Search Results (30,590)

CD44, a structurally diverse cell-surface glycoprotein, plays a multifaceted and indispensable role in neural tissue across both physiological and pathological conditions. It orchestrates complex cell–extracellular matrix interactions and intracellular signaling through its variant isoforms and post-translational modifications and is broadly expressed in neural stem/progenitor cells, microglia, astrocytes, and selected neuronal populations. The interactions of CD44 with ligands such as hyaluronan and osteopontin regulate critical cellular functions, including migration, differentiation, inflammation, and synaptic plasticity. In microglia and macrophages, CD44 mediates immune signaling and phagocytic activity, and it is dynamically upregulated in neuroinflammatory diseases, particularly through pathways involving Toll-like receptor 4. CD44 expression in astrocytes is abundant during central nervous system development and in diseases, contributing to glial differentiation, reactive astrogliosis, and scar formation. Though its expression is less prominent in mature neurons, CD44 supports neural plasticity, circuit organization, and injury-induced repair mechanisms. Additionally, its expression at nervous system barriers, such as the blood–brain barrier, underscores its role in regulating vascular permeability during inflammation and ischemia. Collectively, CD44 emerges as a critical integrator of neural cell function and intercellular communication. Although the roles of CD44 in glial cells appear to be similar to those explored in other tissues, the expression of this molecule and its variants on neurons reveals peculiar functions. Elucidating the cell-type-specific roles and regulation of CD44 variants may offer novel therapeutic strategies for diverse neurological disorders. Full article

α-Cyclodextrin/Moringin (α-CD/MOR) is an isothiocyanate showing neuroprotective and antioxidant properties. In this work, we studied in differentiated NSC-34 motor neurons cell line the molecular pathways activated following a treatment of 96 h with α-CD/MOR at different doses, namely 0.5, 5 and 10 μM. Taking advantage of comparative transcriptomic analysis, we retrieved the differentially expressed genes (DEGs) and we mapped DEGs to synaptic genes using the SynGO database. Then, we focused on the biological pathways in which they are involved. We observed that the prolonged treatment with α-CD/MOR significantly modulated biological processes and cellular components associated with synaptic organization. Interestingly, the KEGG pathway “Regulation of actin cytoskeleton” was overrepresented, alongside pathways related to synapses and axon guidance. Specifically, SPIA analysis indicated that the “Regulation of actin cytoskeleton” pathway was found to be activated with the highest dose of α-CD/MOR. Moreover, α-CD/MOR also modulated transcription factors involved in synaptic plasticity, such as Creb1. These results could indicate that α-CD/MOR can influence synaptic functions and organization, being involved in synaptic plasticity through the modulation of actin dynamics. Full article

Multiple markers exist for breast cancer stem cells (CSCs), which are believed to represent the phenotypes of various CSC types and/or states. The relationship between each CSC subpopulation/state and the primary hallmarks of cancer has not been sufficiently clarified. In this study, six CSC markers (CD44^hi/CD24^lo, CD24, Ep-CAM, ALDH1, CD10, and BMI1) were assessed in a surgical cohort of 73 breast cancer patients. The expression of a single or multiple CSC markers was correlated with clinicopathological parameters, including markers of immune evasion, proliferation, epithelial–mesenchymal transition (EMT), and survival. All CSC phenotypes, except for CD10, correlated with markers indicative of higher proliferation. The CD44^hi/CD24^lo phenotype correlated with markers of EMT and PD-L1 expression, unlike ALDH1^hi. Both Ep-CAM^hi and CD24^hi breast cancer were associated with indicators of immune evasion, including PD-L1 expression, and the infiltration of FOXP3+ and PD-1+ tumor-infiltrating lymphocytes (TIL). While the CD44^hi/CD24^lo, Ep-CAM^hi, and ALDH1^hi phenotypes correlated with shorter overall survival (OS), CD24^hi correlated with reduced disease-free survival (DFS). Interestingly, among all tested CSC markers, the CD44^hi/CD24^lo-ALDH1^hi combination phenotype correlated with the worst DFS (HR 2.8, p = 0.014 in univariate/multivariate analysis) and OS (p < 0.001, HR 6.4 in univariate and 5.4 in multivariate analysis). A side-by-side comparison of multiple CSC markers demonstrated the differential linkage of CSC phenotype/state with distinct features of breast cancer. This comparison demonstrates the advantage of the CD44^hi/CD24^lo-ALDH1^hi combination marker for prognostication, especially after neoadjuvant chemotherapy. In the future, distinct markers of CSCs can hopefully be leveraged to trace/monitor different disease characteristics or treatment outcomes. Full article

