Search Results (19,754)

Importance: Triple-negative breast cancer (TNBC) is characterized by high tumor mutation burden and frequent programmed cell death ligand 1 (PD-L1) expression, making immune checkpoint inhibitors (ICIs) a promising therapeutic approach. However, randomized trials of chemoimmunotherapy (Chemo-IO) in locally recurrent unresectable or metastatic TNBC have shown inconsistent results, necessitating a clearer understanding of efficacy and patient selection. Objective: The aim of this study was to evaluate the efficacy and safety of chemotherapy combined with immunotherapy vs. chemotherapy alone in patients with locally recurrent unresectable or metastatic triple-negative breast cancer and to identify beneficiary populations to guide optimal treatment selection. Data Sources: PubMed, Embase, and the Cochrane Library were searched from database inception through 23 August 2025. Study Selection: Randomized clinical trials (RCTs) comparing chemotherapy combined with ICIs vs. chemotherapy with placebo or control in patients with locally recurrent unresectable or metastatic TNBC were selected. Data Extraction and Synthesis: Two investigators independently performed data extraction and assessed risk of bias using the Cochrane Risk of Bias 2 tool (RoB 2). Heterogeneity was evaluated using the I² statistic. Data were synthesized using random-effects meta-analysis models to calculate hazard ratios (HRs) for time-to-event outcomes and risk ratios (RRs) for dichotomous outcomes according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines. Results: Seven RCTs comprising 3485 patients (2085 in the Chemo-IO group, 1400 in the control group) were included. The median age across trials ranged from 52 to 57 years. Chemo-IO significantly improved PFS (HR, 0.82 [95% CI, 0.76–0.89]; p < 0.01) and OS (HR = 0.88; 95% CI: 0.81–0.96; p = 0.004) in the intention-to-treat (ITT) population, with PFS benefit particularly evident in PD-L1-positive patients (HR = 0.68, 95% CI: 0.59–0.79). However, OS improvement in the PD-L1-positive subgroup was not statistically significant. CBR did not differ significantly in the intention-to-treat population (RR, 1.11 [95% CI, 0.99–1.25]; p =  0.08) but was higher in PD-L1-positive patients (RR, 1.15 [95% CI, 1.01–1.31]; p = 0.04). Safety analyses revealed no significant differences in overall AE (RR, 1.01 [95% CI, 0.99–1.02]; p = 0.35), TEAE (RR, 1.01 [95% CI, 0.99–1.03]; p = 0.19), or grade ≥ 3 TEAE (RR, 1.00; [95% CI, 0.93–1.07]; p =  0.98). However, serious AE (RR, 1.32 [95% CI, 1.11–1.57]; p = 0.001) and irAE (RR, 1.86 [95% CI, 1.41–2.45]; p <  0.01) were more frequent with Chemo-IO. Conclusions and Relevance: Chemotherapy combined with immunotherapy significantly improved PFS and OS in patients with locally recurrent unresectable or metastatic TNBC, without substantially increasing chemotherapy-related toxicities. However, the OS benefit in PD-L1-positive patients was not statistically significant, and the combined regimen was associated with higher rates of serious and immune-related adverse events. These findings support the use of Chemo-IO as a treatment option, highlighting the importance of PD-L1 status and careful monitoring of immune-mediated toxicities in clinical practice. Full article

