Search Results (13,886)

Low-density granulocytes (LDGs) have been implicated in the pathogenesis of several autoimmune diseases, yet their role in Sjögren’s disease (SjD) remains poorly understood. We enrolled 90 SjD patients and 30 healthy controls (HCs) and identified LDGs as CD14^−/lowCD15⁺ cells by flow cytometry, with intracellular interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) staining, and further analyzed CD16 as a maturation marker in LDGs and T helper 17 (Th17) cell frequency. LDG percentages were significantly elevated in active SjD compared with inactive patients (p < 0.001) and HCs (p < 0.0001), and correlated positively with EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI) (r = 0.355, p = 0.0006), erythrocyte sedimentation rate (ESR) (r = 0.325, p = 0.0061), γ-globulin (r = 0.334, p = 0.0177), and Th17 frequency (r = 0.537, p = 0.0068). LDG expansion was accompanied by enrichment of immature CD16^−/low cells (r = −0.798, p = 0.0100). Patients with renal or pulmonary involvement showed higher LDG levels (p = 0.0004), and in SjD -associated interstitial lung disease (SjD-ILD) patients, LDG percentage showed a positive but non-significant trend with serum Krebs von den Lungen-6 (KL-6) levels (r = 0.497, p = 0.102). LDG levels decreased following treatment in longitudinally followed patients, and LDGs from active patients exhibited higher IL-6 and TNF-α production ratios relative to monocytes than those from inactive patients. Stratification by LDG levels revealed significant associations with disease activity, laboratory parameters, and organ involvement. These findings suggest that LDGs are associated with disease activity and organ involvement, may serve as potential biomarkers, and may contribute to the pathogenesis of SjD. Full article

Introduction: Cystinuria is an inherited disorder characterized by impaired proximal tubular reabsorption of cystine, resulting in recurrent cystine stone formation. Mutations in the SLC3A1 and SLC7A9 genes are the main genetic causes of the disease, while variants in PBX1 have also been associated with cystinuria in specific populations. Despite advances in understanding its molecular basis, cystinuria remains clinically heterogeneous, making disease progression and prognosis difficult to predict. This study aimed to investigate circulating microRNAs (miRNAs) as potential molecular biomarkers, characterize their expression profile in patients with cystinuria, and evaluate their association with clinical indicators of disease severity. Methods: The study group included 16 patients with a clinically established diagnosis of cystinuria, while the control group consisted of 11 healthy individuals without a history of nephrolithiasis. Candidate miRNAs were selected based on their predicted regulatory interactions with genes implicated in cystinuria pathogenesis. Eight microRNAs (miR-29a-3p, miR-29b-3p, miR-29c-3p, miR-1207-3p, miR-10a-3p, miR-3658, miR-141-3p, and miR-200a-3p) were analyzed by quantitative real-time PCR (qPCR). Results: Among the eight miRNAs evaluated, miR-10a, miR-141, miR-200a, and miR-3658 were significantly downregulated in patients with cystinuria compared with healthy controls. Higher expression levels of miR-10a, miR-141, and miR-200a were significantly associated with a greater number of previous surgical procedures (p < 0.05). Additionally, increased miR-10a expression was associated with impaired renal function, defined as serum creatinine levels above 1.2 mg/dL. Conclusions: miR-10a, miR-141, miR-200a, and miR-3658 were significantly downregulated in patients with cystinuria compared with healthy controls. Within the cystinuria cohort, higher expression of miR-10a was associated with impaired renal function, whereas increased expression of miR-10a, miR-141, and miR-200a correlated with a greater number of surgical interventions, suggesting a potential relationship with disease severity. Further studies in larger, genetically characterized cohorts are warranted to clarify the biological role and clinical utility of these miRNAs as biomarkers of cystinuria. Full article

