Search Results (4,019)

Chronic kidney disease (CKD) affects nearly 10% of the global population, ranks among the top ten causes of death, and often progresses silently to end-stage disease without timely intervention. Increasing evidence indicates that many adult-onset cases originate in early life through adverse influences on kidney development, a process termed kidney programming within the Developmental Origins of Health and Disease (DOHaD) framework. Environmental pollutants are now recognized as key drivers of kidney injury across the life course. Heavy metals, air pollutants, plastic contaminants such as bisphenol A, phthalates, and micro/nanoplastics—as well as biocontaminants like mycotoxins and aristolochic acid—and chronic light pollution can accumulate in kidney tissue or act systemically to impair function. These exposures promote oxidative stress, inflammation, and endothelial and circadian disruption, culminating in tubular injury, glomerular damage, and fibrosis. Notably, early-life exposures can induce epigenetic modifications that program lifelong susceptibility to CKD and related complications. Oxidative stress is central to these effects, mediating DNA, lipid, and protein damage while influencing developmental reprogramming during gestation. Preclinical studies demonstrate that antioxidant-based interventions may mitigate these processes, providing both renoprotective and reprogramming benefits. This review explores the mechanistic links between environmental pollutants, oxidative stress, and kidney disease and highlights antioxidant strategies as promising avenues for prevention and intervention in vulnerable populations. Full article

Human cytomegalovirus (HCMV) establishes lifelong latency following primary infection, residing within myeloid progenitor cells and monocytes. To achieve this, the virus employs multiple immune evasion strategies. It suppresses innate immune signaling by inhibiting Toll-like receptor and cGAS-STING pathways. In addition, the virus suppresses major histocompatibility complex (MHC)-dependent antigen presentation to evade T cell recognition. As the downregulation of MHC molecules may trigger NK cell activation, the virus compensates for this by expressing proteins such as UL40 and IL-10, which engage inhibitory NK cell receptors and block activating signals, thereby suppressing NK cell immune surveillance. Viral proteins like UL36 and UL37 block host cell apoptosis and necroptosis, allowing HCMV to persist undetected and avoid clearance. In settings of profound immunosuppression, such as after allogeneic hematopoietic stem cell transplantation (allo-HSCT) or solid organ transplantation, slow immune reconstitution creates a window for viral reactivation. Likewise, immunosenescence and chronic low-grade inflammation during aging increases the risk of reactivation. Once reactivated, HCMV triggers programmed cell death, releasing viral PAMPs (pathogen-associated molecular patterns) and host-derived DAMPs (damage-associated molecular patterns). This release fuels a potent inflammatory response, promoting further viral reactivation and exacerbating tissue damage, creating a vicious cycle. This cycle of inflammation and reactivation contributes to both transplant-related complications and the decline of antiviral immunity in the elderly. Therefore, understanding the immune regulatory mechanisms that govern the switch from latency to reactivation is critical, especially within the unique immune landscapes of transplantation and aging. Elucidating these pathways is essential for developing strategies to prevent and treat HCMV-related disease in these high-risk populations. Full article

Pertussis is an infectious disease that contributes to hundreds of thousands of deaths worldwide each year. Despite the prevalence of preventive vaccination programs, there has been an increasing number of new cases of the disease over the past few decades. This poses a particular problem for the pediatric population among whom the highest mortality from the disease is recorded. Several reasons for this phenomenon can be mentioned, but what is particularly important from the microbiological point of view is the correlation of the increased number of pertussis cases with the introduction of a new form of vaccine—the acellular vaccine in place of the whole-cell vaccine. In this review, we summarized the current state of knowledge on potential factors that may contribute to the decline in immunization efficacy against the pathogen. The post-vaccination response profile, symptomatic of vaccination with vaccination-acellular, is characterized by recruitment of Th₂ and Th₁₇ lymphocytes; it has been reported that in the long term, this results in insufficient activation of B cells and low titers of antibodies to key bacterial antigens (hemagglutinin, pertactin). Moreover, the immune response proceeds by bypassing the recruitment of tissue-resident memory T cells, resulting in a lack of protection against colonization of the nasal cavity by the bacterium despite vaccination. The decline in vaccination efficacy should also be attributed to the phenotypic variability of Bordetella. The popularization of the PtxP3 strain, characterized by its ability to incompletely activate immune mechanisms, poses a real threat to public health. The growing resistance of B. pertussis to standardly used antibiotics including macrolides also remains a problem. This makes it difficult to eradicate pathogens from the nasal cavity area and increases the pool of bacterial carriers in the population area. The increasing prevalence of the disease prompts reflection on more effective methods of prevention. Particularly promising in this field seem to be new vaccines, especially mucosally implemented, e.g., intranasal, or developed on the basis of B. pertussis antigens other than those used so far. Full article