Background: Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality, and although PD-1/PD-L1 immune checkpoint blockade has improved outcomes in some patients, therapeutic responses remain heterogeneous. Tumor-intrinsic heterogeneity within malignant epithelial populations is increasingly recognized as a critical determinant of disease progression and therapy response. Methods: Here, we constructed a comprehensive single-cell atlas of NSCLC by integrating 650,461 cells from 216 tumor and normal samples. Tumor-derived epithelial cells were reclustered to identify transcriptionally distinct subpopulations. Pseudotime analysis, functional experiments, and in vivo validation using a humanized xenograft model were performed to investigate the role of COL3A1. Results: Reclustering of tumor-derived epithelial cells revealed 25 transcriptionally distinct subpopulations. Among these, a high-risk cluster exhibited coordinated activation of epithelial–mesenchymal transition (EMT) and angiogenesis programs and was associated with poor patient survival. Within this aggressive subpopulation, Collagen type III alpha 1 (COL3A1) emerged as a tumor-intrinsic gene associated with extracellular matrix remodeling and angiogenic signaling. Pseudotime analysis indicated that COL3A1⁺ cells represent a late-stage, poorly differentiated malignant state. Functional experiments demonstrated that COL3A1 knockdown impaired NSCLC cell proliferation, migration, and invasion. Virtual knockout further suggested that COL3A1 may be associated with transcriptional programs involved in PD-L1 upstream signaling pathways, indicating a potential indirect link between tumor-intrinsic states and immune regulatory networks. Consistently, in vivo silencing of COL3A1 enhanced the antitumor efficacy of PD-L1 blockade. Conclusions: Collectively, our study identifies COL3A1 as a tumor-intrinsic gene enriched in malignant epithelial cells with mesenchymal features and a potential therapeutic target. These findings provide a rationale for exploring combinatorial strategies integrating tumor-intrinsic pathway inhibition with immune checkpoint blockade in NSCLC. Full article

Background/Objectives: Since 2016, the mutation of isocitrate dehydrogenase 1 (mIDH1) enzymes has become a major molecular marker for glioma classification and diagnosis. Moreover, the recent success of the INDIGO clinical trial on AG-881 (vorasidenib^®), an aminotriazine-based mutated IDH1/2 inhibitor (IC₅₀ = 6 nM/12 nM), validated the need for noninvasive detection of mIDH1 in brain tumors. This work is based on developing a series of novel fluorinated analogues of AG-881 and evaluating their potential in mIDH1 PET detection. Methods: The analogues were tested for their potency and then the best candidate was radiofluorinated and used for in vitro cell uptake studies. Results: Six analogues (6–11) were designed and synthesized, but only compound 6 showed nanomolar inhibitory potency towards mIDH1 (IC₅₀ = 400 nM). Following successful radiofluorination, in vitro cell uptake studies showed no selective accumulation of [¹⁸F]6. Conclusions: This study highlights the critical impact of substituent positioning and halogen substitution within the pyridyl moiety on maintaining inhibitory potency. Further medicinal chemistry research is needed to develop an aminotriazine-based ¹⁸F-radiolabeled mIDH1 ligand. Full article

The most common complication of active brucellosis in humans is osteoarticular injury. In the bone marrow microenvironment, mesenchymal stem cells (MSCs) can differentiate into either adipocytes or osteoblasts, and this balance is tightly regulated because an increase in adipogenesis may negatively affect bone formation and favor bone loss. The differentiation of MSCs into adipocytes or osteoblasts is tightly regulated by mechanisms that promote cell fate toward one lineage while repressing the other. Our study demonstrated that Brucella abortus infects MSCs but does not affect the deposition of organic and mineral matrix during osteoblast differentiation. However, the infection upregulates Receptor Activator of Nuclear Factor Kappa-B Ligand (RANKL) expression in osteoblasts, which may contribute to osteoclast activation and bone resorption. Conversely, B. abortus infection significantly influences adipocyte differentiation by modulating lipolysis, lipogenesis, and interactions between lipid droplets and mitochondria. This leads to increased cellular cholesterol levels and reduced intracellular triglycerides, accompanied by glycerol release. These changes result in more differentiated adipocytes and larger lipid droplets. Consequently, we observed increased IL-6 secretion and a higher leptin/adiponectin ratio. Importantly, these effects were independent of a functional type IV secretion system (T4SS), as purified Brucella DNA fully reproduced the adipogenic phenotype. Moreover, inhibition of TLR9—the primary sensor of bacterial DNA—significantly reduced the DNA-induced adipogenic response, demonstrating that adipocyte modulation is at least in part mediated through TLR9 signaling. In summary, B. abortus promotes MSC differentiation toward an inflammatory adipocyte phenotype. It involves a TLR-9-mediated DNA detection. It may contribute to osteoarticular injury and infection-associated bone resorption. Full article

