Search Results (2,261)

Ovarian cancer (OC) is usually diagnosed at an advanced stage, contributing to its high mortality rate. The presence of concurrent bacterial infections in these patients is a common clinical observation, and the mechanisms by which this coinfection influences tumor progression are still not fully understood. This study investigates the role of polydisperse extracellular vesicles (PEVs) secreted by OC cells in response to bacterial components, aiming to elucidate a potential communication pathway between OC and the bacterial microenvironment. We stimulated a human OC cell line in vitro with a fraction of E. coli. Our results show that this bacterial stimulation significantly increases the secretion of PEVs by cancer cells. A subsequent proteomic analysis of these PEVs revealed an enrichment of proteins, including filamin A, filamin B, alpha-enolase, and heat shock cognate 71 kDa protein. In addition, the PEVs displayed protease activity (on fibronectin and gelatin) and phosphatase activity against para-nitrophenyl phosphate, indicating their capacity to alter cellular signaling. This represents a novel mechanism through which bacterial coinfection may influence the biological behavior of OC if bacteria interact with tumor cells, potentially contributing to their aggressiveness and the challenges associated with their treatment. Our work highlights the importance of studying the interplay between the tumor and its associated microbiota to better understand ovarian cancer progression and identify new therapeutic targets. Full article

Background: The AFFINITY trial (NCT05890872) is a prospective, non-randomized, open-label, single-arm study evaluating the safety, immunological impact, and preliminary efficacy of Aliya pulsed electric field ablation in patients with solid tumors. Thirty-one patients were enrolled; thirty received lung lesion ablation prior to continuation on standard-of-care treatment. This manuscript reports six-month local control outcomes and immunological response characteristics. Radiological outcomes were assessed using a modified RECIST 1.1, and immunological impact was evaluated via changes in peripheral blood immunocyte populations and detection of immunoglobulins (Ig) to tumor-associated antigens in serum post-ablation. Methods: Twenty-eight patients underwent radiological assessment of ablated lesions at approximately 1-, 3-, and 6-month post-ablation to evaluate local control. Peripheral blood was collected for immune monitoring using flow cytometry and to detect IgG responses to biopsy-specific and tumor-associated antigens. Results: At 6 months, two cohorts emerged: 12 received ablation only, and 16 received ablation plus systemic and/or focal therapies (radiotherapy or second ablation). In the ablation-only group, imaging showed local control in all ablated lesions (8/12 SD, 4/12 PR), suggesting local efficacy without systemic therapy in those patients. Immunophenotyping showed dynamic changes in circulating immune cells, including T and B cell activation. A subset also exhibited modulation of tumor antigen-specific IgG, indicating a systemic humoral response. Conclusions: This analysis provides preliminary evidence that this form of ablation may promote local tumor control and modulate systemic immune function. These findings support the immunogenic potential of this specialized energy and warrant further investigation. Extended 12-month data for the full cohort will be reported in a future manuscript. Full article

The urgent need for novel therapeutic strategies in triple-negative breast cancer (TNBC)—characterized by absent ER, PR, and HER2 expression—stems from its association with a paucity of effective treatments and an adverse prognosis. This study identifies TNFRSF12A as a key gene specifically overexpressed in TNBC versus other subtypes. Validation with clinical specimens confirmed its exclusive upregulation in TNBC tissues, correlating significantly with worse patient outcomes. Functional enrichment analysis (STRING/DAVID) indicated TNFRSF12A’s primary involvement in pathways positively regulating cell migration, angiogenesis, and hypoxia response. Immune infiltration profiling (TIMER/TISCH2) revealed selective enrichment of TNFRSF12A in cancer-associated fibroblasts (CAFs). Its expression showed a significant positive correlation with the CAF marker FAP (ρ = 0.304) and CAF infiltration levels, but inverse correlations with CD8⁺ T-cell (Cor = −0.165) and B-cell (Cor = −0.164) infiltration. Regarding chemoresistance, elevated TNFRSF12A expression significantly increased sensitivity to docetaxel. Molecular docking simulations further verified direct binding between TNFRSF12A and docetaxel, mediated by hydrophobic interactions and hydrogen bonds. To elucidate the underlying molecular mechanisms, cellular experiments revealed that TNFRSF12A knockdown resulted in (1) significantly compromised angiogenic capacity in HUVEC tube formation assays (p < 0.01); (2) markedly augmented cytotoxicity of T cells against tumor cells (p < 0.05); and (3) reduced cellular sensitivity to docetaxel, as evidenced by significantly elevated IC₅₀ values in CCK-8 assays (p < 0.01). In summary, this study systematically elucidates how TNFRSF12A propels TNBC malignant progression by remodeling the tumor immune microenvironment and promoting angiogenesis. Concurrently, we reveal a TNFRSF12A-mediated chemosensitizing effect towards docetaxel. Therefore, these results are crucial for improving the targeting of TNFRSF12A and developing precise combination treatment regimens to improve outcomes for patients with TNBC. Full article

