Search Results (4,120)

Background/Objectives: Breast cancer remains a leading cause of cancer-related mortality among women worldwide, necessitating novel therapeutic strategies. This study aimed to investigate the synergistic antitumor effects of caerin peptides (F1/F3) combined with dendritic cell (DC) vaccines in a 4T-1 murine breast cancer model, providing new insights for breast cancer immunotherapy. Methods: In vitro experiments evaluated the effects of F1/F3 on 4T-1 cell proliferation and apoptosis. A 4T-1 breast cancer mouse model was established, and treatments included F1/F3 alone, DC vaccines (DCV₁: loaded with whole tumor antigens; DCV₂: loaded with F1/F3-induced apoptotic antigens), or combination therapy. Flow cytometry analyzed immune cell subsets in the tumor microenvironment and lymph nodes, while ELISA measured cytokine levels. Results: F1/F3 significantly inhibited 4T-1 cell proliferation and induced apoptosis while suppressing tumor growth and lung metastasis in vivo. Flow cytometry revealed increased infiltration of CD4⁺ T cells and cDC₁ in tumors, along with reduced PD-L1 expression. DCV₂ exhibited stronger T-cell proliferation induction and lower IL-10 secretion in vitro. Combination therapy with DCV₂ and F1/F3 demonstrated superior tumor suppression compared to monotherapy. Conclusions: F1/F3 enhances antitumor immunity by modulating the tumor microenvironment, and its combination with DCV₂ yields synergistic effects. This study provides experimental evidence for combination immunotherapy in breast cancer, with potential for further optimization of DC vaccine design to improve efficacy. Full article

Background/Objectives: Checkpoint inhibitors (ICIs) are key therapies for NSCLC, but current selection criteria, such as excluding mutation carriers and assessing PD-L1, lack sensitivity. As a result, many patients receive costly treatments with limited benefit. Therefore, this study aimed to predict which NSCLC patients would achieve durable survival (≥24 months) with immunotherapy. Methods: A comprehensive ensemble radiomics approach was applied to pretreatment CT scans to prognosticate overall survival (OS) and predict progression-free survival (PFS) in a cohort of 220 consecutive patients with inoperable NSCLC treated with first-line ICIs (pembrolizumab or atezolizumab, nivolumab or prolgolimab) as monotherapy or in combination. The radiomics pipeline evaluated four normalization methods (none, min-max, Z-score, mean), four feature selection techniques (ANOVA, RFE, Kruskal–Wallis, Relief), and ten classifiers (e.g., SVM, random forest). Using two to eight radiomics features, 1680 models were built in the Feature Explorer (FAE) Python package. Results: Three feature sets were evaluated: clinicopathological (CP) only, radiomics only, and a combined set, using 6- and 12-month PFS and 24-month OS endpoints. The top 15 models were ensembled by averaging their probability scores. The best performance was achieved at 24-month OS with the combined CP and radiomics ensemble (AUC = 0.863, accuracy = 85%), followed by radiomics-only (AUC = 0.796, accuracy = 82%) and CP-only (AUC = 0.671, accuracy = 76%). Predictive performance was lower for 6-month (AUC = 0.719) and 12-month PFS (AUC = 0.739) endpoints. Conclusions: Our radiomics pipeline improved selection of NSCLC patients for immunotherapy and could spare non-responders unnecessary toxicity while enhancing cost-effectiveness. Full article

