daily medical activity referring to eosinophilic COPD already treated with maximal inhaled therapy, we found relevant therapeutic effects of a four-week add-on treatment with dupilumab. In particular, our patients manifested rapid improvements in symptoms, airflow limitation, and lung hyperinflation, paralleled by significant decrements of type 2 inflammatory signatures. Such encouraging results were associated with a favorable short-term safety profile. However, larger and longer studies are necessary to corroborate these preliminary findings. Full article

The brain’s extracellular matrix (ECM) serves as a dynamic and instructive regulator of glioma progression. The ECM provides structural support while integrating pharmacological and mechanical signals that influence glioma initiation, progression, and treatment resistance. Deviant ECM remodeling fosters tumor heterogeneity, invasion, and immune evasion by altering stiffness, composition, and cellular matrix signaling. We proposed that ECM remodeling in gliomas not only facilitates tumor growth and heterogeneity but also establishes advantageous biophysical and metabolic conditions that foster treatment resistance and recurrence. Our objective is to analyze current findings regarding the structural, biochemical, and mechanical roles of the brain ECM in glioma growth, emphasizing its contribution to tumor heterogeneity, mechanotransduction, immunological modulation, and its potential as a therapeutic target. Method: A comprehensive literature review was conducted using scientific databases including PubMed, Web of Science, and Scopus. Peer-reviewed literature published between 2000 and 2025 was selected for its relevance to ECM composition, stiffness, remodeling enzymes, extracellular vesicles, and mechanobiological processes in gliomas. Results: Recent investigations demonstrate that glioma cells actively alter the ECM by secreting collagens, laminins, and metalloproteinases, establishing a feedback loop that facilitates invasion and resistance. Discussion: Mechanical variables, such as ECM stiffness and solid stress, influence glioma growth, metabolism, and immune exclusion. Moreover, extracellular vesicles facilitate significant extracellular matrix remodeling and improve communication between tumors and stromal cells. The disruption of ependymal and subventricular extracellular matrix niches enhances invasion and cerebrospinal fluid-mediated signaling. The remodeling of the ECM influences glioma growth through interconnected biochemical, mechanical, and immunological mechanisms. Examining ECM stiffness, crosslinking enzymes, and vesicle-mediated signaling represents a potential therapeutic approach. Integrative methodologies that combine mechanobiology, imaging, and multiomics analysis could uncover ECM-related vulnerabilities to improve glioma treatment. Full article

Due to their therapeutic potential and effects on cells, exosomes derived from bovine colostrum (BCE) and milk (BME) are molecules that have been at the center of recent studies. Their properties include the ability to cross biological barriers, their natural biocompatibility, and their structure, which enable them to act as stable nanocarriers. Exosomes derived from milk and colostrum stand out in cancer prevention and treatment due to these properties. BMEs can be enriched with bioactive peptides, lipids, and nucleic acids. The targeted drug delivery capacity of BMEs can be made more efficient through these enrichment processes. For example, BME enriched with an iRGD peptide and developed using hypoxia-sensitive lipids selectively transported drugs and reduced the survival rate of triple-negative breast cancer (TNBC) cells. ARV-825-CME formulations increased antitumor activity in some cancer types. The anticancer effects of exosomes are supported by these examples. In addition to their anticancer activities, exosomes also exhibit effects that maintain immune balance. BME and BCE can regulate inflammatory responses with their miRNA and protein loads. These effects of BMEs have been demonstrated in studies on colon, breast, liver, and lung cancers. The findings support the safety and scalability of these effects. However, significant challenges remain in terms of their large-scale isolation, load heterogeneity, and regulatory standardization. Consequently, BMEs represent a new generation of biogenic nanoplatforms at the intersection of nutrition, immunology, and oncology, paving the way for innovative therapeutic approaches. Full article