Treatment paradigms for B-cell lymphomas have evolved significantly in the last decades. Nevertheless, the widespread clinical use of immunotherapy has demonstrated that it invariably leads to the development of resistance. This review outlines the underlying molecular mechanisms of resistance associated with emerging immunotherapeutic strategies, including Chimeric Antigen Receptor (CAR) T cell therapy and bispecific antibodies (BsAbs). In high-grade B-cell lymphomas, nearly 50% of patients progress following CAR T treatment due to host-related factors affecting CAR T cell proliferation and persistence, as well as tumor-intrinsic factors, such as loss of CD19 epitope expression, trogocytosis, and other genomic alterations (e.g., CD19 mutations, chromothripsis, APOBEC mutational activity, and deletions of RHOA). Additional genomic and epigenetic events, including mutations, alternative splicing of CD19, and aberrant promoter methylation, further contribute to resistance. BsAbs, representing an off-the-shelf T-cell-redirecting strategy, have recently shown promising single-agent efficacy with a manageable toxicity profile, predominantly characterized by T cell overactivation syndromes. Similarly to CAR T cell therapy, BsAb resistance arises through diverse mechanisms, such as antigen loss, T cell dysfunction (exhaustion and regulatory T cell activation), tumor-intrinsic alterations (e.g., TP53 mutations and MYC amplifications), and immunosuppressive influences from the tumor microenvironment. These findings underscore the complexity of immune evasion in B-cell lymphomas and highlight the ongoing need to optimize immunotherapeutic strategies and develop combination approaches to overcome resistance. Full article

Background/Objectives: The solitary fibrous tumor is an uncommon benign mesenchymal neoplasm with relatively indolent and rarely metastasizing behavior. This retrospective study includes 26 cases of head and neck solitary fibrous tumors diagnosed between 2017 and 2024. Methods: The morphological examination with Hematoxylin–Eosin staining was completed via immunohistochemical reactions with specific antibodies. Results: The Ki-67 proliferation index had a median of 11.2%, with an interquartile range of 5% to 15%. CD20-positive B-cells had a score of 0 in 50% of cases (n = 26), while CD3 and CD5 T-cells had a score of 3 in 81% of cases (n = 21). CD4-positive T-cells had a majority score of 1 (81%, n = 21). CD8-positive T-cells had a broader distribution: 65% (n = 17) of cases presented a score of 1, 27% (n = 7) a score of 2, and 8% (n = 8) a score of 0. Antigen-presenting dendritic cells and mast cells presented a majority score of 0 in the entire cohort, being undetectable in 85% (n = 22) and 88% (n = 23) of cases, respectively. CD20-positive B-lymphocytes demonstrated moderately strong correlations with the Ki-67 cell proliferation index (r = 0.77). The time to recurrence was most strongly associated with the Ki-67 mitotic index (r = 0.81), CD4-positive (r = 0.85), and CD5-positive T-lymphocytes (r = 0.55), and CD20-positive B-lymphocyte expression (r = 0.68). Conclusions: This research illustrates our experience with head and neck solitary fibrous tumors, the surgical decisions, and the morphological and immunohistochemical features, while reviewing the cases published in English in the specialized literature. Full article

Background/Objectives: Preclinical and clinical evidence supports a chaperone-based vaccination platform for cancer immunotherapy. The objective of this study is to interrogate the next generation of chaperone-based immune modulator, termed Flagrp170, which was constructed by fusing a defined NF-κB-activating microbial sequence with a large stress protein with a superior antigen-holding/presenting property in the setting of antigen-targeted cancer vaccination. Methods: Bone marrow-derived dendritic cells were treated with Flagrp170 protein or an unmodified parental chaperone molecule (i.e., Grp170), followed by an analysis of DC activation and DC-mediated T cell priming using both in vitro and in vivo models. Antitumor vaccine responses in mice receiving tumor antigens (e.g., gp100, Her2/neu) complexed with Flagrp170 or Grp170 were examined through multiple immune assays. The potential use of a Flagrp170-based chaperone vaccine to sensitize tumors to anti-PD-1 therapy was also evaluated. Results: Flagrp170 not only retains the intrinsic ability of the parent chaperone to facilitate antigen cross-presentation, but also acquires a unique capacity to stimulate DCs efficiently through the engagement of TLR5-NF-κB signaling. This chimeric chaperone shows superior activity compared to the unmodified parental molecule, resulting in enhanced DC activation and T cell priming. Vaccination with Flagrp170 complexed to tumor antigens induces a robust T cell response against primary tumors and metastases, a process critically dependent on CD8⁺ DCs. Additionally, the Flagrp170 chaperone vaccine can efficiently generate and expand tumor-reactive T cells. The consequent remodeling of the tumor microenvironment towards a Th1/Tc1 dominant immune phenotype significantly potentiates cancer responsiveness to anti-PD1 therapy. Conclusions: Given the safety and T cell stimulation profiles of the chaperone–antigen complex vaccine already established in our recent clinical trial, this new generation of chaperone cargo, capable of delivering both antigenic targets and pathogen-associated immunoactivating signals simultaneously, represents a promising strategy to potentially improve the low response rates in patients receiving immune checkpoint inhibitors. Full article