This study evaluated the effects of an Astragalus membranaceus stem and leaf–Angelica sinensis stem and leaf mixture (AASL) as a medicinal feed supplement on immune function, antioxidant status, inflammatory responses, gut microbiota and the serum metabolome in weaned Simmental bull calves. Calves were fed diets containing different levels of AASL, and serum immunoglobulins, inflammatory cytokines, and antioxidant indices were determined. In addition, fecal short-chain fatty acid (SCFA) concentrations, gut microbiota composition, and serum metabolic profiles were analyzed, followed by correlation analyses among the microbiota, SCFAs and metabolites. The results showed that AASL was rich in crude protein, crude fat and trace elements. 4% AASL supplementation increased serum immunoglobulin (IgG and IgM) levels, decreased tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and interleukin-1 beta (IL-1β) levels, and enhanced superoxide dismutase (SOD), glutathione (GSH) and total antioxidant capacity (T-AOC) activities (p < 0.01 or p < 0.001), indicating improved immune and antioxidant status and attenuated inflammatory responses. AASL also enriched beneficial bacterial genera, suppressed potentially harmful taxa, and increased SCFA concentrations. Differential metabolites were mainly enriched in tryptophan metabolism, lipid metabolism, neuroactive ligand-receptor interaction, sphingolipid signaling, and ATP-binding cassette (ABC) transporter pathways. Integrated microbiota metabolite analysis further suggested that AASL improved host metabolic status through the coordinated regulation of gut microbiota, SCFAs production and related metabolic pathways. Overall, AASL shows promise as a functional feed supplement for improving calf health. Full article

Thalassemia is an inherited hemoglobin disorder characterized by chronic hemolytic anemia and substantial long-term healthcare needs. In β-thalassemia major, patients typically require regular red blood cell transfusions with iron chelation to prevent transfusional iron overload. Although supportive care has markedly improved survival, it is associated with a high treatment burden and does not provide a cure. In recent years, curative and disease-modifying therapies have expanded the treatment landscape. Allogeneic hematopoietic stem cell transplantation (HSCT) offers a potentially curative option for selected patients, while autologous gene therapy and gene-editing approaches have shown the capacity to achieve transfusion independence in clinical studies. In parallel, pharmacologic advances—including luspatercept, a transforming growth factor-beta (TGF-β) ligand trap—have been shown to enhance erythropoiesis and reduce transfusion requirements, and emerging agents such as fetal hemoglobin inducers (e.g., thalidomide) and the oral pyruvate kinase activator mitapivat have demonstrated clinically meaningful hemoglobin improvements in selected populations. Adjunctive strategies, including antioxidants, are under investigation to mitigate oxidative stress, and applications of artificial intelligence are increasingly used to support screening, diagnosis, and longitudinal monitoring of iron overload. This review synthesizes recent advances in curative therapies, novel pharmacologic agents, supportive strategies, and AI-enabled tools and highlights priorities for future clinical development and implementation. Full article