Despite broad anti-cancer efficacy as Toll-Like Receptor (TLR) 7/8 agonists, imidazoquinolines remain limited in use via systemic administration or in situ vaccination therapies due to inflammatory toxicity. One approach to address this challenge involves better targeting the action of imidazoquinolines by caging them as glycoconjugate prodrugs. Within cancer cells, imidazoquinoline glycoconjugates are activated by hydrolases prior to efflux by ABC transport proteins, where they then elicit tumoricidal effects from the assistance of bystander immune cells, such as tumor-infiltrating lymphocytes and associated macrophages, in local proximity. While this concept of Bystander-Assisted ImmunoTherapy (BAIT) has been established at a molecular level in vitro, tolerability or efficacy of BAIT has not been reported in vivo. Here, we evaluate the MTD and tumor growth delay efficacy of a lead BAIT prodrug (BAIT628) in a male C57BL/6 mouse TRAMP-C2 prostate cancer model to further establish this methodology. Overall, we find that systemic BAIT628 is well tolerated at over 5-fold the dose-limiting inflammatory toxicity of the parent imidazoquinoline (up to 5 mg/mouse/day I.P. for 10 days). Analyzing serum cytokines reveals that IL-10 production, elicited by the mannoside caging group, likely contributes to the enhanced MTD. Using BAIT628 as an in situ vaccination immunotherapy (seven times over 3 weeks) resulted in significant tumor growth delay and increased survival, both alone and in combination with a murinized α-PD-L1 checkpoint blockade. The tumor histology of tumor-infiltrating immune cell subsets (CD4⁺, CD8⁺, CD11c⁺) reveals significant increases in CD11c⁺ populations, consistent with TLR7/8 agonism. Overall, BAIT628 is well tolerated and exhibits significant efficacy in the TRAMP-C2 model. These results demonstrate how the BAIT approach can optimize imidazoquinolines for in vivo tolerability and subsequent efficacy as cancer immunotherapeutics. Full article

Lung adenocarcinoma (LUAD) remains a leading cause of cancer-related mortality, necessitating the identification of novel biomarkers for improved prognosis and diagnosis. This study investigates the role of epoxide hydrolase 4 (EPHX4), a member of the epoxide hydrolase family, in LUAD. Using data sourced from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases, which were subsequently validated by the Gene Expression Omnibus (GEO), we analyzed levels of EPHX4 expression, mutation, and methylation in tumors versus normal tissues. Our findings revealed a significant upregulation of EPHX4 in LUAD tissues compared to normal lung tissues (p < 0.001), correlating with poorer overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI). Furthermore, EPHX4 exhibited considerable diagnostic potential, as demonstrated by an area under the curve (AUC) of 0.854 in a Receiver Operating Characteristic (ROC) analysis. Notably, EPHX4 expression was associated with immune infiltration, specifically Th2 cells, neutrophils, and macrophages, along with immune checkpoint molecules including PD-L1, PD-L2, and TIM-3. Additionally, EPHX4 was involved in pivotal tumor-associated pathways, particularly cell cycle regulation. In conclusion, an elevated EPHX4 expression is indicative of poorer prognosis in LUAD and may play a role in immune evasion and cell cycle dysregulation, highlighting its potential as a promising biomarker for the diagnosis and prognostic prediction of LUAD. Full article

Background: With its incidence on the rise, a high mortality rate, and great costs associated with its treatment, melanoma represents an important challenge for healthcare systems, clinicians, and pathologists. Therefore, an emphasis should be placed on its early and correct diagnosis, as well as the appropriate assessment of prognostic and predictive factors. Immunohistochemistry (IHC) is an ancillary test that can provide invaluable information for diagnosing melanoma, especially in complex cases. Objective: The aim of this systematic review is to gather the available information regarding the use of IHC markers in the diagnosis, differential diagnosis, prognosis, staging, and treatment of melanoma in a format that is easy to access for clinicians and pathologists. Methods: A comprehensive search of the literature was conducted and resulted in one hundred and forty-seven studies being included in this systematic review. The results were grouped thematically by specific IHC markers. Results: The IHC markers specific to melanocytic differentiation, like S100, SOX10, and Melan-A/MART1, were consistent across studies as being positive in most cases of melanoma, with rare exceptions. HMB-45 and PRAME can provide additional information, especially for differential diagnoses between benign and malignant melanocytic lesions. MITF, Ki67, BRAF, and PD-L1 are associated with prognosis factors, like the Breslow thickness, tumour ulceration, type of inflammatory infiltrate, and response to treatment. Conclusions: IHC markers are an invaluable tool for the diagnosis and differential diagnosis of melanoma, especially in cases that lack the characteristic histopathological aspects. In addition, IHC provides prognostic factors and can help in predicting the tumour’s response to various treatments. Full article