Bovine Norovirus (BNoV) is a member of the enterovirus family that can cause gastroenteritis in calves. This virus poses a significant risk to calf growth and development as well as to the long-term sustainability of the cattle industry in China and elsewhere. No specific treatment or vaccine is currently available; thus, the development of a safe and effective vaccine is paramount. Here, we describe a strategy to assemble BNoV virus-like particles (VLPs) using the insect baculovirus expression system (BEV) to express the major structural protein, VP1, and demonstrate their potentiality as vaccines. The results showed that the BNoV-VLP self-assembled into complete spherical particles with a diameter of approximately 40 nm. When it was immunized in mice, the levels of specific IgG and IgA antibodies peaked at weeks 6 and 7 post-immunization, respectively, with maximum titers of 1:25,600 and 1:200. Moreover, we observed a significant increase in the CD4⁺/CD8⁺ T-cell ratio in splenic lymphocytes of immunized mice (p < 0.05), accompanied by a significant increase in TNF-α⁺CD4⁺ T-cells and TNF-α⁺CD8⁺ T-cells (p < 0.05). These results demonstrate that BNoV-VLPs are promising vaccine candidates for providing immunoprotection in the future. These studies support the significant practical implications of using a scientific basis for the development of a BNoV-VLP vaccine. Full article

Background: Data on the use of dolutegravir (DTG) plus boosted darunavir (DRV/b) in people with 4-class drug-resistant HIV (4DR-PWH) are limited. This study assessed the virological effectiveness of DTG + DRV/b in this population using real-world data from the PRESTIGIO Registry. Methods: We compared three regimen groups: dual DTG + DRV/b (DODA), DTG + DRV/b plus an additional antiretroviral drug (DODA + Other), and regimens excluding DTG + DRV/b (NO-DODA). Virological failure (VF) was defined as ≥2 HIV-RNA values ≥ 50 copies/mL or 1 ≥ 1000 copies/mL. Mixed-effects logistic regression was used to assess VF, adjusting for antiretroviral therapy (ART) duration, age, number of fully active drugs, sex at birth, and nadir CD4+. Individuals could switch regimens during follow-up. Results: Among 249 4DR-PWH (median follow-up: 8.7 years), 844 ART regimens were analyzed: 72 (8.5%) DODA, 264 (31.3%) DODA + Other, and 508 (60.2%) NO-DODA. Compared to NO-DODA, the odds of VF were 77% and 35.9% lower with DODA and DODA + Other, respectively. Notably, in the DODA group, DTG and DRV/b were fully active in only 63.9% and 47.2% of the cases, respectively. Conclusions: DTG + DRV/b regimens were associated with a significantly lower risk of virological failure, even when drug activity was partial. This strategy remains a valuable option for managing multi-drug-resistant HIV. Full article

