Search Results (3,985)

Isothermal titration calorimetry (ITC), circular dichroism (CD) spectroscopy, and molecular dynamics simulations were applied to describe interactions between lipopeptides and decavanadate ions ([V₁₀O₂₈]⁶⁻). The selected lipopeptides are conjugates of the amide of the KR12 peptide, the smallest antimicrobial peptide derived from human cathelicidin LL-37, with lauric acid (C12-KR12) and myristic acid (C14-KR12). The smaller sizes of C12-KR12 and C14-KR12 compared to proteins allow for the rigorous characterization of their non-covalent interactions with highly negatively charged [V₁₀O₂₈]⁶⁻ ions. The stoichiometry of the resulting decavanadate–peptide complexes and the thermodynamic parameters (ΔG, ΔH, and TΔS) of the interactions were determined. The ITC results, supported by the MD simulation, showed that the binding of cationic lipopeptides for decavanadate is rather non-specific and is driven by enthalpic contributions resulting from electrostatic interactions between the positively charged residues of the peptides and the anionic decavanadate. Furthermore, the influence of temperature and the interactions with decavanadate ions on the stability of the α-helical structure of the lipopeptides were assessed based on CD spectra. Under the experimental conditions (50 mM sodium cacodylate buffer, pH 5), the peptides adopt an α-helical conformation, with C14-KR12 showing greater thermal stability. The interactions with vanadium species disrupt the α-helical structure and reduce its thermal stability. Full article

Background/Objectives: Dental pulp stem cells (DPSCs) are of significant interest due to their mesenchymal lineage and relative availability from extracted teeth. This study aims to examine the relationship between fibronectin-adherent, non-fibronectin-adherent, and explant-derived DPSC populations in terms of the population doubling rate in culture and the expression of mesenchymal cell surface markers and their capacity for osteodifferentiation. Methods: Human pulp tissue was removed from healthy extracted human teeth, enzymatically digested prior to seeding onto fibronectin-coated plates, and left to adhere for 20 min, yielding a fibronectin-adherent population. The remaining non-adherent cells were transferred and designated ‘non-fibronectin-adherent.’ Intact pulp was placed on uncoated plastic for 5 days, with the migrated cells designated ‘explant-derived’. DPSCs from these populations were examined in terms of population doubling rates, the expression of CD90, CD44, CD105, and CD73, and the expression of RUNX2, SPP1, and BGLAP after 7 days in osteoinductive media. Results: The fibronectin-adherent cells had the greatest population doubling over time. All populations demonstrated comparable percentages of cells positive for mesenchymal markers, though individual marker expression varied slightly. The explant-derived cells showed increased expression of RUNX2 after 7 days in osteoinductive media, while the treated single-cell-suspension-derived populations showed increased expression of SPP1 mRNA. Conclusions: Fibronectin enrichment resulted in a population with the greatest rate of population doubling over extended culture compared to the other two populations. The proportion of cells positive for all four mesenchymal surface markers was the same between populations. The fibronectin-adherent and non-adherent cultures may have responded more rapidly to osteoinductive media than the explant-derived cells. Full article

Background/Objectives: Predictive tools are needed to assess the response to treatment and guide treatment decisions for locally advanced rectal cancer (LARC). This study explores the value of combining the immunoscore (IS) and magnetic resonance imaging tumor regression grade (mrTRG) with pathologic and radiologic neoadjuvant rectal (NAR) scores in predicting pathologic complete response (pCRs). Methods: The scores were assessed for patients with LARC enrolled in the Averectal study (NCT03503630), who received five fractions of short-course radiotherapy, followed by six cycles of mFOLFOX-6 plus avelumab, and total mesorectal excision. The IS was calculated using the mean density percentiles of CD3- and CD8-positive T-cells on baseline biopsy samples. Baseline and post-treatment MRIs were reviewed to measure the mrTRG. NAR scores were calculated using the pre-treatment T stage and post-treatment pathologic and radiologic N and T stages. Results: Fifteen out of thirty-five patients whose data were available achieved pCR (42.8%), and seven out of fourteen patients with mrTRG = 1 (complete response) attained pCR. In patients with both a mrTRG = 1 and high IS, the pCR rate was 66.7% (6/9). All of the patients who achieved pCR had a low or intermediate pathologic NAR score with a significant correlation between pCR and pathologic NAR scores (p < 0.0001). Both pathologic and radiologic NAR scores were correlated with overall survival and disease-free survival. Conclusions: The IS can supplement the mrTRG to better predict TNT outcomes, along with the use of the NAR score. This combination could potentially help with patient selection for non-operative management and guide treatment strategies for those with different recurrence risks. Full article

Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer. Common treatments following surgical resection include PD-1-targeting checkpoint inhibitors (pembrolizumab), as 20% of tumors are PD-L1 positive with or without systemic chemotherapy. Over the last several years, our laboratory has developed nano-immune conjugates (NIC) in which hydrophobic chemotherapy drugs like paclitaxel (PTX) and SN38, the active metabolite of irinotecan, are made water soluble by formulating them into albumin-based nanoparticles (nab) that are hydrophobically linked to various IgG1 monoclonal antibodies, creating an antigen-targetable nano-immune conjugate. To date, we have successfully tested PTX containing NICs linked to either VEGF- or CD20-targeted antibodies in two phase I clinical trials against multiple relapsed ovarian/uterine cancer or non-Hodgkin’s lymphoma, respectively. Herein, we describe a novel NIC created with either PTX or SN38 that is coated with anti-PD-L1-targeting antibodies for the treatment of a preclinical model of TNBC. In vitro testing suggests that the chemotherapy drug and antibody retain their toxicity and ligand binding capability in the context of the NIC. Furthermore, both the PTX and SN-38 NIC demonstrate superior anti-tumor efficacy relative to antibody and chemotherapy drugs alone in a PD-L1 + MDA-MB-231 human TNBC xenograft model, which could translate clinically to patients with TNBC. Full article

The increase in the concentration of potentially toxic elements in farmland soil attracts more and more attention. To identify the sources of potentially toxic elements in agricultural soils, 148 soil samples in Yingtan were selected as a case study, potentially toxic elements levels were analyzed, and principal component analysis (PCA) and positive matrix factorization (PMF) were employed. The results indicate that the average of Zn (89.62 mg·kg⁻¹ d.w.), Cu (76.30 mg·kg⁻¹ d.w.), Pb (35.56 mg·kg⁻¹ d.w.), Mo (0.66 mg·kg⁻¹ d.w.), and Cd (0.59 mg·kg⁻¹ d.w.) exceed the corresponding soil background values of Jiangxi Province. Moreover, the high spatial coefficient of variation (above 1.00) for these elements suggests a significant influence from long-term external inputs. Among all of the elements above, the soil Cu and Cd concentrations indicate a relatively high pollution ranked by Igeo. Further analysis of sources apportioned by PCA and PMF implies that the potentially toxic elements input into agricultural soil may be attributed to mining activity, natural sources, smelting, and agricultural activity. This study implies that PCA-PMF combined with the field survey may be helpful tools for discerning the pollutants^’ sources, and it addresses a view that the increasing Cu and Cd levels in farmland is concerning, as it is associated with the historical use of mixed fertilizers and a lack of supervision. Full article

Human cytomegalovirus (HCMV) is a high-risk pathogen in immunocompromised individuals, especially in transplant recipients. HCMV viremia must be monitored, and frequently, patients are treated with antiviral agents. HCMV has a variety of strategies to modulate host antiviral responses, and one important player is a viral homolog of the cellular interleukin-10 (cIL-10). The viral UL111A gene produces several HCMV IL-10 transcripts and protein isoforms through alternative splicing. The cmvIL-10 (isoform A) has similar properties to cIL-10, while LAcmvIL-10 (isoform B) has more restricted biological properties. Other isoforms are produced (C to H) but have unknown functions. Here, we investigated the expression of the most abundant transcripts, cmvIL-10 and LAcmvIL-10, in productively and latently infected cells and in peripheral blood mononuclear cells from renal transplant recipients up to 60 days post-transplantation. This study investigated HCMV cmvIL-10 and LAcmvIL-10 transcription profiles in vitro, in productive and latent infection, and in vivo, in peripheral blood mononuclear cells (PBMCs) of renal transplant patients. In vitro, both cmvIL-10 and LAcmvIL-10 transcripts were detected in both types at high levels and low levels in MRC-5 and latent infected (CD14+). When PBMCs from transplant patients were analyzed, LAcmvIL-10 was detected mostly sporadically and in only a few patients, while cmvIL-10 was found in all patients at all time points. Furthermore, it was observed in PBMCs that expression of cmvIL-10 was positively associated with an increase in viral DNA detection in the subsequently collected sample, indicating that expression of cmvIL-10 might precede viral DNA replication. These results contribute to the understanding of HCMV biology in different phases of infection. In addition, our initial analysis suggests that monitoring cmvIL-10, along with viral DNA, could improve early detection of HCMV reactivation in transplant recipients. Full article

