Search Results (4,432)

Background: There is a great deal of knowledge regarding the development of polyomavirus-associated nephropathy and polyomavirus-associated hemorrhagic cystitis in transplant recipients with active BKPyV infection. However, recent studies have revealed a potential association between BKPyV reactivation and certain malignancies, including transitional cell carcinoma, malignant melanoma, colorectal cancer, and prostate cancer. This study aimed to identify a potential link between BKPyV infection and oncogenic transformation in kidney transplant recipients. Methods: Presentation of a case series of kidney transplant recipients diagnosed with polyomavirus-associated nephropathy who developed neoplasms after transplantation. Results: Positive immunohistochemical reactions confirmed the presence of polyomavirus large T antigen in tissue samples from all three patients’ cancers. Furthermore, a case of chromophobe renal cell carcinoma presenting BKPyV proteins in cancer cells was observed for the first time in the literature. Conclusions: BKPyV reactivation was found to be associated with the development of both urothelial cancer, which originates directly from the BKPyV-infected site, and colorectal cancer. Full article

Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy by enhancing the immune response against tumors. However, they can cause immune-related adverse events (irAEs), including rare but potentially fatal myocarditis. We describe a 71-year-old man with stage IIIA lung adenocarcinoma treated with adjuvant pembrolizumab who developed severe ICI-associated myocarditis. Despite early diagnosis, treatment with intensive immunosuppression and mechanical support, he suffered fatal cardiac complications. A systematic review of the literature up to May 2025 identified 44 cases of ICI-associated myocarditis. Data on clinical features, diagnostics, treatment, and outcomes were extracted and analyzed. Most cases involved older patients with lung cancer treated with pembrolizumab or nivolumab. Onset varied from days to years after therapy initiation. Presentations included dyspnea, chest pain, arrhythmias, and elevated cardiac biomarkers. The biopsy showed T-cell and macrophage infiltration. High-dose corticosteroids were the primary treatment; additional immunosuppressants were used in cases that were refractory. Mortality was 45%, mainly due to cardiac failure and sepsis. Discussion: ICI-associated myocarditis arises from immune dysregulation affecting cardiac tissue, potentially involving shared antigens and systemic inflammation. Early detection and aggressive immunosuppression are crucial but often insufficient, resulting in high mortality. This underscores the urgent need for a better understanding of pathogenesis and the development of effective management strategies to improve patient outcomes. Finally, a multidisciplinary approach is important to improve outcomes in ICI-associated myocarditis. Full article

High-grade gliomas (HGGs) and diffuse midline gliomas (DMGs) in pediatric patients carry a poor prognosis, necessitating the rapid development of novel therapies. Peptide vaccines represent a safe, repeatable, and rational immunotherapeutic modality aimed at inducing potent, tumor-specific T-cell responses. In this review, we define the scope of current progress by arguing that immunogenicity in children with HGG/DMG hinges on three factors: appropriate antigen class (neoantigen vs. TAA), the use of potent immunoadjuvants, and successful navigation of immune suppression. To address the gap between biological promise and clinical reality, we analyze clinical trials targeting shared tumor-associated antigens (e.g., CMV pp65, Survivin) and specific shared neoantigens (H3.3K27M). Crucially, we highlight pivotal data from the PNOC007 trial, where the magnitude of H3.3K27M-specific T-cell expansion correlated directly with significantly longer overall survival (OS), establishing a causal link between pharmacodynamics and clinical benefit. However, the unique challenges of the immunosuppressive tumor microenvironment and the detrimental effect of necessary corticosteroids remain paramount barriers. Future success relies on multi-modal combination strategies, the development of next-generation personalized neoantigen vaccines, and the application of advanced neuroimaging to accurately assess treatment response. Full article