Introduction: Cutaneous squamous cell carcinoma (cSCC) is one of the most common skin cancers, with a subset progressing to locally advanced (laSCC) or metastatic (mSCC) stages. The introduction of anti-PD1 immunotherapy has transformed treatment, but real-world data remain limited, particularly in immunosuppressed patients. Methods: This single-centre, retrospective study included 189 patients with advanced cSCC treated between 2012 and 2022. Demographic, clinical, and treatment data were analyzed to assess clinical management and outcomes before and after the introduction of anti-PD1. Results: Among the 189 patients, 72.5% were male, with a median age of 79 years. Overall, 86 patients presented with laSCC and 103 with mSCC. In 100 patients, a preceding primary cSCC was documented, and its complete resection (R0) was associated with significantly better overall survival (OS) after diagnosis of advanced disease (p < 0.001). Immunosuppressed patients, including organ transplant recipients and those with chronic lymphocytic leukemia (CLL), had significantly reduced OS (p = 0.017 and p = 0.0059, respectively). First-line treatment prior to 2018 predominantly involved surgery and radiotherapy. Following the introduction of anti-PD1 therapy, its use increased rapidly in both first- and second-line settings. From 2018 onward, the number of advanced cSCC cases discussed at the multidisciplinary tumorboard increased approximately threefold. Median OS was significantly longer for mSCC patients treated in the post-2018 era (p = 0.025), while the survival disadvantage of CLL patients compared to non-CLL patients widened, suggesting limited benefit from advances in systemic therapy in this subgroup. Best overall response to first-line anti-PD1 correlated significantly with OS, with complete responders achieving a 1-year progression-free survival of 83.3%. Conclusions: The introduction of anti-PD1 has demonstrated improved survival outcomes in advanced cSCC, though significant challenges remain for immunosuppressed patients, particularly those with CLL and solid organ transplant recipients. Future research should focus on optimizing treatment for these high-risk groups, therapeutic sequencing, and the role of perioperative (neoadjuvant and adjuvant) immunotherapy strategies. Full article

Therapeutic cancer vaccines are designed to initiate tumor-specific immunity, yet their clinical success depends not only on antigen selection but also on the capacity to overcome the profoundly suppressive tumor microenvironment. Within tumors, abnormal vasculature, hypoxia, nutrient competition, acidic pH, and suppressive myeloid and stromal cells collectively constrain antigen presentation, T-cell priming, trafficking, and effector function, often converting otherwise immunogenic vaccination into an ineffective immune stimulus. Recent advances in neoantigen discovery, dendritic cell engineering, and nucleic acid-based vaccine platforms have improved the precision of antigen delivery, but these gains remain insufficient unless vaccine-induced responses can be sustained and executed within the hostile metabolic and immunologic landscape of the tumor niche. In this context, the tumor microenvironment is not merely a barrier to be overcome, but an active determinant of vaccine outcome that shapes immune editing, promotes exhaustion, and limits intratumoral expansion of cytotoxic lymphocytes. Accordingly, the most promising therapeutic strategies now combine vaccination with checkpoint blockade, radiotherapy, stromal remodeling, or metabolic reprogramming to recondition the tumor ecosystem and permit productive antitumor immunity. Here, we discuss how tumor microenvironmental constraints govern vaccine performance, review emerging platform technologies, and outline combinatorial strategies aimed at converting immune priming into durable tumor control. Full article