Worldwide, cadmium (Cd) contamination severely threatens rice production and public health. Jasmonic acid (JA) is recognized to be involved in rice Cd stress responses, but the underlying mechanism remains unclear. In this study, we show that JA positively regulates Cd tolerance in rice by repressing Cd uptake and root-to-shoot translocation. Cd exposure rapidly elevated the endogenous JA in rice roots, which was associated with increased expression of JA synthesis and JA-responsive genes. Moreover, silencing the expression of either allene oxide synthase (OsAOS; active in JA biosynthesis) or CORONATINE INSENSITIVE1 (OsCOI1; active in JA perception) resulted in aggravated Cd toxicity and increased Cd accumulation in both the roots and shoots, as well as increased translocation from the root to the shoots. A short-term uptake experiment revealed that silencing of OsAOS and OsCOI1 enhanced root Cd uptake ability. Furthermore, the elevated transcript levels of genes for Cd uptake (OsNramp5, OsNramp1, and OsIRT1) and root-to-shoot translocation (OsHMA2) were observed in OsAOS and OsCOI1 RNAi plants in comparison with wild-type plants. Taken together, our findings suggest that JA enhances rice cadmium tolerance by suppressing Cd uptake and translocation. Full article

The detection of circulating tumor cells (CTCs) using immunoaffinity-based methods often relies on epithelial-related markers, which may bias the selection of CTCs and limit the biological information obtained, depending on the targeted antigens. Herein, we compared the molecular profiles and clinical significance of CTCs based on the expression of epithelial-related markers (EPCAM, EGFR, and MET) in patients with head and neck squamous-cell carcinoma (HNSCC). CTCs were detected using density gradient separation and CD45-negative selection, followed by quantitative PCR for epithelial-related marker expression. Expression profiles of epithelial–mesenchymal transition (EMT)-related (VIM, CDH1, CDH2, SNAI1, ZEB1, ZEB2, and TWIST1) and immune-regulatory (CD274 and PDCD1LG2) genes were compared. Moreover, the association between marker expression and clinical factors was analyzed. Among the 60 patients with CTCs, 48 (80.0%), 20 (33.3%), and 31 (51.7%) were positive for EPCAM, EGFR, and MET, respectively. A significant correlation was observed between CTCs expressing EPCAM and EGFR. CTCs expressing distinct markers showed differing EMT-related and immune-regulatory gene expression. EPCAM+ CTCs were associated with advanced-stage disease, while EGFR+ CTCs were correlated with locoregional relapse and shorter progression-free survival (p = 0.007; hazard ratio = 3.254). Patients with EPCAM/EGFR double-positive CTCs had the poorest prognosis. These findings emphasize the importance of marker selection in liquid biopsy technologies and highlight the need for improved detection methods and the further investigation of CTC biology. Full article

Recent evidence indicates that FAM111B is significantly involved in the progression of various cancers. Nonetheless, the potential pan-cancer implications of FAM111B have not been systematically investigated. In this study, FAM111B’s expression and oncogenic potential were studied using TCGA and GTEx data via GEPIA2, TIMER2.0, and STRING tools. Pathway enrichment analyses with the GO, KEGG, Reactome, and WikiPathways databases were conducted to explore its role in cancer development. The results were validated via multiplex immunofluorescence assays of pancreatic cancer tissues, microarray assays of ovarian cancer tissues, and protein transcriptomics of ovarian cancer cells. The expression levels of FAM111B were elevated in most cancer types and were associated with poor prognostic outcomes. Mechanistically, FAM111B expression was positively correlated with the expression of genes involved in DNA homologous recombination repair and with the infiltration of Th2 CD4+ T cells. These observations were further substantiated in ovarian cancer cell lines and tissue specimens from pancreatic and ovarian cancers. FAM111B functions as a biomarker for the DNA repair pathway and Th2 CD4+ T-cell infiltration in human malignancies. Full article