Nephrotic syndrome (NS) is a complex kidney disorder characterized by profound proteinuria, hypoalbuminemia, hyperlipidemia, and edema, significantly impacting patients’ quality of life. While corticosteroids and calcineurin inhibitors (CNIs) have traditionally been the primary treatments, B cell-targeted therapies, especially the anti-CD20 monoclonal antibody rituximab, have transformed the management of steroid-dependent and multidrug-resistant NS (MRNS). Rituximab has demonstrated efficacy in reducing relapse rates and steroid dependence by depleting CD20+ B cells, which play a pivotal role in autoantibody production and immune dysregulation. However, limitations such as incomplete B cell depletion, immunogenicity leading to anti-rituximab antibodies, and variable efficacy in refractory cases have led to the development of next-generation therapies. This review critically examines recent advances in B cell-targeted therapies for NS, with a particular focus on overcoming the limitations of conventional rituximab treatment. This review systematically analyzes next-generation anti-CD20 monoclonal antibodies, CD38-targeted therapies, and emerging CAR-T cell approaches, evaluating their distinct mechanisms of action and clinical trial outcomes. The analysis extends to innovative combination strategies and biomarker-guided treatment algorithms for refractory cases. By synthesizing preclinical data with clinical evidence, this work provides a framework for optimizing therapeutic decision-making in NS, while identifying key knowledge gaps that warrant future investigation. Collaborative research and translational studies are essential for advancing precision medicine in NS, ensuring that new therapies provide lasting clinical benefits for patients. The evolving field of anti-B cell therapies marks a new era in managing refractory NS, offering hope for better long-term prognoses. Full article

Parkinson’s disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra, and key pathways such as neuroinflammation, oxidative stress, and autophagy are believed to significantly contribute to the mechanisms of neurodegeneration. Calpain activation plays a critical role in neuroinflammation and neurodegeneration, as demonstrated by its impact on microglial activation, reactive oxygen species (ROS) production, and neuronal survival. In this study, we investigated the effects of calpain inhibition using calpeptin (CP) and calpain-2-specific inhibitors in cellular and murine models of neuroinflammation and PD. In BV2 microglial cells, LPS-induced production of pro-inflammatory cytokines (TNF-α, IL-6) and chemokines (MCP-1, IP-10) were significantly reduced by CP treatment with a concomitant decrease in ROS generation. Similarly, in VSC-4.1 motoneuron cells, calpain inhibition attenuated IFN-γ-induced ROS production and improved cell viability, demonstrating its neuroprotective effects. Moreover, in a murine MPTP model of PD, calpain inhibition reduced astrogliosis, ROCK2 expression, and levels of inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-7, and IL12p70) and chemokines (MCP-1 and IP-10) in the dorsal striatum and plasma. The specific role of calpain-2 in immune modulation was further highlighted in human microglia, SV-40 cells. With respect to immune modulation in these cells, siRNA-mediated knockdown of calpain-2, but not calpain-1, significantly reduced antigen presentation to CD4+ T cells. Thus, calpain-2 is likely involved in regulating antigen presentation and activation of inflammatory CD4+ T cells. These findings underscore the therapeutic potential of calpain-2 inhibition in mitigating neuroinflammation and neurodegeneration, particularly in PD, by targeting microglial activation, ROS production, and neuronal survival pathways. Full article