Extramedullary disease (EMD)—the proliferation of clonal plasma cells in soft tissues without direct bone connection—represents one of the most challenging manifestations of multiple myeloma, associated with aggressive biology, treatment resistance, and poor outcomes. EMD is driven by distinct pathophysiologic mechanisms including downregulation of adhesion molecules, acquisition of high-risk cytogenetic abnormalities (del(17p), gain(1q)), activation of the RAS–MAPK pathway, epigenetic dysregulation such as EZH2 upregulation, and remodeling of the immune microenvironment toward an immunosuppressive, T-cell-depleted phenotype. Conventional therapies, including anti-CD38-based regimens, yield limited efficacy in EMD, with pooled overall response rates of approximately 20% in triple-class-exposed relapsed/refractory disease. T-cell-redirecting therapies have emerged as the most promising treatment strategy. Both chimeric antigen receptor (CAR) T-cell therapy and bispecific antibodies have demonstrated clinically meaningful activity in soft tissue EMD, with CAR T-cell therapy providing the deepest and most durable responses, and dual-targeting bispecific combinations showing particularly encouraging efficacy. Central nervous system (CNS) myeloma, the most devastating form of EMD, has historically carried a dismal prognosis. Emerging retrospective data suggest that both CAR T-cell therapy and bispecific antibodies can achieve meaningful CNS responses with acceptable safety profiles, as part of multimodal approaches incorporating CNS-directed therapies. Despite these advances, EMD remains associated with inferior outcomes even in the immunotherapy era, underscoring the need for strategies targeting the immunosuppressive microenvironment, novel therapeutic approaches, and prospective EMD-focused clinical trials. This review provides a comprehensive overview of the biology, classification, and evolving treatment landscape of both non-CNS and CNS EMD in the era of T-cell-redirecting immunotherapy. Full article

Background/Objectives: Recent advances in immunotherapy have revolutionized cancer treatment, as exemplified by multiple monoclonal antibodies against programmed cell death protein 1 (PD-1) or programmed death-ligand 1 (PD-L1). Nevertheless, immunotherapeutic antibodies exhibit certain limitations, which drives the development of alternative approaches, such as small interfering RNA (siRNA)-based therapeutics. The aim of this study was to design and produce new biological PD-L1 siRNA (BioRNA/PD-L1-siRNA) molecules and further define their immunotherapeutic efficacy against non-small cell lung cancer (NSCLC) in vitro. Methods: A novel RNA molecular bioengineering platform was employed to produce new BioRNA/PD-L1-siRNA agents. The functions of BioRNA/PD-L1-siRNAs were determined by quantitative PCR, Western blot, immunofluorescence confocal imaging, flow cytometry, and PD-1/PD-L1 blockade assays in human NSCLC cells, alone and co-cultured with human peripheral blood mononuclear cells (PBMCs). Results: After heterologous overexpression and purification of five BioRNA molecules, one siRNA named BioRNA/PD-L1-siRNA-1 was identified as the most effective to selectively suppress human PD-L1 mRNA and protein levels in H460 and H1975 cells. Disruption of PD-1/PD-L1 interactions by BioRNA/PD-L1-siRNA-1 was further demonstrated via a PD-1/PD-L1 blockade bioassay. In addition, the immunomodulatory effectiveness of BioRNA/PD-L1-siRNA-1 was established in co-culture models, as indicated by the induction of T-cell and natural killer cell populations and an increase in specific cytokines and cytotoxic granules, and subsequent enhancement of apoptosis and greater inhibition of NSCLC cell viability. Conclusions: Overall, these findings demonstrate the potential of bioengineered PD-L1 siRNA entities for NSCLC immunotherapy. Full article

Immune checkpoint inhibitors (ICIs) have translated the scope of cancer therapy, but their immune-restorative mechanism can lead to immune-related adverse events (irAEs), which can affect several organs with varying severity. Early identification of patients at risk of irAEs is prudent to inform clinical decisions in precision oncology and remains a challenge as current clinical and biomarker methods still lack predictive accuracy. Artificial Intelligence (AI) presents a promising strategy for improving early detection, risk stratification as well as monitoring of irAEs. This narrative review summarizes the current AI modalities for detecting and predicting irAEs risk occurring with ICI therapy, including clinical Machine Learning models, radiomics-based approaches, natural language processing (NLP) systems and the integration of modalities with multimodal AI frameworks. Clinical Machine Learning models demonstrate moderate predictive performance whereas radiomics-derived modeling appears promising for pneumonitis. NLP and language models have achieved higher accuracy for retrospective irAEs detection. Multimodal AI applications offer theoretical potential through diverse data integration that captures the complex biology of irAEs; however, current evidence is limited. All these modalities face limitations of inadequate sample sizes, retrospective design, heterogeneous outcome definitions, class imbalance, and insufficient external validation. AI-based models have significant potential for personalized immunotherapy monitoring but require prospective multicenter validation, standardized datasets and clinically interpretable frameworks prior to implementation. Future advances in multimodal modeling can also enable precise prediction and early detection of irAEs, ultimately improving the safety and effectiveness of cancer immunotherapy. Full article