Background: The predictive value of muscle-related indicators in triple-negative breast cancer (TNBC) patients undergoing neoadjuvant chemotherapy (NAC) remains unclear. This study aimed to evaluate the association between the skeletal muscle density (SMD) and clinical variables related to the physical reserve with respect to its impact on the pathologic complete response (pCR). Methods: We retrospectively analyzed TNBC patients who underwent NAC at Seoul St. Mary’s Hospital, Catholic University of Korea, from March 2021 to March 2024, via receiving paclitaxel/carboplatin followed by doxorubicin/cyclophosphamide, with or without pembrolizumab. Muscle indices were assessed from CT measurements of the entire cross-sectional muscle area at the L3 level using commercial deep learning software (ClariMetabo version 1.03). Results: A total of 144 patients were included, where 102 received chemoimmunotherapy (NACIT) and 42 received chemotherapy alone (NACT). A higher SMD was significantly associated with a younger age, lower BMI, and fewer comorbidities. In the NACIT group, patients in the high-SMD group (n = 68) demonstrated a higher relative dose intensity (p = 0.003) and improved pCR rates (63.2% vs. 44.1%, p = 0.066) compared with the low-SMD group (n = 34). The multivariable regression analysis identified a higher SMD (per 5-unit increment: OR = 1.67, p = 0.003) and increased PD-L1 combined positive score (per 10-unit increment: OR = 1.38, p = 0.019) as independent predictors of a pCR. The event-free survival was significantly longer in the high-SMD group (p = 0.017) and among patients that achieved a pCR (p < 0.001). In the NACT group, the SMD was not associated with a pCR or survival. Conclusions: The CT-measured SMD reflected the physical reserve in the TNBC patients that received NAC. Alongside the CPS, SMD may serve as a predictive marker for NACIT efficacy. Full article

Background and Objectives: Neuronal nitric oxide synthase (nNOS) overexpressed in melanoma plays a critical role in disease progression. Our previous studies demonstrated that nNOS inhibitors exhibited potent anti-melanoma activity and regulated PD-L1 expressions in the presence of interferon-gamma (IFN-γ). However, the role of nNOS in the melanoma immune response has not been well defined. Methods: Changes in gene expression profiles after nNOS inhibitor treatment were determined by transcriptomic analysis. A melanoma mouse model was used to determine the effects of nNOS inhibition on peripheral T cells and the in vivo anti-tumor activity of combining nNOS inhibitors with immune checkpoint blockade. Changes in human T cell activation through interleukin-2 (IL-2) production were investigated using an ex vivo co-culture system with human melanoma cells. Results: Cellular RNA analysis revealed significant changes in the genes involved in key signaling pathways after nNOS inhibitor HH044 treatment. Immunophenotyping of mouse peripheral blood mononuclear cells (PBMCs) after prolonged HH044 treatment showed marked increases in CD4⁺ and CD8⁺PD-1⁺ T cells. Ex vivo studies demonstrated that co-culturing human PBMCs with melanoma cells inhibited T cell activation, decreasing IL-2-secreting T cells both in the presence and absence of IFN-γ. PBMCs from a significant portion of donors (7/11, 64%), however, were reactivated by nNOS inhibitor pretreatment, displaying a significant increase in IL-2⁺ T cells. Distinctive T cell characteristics were noted at baseline among the responders with increased CD4⁺RORγt⁺ and reduced CD4 naïve T cells. In vivo mouse studies demonstrated that nNOS inhibitors, when combined with PD-1 blockade, significantly reduced tumor growth more effectively than monotherapy. Additionally, the median survival was extended from 43 days in the control mice to 176.5 days in mice co-treated with HH044 and anti-PD-1. Conclusions: Targeting nNOS is a promising approach to enhancing the anti-melanoma activity of immune checkpoint inhibitors, not only interfering with melanoma biological activities but also regulating the tumor microenvironment, which subsequently affects T cell activation and tumor immune response. Full article