Despite advances in immunotherapy, the treatment of breast cancer still remains a major global problem. In a previous study, we showed that co-blockade of Interleukin-33/ST2 and Programmed death-1/Programmed death-ligand (PD-1/PD-L) signaling pathways strongly slows progression by enhancing the antitumor capacity of natural killer (NK) cells. The main aim of this study is to elucidate the exact effect of co-blockade on the T lymphocyte and macrophage effector cells. 4T1 cells were used to induct breast cancer in female BALB/C and BALB/C ST2^−/− mice. The mice, both BALB/C and BALB/C ST2^−/−, were treated with anti-PD-1 antibody on certain days. After the mice were sacrificed, T cells and macrophages were analyzed using flow cytometry; dual co-blockade increased significantly the percentage of M1 macrophages in the tumor microenvironment, followed by an increase in expression of CD86⁺ and TNFα⁺. T cell accumulation was significantly higher in the spleen and within the tumor microenvironment, with elevation in activation markers such as Interleukin-17, CD69, NKG2D, and FasL and a decrease in Interleukin-10 and FoxP3 expression. Co-blockade of the PD-1/PD-L axes and IL-33/ST2 axes shows promising results in reestablishing an effective immune response and offers a new perspective on improving immune response to breast carcinoma. Full article

Introduction: The “revolving” door is a phenomenon that refers to the rehospitalization of older patients who, after being discharged, soon require specialized hospital care again. Unfortunately, the use of tools able to predict this phenomenon is still limited. The aim of this study was to highlight the validity of the Blaylock Risk Assessment Screening (BRASS) Scale in objectively assessing the risk of rehospitalization and mortality among older patients. Methods: Patients were classified as low, medium, or high risk using the BRASS scale. Adverse events (rehospitalization or death) were recorded at baseline and at 12 months. Kaplan–Meier curves evaluated survival and rehospitalization across risk groups, and ROC analysis assessed the BRASS Scale’s predictive value for mortality. Results: Out of 179 enrolled older adults (mean age 67.7 years), 54.2% were classified as low risk, 29.5% as medium, and 16.8% as high risk based on the BRASS Scale. High-risk patients had significantly higher mortality (HR: 4.40; 95% CI: 1.60–12.19, p = 0.004) and lower survival rates, while intermediate-risk patients had increased rehospitalization (HR: 2.11; 95% CI: 1.09–4.08, p = 0.02). The BRASS scale showed good predictive value for mortality (AUC 0.76). Conclusion: The BRASS Scale has a good predictive value for negative outcomes, and it confirms that a substantial proportion of older patients are at risk of future hospital readmissions and complex discharges. These findings underscore the importance of early post-discharge care planning and the implementation of protected discharge programs. Full article