This study aimed to assess the genetic diversity of HIV-1 in the Far Eastern Federal District (Russia) to implement effective anti-epidemic measures, including the development of an anti-HIV vaccine and the selection of optimal antigens. The first stage of the study included an analysis of HIV-1 nucleotide sequences obtained in Khabarovsk city from 2022 to 2024. The second stage of the study included an additional download of nucleotide sequences from the Los Alamos HIV Sequence Database for phylogenetic cluster analysis. Additionally, an analysis of drug resistance mutations was conducted. The results showed the following distribution of HIV-1 genetic variants: A6—72.15%, CRF63—10.13%, URFs—7.59%, C—5.06%, B—3.8%, and CRF157—1.27%. The phylogenetic cluster analysis revealed a statistically significant difference in the number of clusters depending on the genetic variant. Among drug resistance mutations (DRMs), those associated with nucleoside reverse transcriptase inhibitors (NRTIs) were the most frequently observed, accounting for 55.7% (95% CI: 44.75%—66.65%). The most commonly detected NRTI DRMs were A62V (43.04%) and M184V (13.92%). The results of this study highlight several important indicators for public health, particularly in the development of vaccines aimed at combating HIV infection. Full article

Multiple myeloma (MM) is a clonal malignancy of terminally differentiated plasma cells characterized by bone marrow infiltration and excessive production of monoclonal immunoglobulins, leading to end-organ damage such as osteolytic bone lesions. Despite substantial therapeutic progress achieved with proteasome inhibitors, immunomodulatory drugs, and anti-CD38 monoclonal antibodies, multiple myeloma remains incurable, and outcomes for triple-class-refractory patients remain dismal, with median survival below one year. Bispecific T cell engaging antibodies (TCEs) have recently emerged as a promising immunotherapeutic approach capable of redirecting cytotoxic T cells to eliminate malignant plasma cells. These engineered antibodies simultaneously engage CD3 on T cells and a tumor-associated antigen such as B cell maturation antigen (BCMA), G protein-coupled receptor family C group 5 member D (GPRC5D), or Fc receptor homolog 5 (FcRH5), thereby forming an immune synapse that triggers T cell activation, cytokine secretion, and perforin–granzyme-mediated apoptosis of the targeted B cell. This review summarizes the molecular design, mechanism of action, and clinical development of TCEs in MM, encompassing early bi-specific T cell engagers (BiTE) constructs such as AMG 420 and next-generation IgG-like molecules including teclistamab. Pivotal clinical trials have demonstrated overall response rates between 43% and 73%, accompanied by durable remissions and manageable safety profiles. Future directions include earlier-line integration, synergistic combinations with immunomodulatory or costimulatory agents, and the development of trispecific formats to overcome antigen escape and T cell exhaustion. Collectively, TCEs represent a paradigm shift toward durable, immune-mediated disease control in multiple myeloma. Full article

Prostate Cancer (PCa) screening using Prostate-Specific Antigen (PSA) has significantly improved early detection but has also led to substantial overdiagnosis and overtreatment, particularly of indolent tumors. While active surveillance and focal therapies have mitigated some harms, distinguishing aggressive from non-threatening disease remains a critical clinical challenge. Emerging evidence highlights the epigenetic regulation of the human Telomerase Reverse Transcriptase (hTERT) gene as a promising biomarker for risk stratification. Cancer-specific hypermethylation within the TERT Hypermethylated Oncological Region (THOR) and the broader CpG island termed “Acheron” correlates with hTERT reactivation, tumor progression, and adverse outcomes. Additionally, suppression of the long non-coding (lnc) RNA human TERT Antisense Promoter-Associated (hTAPAS) contributes to the derepression of hTERT, providing a mechanistic link between DNA methylation and telomerase activation. Collectively, these epigenetic signatures, referred to as EpihTERT, can be detected in tissue and liquid biopsies, offering non-invasive assessment of tumor aggressiveness. Integration of EpihTERT profiling into clinical practice may enhance early diagnosis, refine patient selection for intervention, and reduce unnecessary treatments, bridging the gap between overdiagnosis and timely identification of clinically significant disease. Prospective multicenter validation is warranted to establish EpihTERT as a robust, translational biomarker in PCa management. Full article