Background/Objectives: Occupational therapy (OT) plays a crucial role in addressing functional limitations and promoting independence in Parkinson’s disease (PD) patients. OT interventions target motor skills, daily activities, and engagement in meaningful tasks. Telehealth, the remote delivery of healthcare services, has expanded access to rehabilitation, including OT for PD. While several studies have examined the benefits of online OT, a comprehensive assessment of its impact on functional outcomes and quality of life (QoL) is needed. This review aimed to evaluate the effects of online OT interventions on functional outcomes and QoL of patients with PD. Methods: This review employed a systematized approach, guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) framework, though it did not constitute a full systematic review or meta-analysis. A comprehensive search was conducted across PubMed, Web of Science, Scopus, and Embase databases between August 2023 and September 2024. The search targeted randomized controlled trials (RCTs) investigating telerehabilitation interventions in OT for individuals with PD. Studies were excluded if they were not published in English, did not employ an RCT design, or lacked a focus on telerehabilitation within the scope of occupational therapy for PD. Additionally, systematic reviews, meta-analyses, qualitative studies, and studies without measurable outcomes were excluded. Nine studies met the inclusion criteria, with four involving occupational therapists directly and five evaluating interventions within the scope of OT practice. Results: The primary outcomes of this review focused on mobility improvements in PD patients, assessed through gait metrics such as gait speed, stride length, and gait variability. Secondary outcomes evaluated the impact of telerehabilitation on QoL, using tools such as the Parkinson’s Disease Questionnaire (PDQ-39) and other disease-specific instruments. The findings demonstrated that online OT interventions significantly improved motor skills, cognitive function, and activities of daily living in PD patients. Furthermore, these interventions enhanced overall well-being and QoL. The remote format fostered sustained engagement and adherence to therapy, contributing to better long-term outcomes. Conclusions: Online OT interventions show promising potential for improving functional outcomes and QoL in PD patients. These findings underscore the potential of telehealth to expand access to OT services, thereby enhancing long-term rehabilitation outcomes for this population. Full article

The PD-L1/PD-1 signaling axis is a pivotal regulator of T-cell activity and a key mechanism by which tumors evade immune surveillance. Inhibiting this pathway has resulted in significant anti-tumor responses, establishing immune checkpoint blockade (ICB) as a crucial component of modern cancer therapy. However, many patients with high PD-L1 expression do not respond to PD-1/PD-L1 blockade, underscoring the necessity for a deeper investigation into the mechanisms underlying this resistance. Recent studies have identified DRG2 as a critical modulator of anti-PD-1 therapeutic efficacy. While DRG2 depletion enhances IFN-γ signaling and increases the overall PD-L1 levels, it disrupts the recycling of endosomal PD-L1, resulting in reduced surface expression and impaired PD-1 interaction, ultimately compromising therapeutic outcomes. Furthermore, TRAPPC4, HIP1R, and CMTM6 help stabilize PD-L1 by preventing lysosome degradation. When depleted, these proteins have been shown to boost the body’s immune response against tumors. Research into the complex regulatory mechanisms of PD-L1 suggests that targeting DRG2, TRAPPC4, HIP1R, and CMTM6 could enhance the effectiveness of PD-1/PD-L1 blockade therapies. This strategy could create exciting new possibilities for cancer immunotherapy and improve patient outcomes. Full article

Assessment of Programmed Death-Ligand 1 (PD-L1) immunohistochemical (IHC) expression on tumor cells (TCs) and immune cells (ICs) in bladder cancer (BC) is challenging. Artificial Intelligence (AI) has potential for accurate PD-L1 IHC scoring, but its efficiency remains debatable. Our aim was to compare two AI protocols provided by the free QuPath software (v0.5.1) (Selected Area Interpretation (AI-SAI) and Whole Slide Imaging (AI-WSI)) with manual PD-L1 IHC scoring. A total of 43 BCs were included. PD-L1 IHC was performed using the SP263 clone. The IHC slides were digitized and further imported into QuPath. The PD-L1 positivity threshold was set at 25%. Statistically significant correlations were observed between AI-SAI and manual interpretation for both TCs (r = 0.85) and ICs (r = 0.57). AI-WSI yielded comparable results, with correlation coefficients of r = 0.82 for TCs and r = 0.56 for ICs. However, AI-SAI demonstrated stronger agreement with manual assessment (κ = 0.86) compared to AI-WSI (κ = 0.65). Receiver Operating Characteristic (ROC) analysis further supported the superiority of AI-SAI, with higher AUC values for both TCs (0.96 vs. 0.92) and ICs (0.92 vs. 0.90). Our findings indicate that AI-SAI is preferable to AI-WSI, particularly in BC cases with high PD-L1-positive TC content. Nevertheless, supervision by an experienced pathologist is mandatory. Full article

