Search Results (499)

Glioblastoma is the most aggressive tumor among gliomas, and recurrence remains inevitable despite aggressive therapies. Resistance to existing treatment modalities is attributed in part to the presence of glioma stem cells, which comprise a distinct cell subpopulation that sustains cell renewal and tumor evasion through multiple mechanisms. Therapeutic strategies using herpesviruses have been evaluated following the discovery of differential human cytomegalovirus (HCMV) expression in glioblastoma tumor cells. The absence of expression in normal brain tissue led to multiple clinical trials demonstrating the potential clinical utility of targeted HCMV via herpesvirus-based oncolytic therapeutic strategies. This review provides a comprehensive overview of existing studies evaluating the expression and biological significance of HCMV within glioma stem cells. Targeting HCMV in this cellular compartment may disrupt the continuous cellular support and resilience of glioblastoma stem cells, thereby enhancing the efficacy of current treatments. Full article

Plastic pollutants, including phthalates, bisphenol A (BPA), per- and polyfluoroalkyl substances (PFAS), and microplastics (MPs), are increasingly recognized as emerging environmental cofactors that intersect with infectious disease dynamics. These compounds, once considered inert, can alter immune function, reshape host–pathogen interactions, and directly influence viral survival and transmission. In this review, we compile current evidence on the chemistry, environmental occurrence, and biological activity of major plastic-associated pollutants with emphasis on their role in viral infections. Phthalates such as di(2-ethylhexyl) phthalate (DEHP) and its metabolite MEHP modulate innate immune signaling and have been shown to exacerbate infections, including Dengue and Coxsackievirus B3. Other DEHP-like phthalates, such as dibutyl phthalate (DBP), exhibit consistent infection-enhancing effects, while high molecular weight or cyclical phthalates such as polyvinyl acetate phthalate (PVAP) display conflicting results in their modulation of viral infections. BPA, widely detected in human tissues, acts through endocrine and immune disruption, worsening viral myocarditis, and altering influenza outcomes. PFAS, persistent “forever chemicals,” reshape adaptive immune responses and are associated with increased susceptibility, viral persistence, or severity of infection of herpesvirus (HCMV, EBV, HSV-1), hepatitis virus, and influenza infection. Microplastics represent a distinct risk by acting as physical carriers for viruses and bacteria, stabilizing viral RNA, enhancing host cell uptake, and skewing immune responses. Together, these pollutants extend beyond toxicology into virology, providing novel insights into how environmental exposures converge with viral pathogenesis. We highlight mechanistic advances and critical knowledge gaps and propose future directions for integrating environmental health and infectious disease research. Full article

Persistent oncovirus infections account for 15–20% of the global cancer burden, driving multiple forms of human cancer. To maintain persistent infection and spread, oncoviruses drive alterations in host cell metabolism, immune signaling, and cell-to-cell communication throughout tumor microenvironments. Accumulating evidence has indicated that these alterations occur in conjunction with a range of organelle remodeling events that can differ between “dormant” viral latency and active lytic replication. Throughout each phase of infection, oncoviruses alter the morphology, composition, and function of organelles to promote cellular survival and proliferation, while periodically supporting viral replication. Here, we review oncovirus-driven organelle remodeling strategies across distinct infection states, including viral latency, reactivation from latency, and chronic active replication. We focus on the molecular mechanisms by which oncovirus-driven organelle remodeling promotes cellular transformation, impedes immune responses, and facilitates virion assembly and egress. We also draw parallels between remodeling strategies employed by oncogenic and oncomodulatory viruses, emphasizing broadly conserved mechanisms across cancer-associated infections. Lastly, we highlight how studies of oncovirus organelle remodeling are critical for discovering vulnerabilities in both oncogenic virus infection and viral oncogenesis, with therapeutic potential for multiple cancers. Full article

Human cytomegalovirus (HCMV) and Human Immunodeficiency Virus (HIV) are two pathogens known to have dramatic consequences when contracted early in life. In addition to having a significant impact when acquired individually, these two viruses are known to frequently cause coinfections. Indeed, also in the modern era, HCMV remains one of the most prevalent coinfections in newborns of mothers living with HIV, including both HIV-positive children regardless of their immune status, and those exposed to HIV but uninfected (HEU). In children with HIV infection, HCMV coinfection has historically been associated with AIDS-defining disease, high mortality, and prolonged, elevated HCMV viral load. Although timely administration of antiretroviral therapy prevents immunodeficiency in people living with HIV and thus reduces the incidence of full-blown HCMV disease in cases of coinfection, emerging data suggest that HCMV-induced immune activation and aging persist, potentially contributing to long-term, non-AIDS-related comorbidities. Growing evidence indicates that also HCMV amplifies HIV susceptibility, disease progression, and immune dysregulation through multiple synergistic mechanisms. Moreover, congenital and early postnatal HCMV infections occur at significantly higher rates in HEU newborns than in HIV-unexposed children and are associated with worse clinical outcomes, particularly when HCMV viral loads are high. This review summarizes current knowledge on the epidemiology, clinical impact, and immunopathogenetic interactions of early HCMV–HIV coinfection in pediatric populations. By integrating recent findings with historical evidence, it highlights critical mechanistic and epidemiological gaps that warrant further investigation. Full article