Background and objectives: Prostate-specific antigen (PSA) concentration is considered an important prognostic marker, with rapid and large reductions associated with a favorable outcome and prolonged survival. Material and Methods: We conducted a single institution and tertiary cancer center retrospective analysis of metastatic hormone-sensitive prostate cancer (mHSPC) patients undergoing active treatment at Division of Oncology and Radiotherapy, University Hospital Dubrava, between December 2022 and August 2025. This study aimed to assess the association between the PSA levels and survival in mHSPC patients undergoing active treatment. Results: A total of 42 (59.2%) in our cohort achieved UL PSA levels, while 29 patients (40.8%) had PSA levels > 0.2 ng/mL. Cox regression analysis identified age > 71 years at the diagnosis of mHSPC and UL PSA levels as statistically significant factors associated with favorable outcome. Conclusions: Our real-world data demonstrated that UL PSA is a favorable prognostic factor associated with prolonged survival and improved prognosis. However, we identified patients achieving UL PSA levels, who experienced radiographic progression. Our finding suggests that even among “best” PSA responders, some might develop resistant clones that manifest via imaging progression without PSA rise. Full article

Background/Objectives: Benign prostatic hyperplasia (BPH) is a common condition in older men and represents a major contributor to lower urinary tract symptoms, prostate enlargement, and features of metabolic syndrome (MetS). Androgen receptor (AR) signaling and extracellular matrix (ECM) remodeling play central roles in BPH pathology, yet the clinical relevance of AR coactivators and structural genes remains incompletely understood. Methods: Prostate tissues from 76 BPH patients and five non-hyperplastic controls were analyzed by quantitative PCR to assess AR coactivators (SRC-1, SRC-2, SRC-3, PCAF, p300) and ECM-related genes (COL1A1, COL3A1). Results: BPH tissues showed marked overexpression of AR coactivators and collagen genes compared to controls (fold changes ≥ 7.8). Higher prostate-specific antigen (PSA) levels (≥10 ng/mL) and enlarged prostate volumes (≥100 mL) were associated with increased expression of PCAF, p300, SRC-1, and COL1A1. PSA and prostate volume correlated positively with triglycerides and VLDL, and inversely with HDL. Strong associations between collagen genes and p160 coactivators suggest coordinated androgenic and stromal remodeling activity. COL1A1 expression was reduced in patients under pharmacological treatment, particularly with alpha-blockers or combination therapies. PCAF and p300 were elevated in patients with MetS, hyperlipidemia, or hyperglycemia. Conclusions: These findings define a molecular signature in BPH linking androgenic, metabolic, and stromal pathology. SRC-1, PCAF, p300, and COL1A1 emerge as potential biomarkers and therapeutic targets, providing new insights into the molecular mechanisms of BPH progression. Full article

Radiolabeled monoclonal antibodies represent a promising approach to integrate molecular imaging with immunotherapy for cancer diagnosis and treatment. These antibodies target immune checkpoints and tumor-associated antigens, enabling non-invasive visualization of tumor dynamics through PET and SPECT imaging. Evidence from preclinical and clinical studies suggests that such imaging can provide insights into antibody distribution, immune cell infiltration, and potential treatment responses within the tumor microenvironment. By combining diagnostic and therapeutic capabilities, antibody-based theranostics offer opportunities for personalized treatment planning and understanding mechanisms of resistance. This review highlights current advances in antibody-based molecular imaging, discusses challenges in translation, and explores future directions for integrating imaging with immuno-oncology strategies to improve patient outcomes. Radiolabeled antibodies allow non-invasive assessment of tumor–immune interactions, supporting adaptive treatment planning and bridging immunotherapy with molecular imaging. Full article