Bee-derived products such as apitoxin, royal jelly, propolis, bee pollen, and honey are increasingly being used as part of cosmetic products because all of them contain a large number of bioactive compounds with antioxidant, anti-inflammatory, antimicrobial, and regenerative properties, which enable them to be used for therapeutic purposes. The aim of this investigation was to assess the performance of an automated growth-based system in order to make a quantitative examination of the total aerobic viable counts in bee-derived personal care products using NF-TVC vials that contained a nutrient-based medium with dextrose as the carbon source. According to USP general chapter <1223>, pivotal validation criteria such as linearity, equivalence of results, operative range, precision, accuracy, ruggedness, limit of quantification, and limit of detection have demonstrated that the automated system can be used for a reliable total aerobic viable count. Moreover, the actual research demonstrated that polysorbates efficiently block the antimicrobiological potential of bioactive compounds, such as phenols, flavonoids, enzymes, peptides, and fatty acids, which naturally occur in apitoxin, royal jelly, propolis, bee pollen, and honey, allowing for efficient microorganism recovery from the bee-made products tested. Therefore, this AGBS could be applied efficiently within the cosmetic industry to assess the total aerobic viable count in bee-derived products such as capillary treatments, toothpaste, and anti-aging cream, affording several benefits associated with faster product release into the market. Full article

Ovarian cancer is one of the deadliest gynecological malignancies, where most patients become clinically symptomatic at advanced stages of disease due to the lack of effective diagnostic screening. Despite recent advances in surgical resection and chemotherapy, recurrent ovarian cancer remains largely refractory to treatment, resulting in poor prognosis. The ovarian cancer tumor microenvironment (TME) is highly abnormal and presents a significant barrier to successful therapy. A combination of abnormal vasculature, desmoplastic extracellular matrix, and aberrantly activated hypoxic and immune-suppressive pathways culminates in promoting tumor growth, dissemination, chemoresistance, and immunosuppression. Whilst immune checkpoint inhibitors have shown success in other cancers, their application in ovarian cancer, particularly at advanced stages, remains limited. In this review, we discussed the application of tumor extracellular matrix normalizing therapies in preclinical models of advanced ovarian cancer, and their synergistic benefit to chemotherapy and immunotherapy. Collectively, these insights underscore TME normalization as a promising therapeutic strategy with the potential to improve ovarian cancer management. Full article

Parkinson’s disease (PD) is a common neurodegenerative disorder characterized by motor dysfunction and non-motor symptoms, including cognitive decline. Animal models that replicate PD’s clinical features are essential for therapeutic research. The widely used subacute 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP)-induced mouse model effectively mimics motor deficits but fails to fully represent aging-related non-motor symptoms. In this study, we established an aging-associated PD mouse model by combining MPTP with D-galactose treatment. Compared to mice treated with MPTP alone, MPTP + D-galactose-treated mice exhibited typical motor impairments alongside cognitive deficits in the Morris water maze and Y-maze tests. D-galactose alone induced cognitive impairment without motor dysfunction. Pathological analysis showed that the MPTP + D-galactose treatment caused tyrosine hydroxylase-positive neuron loss similar to MPTP, while D-galactose did not damage these neurons. Additionally, Micro-CT revealed bone loss in both the MPTP + D-galactose and D-galactose groups. This model recapitulates both the motor and aging-related non-motor symptoms of PD, including cognitive impairment and bone loss, providing a more comprehensive tool for studying PD pathogenesis and evaluating potential therapies. Full article