Introduction and Aims: Androgen deprivation therapy (ADT) with systemic anti-cancer treatment (SACT) ± palliative radiotherapy (pRT) is the current standard of care for Oligo-metastatic hormone-sensitive prostate cancer (o-mHSPC). Cytoreductive radical prostatectomy (cRP) has gained interest in this group of patients, with potential benefits including reduced tumour burden and a lower risk of local events from disease progression. In this review, we compare both survival outcomes and local event rates between cRP and upfront ADT ± SACT. Methods: All randomised trials and observational studies comparing cRP with standard treatment (ST), which we defined as ADT ± SACT for o-mHSPC, were included in the review. The study protocol was registered in PROSPERO (CRD42024516586), and the review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). The databases searched included Embase, Medline, Cochrane Library, PubMed, and Web of Science. A risk of bias assessment was performed for the included studies as recommended by the Cochrane Handbook of Systematic Reviews and Interventions. The primary outcome measures were Overall Survival (OS), Cancer-Specific Survival (CSS), Progression-free Survival (PFS), Castrate-resistant Prostate Cancer-free Survival (CRPC-FS), and local complication rates. The secondary outcome measures were complication rates and functional outcomes post-cRP. Results: A total of 5130 studies were identified for this review (5119 by database searching and 11 through manual searching). Eight studies were included in the review, comprising 611 patients. cRP was identified to have superior OS (HR: 0.56 (95% CI: 0.34–0.92), I² = 0%, p = 0.02 (very low certainty)) and CSS (HR: 0.27 (95% CI: 0.15–0.47), I² = 0%, p < 0.0001 (very low certainty)). The PFS (HR: 0.67 (95% CI: 0.34–1.33), I² = 58%, p = 0.25 (very low certainty)) and CRPC-FS (HR: 0.67 (95% CI: 0.32–1.43), I² = 57%, p = 0.30 (very low certainty)) were similar between the two groups. The rates of local events were significantly lower in patients undergoing cRP (RR 0.27 (95% CI: 0.13–0.59), I² = 17%, p = 0.001 (low certainty)). The rates of Clavien–Dindo (CD) grade 3 or higher complications ranged from 0% to 13.1%. Additionally, the reported continence rates ranged from 81.5% to 91.3%. The review is limited by the lack of a uniform definition for o-mHSPC and the predominance of low-quality, heterogeneous studies. Despite mitigation strategies, the overall certainty of evidence remains very low per GRADE assessment. Conclusion: cRP significantly reduces local event rates compared with ST and offers comparable PFS and CFPC-FS, with superior OS and CSS in the cRP arm compared to the ST arm in patients with o-mHSPC. However, there is a paucity of high-quality literature on this subject. Ongoing randomised controlled trials may soon clarify the role of cRP in the context of o-mHSPC concerning survival benefits. Full article

Background/Objectives: Despite the significant advancements made in the diagnosis of lung cancer, the traditional diagnostic methods remain limited because they are often invasive, expensive, and not suitable for regular screening, creating a need for more accessible and non-invasive alternatives. In this context, the analysis of miRNAs in EVs and free circulating microRNA may be used as liquid biopsies in lung cancer to identify individuals at risk. This study aimed to compare miRNA profiles in the serum and EVs derived from lung cancer patients by focusing on Let-7a-5p and miR-21-3p. Materials and Methods: Serum and EVs were isolated from lung cancer patients and healthy controls. EVs were characterized using nanoparticle tracking analysis, electron microscopy, and Western blotting for surface markers (CD63, CD81, TSG101). Total miRNA levels were quantified in the serum and EVs, and specific miRNAs (hsa-let-7a-5p and hsa-miR-21-3p) were analyzed using RT-qPCR. Statistical analysis evaluated miRNA expression across clinicopathological features, including age, gender, smoking status, tumor stage, cancer type, and EGFR mutation status. Results: Total miRNA levels were significantly enriched in EVs compared to the serum. Let-7a-5p was downregulated in EVs from patients with advanced-stage lung cancer (Stage III–IV) compared to those with early-stage cancer and controls (p < 0.05), while no differences were observed in the serum. Conversely, miR-21-3p was significantly upregulated in EVs and serum from advanced-stage patients (p < 0.01) and in adenocarcinoma compared to squamous cell carcinoma (p < 0.05). No significant differences were observed for age, gender, or smoking status. Conclusions: Our findings highlight the differential expression of miRNAs in EVs and the serum, emphasizing the diagnostic potential of EV-associated Let-7a-5p and miR-21-3p in lung cancer. These results suggest that EVs are a more robust source for miRNA biomarkers compared to the serum. Full article

This study introduces novel experimental systems that facilitate the nucleation, growth, aggregation, and agglomeration of ionic salt solutions, leading to structurally and functionally distinctive crystal formations. Through evaporative crystallization in hanging drops—including layered binary solutions—a range of macroscopic agglomerates were produced, such as hollow spheroidal NaCl/NiSO₄ structures, octahedral NaCl films, pentagonally arranged CdSO₄ spherulites, and NH₄Cl dendritic shells. Additionally, NaCl spheroids were used as templates to fabricate carbon-based morphologies and colloidal photonic crystals with convex or concave geometries, which were subsequently analyzed optically. The study reveals that crystallization and self-assembly, whether independently or synergistically applied, can yield complex architectures with potential applications in advanced device manufacturing beyond conventional processing methods. Full article