Mutations in the NF1 gene cause Neurofibromatosis Type 1 (NF1), one of the most common genetic disorders. This gene encodes neurofibromin, a member of the GTPase-activating protein (GAP) family that functions as a negative regulator of RAS signaling. Loss of NF1 function leads to persistent RAS activation and promotes tumor growth. The clinical manifestations of NF1 mainly include pigmentary changes, benign and malignant peripheral nerve sheath tumors, as well as gliomas affecting the central nervous system. Currently, MEK inhibition is the only approved therapy and is primarily effective in controlling plexiform neurofibromas (pNFs). However, more comprehensive treatments are needed to address the full spectrum of NF1 manifestations and malignant transformation. Novel therapeutic strategies, including AAV-based gene therapy aimed at restoring NF1 function, oncolytic herpes simplex virus (oHSV) therapy targeting RAS-dysregulated tumor cells, and chimeric antigen receptor T cell (CAR-T) therapy targeting NF1-associated tumors, are under active investigation. In this review, we explore the genetic mechanisms underlying NF1 and highlight recent advances in therapeutic development with a special focus on AAV-based gene therapies alongside other approaches with recent clinical and translational advancements. Full article

In recent years, the development of new immunotherapy strategies has been a significant breakthrough in cancer treatment. Among these, engineered T cell therapy with chimeric antigen receptors (CAR-T) has produced notable clinical results, especially in hematological malignancies. This success has sparked growing interest in extending the application of CAR-Ts to solid tumors, including gliomas. Gliomas—in particular, glioblastoma multiforme (GBM)—are among the most aggressive primary brain tumors, associated with a poor prognosis and a median survival of approximately one year after diagnosis. However, the translation of CAR-T therapy to gliomas presents significant challenges, related to factors such as tumor heterogeneity, presence of the blood–brain barrier (BBB), and a strongly immunosuppressive tumor environment. Despite this, in recent years, there has been an intensification of research efforts aimed at the identification of new antigenic targets and the development of preclinical models—both in vitro and in vivo—to evaluate the efficacy and safety of CAR-Ts in the treatment of gliomas. Despite promising results, currently available models still have essential limitations in faithfully reproducing the complexity of human gliomas. This review aims to offer an exhaustive overview of the most recent preclinical studies on CAR-T therapy in gliomas, with a focus on the identification of molecular targets, experimental strategies aimed at overcoming immunological barriers, and translational challenges that need to be addressed for future successful clinical implementation. Full article

Chimeric antigen receptor (CAR) therapy represents a promising modality for treating cancer and autoimmune diseases, employing genetically engineered immune cells. Despite remarkable clinical outcomes, its broad implementation is constrained by significant challenges, including toxicity, limited specificity, and complexities associated with genetic material delivery. Biological nanoparticles, such as exosomes, virus-like particles, and biomimetic nanostructures, possess unique properties that can address these limitations. These nanoplatforms enable targeted delivery of genetic constructs, mitigate the risk of cytokine release syndrome, modulate CAR cell activity, and can function as biosensors. Furthermore, they facilitate non-viral, in vivo CAR cell engineering, streamlining the process compared to conventional ex vivo methods. The advancement of in vivo strategies underscores the critical need to overcome toxicity hurdles inherent to current CAR-T platforms. In this context, exosomes and biomimetic nanoparticles offer considerable potential due to their innate biocompatibility, programmability, and versatile cargo capacity for payloads like mRNA and circular RNA. This review comprehensively outlines contemporary genetic platforms for CAR expression and examines the opportunities presented by biological delivery vehicles. It focuses on recent achievements and revisits fundamental CAR principles through the lens of emerging technologies aimed at confronting persistent challenges in the field. Full article