Over the past 20 years, the iron-activated persulfate systems have been widely used for removing pharmaceuticals and personal care products (PPCPs) from water. However, slow Fe(III)/Fe(II) redox cycling and precipitation of iron, unless in very acidic conditions, were the main limitations. Thus, two ligand-assisted Fe(III)/persulfate systems, Fe(III)-acetohydroxamic acid (AHA)/peroxydisulfate (PDS) and Fe(III)-nitrilotriacetic acid (NTA)/peroxymonosulfate (PMS), were comparatively investigated for the degradation of atenolol (ATL) in this study. The experimental results showed that the Fe(III)-NTA/PMS system worked much better than the AHA system. However, the cost of PMS is higher than that of PDS, which should be considered. The primary advantage of the NTA system was its ability to overcome the pH limitations. It worked well over a wide pH range (3.0–10.0), whereas the AHA system could only be used in a narrower pH window (pH 2.4 to 6.5). The investigation of radicals that contributed to ATL degradation revealed that sulfate radicals (SO₄^•−) were dominant in the NTA system, while hydroxyl radicals (^•OH) and SO₄^•− were the primary and secondary radicals in the AHA system. These results provided useful insight into the comparative behavior of two ligand-assisted Fe(III)/persulfate systems for ATL degradation, with the Fe(III)-NTA/PMS system showing clear potential under neutral or near-neutral conditions, while Fe(III)-AHA/PDS may still represent a lower-cost option under acidic conditions. Full article

Lipid nanoparticles (LNPs) have become an important platform for the delivery of RNA therapeutics, including messenger RNA (mRNA) and small interfering RNA (siRNA). However, most clinically approved LNP formulations exhibit strong liver tropism following systemic administration, which limits efficient delivery to extrahepatic tissues. This inherent biodistribution profile has therefore been recognized as a key challenge for expanding the therapeutic applications of RNA nanomedicine. Recent efforts have focused on engineering functionalized LNP systems to improve delivery specificity beyond the liver. Surface modification with targeting ligands—such as antibodies, peptides, and nucleic acid aptamers—can promote receptor-mediated uptake by specific immune cell populations, including macrophages, dendritic cells and T lymphocytes. In parallel, advances in lipid design have improved intracellular RNA delivery by facilitating endosomal escape. These developments have broadened the potential use of RNA nanomedicine for inflammatory disorders, including autoimmune diseases, neuroinflammation, and cardiovascular inflammation. Functionalized LNPs are also being investigated for in vivo engineering of immune cells. This review summarizes current strategies for designing functionalized LNP systems, highlights their emerging applications in immune and inflammatory diseases, and discusses key challenges for clinical translation. Full article

Milk is a complex biochemical mixture in which proteins significantly influence the behaviour of xenobiotics and bioactive compounds. Interactions between milk proteins and substances such as veterinary drugs or natural bioactives can modify molecular stability, binding dynamics, and exposure pathways, affecting food safety and the One Health concept. This study presents a comparative, matrix-focused investigation on how three chemically distinct ligand classes, sulfanilamide antibiotics, naturally occurring phenolic compounds and zinc–polyphenol complexes, interact with major milk proteins, β-lactoglobulin and casein. Protein–ligand interactions were examined using steady-state fluorescence spectroscopy to assess quenching behaviour and comparative interaction trends. Molecular docking was employed as a qualitative tool to provide structural context. Distinct interaction patterns were observed across ligand classes, reflecting differences in molecular structure, hydrophobicity, and coordination chemistry. Importantly, zinc coordination modified interaction profiles relative to the corresponding free ligands, indicating that metal coordination can affect ligand–protein interactions within the milk matrix. These findings support the concept that milk proteins may function as matrix-dependent modulators of ligand behaviour. The study is positioned as a hypothesis-generating framework highlighting the importance of food matrices as active biochemical environments. Herein, we provide a foundation for hypothesising how the milk matrix affects residue behaviour and bioactive interactions, with relevance to veterinary pharmacology and food safety risk assessment. Full article