Background/Objectives: Brentuximab vedotin (BV) has been shown to be effective in the treatment of classical Hodgkin’s lymphoma (cHL), systemic anaplastic large cell lymphoma (sALCL), and CD30-positive cutaneous T-cell lymphoma (CTCL). This study aimed to evaluate the effectiveness and safety of BV retreatment in patients with relapsed/refractory cHL, sALCL, and CD30-positive CTCL. Methods: This multicenter, non-interventional, retrospective medical chart review study analyzed medical records from 43 patients retreated with BV in Spain. Patients were included if they had relapsed or refractory cHL, sALCL, or CD30-positive CTCL and were previously treated with BV. Demographic characteristics, disease stage, response to treatment, survival outcomes, and adverse events were analyzed. Results: The study population included 16 patients with cHL, 13 with sALCL, and 14 with CTCL. The majority were male (58.1%) with a mean age of 46.2 years and baseline ECOG scores of 0–1. Among cHL and sALCL patients, disease stage, according to the Ann Arbor classification, ranged from I to IVB, while in CTCL, EORTC clinical stages ranged from IA to IVB. The overall response rate to BV retreatment was 76.7%, with the highest response observed in sALCL (92.3%). Complete remission was achieved in 60.5% of patients. Median progression-free survival was 25.4 months, and overall survival reached 50 months. Treatment failure occurred in 37.2% of patients. BV was generally well tolerated, with peripheral neuropathy being the most frequently reported adverse event. Conclusions: The BELIEVE study is the largest study to date demonstrating that retreatment with BV is an effective and well-tolerated option for patients with relapsed or refractory CD30-positive malignancies. Full article

Background/Objectives: Cyclophosphamide (CTX) treatment in vivo kills proliferating tumor cells by DNA crosslinking; however, the suppression of tumor growth by CTX in several murine models requires CD8⁺ T cells. Given that CTX induces DNA damage and type I interferon (IFN-I), we investigated the role of host cGAS and STING in the anti-tumor effect of CTX in vivo. Methods: A metastasized EO771 breast cancer model with chromosomal instability and bone marrow (BM) chimera approach were used in this study. Results: We found that CTX therapy induces long-term survival of the mice, with this outcome being dependent on CD8⁺ T cells and cGAS/STING of BM-derived cells. Furthermore, the STING of type 1 conventional dendritic cells (cDC1s) and LysM⁺ cells and the IFN-I response of non-cDC1 myeloid cells are essential for CTX efficacy. We also found that the cGAS and STING of BM-derived cells positively modulate intratumoral exhausted and stem-cell-like CD8⁺ T cell populations under CTX treatment, with the latter only being affected by cGAS. Conclusions: Our study demonstrates that the CD8⁺-T-cell-dependent anti-tumor mechanisms of CTX critically involve the cGAS–STING–IFN-I axis, IFN-I response, and STING-independent cGAS function in host myeloid cells. These findings suggest the deployment of CTX in treating advanced solid tumor to bypass the often-failed IFN-I production by tumor cells due to the chronic activation of intrinsic cGAS–STING caused by chromosomal instability. Full article

Bergamot [Citrus × limon (L.) Osbeck, syn. C. × bergamia (Risso) Risso & Poit.] is primarily cultivated in the Calabria region of Italy and exploited in the food and perfumery industry. The epicarp of its fruit is a rich source of essential oil (BEO) containing mainly monoterpenes, which are known for their diverse biological activities, including antimicrobial, anti-inflammatory, antiproliferative, and neuromodulatory effects. Emerging evidence suggests that oxidative stress plays a central role in the pathogenesis of neurodegenerative diseases, particularly Alzheimer’s disease (AD), where it contributes to neuronal dysfunction and cell death. Moreover, heavy metal exposure has been identified as a key environmental factor exacerbating oxidative stress and neurodegeneration in AD. This study aimed to explore whether BEO could mitigate heavy metal (Cd²⁺, Hg²⁺, and Pb²⁺)-induced neurotoxicity in SH-SY5Y cells, a model system for brain cells. MTT and calcein-AM assays were performed to examine the viability of the SH-SY5Y cells after exposure to each heavy metal itself, or in combination with BEO, whereas the LDH assay was carried out to determine the effects of BEO towards necrotic cell death induced by heavy metals. Furthermore, DCFH-DA was performed to determine whether BEO could protect SH-SY5Y from heavy metal-induced oxidative stress. This study also investigated the antibacterial properties of BEO on different Gram-positive and Gram-negative bacterial strains belonging to the ATCC collection. These results suggest that BEO may help counteract heavy metal-induced neuronal damage, particularly Cd²⁺ toxicity, potentially reducing one of the environmental risk factors associated with AD. Additionally, its antimicrobial properties reinforce its relevance in preventing infections that may contribute to neuroinflammation in AD. Full article