Background: Cancer immunotherapy has advanced, yet therapeutic resistance and low response rates remain problematic. This study explores histone deacetylase inhibitors (HDACis) as adjuvants for cancer vaccines to enhance anti-tumor immunity and overcome these challenges. Methods: A comprehensive review of relevant literature was conducted. Studies on the immunomodulatory mechanisms of HDACis, their effects on Individualized neoantigen therapy (INT), and clinical applications were analyzed. Results: HDACis enhance anti-tumor immunity through multiple mechanisms. They activate endogenous retroelements, expanding the “antigen repository”. HDACis also upregulate MHC class I and II molecules, enhance the antigen processing machinery, improve MHC—I complex stability, and remodel the tumor immune microenvironment. Early clinical trials of HDACis combined with peptide vaccines show promising safety and immunological responses. However, challenges exist, such as HDACi-mediated PD-L1 regulation, optimal sequencing strategies, and biomarker development. Conclusions: The combination of HDACis and cancer vaccines has significant potential in cancer immunotherapy. Despite challenges, it offers a new approach to overcome tumor heterogeneity and immune evasion, especially for patients with limited treatment options. Further research on toxicity management, triple-drug combinations, biomarker identification, and delivery systems is needed to fully realize its clinical benefits. Full article

Marfan syndrome is caused by a mutation in the FBN1 gene encoding fibrillin-1. This extracellular matrix glycoprotein, which assembles into microfibrils, is best known for its scaffolding role in the production of elastic fibers responsible for connective tissue elasticity and tensile strength. Research into Marfan syndrome mainly focuses on the pathophysiology involved in the degeneration of elastin-rich elastic fibers, which are essential components of the aortic wall. However, fibrillin-1 also exists in elastin-poor (elaunin) or elastin-free (oxytalan) microfibril bundles that were first described in the periodontal ligament (PDL). This dynamic, densely cellular, and highly vascularized tissue anchors teeth in their bone sockets and acts as a protective shock absorber during chewing. Current knowledge suggests that fibrillin microfibrils mechanically support blood vessels in the PDL and ensure their proper functioning. However, many more insights on the roles of fibrillin, especially independently of elastin, can be extracted from this tissue. Here, we review the phenotypic and functional characteristics of the PDL in connection with fibrillin-1, focusing on those related to microvessels. This review aims to shed light on this often-overlooked fibrillin-rich resource as a model for future studies investigating fibrillin functions in health and Marfan disease. Full article