Noninvasive liquid biopsy for monitoring circulating tumor cells offers valuable insights for predicting therapeutic responses. We developed TelomeScan^® (OBP-401), based on the detection of telomerase activity as a universal cancer cell marker and an indicator of the presence of viable circulating tumor cells (CTCs) for patients with advanced non-small cell lung cancer (NSCLC). This system evaluated CTC subtypes characterized by programmed death ligand 1 (PD-L1), an immune checkpoint molecule, and vimentin, an epithelial–mesenchymal transition (EMT) marker, using a multi-fluorescent color microscope reader. The prognostic value and therapeutic responses were predicted by dynamically monitoring CTC counts in 79 patients with advanced NSCLC. The sensitivity and specificity values of TelomeScan^® for PD-L1⁽⁺⁾ cells (≥1 cell) were 75% and 100%, respectively, indicating high diagnostic accuracy. PD-L1⁽⁺⁾ and EMT⁽⁺⁾ in CTCs were detected in 75% and 12% of patients, respectively. Detection of PD-L1⁽⁺⁾CTCs and PD-L1⁽⁺⁾EMT⁽⁺⁾ CTCs before treatment was associated with poor prognosis (p < 0.05). Monitoring of reducing and increasing PD-L1⁽⁺⁾ CTC counts in two sequential samples (baseline, cycle 2 treatment) correlated significantly with partial response (p = 0.032) and progressive disease (p = 0.023), respectively. Monitoring PD-L1⁽⁺⁾CTCs by TelomeScan^® will aid in anticipating responses or resistance to frontline treatments, optimizing precision medicine choices in patients with NSCLC. Full article

The clinical pathway of a patient who experiences cardiac arrest and subsequently dies (with or without organ donation) is complex. It involves uncontrolled (u-) donation after circulatory death (DCD), controlled (c-) DCD, and donor after brain death (DBD). The present paper aims to summarize existing evidence on organ donation rates among out-of-hospital cardiac arrest (OHCA) patients, with a focus on these three donor categories (uDCD, DBD, and cDCD). Furthermore, the potential to expand each donor pathway in OHCA patients will be highlighted, based on available evidence. Among non-survivor OHCA patients, the prevalence of brain death (BD) is estimated to be low, though reported data are not uniform. The diagnosis of BD is made 3 to 6 days after return of spontaneous circulation. The implementation of uDCD is known to be quite challenging due to logistical, ethical, and resource issues. Its rationale is still well grounded, mainly considering two factors: (a) the high incidence of OHCA, such that uDCD donors can be considered an existing pool of potential donors; (b) the uDCD pathway shows feasibility both under organizational (i.e., only lung uDCD program) and clinical views (normothermic regional perfusion, ex vivo machine perfusion, and an appropriate donor–recipient match). Controlled DCDs are donors who died after a planned withdrawal of life-sustaining therapy (WLST). Data on the percentage of cDCD among OHCA patients is not uniform since the percentage of utilized cDCD has been estimated at around 10%. According to available evidence, each donor pathway in OHCA has the potential to be expanded, mainly by the identification of potential donors and the implementation of DCD programs. Full article

Breast cancer (BC) is the most frequently diagnosed malignancy in women. Currently, BC is treated with a holistic and multidisciplinary approach from diagnostic, surgical, radio-oncological, and medical perspectives, and advances including in early detection and treatment methods have led to improved outcomes for patients in recent years. Yet, BC remains the second most common cause of cancer-related deaths among women and there is an array of gaps to achieve optimal care. To close gaps in cancer care, here we describe a collaborative Request For Proposals (RFP) framework supporting independent initiatives for metastatic breast cancer (MBC) patients and aiming at improving their quality of care. We set up a collaborative framework between Pfizer and Sharing Progress in Cancer Care (SPCC). Our model is based on an RFP system in which Pfizer and SPCC worked together ensuring the independence of the funded projects. We developed a three-step life cycle RFP. The collaborating framework of the project was based on an RFP with a USD 1.5 million available budget for funding independent grants made available from Pfizer and managed in terms of awareness, selection, and monitoring by SPCC. Our three-step model could be applicable and scalable to quality improvement (QI) initiatives that are devoted to tackling obstacles to reaching optimal care. Through this model, seven projects from five different European countries were supported. These projects covered a range of issues related to the experience of patients with MBC: investigator communication, information, and shared decision-making (SDM) practices across Europe; development, delivery, and evaluation of a scalable online educational program for nurses; assessment of disparities among different minority patient groups; development of solutions to improve compliance or adherence to therapy; an information technology (IT) solution to improve quality of life (QoL) of patients with MBC and an initiative to increase awareness and visibility of MBC patients. Overall, an average of 171 healthcare professionals (HCPs) per project and approximately 228,675 patients per project were impacted. We set up and describe a partnership model among different stakeholders within the healthcare ecosystem―academia, non-profit organizations, oncologists, and pharmaceutical companies―aiming at supporting independent projects to close gaps in the care of patients with MBC. By removing barriers at different layers, these projects contributed to the achievement of optimal care for patients with MBC. Full article