Background: Diabetic ketoacidosis (DKA) remains a preventable yet frequent complication at the onset of type 1 diabetes (T1D) in children, driven by delayed symptom recognition, socioeconomic disparities, and inconsistent access to care. Early identification of presymptomatic T1D through autoantibody-based screening, together with emerging disease-modifying therapies, may reduce the incidence of DKA. This review synthesizes evidence on epidemiology, risk determinants, screening strategies, and immunological interventions relevant to DKA prevention. Methods: A narrative review was conducted using PubMed, EMBASE, Scopus, Web of Science, and Google Scholar (2011–2026). Eligible sources included clinical studies, guidelines, systematic reviews, meta-analyses, and prevention trials addressing staging, screening, epidemiology, and disease-modifying treatments in pediatric T1D. Landmark publications outside this timeframe were included when essential. Evidence was integrated to identify determinants of DKA and strategies to reduce its occurrence. Results: DKA risk is influenced by younger age, socioeconomic disadvantage, rural residence, misdiagnosis, and limited access to specialized care. Sustained public awareness and community-based education reduce DKA incidence, whereas short-term campaigns show transient effects. Structured screening programs, including TrialNet and TEDDY, demonstrate near-elimination of DKA among monitored children. Teplizumab delayed progression from stage 2 to stage 3 T1D by a median of approximately 24 months in the original TN-10 trial, with extended follow-up demonstrating a median delay of 32.5 months. It is approved for individuals with stage 2 T1D aged ≥ 1 year and has recently gained approval for selected patients with newly diagnosed T1D, expanding opportunities for early disease modification. Global networks such as INNODIA strengthen prevention through coordinated biomarker-driven research. Conclusions: Reducing DKA at T1D onset requires integrated, sustained strategies combining public awareness, systematic autoantibody screening, structured follow-up, and access to emerging immunotherapies. Coordinated care across primary providers, pediatric endocrinologists, and research networks is essential to advance a proactive, prevention-oriented model of pediatric T1D care. Full article

Virus-based cancer therapy (virotherapy) is currently being researched as a novel form of immunotherapy and has already entered the clinical application phase. Among various types of virotherapy, oncolytic virotherapy involves infecting tumors with tumor-selective viruses, such as herpes simplex virus, adenoviruses, and vaccinia virus, and utilizing their replicative capacity to induce cell destruction within tumors. In addition, this therapy aims to enhance tumor immunity by changing the tumor microenvironment through viral infection. Genetic deletion in viruses is used to reduce their virulence and confer tumor selectivity, while the expression of foreign genes is utilized to enhance antitumor effects. Oncolytic viruses for head and neck cancer (HNC) are administered locally or systemically and are sometimes used as adjuvant therapy or in combination with immune checkpoint inhibitors. Another form of virotherapy involves non-replicating viruses, which are used to produce antitumor cytokines or as cancer vaccines expressing tumor antigens. Research on the efficacy of cancer vaccines in preventing postoperative recurrence is currently underway. A number of challenges have yet to be overcome for further advances in virotherapy, including the efficient delivery of viruses to tumor cells, avoiding viral inactivation in the bloodstream, ensuring efficient replication of the virus, and enhancing antitumor immunity. The development of effective strategies based on the findings of clinical studies will lead to improvements in virotherapy for HNC. Full article