Introduction: Prostate cancer has been generally resistant to immunotherapy approaches. Radiation can be immunostimulatory, but the extent to which standard prostate cancer treatments induce immune activation has not been well described. The bone-targeted radiopharmaceutical Radium223 (Ra223) has been proposed to enrich immune function, but clinical studies have not fully delineated whether this is true, or by what mechanisms. Enzalutamide has been shown to increase PD-L1 expression on dendritic cells, which could impact immune activation, though the extent to which this is associated with other evidence of immune activation remains uncertain, and combination strategies remain of interest. We performed a randomized phase II trial to evaluate whether Radium223 (Ra223) added to enzalutamide would induce greater immune activation and clinical responses compared to enzalutamide alone in men with metastatic castration-resistant prostate cancer (mCRPC). Methods: Eligible patients were randomized 2:1 to Arm A (enzalutamide 160 mg PO daily + Ra223 55 kBq/kg IV q4 weeks × 6 doses) or Arm B (enzalutamide 160 mg PO daily). Blood was collected at treatment start and during treatment to measure soluble immune checkpoint biomarkers (BTLA, TIM3, HVEM, GITR, LAG3, PD-1, CTLA-4, PD-L1, PD-L2, ICOS). Immunophenotyping by mass cytometry time of flight (CyTOF) was performed to measure peripheral blood mononuclear cell populations before and after treatment. CyTOF was used to determine changes in circulating immune cell population subsets before and after treatment. Biopsies were performed of an active bone metastatic lesion prior to study treatment and after at least 3 months. IHC was subsequently performed to examine changes in immune cell population subsets before and after treatment, and changes in pSTAT3 levels. Results: In total, 30 patients were enrolled, with median age 68. The median duration of follow up was 36 months. PSA responses, PFS, and OS were not significantly different between the two arms; however, the study was not powered for clinical endpoints. Peripheral blood and bone biopsy specimens were analyzed for immune correlatives. Soluble receptor concentrations showed significantly increased expression of PDL-2 in the combination arm, but this was not seen on CyTOF. Otherwise, there were no significant differences in markers of immune activation/exhaustion or immune cell population subsets in the combination arm and enzalutamide monotherapy arm. IHC also did not show a significant difference in immune cell population subsets in bone biopsy specimens before and after treatment in both arms. However, treatment with the combination arm did show significantly increased levels of pSTAT3 (p = 0.04), which was not seen in the enzalutamide monotherapy arm. Conclusions: Our study showed an overall lack of evidence for immune activation or cytokine induction with the combination, which does not make a strong case for combinatorial immunotherapy approaches. However, the combination did induce higher levels of pSTAT3, which has been implicated in radio-resistance. Therefore, the addition of a STAT3 inhibitor to the combination may be of interest to improve efficacy. Full article

Soybean (Glycine max L.) is a vital grain and oil crop, serving as a primary source of edible oil, plant-based protein, and livestock feed. Its production is crucial for ensuring global food security. However, soybean yields are severely impacted by various diseases, and the development of disease-resistant cultivars remains the most sustainable strategy for mitigating these losses. While stable genetic transformation is a common approach for studying gene function, virus-induced gene silencing (VIGS) offers a rapid and powerful alternative for functional genomics, enabling efficient screening of candidate genes. Nevertheless, the application of VIGS in soybean has been relatively limited. In this study, we established a tobacco rattle virus (TRV)-based VIGS system for soybean, utilizing Agrobacterium tumefaciens-mediated infection. The TRV vector was delivered through cotyledon nodes, facilitating systemic spread and effective silencing of endogenous genes. Our results demonstrate that this TRV–VIGS system efficiently silences target genes in soybean, inducing significant phenotypic changes with a silencing efficiency ranging from 65% to 95%. Key genes, including phytoene desaturase (GmPDS), the rust resistance gene GmRpp6907, and the defense-related gene GmRPT4, were successfully silenced, confirming the system’s robustness. This work establishes a highly efficient TRV–VIGS platform for rapid gene function validation in soybean, providing a valuable tool for future genetic and disease resistance research. Full article

Background: Parkinson’s disease (PD) affects both motor and non-motor functions, but their interactions are understudied. This study aims to explore the relationships between non-motor and motor effects of PD, focusing on depression, fatigue, gait parameters, concentration, and physical function. Methods: This is a secondary analysis of baseline data from a randomized feasibility study using a commercially available Heel2Toe™ sensor, providing auditory feedback for gait quality. The sample included PD patients with gait impairments who walked without aids. Non-motor measures were depression, fatigue, and concentration, while motor measures included gait quality (angular velocity and variability during heel strike, push-off, foot swing) and physical function (6MWT, Mini-BESTest, Neuro-QoL). Path analysis was used to assess direct and indirect effects. Results: Among 27 participants, fatigue impacted heel strike, which affected Neuro-QoL. Mood influenced push-off and Neuro-QoL, with a direct link to 6MWT. Foot swing affected Mini-BESTest and Neuro-QoL directly. Conclusions: Non-motor PD effects directly influenced specific gait parameters and physical function indicators, highlighting potential digital biomarkers of fatigue and mood for targeted interventions. Full article