Immune dysregulation presents a significant clinical challenge due to its rapid progression and complex interplay between hyperinflammatory and immunosuppressive responses. Different responses from the innate and adaptive immune systems can result in diseases such as immunoparalysis, cytokine storms, and secondary infections. Current diagnostic methods remain non-specific and time-consuming, delaying targeted interventions. A compartmentalized approach to immune monitoring, distinguishing innate and acquired immune response functional differentiation, is essential for distinguishing between hyperactivation and suppression. Key biomarkers, including cytokines, Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF), and CD4/CD8 counts, as well as Programmed Death Ligand-1 (PDL-1) and V-type immunoglobulin domain-containing suppressor of T cell activation (VISTA) regulators, can guide personalized treatment strategies. Although they need more clinical validation, novel therapeutic methods such as cytokine inhibitors, immunological stimulants, and immunomodulators have demonstrated promise. Early diagnosis and precision medicine developments could lead to better patient outcomes. Advances in non-coding RNAs have led to specific diagnostic panels based on microRNA (MiRNA) levels. A deeper understanding of immune imbalance in sepsis is critical for optimizing treatment and reducing mortality rates. This review highlights emerging diagnostic and therapeutic strategies to address the multifaceted nature of sepsis-related immune dysregulation. Full article

Shikonin, a dietary naphthoquinone phytochemical from the roots of Lithospermum erythrorhizon, has gained attention for its anticancer potential. Preclinical studies show that shikonin regulates multiple programmed cell death pathways, including apoptosis, necroptosis, ferroptosis, and pyroptosis, through mechanisms involving reactive oxygen species (ROS) accumulation, mitochondrial dysfunction, and kinase-mediated signalling. Beyond cytotoxicity, shikonin suppresses metastasis by blocking epithelial–mesenchymal transition (EMT) and downregulating matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9). It also disrupts tumour metabolism by targeting pyruvate kinase isoform M2 (PKM2) and modulating the Warburg effect. Evidence further indicates that shikonin can enhance the efficacy of chemotherapy, targeted therapy, immunotherapy, and radiotherapy, thereby contributing to the reversal of therapeutic resistance. To address limitations related to solubility and bioavailability, novel formulations such as nanoparticles, liposomes, and derivatives like β,β-dimethylacrylshikonin have been developed, showing improved pharmacological profiles and reduced toxicity in experimental models. Overall, the current literature identifies shikonin as a promising dietary phytochemical with diverse anticancer activities, therapeutic synergy, and formulation advances, while highlighting the need for clinical studies to establish its translational potential. Full article