Background/Objectives: Malaria remains a major global health burden, increasingly complicated by resistance to artemisinin-based therapies. Because artemisinin activation depends on heme and porphyrin chemistry, we sought to exploit host red blood cell (RBC) heme metabolism as a therapeutic vulnerability. This study aims to develop and evaluate a host-directed “bait-and-kill” strategy that selectively sensitizes malaria-infected RBCs to artemisinin. Methods: We integrated quantitative proteomics, erythropoiesis transcriptomic analyses, flow cytometry, and in vitro malaria culture assays to characterize heme metabolism in mature RBCs and Plasmodium falciparum-infected RBCs (iRBCs). The heme precursor 5-aminolevulinic acid (ALA) was used to induce porphyrin accumulation, and dihydroartemisinin (DHA) was applied as the killing agent. Drug synergy, porphyrin accumulation, reactive oxygen species (ROS) induction, and parasite survival were assessed, including ring-stage survival assays using artemisinin-resistant clinical isolates. Results: Mature RBCs retain a truncated heme biosynthesis pathway capable of accumulating porphyrin intermediates, while uninfected RBCs are impermeable to ALA. In contrast, iRBCs exhibit increased membrane permeability, allowing selective ALA uptake and porphyrin accumulation. ALA alone did not induce cytotoxicity or ROS, whereas DHA induced ROS and parasite killing. The ALA + DHA combination resulted in synergistic parasite elimination, including complete clearance of artemisinin-resistant P. falciparum isolates from the Greater Mekong Subregion, with no recrudescence observed over three weeks of culture. Evidence supports a predominant role for host-derived heme metabolites in mediating this synergy. Conclusions: The bait-and-kill strategy selectively exploits host RBC heme metabolism to restore and enhance artemisinin efficacy while sparing uninfected cells. Using clinically safe compounds, this host-directed approach provides a promising, resistance-bypassing framework for malaria treatment and combination drug development. Full article

Background: Repetitive peripheral magnetic stimulation (rPMS) has emerged as a promising non-invasive treatment modality for reducing muscle hypertonus and spasticity. However, standardized protocols regarding stimulation parameters, particularly the number of stimuli required to achieve therapeutic effects, remain largely undefined. Methods: In an exploratory study, seventeen healthy participants (15 male, 2 female) underwent progressive rPMS treatments at 5 Hz frequency with incrementally increasing stimulus counts (105, 210, 315, 420, and 840 stimuli). Seventeen participants served as controls (11 male, 6 female) receiving sham stimulation. Achilles tendon reflexes were elicited using a computer-controlled reflex hammer, and compound muscle action potential (CMAP) peak-to-peak amplitudes were recorded via surface electromyography before and immediately after each stimulation session. Results: The overall repeated-measures ANOVA indicated a significant main effect (F(5, 80) = 4.98, p = 0.001, η²_p = 0.237). All rPMS treatments produced significant reductions in CMAP amplitudes compared to baseline (p < 0.05). No progressive dose-dependent relationship was observed between stimulus count and response magnitude, suggesting a threshold effect rather than progressive inhibition. Control group showed no significant changes (p ≤ 0.56). Conclusions: Low-frequency (5 Hz) rPMS produces rapid inhibitory effects on spinal reflex circuits with onset after as few as 105 stimuli. These findings indicate that treatment effects can be achieved with substantially fewer stimuli than previously assumed. Further research is needed to identify parameters capable of achieving greater reflex suppression. Full article

Background/Objectives: Acute ischemic stroke (AIS) associated with cervical carotid artery pathology remains a therapeutic challenge due to uncertainty regarding emergent carotid artery stenting (eCAS) and the need for intensified antithrombotic therapy, which may increase the risk of hemorrhagic transformation (HT). This retrospective cohort study evaluated the functional and safety outcomes of eCAS within an extended treatment time window. Methods: We analyzed 139 consecutive patients with anterior circulation AIS and large vessel occlusion treated with mechanical thrombectomy between 2019 and 2024. Patients were eligible for MT within 24 h based on clinical–core mismatch (DAWN) or perfusion–core mismatch (DEFUSE 3) criteria. Outcomes were compared between patients treated with eCAS and those undergoing MT without stenting. Results: Twenty-five patients underwent eCAS, predominantly for tandem lesions (80%). Median age was 66 years, median baseline NIHSS was 14, and median infarct core volume on DWI/CTP was 15 mL. Baseline characteristics were comparable between groups, except for the site of occlusion (p < 0.001). A good functional outcome (modified Rankin Scale, mRS 0–2 at 90 days) was observed in 60% of patients in the eCAS group versus 43% in the non-stenting group, without statistical significance (p = 0.067). Rates of parenchymal hematoma (12% vs. 18.4%) and symptomatic intracerebral hemorrhage (8% vs. 3.5%) were similar between groups. Conclusions: In this single-center cohort, eCAS performed in an extended time window did not demonstrate a clear signal of increased hemorrhagic risk. However, residual confounding and imbalance between treatment groups persisted despite the application of inverse probability weighting (IPW), and the findings should be interpreted cautiously. Full article