The significant side effects associated with platinum-based anticancer agents have driven the continuous pursuit of novel, non-platinum-based metal compounds. Ruthenium-based organometallic compounds have emerged as promising alternatives, owing to their distinctive and adaptable biochemical properties. The research efforts are focused on the development of ruthenacarborane-based anticancer drugs. The combination of ruthenium(II) complexes, recognized for their inherent anticancer potential, with carboranes, boron-rich clusters possessing unique chemical and physical characteristics, and NSAIDs, known to inhibit COX, an enzyme overexpressed in tumors, offers a novel approach for cancer therapy. Consequently, combining these three moieties into a single molecule represents a compelling strategy to develop drugs with a dual mode of action. Herein, we report the synthesis of a series of ruthenacarborane-(η⁶-p-cymene)–NSAID conjugates (4a, 4b, 5b, and 6b) by linking NSAIDs (flurbiprofen, fenoprofen, and ibuprofen) to ruthenacarborane complexes using methylene and ethylene spacers, while maintaining the integrity of the sensitive ester groups present in the system. The synthesized conjugates were thoroughly characterized using multinuclear (¹H, ¹¹B, and ¹³C) NMR spectroscopy. Notably, the conjugates demonstrated low COX inhibition and no cytotoxic potential against different cancer cell lines, probably due to oxidative deactivation confirmed by cyclic voltammetry (CV). This indicates that the conjugation of this type of ruthenacarborane with NSAIDs does not result in novel anticancer drugs. Full article

Background: Glioblastoma (GBM) is a highly aggressive tumor characterized by elevated plasticity and poor differentiation. Platelet-derived preparations such as Concentrated Growth Factors (CGF) are rich in bioactive molecules, but their effects on tumor biology remain underexplored. Methods: U87MG glioblastoma cells were cultured with a conditioned medium obtained from CGF over 14 days (CGF-CM). We analyzed cell viability, morphology, DNA integrity, migration, proliferation, and expression of astrocytic markers. Results: CGF-CM treatment induced early enhancement of cell viability, followed by decreased proliferation and reduced migration at later time points. Morphological analyses revealed astrocyte-like features. The expression of glial fibrillary acidic protein (GFAP), an astrocytic marker, and its α/δ isoform ratio increased over time, while GBM -GBM-associated markers, such as AQP-4 and S100B, were downregulated. Conclusions: Our findings demonstrate that CGF-CM modulates the phenotypic plasticity of U87MG cells and promotes differentiation toward an astroglial-like profile. These results provide a basis for future studies on the modulation of GBM aggressiveness using bioactive autologous derivatives. Full article

Thymic carcinoma (TC) is a rare, aggressive cancer that originates from thymus’s epithelial cells. It distinguishes itself from other thymic epithelial tumors with its unique pathological structure, clinical behavior, and immune characteristics. Immune checkpoint inhibitors (ICIs) targeting the Programmed cell death protein 1/Programmed cell death protein ligand 1 (PD-1/PD-L1) pathway have shown promise in advanced TC, potentially benefiting from frequent PD-L1 overexpression and abundant CD8⁺ tumor-infiltrating lymphocytes (TILs), despite typically low tumor mutational burden (TMB). While ICI monotherapy can achieve disease control in some patients, its overall efficacy is limited and it is associated with a distinct profile of immune-related adverse events (irAEs) which occur less often than in thymomas. The predictive value of biomarkers—particularly PD-L1 expression—remains uncertain, underscoring the importance of consistent assessment criteria. In this review, we summarize evidence on ICI monotherapy as well as combination approaches that incorporate anti-angiogenic agents, chemotherapy, or dual checkpoint blockade. Emerging therapeutic targets—such as CD70, TIM-3, and B7-H4—are also considered in the context of their potential clinical relevance. Finally, we discuss future directions aimed at improving efficacy, extending response durability, and reducing treatment-related toxicity through biomarker-based patient selection and tailored therapeutic strategies. Full article