Background/Objectives: The combination of anti-programmed death-1 (PD-1) inhibitors and chemotherapy is the standard first-line treatment for unresectable or metastatic esophageal squamous cell carcinoma (ESCC). However, real-world data remain limited, particularly regarding prognostic biomarkers. Methods: This multi-institutional retrospective study analyzed patients with metastatic or unresectable ESCC who received first-line pembrolizumab or nivolumab plus fluoropyrimidine and platinum-based chemotherapy. Treatment regimens mirrored those in KEYNOTE-590 and CheckMate 648. Efficacy, safety, and prognostic factors were assessed. Prognostic factors were identified using multivariable Cox regression, and a point-based risk scoring system was developed. Results: Among 87 patients, the objective response rate was 48.3%, and the disease control rate was 77.0%. Median progression-free survival (PFS) was 5.6 months (95% CI, 4.5–8.7), and the median overall survival (OS) was 13.1 months (95% CI, 10.6–not reached). Grade 3–4 treatment-related adverse events occurred in 51.7% of patients. Eastern Cooperative Oncology Group (ECOG) performance status ≥ 2, elevated C-reactive protein, and lower programmed death-ligand 1 (PD-L1) combined positive score (CPS) were independently associated with worse PFS and OS. A prognostic risk score ranging from 0 to 5 based on these factors stratified patients into four prognostic groups with distinct survival outcomes. Median PFS ranged from not reached in the low-risk group to 2.1 months in the high-risk group. Stratifying PD-L1 CPS into three levels (<10, 10–49, ≥50) revealed a graded association between CPS and treatment outcomes, supporting the need for more nuanced PD-L1 evaluation beyond binary classification. Conclusions: First-line anti-PD-1 therapy combined with chemotherapy demonstrated favorable real-world outcomes in ESCC. The proposed prognostic scoring system may help personalize treatment strategies. Full article

Background/Objectives: Whilst adoptive cell therapy (ACT) using chimeric antigen receptor-engineered T (CAR-T) cells represents an efficient approach for the treatment of patients suffering from several hematological malignancies, solid tumors have been shown to be far more challenging to tackle, mainly due to the hostile tumor microenvironment that inhibits optimal T cell functionality. As proven by the broad clinical success of immune checkpoint inhibitors, blocking the interaction of programmed cell death ligand 1 (PD-L1) expressed on tumor cells and the checkpoint receptor programmed cell death 1 (PD-1) expressed on activated T cells allows an intrinsic T cell-mediated anti-tumor response to be unleashed. We developed a cellular product (MDG1015) consisting of New York esophageal squamous cell carcinoma-1 (NY-ESO-1)/L antigen family member 1a (LAGE-1a)-specific CD8+ T cell receptor-transduced (TCR-)T cells co-expressing the costimulatory switch protein (CSP) PD1-41BB, which turns an inhibitory signal mediated by the PD-1:PD-L1 axis into positive T cell costimulation. Methods: In vitro co-cultures of MDG1015 and PD-L1-positive or -negative target cells were used to analyze TCR-T cell functionality, such as TCR-T (poly-)cytokine release, the killing of target cells, and TCR-T proliferation. The safety of MDG1015 was evaluated via different panels of antigen-negative cell lines or primary cells expressing or lacking PD-L1. Results: Preclinical analyses demonstrated TCR-gated activation of the CSP, leading to enhanced functionality of MDG1015 against antigen-expressing, PD-L1-positive tumor cells without any impact on antigen-negative target cells. Conclusions: The favorable, preclinical functionality and safety profile qualifies MDG1015 as a promising cellular therapy for explorative clinical testing in hard-to-treat solid tumor indications. Full article

Background/Objectives: Programmed cell death-ligand 1 (PD-L1) is one of the key biomarkers for immune checkpoint inhibitors. We are developing a novel PD-L1 CAL10 immunohistochemistry (IHC) assay (Leica Biosystems) on BOND-III staining system and have analyzed its initial performance by comparing it to the PD-L1 SP263 assay (Ventana) assay in a feasibility study. The study objective was to determine the concordance of the Leica Biosystems PD-L1 CAL10 assay with the comparator SP263 assay at the tumor proportion score (TPS) cutoff of ≥50% in non-small cell lung cancer (NSCLC) tissue samples. Additionally, the concordance between the two assays at the TPS cutoff of ≥1% was also evaluated. For informational purposes, we also evaluated the concordance between manual slide reads vs. digital reads (whole slide images generated using the Aperio GT 450) for the CAL10 assay. Methods: Two pathologists read and scored the glass slides. The CAL10 PD-L1 assay concordance with the PD-L1 SP263 assay was evaluated by assessing the agreement rates between the two assays. Results: The lower bound of the 95% confidence interval (CI) of the overall percent agreement (OPA) at ≥50% cutoff was 86.2%, while for ≥1% TPS cutoff, it was 94.0%, which met the predefined target of a minimum OPA lower bound of the 95% CI value of 85%. Conclusions: The Leica Biosystems CAL10 PD-L1 assay has demonstrated comparable performance to the SP263 assay. Additionally, the PD-L1 CAL10 stained glass slides and the corresponding whole side images generated by GT 450 showed comparable concordance rate. Full article