Background/Objectives: Aging and immune mechanisms play a key role in the development of cardiovascular disease (CVD), especially in the context of chronic inflammation. Therefore, in order to detect early aging in the elderly, we have developed a prognostic model based on clinical and immunological markers using machine learning. Methods: This paper analyzes the relationships between immunological markers, clinical parameters, and lifestyle factors in individuals over 60 years of age. A machine learning (ML) model including random forest, logistic regression, k-nearest neighbors, and XGBoost was developed to predict the aging rate and risk of CVD. Correlation anal is revealed significant associations between immune markers (CD14+, HLA-DR, IL-10, CD8+), clinical parameters (BMI, coronary heart disease, hypertension, diabetes), and behavioral factors (physical activity, smoking, alcohol). Results: The results of the study confirm that systemic inflammation, as reflected by markers such as CD14+, HLA-DR, and IL-10, plays a central role in the pathogenesis of aging and related diseases. CD14+ shows a moderate positive correlation with post-infarction cardiosclerosis, accounting for 37%. HLA-DR correlates with body mass index at 39%. A negative association between IL-10 level and BMI was also found, where the correlation reaches 52% (r = −0.52). The level of CD8+ cells shows a negative correlation with smoking and their number, being 40%. Training was performed on clinical and immunological data and models were evaluated using accuracy, ROC-AUC, and F1-score metrics. Among all the trained models, the XGBoost model performed best, achieving an accuracy of 91% and an area under the ROC curve (AUC) of 0.8333. Conclusions: The study reveals significant correlations between immunological markers and clinical parameters, which allows the assessment of individual risks of premature cardiovascular aging. R (version 4.3.0) and specialized libraries for correlation matrix construction and visualization were used for data analysis, and Python (version 3.11.11) was used for model development and training. Full article

Background/Objectives: Anterior disc displacement without reduction (ADDwoR) is a temporomandibular joint (TMJ) disorder characterized by progressive dysfunction and potential complications. Persistent displacement leads to abnormal mechanical stress, predisposing the TMJ disc to structural degeneration, including perforation. This case report aimed to examine the histological and immunofluorescence characteristics of perforated disc tissue to elucidate the mechanisms contributing to its pathology. Methods: A 50-year-old patient with bilateral ADDwoR and disc perforation underwent functional arthroplasty. Tissue samples from the perforated disc were histologically analyzed using hematoxylin–eosin and Azan Mallory staining. Immunofluorescence was performed to assess the expression of collagen type I, fibrillin-1, matrix metalloproteinases (MMPs)-3 and -9, and cluster of differentiation 68 (CD68). Results: Histological analysis revealed disorganized collagen fibres and fibro-chondrocyte cell predominance in the perilesional zone, accompanied by vascular proliferation. Adjacent tissue to perforation exhibited normal fibrous organization. Immunofluorescence showed reduced collagen type I and fibrillin-1 patterns in the perilesional area, indicating an alteration in the fibrillar component of the extracellular matrix (ECM). Increased expression of MMP-3 and MMP-9, as well as elevated numbers of CD68-positive macrophages, suggested active ECM degradation and inflammation localized to the perforation site. Conclusions: This case report underscores the critical role of biomechanical stress and inflammation in disc perforation. Decreased ECM integrity, driven by altered collagen and fibrillin composition, as well as heightened MMP activity, compromises the disc’s capacity to absorb and distribute mechanical loads. These findings advance our understanding of TMJ pathophysiology, emphasizing the need for therapeutic approaches that target both biomechanical stabilization and inflammation. Full article

Soil heavy metal (HM) contamination has become a critical global environmental issue, predominantly caused by industrial and agricultural operations. This study focuses on Mount Wuyi, a UNESCO biodiversity hotspot and major tea production base, to examine vegetation-mediated soil HM accumulation under anthropogenic impacts. We analyzed nine HMs (Mn, Cu, Zn, Cd, Hg, As, Pb, Cr, Ni) across diverse vegetation types using geochemical indices and Positive Matrix Factorization (PMF) modeling. The findings revealed Mn and Zn were dominant elements, and Cr and Pb concentrations exceeded regional background values by 3.47 and 1.26 times, respectively. Cr, Cd, and Pb demonstrated significant pollution levels, while Cd and Hg posed the highest ecological risks. Vegetation type significantly influenced HM distribution patterns, with cultivated areas and shrublands (including tea gardens) accumulating higher concentrations of Cu, Cd, Pb, and Hg from agricultural and transportation sources. Notably, bamboo forests exhibited natural resistance to HM contamination. PMF analysis identified four primary pollution sources: urbanization (27.94%), transport–agriculture activities (21.40%), agricultural practices (12.98%), and atmospheric deposition (12.96%). These results underscore the need for implementing clean energy solutions, phytoremediation strategies, and tea-specific detoxification measures to maintain ecological security and agricultural sustainability in this ecologically significant region. Full article