Burkitt lymphoma (BL) is a rare, aggressive B-cell lymphoma that is characterized by rapid tumor proliferation and frequent extra-nodal involvement. While prompt diagnosis and initiation of highly intensive chemotherapy results in cure rates over 90% in children and adolescents, outcomes in adults are more modest, as comorbidities and advancing age may compromise treatment tolerability. In recent years, intermediate-intensity regimens have been developed for BL. These are highly effective in patients of all ages and associated with significantly less treatment-related toxicity compared to traditional high-dose chemotherapy. This was demonstrated in a recent randomized study of dose-intensive R-CODOX-M/R-IVAC compared to the reduced-intensity DA-EPOCH-R regimen, which was associated with equivalent outcomes but with significantly fewer side effects. Regardless of the chemotherapy platform, CNS involvement at baseline predicts a significantly inferior outcome, and the development of an optimal approach for these patients is an area of unmet need in BL therapeutics. Patients with relapsed or refractory disease following frontline therapy have very short survival times, as currently available salvage options are largely ineffective. In this regard, novel agents such as anti-CD19 CAR-T cells and bi-specific antibodies are under development in BL. It is hoped that progress in novel drug development, alongside improved understanding of BL biology, to further elucidate its genetic and epigenetic vulnerabilities, will lead to improved outcomes for patients in the future. Full article

Background: Seminoma is a malignant germ cell tumor that most commonly involves the testicles but may involve the mediastinum, the retroperitoneum, and other extra-gonadal sites as well. This study aims to investigate the somatic genomic landscape of seminoma. Methods: Data for a retrospective observational analysis of seminoma was acquired from the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) with clinical and genomic data from 2017 and beyond. Using the R and R Studio software (R 4.5.0), analyses for common somatic mutations and copy number alterations were run with a statistical significance of p < 0.05. Results: The most mutated genes included KIT (22.6%), KRAS (17.1%), and MTOR (5.1%), with significant copy number alterations in CDKN1B (17.2%), KRAS (14.7%), CCND2 (10.3%), and H3F3C (9.8%). These suggest involvement within the KIT/RAS/MAPK and PI3K/AKT/mTOR (PAM) pathways for seminoma development. A novel finding within comparative evaluation of PMS1 and AMER1 mutations were found in Black individuals. Additionally, our findings were consistent with a lower testicular cancer rate among individuals with African ancestry than European ancestry. BRD4 mutations were found only in metastatic samples while KMT2C, STAG2, ALK, AXL, and EGFR were only found in primary samples, suggesting a possible association. Conclusions: This study provided a comprehensive molecular and genetic profiling of seminoma including key genetic alterations, affected pathways, and potential therapeutic strategies. Moreover, overlap between pathways and gene mutations provides the potential for alternative treatment options for seminoma via multiple pathways. Full article

Background/Objectives: The larvae of Protaetia brevitarsis seulensis (PB), an edible insect, exhibit diverse bioactivities, but their effects on inflammatory bone loss remain unclear. We investigated whether a 70% ethanol extract of PB larvae (PBE) suppresses osteoclast differentiation and bone loss under inflammatory conditions. Methods: Osteoclast differentiation was assessed in co-cultures of mouse bone marrow cells and osteocytic cells stimulated with interleukin-1 (IL-1). Direct effects on osteoclast precursors were tested in bone marrow–derived macrophages exposed to receptor activator of nuclear factor-κB ligand (RANKL) or tumor necrosis factor-α (TNF-α). Skeletal effects were evaluated in a mouse model of lipopolysaccharide (LPS)-induced bone loss. Results: PBE inhibited IL-1–induced osteoclast differentiation in co-culture, reduced osteocytic RANKL expression and prostaglandin E2 (PGE2) production, and dampened early IL-1 signaling. In osteoclast precursors, PBE directly suppressed osteoclastogenesis driven by RANKL or TNF-α. In vivo, PBE attenuated LPS-induced bone loss and blunted the associated increases in bone RANKL and PGE2. Conclusions: PBE limits inflammatory osteoclastogenesis by downregulating PGE2 and RANKL production in osteoclast-supporting cells and directly inhibiting osteoclast precursor differentiation, thereby attenuating LPS-induced bone loss. These findings identify PBE as a food-derived candidate for managing inflammation-associated bone loss and support further preclinical and nutritional intervention studies. Full article