Despite increasing evidence that cigarette smoke is a significant source of indoor fine particulate matter (PM_2.5), quantitative emission factors (EFs) for PM_2.5 and its toxic chemical composition in mainstream (MS) and sidestream (SS) smoke are still not well defined. In this study, we employed a custom-designed chamber to separately collect MS (intermittent puff) and SS (continuous sampling) smoke from eleven cigarette models, representing six brands and two product types, under controlled conditions. PM_2.5 was collected on quartz-fiber filters and analyzed for carbon fractions (using the thermal–optical IMPROVE-A protocol), nine water-soluble inorganic ions (by ion chromatography), and twelve trace elements (via ICP-MS). SS smoke exhibited significantly higher mass fractions of total analyzed species (84.7% vs. 65.9%), carbon components (50.6% vs. 44.2%), water-soluble ions (17.1% vs. 13.7%), and elements (17.0% vs. 7.0%) compared to MS smoke. MS smoke is characterized by a high proportion of pyrolytic organic carbon fractions (OC₁–OC₃) and specific elements such as vanadium (V) and arsenic (As), while SS smoke shows elevated levels of elemental carbon (EC1), water-soluble ions (NH₄⁺, NO₃⁻), and certain elements like zinc (Zn) and cadmium (Cd). The toxicity-weighted distribution indicates that MS smoke primarily induces membrane disruption and pulmonary inflammation through semi-volatile organics and elements, whereas SS smoke enhances oxidative stress and cardiopulmonary impairment via EC-mediated reactions and secondary aerosol formation. The mean OC/EC ratio of 132.4 in SS smoke is an order of magnitude higher than values reported for biomass or fossil-fuel combustion, indicative of extensive incomplete combustion unique to cigarettes and suggesting a high potential for oxidative stress generation. Emission factors (µg/g cigarette) revealed marked differences: MS delivered higher absolute EFs for PM_2.5 (422.1), OC (8.8), EC (5.0), Na⁺ (32.6), and V (29.2), while SS emitted greater proportions of NH₄⁺, NO₃⁻, Cl⁻, and carcinogenic metals (As, Cd, Zn). These findings provide quantitative source profiles suitable for receptor-oriented indoor source-apportionment models and offer toxicological evidence to support the prioritization of comprehensive smoke-free regulations. Full article

Background/Objectives: Electrochemotherapy (ECT) has been shown to be effective in treating colorectal liver metastases when combined with bleomycin (BLM). Based on this promising finding, we compared in this study the efficacy of BLM with oxaliplatin (OXP) and bevacizumab (BVZ) in ECT. Methods: WAG/Rij rats were randomized into three groups and underwent ECT with intravenous injection of BLM, OXP, or OXP with BVZ for eight days following hepatic tumor cell implantation. Ultrasound and photoacoustic imaging served to assess oxygen saturation (SO₂) and hemoglobin concentration (HbT) of the developing tumors. Tissue samples were analyzed by histology and immunohistochemistry. Results: BLM treatment significantly reduced SO₂ (33.7%) and HbT (12.7%) levels compared to pretreatment values. In contrast, the OXP-treated groups exhibited only modest reductions in both parameters. BLM also induced a markedly higher necrosis rate (82.6%) compared to OXP and OXP/BVZ (11.0% and 26.3%). Conversely, OXP-treated tumors exhibited higher apoptosis rates. Furthermore, BLM treatment led to a decrease in tumor cell proliferation and a reduction in inflammatory response compared to the other treatments. Notably, BLM caused a 26.2% reduction in CD31-positive microvessels, which was significantly higher than that observed in the OXP group. Conclusions: BLM showed a more effective anti-tumor activity than OXP, suggesting its preferred use as chemotherapeutic agent in ECT. Full article