One of the main issues in oncology is tumor recurrence following resection, which is responsible for a large number of patient deaths and treatment failures in a variety of malignancies. Despite advancements in adjuvant chemotherapy and radiation, residual disease that remains inside or close to the resection cavity and is difficult for systemic therapies to eradicate is the cause of further local recurrence. Hydrogel-nanoparticle (HNP) composites are a new class of therapeutic platforms that emerged from the recent convergence of biomaterial science and nanomedicine. Their specific goals are to fill the surgical gap, provide long-term localized drug release, and energetically remodel the post-surgical tumor microenvironment (TME). This paper includes the biological foundations of localized post-surgical therapy, important physicochemical considerations of the hydrogel matrix and nanoparticle carrier design, and a compilation of mechanistic and preclinical evidence for HNP hybrid platforms. Immunomodulatory strategies, stimuli-responsive release mechanism engineering, and novel techniques, including combination immunotherapy and 3D-printed customized scaffolds, are all given special attention. Examples of translational challenges are also addressed, such as manufacturing repeatability, biocompatibility, and regulatory classification. When considered collectively, the data demonstrate that HNP platforms are a convincing, practically feasible approach to reducing post-surgical recurrence rates and enhancing patient outcomes. Full article

Background: Cetuximab-based therapies continue to play an important role in the management of recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) despite the increasing use of immunotherapy. However, data regarding treatment outcomes and prognostic factors remain limited. This study aimed to evaluate treatment outcomes and prognostic factors associated with survival in patients with R/M HNSCC treated with cetuximab-based regimens. Methods: This retrospective single-center cohort study included patients with recurrent/metastatic HNSCC who received cetuximab-based systemic therapy at the Department of Medical Oncology, Manisa Celal Bayar University Faculty of Medicine, between May 2012 and September 2025. Demographic, clinical, laboratory, and PET/CT data were retrospectively analyzed. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method and compared using the log-rank test. Prognostic factors associated with survival were evaluated using univariable and multivariable Cox proportional hazards regression analyses. Results: A total of 57 patients were included in the study. The median age was 65 years, and 91.2% of patients were male. Most patients had ECOG performance status 0–1 (94.7%) and stage IV disease (71.9%). The larynx was the most common primary tumor site (50.9%), while distant lymph node metastasis (63.2%) and lung metastasis (61.4%) were the predominant metastatic sites. Median PFS and OS were 4.6 months and 13.8 months, respectively. Kaplan–Meier analysis demonstrated that patients with a body mass index (BMI) > 25 had longer OS, whereas chronic kidney disease (CKD), primary tumor localization, and best response to first-line treatment were significantly associated with survival. In multivariable Cox regression analysis, chronic kidney disease (CKD) (HR: 5.15, p = 0.004), oral cavity primary tumor localization (HR: 2.55, p = 0.013), progressive disease as the best response to first-line treatment (HR: 4.44, p < 0.001) and the absence of grade 1–2 cetuximab-related dermatologic toxicity (HR: 3.20, p = 0.027) remained independent adverse prognostic factors. BMI was not independently associated with survival in multivariable analysis. Conclusions: Cetuximab-based therapy demonstrated clinically meaningful activity in patients with R/M HNSCC. Comorbidities, primary tumor localization, the absence of grade 1–2 cetuximab-related dermatologic toxicity and treatment response appear to substantially influence survival outcomes. Larger prospective studies are warranted to validate these findings. Full article

Diffuse midline glioma, H3K27-altered (DMG) is a group of central nervous system (CNS) tumors with no curative treatment options. First described in the early 20th century, prognosis and clinical outcome for patients have changed very little, and the only standard treatment modality remains radiation therapy. The development of targeted therapies against DMG has long been hindered due to the paucity of tumor tissue and disease models for laboratory research. However, access to patient-derived tumor tissue and the subsequent establishment of DMG preclinical models in recent years has led to a deeper understanding of underlying disease mechanisms and aided the development of novel therapeutic agents. Here, we provide an overview of newly established DMG modeling systems in the preclinical setting leading toward immunotherapy clinical trials for patients with DMG. Full article