Background: Esophageal cancer remains a highly aggressive malignant tumor with poor prognosis, despite advances in combination therapies and novel immunotherapies. Tertiary lymphoid structures (TLSs), characterized by densely packed CD20⁺ B cells in a germinal-center-like structure, have recently been recognized as immune-stimulating components within the tumor microenvironment. In contrast, cancer-associated fibroblasts (CAFs) are stromal cells expressing fibroblast-activating protein (FAP) involved in immunosuppression. Methods: In this retrospective study, 124 clinical samples from patients who underwent radical surgery for esophageal cancer at our institute were analyzed. We investigated whether TLSs could serve as a prognostic factor and examined their association with tumor microenvironment factors. Results: The presence of TLSs was an independent prognostic factor for overall and progression-free survival in multivariate analyses. A high level of TLS formation correlated with better nutritional status, fewer M2 macrophages, and greater plasma cell infiltration. Additionally, little TLS formation was observed in areas with abundant CAFs, and quantitative analyses revealed a significant negative correlation between TLSs and CAFs. Conclusions: TLSs enhance antitumor immunity via macrophages and plasma cells and can be a valuable prognostic indicator in patients undergoing surgery for esophageal cancer. Targeting CAFs may prove to be a promising therapeutic strategy to enhance tumor-immunity-related TLSs. Full article

Psoriasis is a chronic inflammatory skin disease characterized by keratinocyte hyperactivation and dysregulated cytokine signaling, with nuclear factor kappa B (NF-κB), a master transcription factor that regulates immune and inflammatory gene expression, playing a central role. Adalimumab, a monoclonal antibody that inhibits tumor necrosis factor alpha (TNF-α), is widely used in psoriasis therapy, yet its molecular effects on NF-κB-associated genes and microRNAs (miRNAs) in keratinocytes remain insufficiently defined. In this study, immortalized human keratinocytes (HaCaT cells) were exposed to lipopolysaccharide (LPS) to induce inflammatory stress and treated with adalimumab for 2, 8, and 24 h. Transcriptome-wide profiling was performed using messenger RNA (mRNA) and miRNA microarrays, followed by validation with reverse transcription quantitative polymerase chain reaction (RT-qPCR) and enzyme-linked immunosorbent assay (ELISA). Bioinformatic analyses included prediction of miRNA–mRNA interactions, construction of protein–protein interaction (PPI) networks, and gene ontology (GO) enrichment. Adalimumab reversed LPS-induced upregulation of NF-κB-associated genes, including inhibitor of nuclear factor kappa-B kinase subunit beta (IKBKB), interleukin-1 receptor-associated kinase 1 (IRAK1), TNF receptor-associated factor 2 (TRAF2), mitogen-activated protein kinase kinase kinase 7 (MAP3K7), and TNF alpha-induced protein 3 (TNFAIP3), with concordant changes observed at the protein level. Several regulatory miRNAs, notably miR-1297, miR-30a, miR-95-5p, miR-125b, and miR-4329, showed reciprocal expression changes consistent with anti-inflammatory activity. STRING analysis identified IKBKB as a central hub in the PPI network, while GO enrichment highlighted immune regulation, apoptosis, and NF-κB signaling. These findings demonstrate that adalimumab modulates NF-κB activity in keratinocytes through coordinated regulation of gene, protein, and miRNA expression, providing mechanistic insight into TNF-α blockade in psoriasis. Full article

For patients with metastatic uveal melanoma (UM), tebentafusp is currently the only systemic therapy approved by the EMA and FDA, but its use is limited to HLA-A*02:01-positive individuals. Immune checkpoint blockade (ICB) represents another option, though only a small subgroup of patients benefits, and no reliable predictive biomarkers are available to date. The aim of this study was therefore to identify parameters associated with favorable ICB response. Tumor samples and clinical data from 30 patients were analyzed. Group A (n = 16) showed clinical benefit, while Group B (n = 14) experienced disease progression. NanoString^® analyses revealed 258 upregulated genes in Group A, including IDO1, CD28, and CCL8. The enriched pathways were predominantly linked to immune activation, leukocyte adhesion, and responses to external stimuli. Immunohistochemistry confirmed significantly higher CD28 expression on infiltrating immune cells in Group A, while a machine learning approach identified CCL8 as a predictive marker with ~78% accuracy. Overall survival differed significantly between the groups. These findings indicate that patients responding to ICB display tumors with enhanced immune activation. CD28 and CCL8 emerged as promising candidates and should be validated in prospective studies to determine their clinical utility. Full article