Quaternary ammonium compounds (QACs) are a class of chemicals used for their antimicrobial, surfactant, and antistatic properties. QACs are present in many consumer products, and people are regularly exposed to them. We have previously shown reproductive toxicity in mice exposed to the disinfectants alkyl dimethyl benzyl ammonium chloride (ADBAC) and dodecyl dimethyl ammonium chloride (DDAC). To assess the long-term reproductive impacts, a generational reproductive study was conducted. Sperm parameters were determined by CASA and epigenetic enzyme mRNA expression was determined by pathway-focused RT-PCR. Mice ambiently exposed to ADBAC+DDAC exhibited decreases in reproductive indices that persisted through the F1 generation. Male mice (F0) dosed with 120 mg/kg/day of ADBAC+DDAC exhibited decreased sperm concentration and motility that persisted through the F1 generation. Changes in the mRNA expression of chromatin-modifying enzymes in the testes were seen. Two histone acetyltransferases (Hat1 and Kat2b) were upregulated, and one lysine-specific demethylase (Kdm6b) was downregulated in the F0 generation. The DNA methyltransferase Dnmt1 was downregulated in F1 males. These changes in chromatin-modifying enzymes are known to decrease fertility and could be a mechanism for ADBAC+DDAC reproductive toxicity. In all experiments, the F2 generation was similar to the controls, showing multi-generational but not trans-generational epigenetic inheritance. Full article

The therapeutic landscape of adults with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is undergoing a paradigm shift, driven by the development of immunotherapy-based “chemo-free” and “chemo-light’ regimens. These strategies aim to achieve high efficacy with reduced toxicity, particularly in older adults who may not tolerate intensive chemotherapy. In Philadelphia chromosome-positive (Ph+) BCP-ALL, the incorporation of ABL tyrosine kinase inhibitors (TKIs) with blinatumomab (CD3/CD19 bispecific T-cell engager) has shown remarkable efficacy, with some studies reporting molecular response rates in the range of 90–100% and long-term survival exceeding 80% without the need for intensive chemotherapy or allogeneic hematopoietic cell transplantation (allo-HCT). In Philadelphia-negative (Ph−) BCP- ALL, an immunotherapy-based combination of blinatumomab and inotuzumab ozogamicin (anti-CD22 antibody-drug conjugate) has demonstrated high rates of complete remission and measurable residual disease (MRD) negativity, with manageable toxicity. While chimeric antigen receptor (CAR) T-cell therapy remains a transformative option for relapsed/refractory B-ALL, its integration into frontline treatment is still under investigation. Ongoing trials are evaluating the optimal sequencing and combinations of these agents and their potential to obviate the need for chemotherapy and/or allo-HCT in selected patients. As evidence continues to accumulate, chemo-free and chemo-light regimens, incorporating minimal chemotherapy with targeted agents to balance efficacy and reduced toxicity, are poised to redefine the standard of care for adults BCP-ALL, offering the possibility of durable remissions with reduced treatment-related morbidity. Full article

Chicken meat represents the most widely consumed source of animal protein globally. The identification of non-coding RNAs (ncRNAs) that affect muscle development provides new selection targets for poultry breeding. In this study, muscle samples from high- and low-breast-weight chickens were collected and sequenced for long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), and mRNAs. Using weighted gene co-expression network analysis, we found 95 lncRNAs and 46 circRNAs that were significantly associated with breast muscle traits. Subsequently, 51 candidate lncRNAs and 22 candidate circRNAs were screened through differential expression analysis. Finally, by constructing an ncRNA–mRNA regulatory network and performing pathway enrichment analysis, we identified four lncRNAs (e.g., MSTRG.9172.1) and seven circRNAs (e.g., novel_circ_009419) as key regulatory molecules. Functional analysis revealed that these molecules modulate genes such as CD28, CCND2, TIAM1, and RRM2 through pathways including the actin cytoskeleton, p53 signaling pathway, and other pathways. In conclusion, this study provides clearer insight into the epigenetic regulatory network involved in chicken breast muscle development and offers important molecular markers for chicken genetic selection. Full article