Small-cell lung cancer (SCLC) is a recalcitrant form of cancer, accounting for 15% of lung cancer cases worldwide. In recent years, the histological transformation from non-small-cell lung cancer (NSCLC) to SCLC has become a significant mechanism of acquired resistance, especially in patients undergoing treatment with tyrosine kinase inhibitors (TKIs) or immunotherapy. Although there is growing clinical understanding, the crucial biological mechanisms that drive this phenotypic switch are still not fully understood. Transformed SCLC (T-SCLC) seems to exhibit differences from de novo SCLC regarding molecular characteristics and tumor microenvironment, indicating unique evolutionary paths. While traditional chemotherapy has been the main treatment method after transformation, patient outcomes continue to be unsatisfactory, highlighting the necessity for a more profound mechanistic insight and the development of more effective treatments. Full article

Background: Successful translation of cancer immunotherapy is underscored by the efficacy of PD-1/PD-L1 and CTLA-4 inhibitors in the treatment of various malignancies. However, their limited efficacy in glioma indicates alternative immune escape mechanisms. We investigated B and T Lymphocyte Attenuator (BTLA), a co-inhibitory receptor structurally and functionally analogous to PD-1, to determine if it constitutes a key, unaddressed mechanism of immune escape and a novel therapeutic target in glioma. Methods: We analyzed BTLA expression and function within the tumor microenvironment of a Moroccan cohort (n = 44). This was complemented by multiparameter flow cytometry on peripheral blood from glioblastoma (GBM) patients (n = 8) to assess circulating T cell profiles. Findings were corroborated using independent transcriptomic datasets from TCGA and CGGA cohorts. Single-cell RNA-seq and citeSeq identified specific BTLA-expressing cell populations. Results: Elevated BTLA expression was significantly associated with aggressive features and poor overall survival in glioma patients. Mechanistically, BTLA levels were positively correlated with pro-tumorigenic factors, immune infiltration, and immunosuppressive checkpoints. Single-cell and citeSeq analyses revealed that BTLA was primarily expressed by exhausted T cells and conventional type 1 dendritic cells (cDC1) within the GBM microenvironment. Crucially, this phenotype was translated systemically; BTLA defined dysfunctional circulating CD8⁺ and CD4⁺ T cells characterized by diminished IFN-γ production, alongside reduced granzyme B and perforin in CD8⁺ T cells. Conclusions: Our findings indicate that BTLA may represent a relevant pathway associated with an immunosuppressive glioma microenvironment. The therapeutic potential of targeting this pathway, particularly in combination with PD-1/PD-L1 blockade, warrants further investigation. Full article

Gynecological malignancies and breast cancer impose substantial health and economic burdens. This review examines how local and systemic microbiota may affect epithelial integrity, inflammation, estrogen metabolism, and immunity. The vaginal ecosystem is the most extensively studied female microbial niche. Cervical cancer serves as the most illustrative clinical example: loss of stable Lactobacillus crispatus dominance and increased prevalence of anaerobic bacteria (anaerobic dysbiosis) are associated with persistent HPV infection, which directly elevates the risk of cervical precancerous lesions. The estrobolome is particularly relevant in endometrial cancer, where intestinal bacterial beta-glucuronidase activity may increase estrogen reabsorption, particularly in obesity and metabolic disease. In ovarian cancer, microbiota is being studied as a possible risk modifier in BRCA1 carriers, but the evidence remains exploratory. In breast cancer, intratumoral bacteria may shape the immune microenvironment, particularly in triple-negative disease. The primary limitation of current research is methodological heterogeneity. Low-biomass samples, such as those from the ovary or endometrium, are highly susceptible to technical contamination. Most studies are cross-sectional and cannot establish causality. Current evidence supports microbiota as a modifier, not a standalone marker or a substitute for standard diagnosis and treatment. Its most plausible near-term role is in multiparameter risk or response models, pending standardized prospective validation. Full article