Gastrointestinal cancers, including gastric, gastroesophageal junction, pancreatic, and biliary tract cancers, remain associated with poor outcomes due to late diagnosis and limited effective treatment options. Claudin-18.2 (CLDN18.2), a tight junction protein primarily found in the gastric epithelium and ectopically expressed in gastrointestinal tumors, has emerged as a promising therapeutic target across these diseases. This narrative review expands on existing discussions surrounding CLDN18.2-directed therapy in gastric and gastroesophageal cancer and provides a comprehensive, updated analysis of the rapidly evolving therapeutic landscape across multiple gastrointestinal malignancies, including pancreatic and biliary tract cancers. We summarize key developments following the approval of the monoclonal antibody zolbetuximab and critically evaluate emerging modalities, including bispecific antibodies, antibody–drug conjugates, and chimeric antigen receptor T-cell therapies, highlighting differences in mechanisms of action, efficacy, toxicity profiles, and mitigation strategies. We also discuss the clinical relevance of CLDN18.2 and PD-L1 co-expression, the rationale for pairing CLDN18.2-targeted therapy with immune checkpoint inhibitors, and early data supporting combination approaches. Additionally, we examine tumor heterogeneity, biomarker challenges, and emerging resistance mechanisms, alongside strategies to overcome them. Finally, we identify current limitations in the field, including inconsistent CLDN18.2 testing criteria, and outline prioritized future directions to optimize integration of CLDN18.2-directed therapies across gastrointestinal cancers. By looking beyond zolbetuximab and incorporating cross-platform comparison, immuno-oncology considerations, and multi-tumor context, this review provides a broad and forward-looking framework to guide clinical application and next-generation research in CLDN18.2-targeted therapy. Full article

The human immunodeficiency virus (HIV) is a retrovirus discovered in 1983 as the causative agent of acquired immunodeficiency syndrome (AIDS). Following several zoonotic spillover events from non-human primates, the virus spread between humans for more than 60 years under the radar. HIV infects and kills CD4 T cells, the cells that coordinate adaptive immune responses. Primoinfection is associated with a flu-like symptomatology and chronic infection is clinically silent, and mostly not diagnosed, contributing to viral spread and leading to fatal long-term outcomes. HIV genome codes for a poor reading-proof reverse transcriptase, which facilitates high sequence variability, particularly in the envelope glycoprotein complex, the sole external viral protein and main target of humoral immune responses. This antigenic variability precludes the development of an efficacious vaccine despite 40 years of research. In contrast, the development of antiretroviral drugs represents a scientific and medical success which saved the lives of millions of infected people and provides today an excellent protection against AIDS, although it does not permit viral eradication. Indeed, HIV can integrate its genome in target cells and generates a pool of latently infected cells which escape eradication by both the natural immune response and treatments. In summary, the efforts to tackle HIV have been suboptimal, and the virus has infected more than 90 million people and caused 44 million deaths worldwide. In the absence of a vaccine, a better deployment of available preventative and therapeutic tools is needed, particularly in geographical areas and communities with the highest incidence of infection. Full article

Background: BRCA1/2 mutations are the most recognized causes of hereditary breast cancer (BC), but their penetrance is incomplete. BRCA1-driven tumors are often chromosomally unstable and exhibit increased antigenicity. We hypothesized that inherited variations in immune-related pathways may influence BRCA1 penetrance. Methods: Case–control comparison of BC-affected versus non-affected BRCA1-mutated women is generally complicated because the latter groups are often low in numbers, represented by younger subjects and may contain relatives of the analyzed patients. We utilized a novel approach, i.e., we compared young-onset and late-onset BRCA1-associated BC cases, assuming that the early age at disease manifestation may be an indicator of increased BRCA1 penetrance. Results: NGS for 353 genes implicated in inborn errors of immunity was performed on 42 young-onset (<39 y.o.) and 35 late-onset (>57 y.o.) BC patients carrying BRCA1 pathogenic variants. This effort identified 22 potentially relevant variants, which were further analyzed in an extended cohort (up to 90 patients per group). The PRF1 p.Ala91Val variant, associated with familial hemophagocytic lymphohistiocytosis, was found in 9.6% of young-onset patients and none of the late-onset group (7/73 vs. 0/78, p = 0.005). The significance of this allele was further validated in an additional group of Russian patients (14/164 (8.5%) vs. 8/236 (3.4%), p = 0.042). This trend also retained upon the pooled analysis of Russian and Polish subjects (24/278 (8.6%) vs. 15/337 (4.4%), p = 0.045). Conclusions: Rare variants in immune-related genes, such as PRF1 p.Ala91Val, may influence BRCA1 penetrance. Broader exome-wide analyses comparing affected vs. unaffected BRCA1/2 mutation carriers, or women stratified by age at cancer onset, could help identify additional genetic modifiers of cancer risk. Full article