Background/Objectives: Breast cancer represents a diverse group of malignancies and continues to rank among the leading causes of cancer-related deaths in women. Altered Hippo pathway signaling has been increasingly recognized as a contributor to tumor growth, therapeutic resistance, and metastatic spread. This study aimed to identify miRNAs targeting Hippo pathway-related genes that are consistently dysregulated across all five breast cancer subtypes. Methods: The study cohort included patients representing five breast cancer subtypes: 130 luminal A, 96 HER2-positive luminal B, 100 HER2-negative luminal B, 36 non-luminal HER2-positive, and 43 triple-negative breast cancer (TNBC). Tumor samples were collected during surgery, along with adjacent healthy tissue that served as controls. Expression of Hippo-related genes was analyzed using mRNA microarrays and validated with reverse transcription quantitative polymerase chain reaction (RT-qPCR). Protein levels were assessed via enzyme-linked immunosorbent assay (ELISA), while miRNA expression profiling was performed with miRNA microarrays. Potential mRNA targets were predicted using the miRDB database. Results: We identified consistent downregulation of STK4, RASSF6, and FGF1, alongside overexpression of BIRC5 and SERPINE1. miRNA analysis revealed that STK4 is potentially regulated by miR-522-3p, SERPINE1 by miR-199b-5p and miR-30a-3p, whereas RASSF6, FGF1, and BIRC5 appeared to be predominantly regulated at the transcriptional level. These alterations reflect both the suppression of upstream Hippo activation and activation of downstream oncogenic effectors across all subtypes. Conclusions: Our findings reveal a conserved Hippo dysregulation program in breast cancer, highlighting subtype-independent Hippo-related genes and their miRNA regulators as potential universal biomarkers and therapeutic targets, complementing subtype-specific treatment strategies. Full article

Background: Status epilepticus (SE) is a neurological emergency associated with neuronal injury and activation of apoptotic pathways. While these mechanisms are well described in experimental models, evidence in humans is limited. This study evaluated Bcl-2 and FAS—key apoptosis-related proteins—in the serum and cerebrospinal fluid (CSF) of patients with convulsive SE. Methods: Between February 2024 and January 2025, CSF and serum samples were collected from 18 adults with convulsive SE within 48 h of onset, and from 15 control subjects. Patients with acute brain injury, stroke, tumors, or central nervous system infections were excluded. Bcl-2 and FAS concentrations were quantified using ELISA. Serum samples were obtained at diagnosis (S1), 24 h (S2), and 7 days (S3). Results: CSF Bcl-2 levels were significantly higher in SE patients compared with controls (z = 4.1, p < 0.001). CSF FAS levels did not differ significantly (z = 0.07, p = 0.94). No differences in serum Bcl-2 were observed. In contrast, serum FAS concentrations were significantly elevated at all three time points in SE patients compared with controls (S1–S3; all p < 0.001). Conclusions: Convulsive SE is associated with distinct apoptotic responses in the central nervous system and periphery. Elevated CSF Bcl-2 may reflect acute neuroprotective or stress-related responses, whereas persistently increased serum FAS suggests systemic apoptotic activation. These findings highlight the potential prognostic and therapeutic relevance of apoptosis-related biomarkers in SE. Full article