Microbial resistance to antibiotics necessitates the development of alternative treatments to address the challenges posed by severe bacterial infections. Bacteriophages are regaining clinical relevance, but the effectiveness of phage therapy depends directly on the route of administration and the carrier used. This review provides a critical overview of the therapeutic potential of phages, emphasizing different strategies for delivery to the site of infection. We focus on the preclinical and clinical data on phage therapies using various routes of administration, such as oral, intravenous, inhalation, topical, and local administration to joints and bones. In view of different phage formulations, including liquid suspension, phages immobilized in polymers or liposome-based carriers, we highlight the potential challenges and obstacles that may affect phage stability and bioavailability and limit the successful outcome of therapy. This review serves to enhance the understanding of the integration of materials engineering with clinical practice and production standardization, to address these issues. Additionally, a clear knowledge of the bacteriophage and pharmacokinetics of phage preparations is necessary to implement safe and efficacious bacteriophage treatment in the era of antimicrobial resistance. Full article

Background: The prognostic value of treatment-induced necrosis in soft STS remains uncertain. This study evaluated whether MRI-based changes in necrosis (Δ necrosis) between pre- and post-neoadjuvant chemotherapy scans correlate with pathologic necrosis and clinical outcomes. Methods: In this retrospective cohort, 27 patients with STS who received neoadjuvant chemotherapy and underwent pre- and post-treatment MRI were analyzed. Necrosis was graded categorically (<5%, 5–25%, 25–50%, 50–75%, 75–95%, and >95%), and Δ necrosis was calculated as the change in estimated necrosis between scans. Correlations between MRI-derived and pathologic necrosis were assessed using Spearman’s rank coefficient. Survival analyses (progression-free, local recurrence-free, and disease-specific overall survival) were performed using Kaplan–Meier and log-rank tests. Results: Post-treatment MRI necrosis moderately correlated with pathologic necrosis (ρ = 0.44, p = 0.028), whereas Δ necrosis showed a weaker, nonsignificant correlation (ρ = 0.24, p = 0.24). Neither MRI-based nor pathologic necrosis thresholds were associated with survival outcomes. Conclusions: MRI-based Δ necrosis did not predict pathologic necrosis or oncologic outcomes in STS, suggesting that radiologic changes in necrosis may not serve as reliable markers of therapeutic response. Future studies integrating quantitative imaging and standardized pathology protocols together with future exploration of molecular tools such as ctDNA are needed to refine treatment assessment in STS. Full article

Background: Sarcomas are rare, aggressive malignancies with limited therapeutic options in advanced stages. This is the first real-world study in the MENA region evaluating the clinical utility of Next-Generation Sequencing (NGS) in guiding sarcoma treatment and improving outcomes. Methods: We retrospectively reviewed sarcoma patients who underwent NGS at a major referral center (2021–2024), comparing clinical and molecular outcomes between those who received NGS-based treatment adjustments (NBTA) and those who did not. Results: Seventy-eight patients were included (60% male; median age 44 years). Soft tissue sarcomas accounted for 70.5% of cases (n = 55), while bone sarcomas represented 29.5% (n = 23). Prior to NGS, 64.1% of patients had received a median of one line of systemic therapy. NGS was performed late in the disease course in 73% of cases. At least one mutation was detected in 87% (median 3 mutations). Targetable alterations were identified in 33% at the time of testing, rising to 42% with updated genomic knowledge and therapeutic advances. Overall, 20.5% received NBTA. Among non-NBTA patients, 67% had no actionable targets, 17% had no detectable mutations, and 16% were ineligible due to cost, limited access, or clinical deterioration. Tumor Mutational Burden was low in 79%, intermediate in 19%, and high in 2%, and all tumors were microsatellite stable. Patients receiving NBTA had a longer median Progression-Free Survival (9 vs. 2 months; p = 0.023). Median Overall Survival was longer in the NBTA group (74 vs. 48 months), though not statistically significant (p = 0.207). Genomic alterations were subtype-specific: EWSR1 rearrangements (Ewing and Desmoplastic small round cell tumors), CDK4 and MDM2 amplifications (Liposarcoma and Osteosarcoma), TP53 and RB1 mutations (Leiomyosarcoma), CDKN2A/B deletions (Undifferentiated Pleomorphic Sarcoma and Chondrosarcoma), and SS18 rearrangements (Synovial Sarcoma). Conclusions: Genomics-guided therapy in sarcoma is feasible and impactful. Expanding timely access to molecular profiling is essential for advancing precision oncology in the MENA region. Full article