A zinc complex of chelidonic acid (4-oxo-4H-pyran-2,6-dicarboxylic acid) was obtained by reaction with zinc oxide under isothermal conditions. Its composition was confirmed by elemental and thermogravimetric analyses, and its molecular structure was characterized using NMR and IR spectroscopy. Single-crystal X-ray diffraction revealed that the complex crystallizes as a one-dimensional coordination polymer, [ZnChel(H₂O)₄]_n, in the triclinic space group P-1, featuring a distorted octahedral Zn(II) center coordinated by two chelidonate ligands and four water molecules. This six-coordinate arrangement contrasts with previously described tetra-coordinated Zn–chelidonate complexes. Quantum-chemical calculations and molecular dynamics simulations indicated that, in aqueous solution, Zn(II) preferentially forms a monodentate ZnChel(H₂O)₅ species, consistent with the solid-state coordination environment. The interaction of the complex with bovine serum albumin (BSA) was examined by fluorescence, UV–Vis absorption, and circular dichroism spectroscopy, revealing a mixed static–dynamic quenching mechanism, moderate binding affinity, and hydrogen-bonding/van der Waals contributions accompanied by alterations in BSA secondary structure. These results expand the structural chemistry of chelidonic acid and provide biophysical insight into the protein-binding behavior of zinc chelidonate, supporting its potential relevance as a zinc-based bioactive compound. Full article

Multiple studies have demonstrated that the conjugation of various metal cores to a modified tamoxifen vector amplifies its antitumor activity, rendering such engineered structures effective even in triple-negative breast cancer (TNBC), a tumor subtype traditionally considered irrelevant for endocrine therapy. With a focus on TNBC cell line, this study shows that hybrids with Pd- and Cu- in comparison to Pt-based counterparts exerted an advanced cytotoxic profile in terms of sustained cytotoxicity throughout all tested periods, well synchronized with an intensive and prolonged oxidative burst measured by 4-amino-5-methylamino-2′,7′-difluorofluorescein diacetate (DAF-FM), dihydroethidium (DHE), and dihydrorhodamine 123 (DHR-123) in the background. Translation to the orthotopic syngeneic mouse in vivo model confirmed their superiority toward Pt-based conjugates, as well as tamoxifen alone, with a more profound tumor-reducing potential of Cu-tamoxifen, which was finally restricted by its toxicity. Surprisingly, the tamoxifen vector per se, with an approx. 2-fold lower cytotoxic potential than Pt- and Cu-hybrids in vitro, showed exceptional tumor-reducing potential in vivo, profiled in the last days of the treatment period. Intensive infiltration of immune cells, preferentially lymphocytes, was observed in tumor samples from animals exposed to the tamoxifen vector, underscoring the ligand’s immune potential and again suggesting that cytotoxicity is not a measure of successful treatment. Full article

The search for new anticancer agents with improved efficacy and reduced toxicity has intensified interest in metal-based compounds. In this study, two novel palladium(II) complexes, synthesized from Schiff base ligands derived from 5-chloro-salicylaldehyde and p-hydroxybenzylamine or tyramine, were chemically characterized and biologically evaluated. Both complexes exhibited significant cytotoxic activity against the MCF-7 breast cancer cell line in a dose- and time-dependent manner, with Pd2 showing slightly higher potency. Morphological analysis of treated cells indicated that apoptosis is the predominant mechanism of cell death. To gain deeper insight into the potential mechanisms underlying the observed anticancer activity, several biologically relevant targets were investigated. Enzyme kinetics revealed that the complexes act as uncompetitive inhibitors of liver catalase, suggesting a possible role in the induction of oxidative stress. Fluorescence studies demonstrated that Pd2 interacts with CT-DNA through combined intercalative and minor groove binding modes and exhibits significant binding affinity toward human serum albumin, predominantly at Sudlow’s site I. Molecular docking analysis further supported favorable interactions with catalase, estrogen receptor α, and B-form DNA, providing structural insight into the experimentally observed biological effects. Overall, the study explores multiple potential mechanisms of anticancer action, underscoring the promising therapeutic potential of these palladium(II) complexes, while antitumor activity has been initially assessed using a MCF-7 cell line as a preliminary model. Full article