Liver cancer, also known as hepatocellular carcinoma (HCC), remains a major global health concern, with high mortality driven by late-stage diagnosis, limited treatment efficacy, and frequent therapeutic resistance. Matrix metalloproteinases (MMPs), a large family of zinc-dependent endopeptidases, are central to the biological processes that drive liver tumor initiation and progression. By degrading and reorganizing extracellular matrix components, MMPs facilitate tumor expansion, tissue invasion, and metastatic dissemination. In addition, these enzymes regulate the availability of growth factors, cytokines, and chemokines, thereby influencing angiogenesis, inflammation, immune cell recruitment, and the development of an immunosuppressive tumor microenvironment. Aberrant expression or activity of multiple MMP family members is consistently associated with aggressive clinicopathologic features, including vascular invasion, increased metastatic potential, and reduced patient survival, highlighting their promise as prognostic markers and actionable therapeutic targets. Past attempts to modulate MMP activity were hindered by broad inhibition profiles and dose-limiting toxicities, underscoring the need for improved specificity and delivery strategies. Recent advances in molecular design, biologics engineering, and nanotechnology have revitalized interest in MMP targeting by enabling more selective, context-dependent modulation of proteolytic activity. Preclinical studies demonstrate that carefully tuned MMP inhibition can limit tumor invasion, enhance anti-angiogenic responses, and potentially improve the efficacy of existing systemic therapies, including immuno-oncology agents. This review synthesizes current knowledge on the multifaceted roles of MMPs in HCC pathobiology and evaluates emerging therapeutic strategies that may finally unlock the clinical potential of targeting these proteases. Full article

Glioblastoma (GBM) remains one of the most treatment-resistant human malignancies, largely due to the interplay between disrupted fluid dynamics, immune evasion, and the structural complexity of the tumor microenvironment; in addition to these, treatment resistance is also driven by intratumoral heterogeneity, glioma stem cell persistence, hypoxia-induced metabolic and epigenetic plasticity, adaptive oncogenic signaling, and profound immunosuppression within the tumor microenvironment. Emerging evidence shows that dysfunction of the glymphatic system, mislocalization of aquaporin-4, and increased intracranial pressure compromise cerebrospinal fluid–interstitial fluid exchange and impair antigen drainage to meningeal lymphatics, thereby weakening immunosurveillance. GBM simultaneously remodels the blood–brain barrier into a heterogeneous and permeable blood–tumor barrier that restricts uniform drug penetration yet enables tumor progression. These alterations intersect with profound immunosuppression mediated by pericytes, tumor-associated macrophages, and hypoxic niches. Advances in imaging, including DCE-MRI, DTI-ALPS, CSF-tracing PET, and elastography, now allow in vivo characterization of glymphatic function and interstitial flow. Therapeutic strategies targeting the fluid-immune interface are rapidly expanding, including convection-enhanced delivery, intrathecal and intranasal approaches, focused ultrasound, nanoparticle systems, and lymphatic-modulating immunotherapies such as VEGF-C and STING agonists. Integrating barrier modulation with immunotherapy and nanomedicine holds promise for overcoming treatment resistance. Our review synthesizes the mechanistic, microenvironmental, and translational advances that position the glymphatic–immune axis as a new frontier in glioblastoma research. Full article