Pathogen manipulation of host behavior is a widespread evolutionary strategy to enhance its transmission, yet whether different pathogens elicit distinct behavioral and molecular responses in the same host remains poorly understood. We performed parallel behavioral assays and comparative transcriptomic analyses on third-instar Lymantria dispar larvae infected with Lymantria dispar multiple nucleopolyhedrovirus (LdMNPV, virus), Staphylococcus aureus (bacterium) and Metarhizium anisopliae (fungus). Climbing height was recorded over 72 h post-infection, and gene expression pattern was profiled using RNA-seq at 72 h. Only LdMNPV infection induced significant, sustained upward climbing behavior among the three pathogen infection groups. All three pathogens activated Toll and IMD immune pathways, but LdMNPV triggered substantially broader transcriptomic reprogramming. Notably, the virus specifically upregulated multiple energy metabolism pathways (nicotinate/nicotinamide metabolism, pyruvate metabolism, TCA cycle and oxidative phosphorylation) and the neuroactive ligand-receptor interaction pathway—a pattern absent in bacterial and fungal infections. LdMNPV drove tree-top disease through a virus-specific, multi-system manipulation strategy that couples metabolic activation with neural signaling modulation. This comparative study reveals fundamental differences in behavioral manipulation across pathogen kingdoms and provides candidate pathways for functional validation. Full article

Tuberculosis (TB) is the leading cause of infectious disease-related death globally. Most TB vaccine strategies have focused on conventional CD4 T cell responses, but to date, these have failed to deliver durable sterilizing protection. Donor unrestricted T cells (DURTs), including CD1-restricted T cells, HLA-E-restricted T cells, MR1-restricted T cells and γδ T cells represent an attractive complementary target for future TB vaccine development. They recognize antigens through conserved, non-polymorphic restricting elements and are therefore broadly targetable across genetically diverse populations. They are also enriched at mucosal sites, have rapid effector and cytotoxic capacities and recognize conserved mycobacterial ligands. Emerging human and animal data support their participation in antimycobacterial immunity and suggest they can be shaped by BCG vaccination and other immunization strategies. Here, we review the evidence for DURT involvement in TB host defense, assess their strengths and current limitations as vaccine targets, and discuss how DURT-directed approaches may help to enable faster, broader, and more durable protection against Mycobacterium tuberculosis. Full article

Temporomandibular disorders (TMDs) are the prevalent causes of orofacial pain and dysfunction of the temporomandibular joint (TMJ) and masticatory muscles. Previous studies have revealed that proinflammatory cytokines play a key role in promoting inflammation, pain, and degeneration within the TMJ. In this context, the present systematic review synthesizes current evidence on various cytokines involved in the pathophysiology of TMDs and evaluates their associations with clinical signs and structural TMJ damage. A PRISMA-guided search (PROSPERO: CRD420251163290) was conducted in PubMed/MEDLINE, Embase, Scopus, and the Cochrane Library to identify human-based, in vivo, and in vitro studies (January 2014 to September 2025) that assessed the roles of proinflammatory cytokines in TMDs. The following data were extracted from the identified studies: cytokine profiles, sampling methods, clinical outcomes, and TMJ structural changes. Study quality and risk of bias were systematically evaluated. A total of 15 studies (clinical, animal, and mechanistic) were included in the review. Tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and interleukin-17 (IL-17) consistently emerged as the major contributors to synovitis, cartilage degradation, nociceptive sensitization, and bone resorption. Human studies showed that high levels of TNF-α, IL-1β, and IL-6 and chemokines such as C-C motif chemokine ligand 2 (CCL2) and regulated on activation, normal T-cell expressed and secreted (RANTES) were associated with TMJ pain, restricted mandibular motion, crepitus, malocclusion, and erosive changes on imaging. An increased ratio of TNF to soluble TNF receptor in synovial fluid correlated with both pain and condylar damage, suggesting that loss of cytokine control contributes to progressive joint destruction. TMDs, particularly inflammatory and degenerative subtypes, are cytokine-driven pathologies rather than purely mechanical disorders. TNF-α, IL-1β, and IL-6 are the promising candidate biomarkers of local inflammation and structural joint pathology. Standardized longitudinal studies are required to validate cytokine-based diagnostics and develop anti-cytokine therapeutics. Full article