Background and Clinical Significance: Hypoglossal nerve palsy is an uncommon neurological complication of infectious mononucleosis and is only rarely reported. Putative mechanisms include virus-triggered neuritis (Epstein–Barr virus (EBV) or Cytomegalovirus (CMV)) and/or mechanical compression related to cervical lymphadenopathy. Case Presentation: We report two children with infectious mononucleosis and transient unilateral hypoglossal nerve palsy. Case 1 was a 15-year-old boy with 7 days of fever and typical mononucleosis features who developed leftward tongue deviation accompanied by sialorrhea, dysarthria, and dysphagia. Laboratory testing showed marked hepatocellular injury and EBV-specific IgM positivity. Case 2 was a 9-year-old girl with a 24 h history of bilateral lateral cervical lymphadenopathy with overlying inflammatory signs; examination revealed rightward tongue deviation with similar associated symptoms. CMV-specific IgM antibodies were detected on serological testing. Both patients received systemic corticosteroids and empiric intravenous antibiotics, with supportive care. Hypoglossal nerve function fully recovered within 2–4 weeks of treatment initiation. Conclusions: These cases underscore that isolated hypoglossal nerve palsy may complicate EBV- or CMV-associated mononucleosis in children. Although the prognosis is generally favorable, the presentation warrants careful evaluation to exclude alternative causes of lower cranial neuropathies and close follow-up until complete neurological resolution. Full article

(1) Background: Sepsis is characterized by profound heterogeneity of immune responses, complicating biomarker-based prediction of clinical outcomes. Latent human cytomegalovirus (HCMV) infection is one of the strongest modulators of the human immune system and may influence cytokine-mediated signaling during sepsis. (2) Methods: In this post hoc analysis of 331 patients from the prospective multicenter SepsisDataNet.NRW cohort (German Clinical Trial Registry No. DRKS00018871), we quantified 13 serum cytokines on day 1 after sepsis diagnosis and determined HCMV IgG serostatus via ELISA. Using nested cross-validated logistic regression with exhaustive feature selection, we identified cytokine panels predictive of 30-day survival in the total cohort and in subgroups stratified by HCMV serostatus. (3) Results: In the total cohort, a four-cytokine panel (IL-6, IL-10, TNF-α, IL-12p70) predicted 30-day survival with a cross-validated area under the curve (AUC) of 0.66 [95% CI: 0.59–0.72]. Stratification by HCMV serostatus revealed distinct predictive profiles: in HCMV-seropositive patients, a two-cytokine model (IL-10, IL-23) achieved an AUC of 0.69 [95% CI: 0.61–0.77], whereas in seronegative patients, a model based on IL-8 and IL-17A failed to generalize (AUC = 0.47 [95% CI: 0.33–0.61]). Kaplan–Meier analysis confirmed a significant separation of survival curves for the HCMV-seropositive group (p < 0.001) but not for seronegative patients (p = 0.282). (4) Conclusions: HCMV serostatus defines an immunological context in which cytokine-based prediction of sepsis outcome becomes feasible. These data suggest that viral serostatus should be systematically incorporated into biomarker discovery and immunophenotyping approaches to improve the reproducibility and biological interpretability of sepsis endotyping. Full article

Human cytomegalovirus (HCMV) infection is a significant complication in transplant recipients. Following HCMV reactivation, the recovery of T-cell responses serves as a key indicator of protection from HCMV disease. This study aimed to assess the HCMV-specific CD4⁺ and CD8⁺ T-cell responses and their cytokine production (IFNγ, TNFα, IL2) against various HCMV proteins (IE-1, pp65, gB, gH/gL/pUL128L) in solid organ transplant recipients (SOTRs) and hematopoietic stem cell transplant recipients (HSCTRs) with active HCMV infection. The cohort consisted of 16 SOTR and 16 HSCTR categorized into two groups: (i) Controllers, who spontaneously controlled the infection, and (ii) Non-Controllers, who required antiviral treatment. T-cell responses were analyzed following stimulation with peptide pools and intracellular cytokine staining. Prior to transplantation, all patients exhibited a significantly higher frequency of CD4⁺ T cells specific to pp65 compared to gH and gL/pUL128L. During the peak of infection, T-cell frequencies across all peptides were similar, but at infection resolution, the frequency of pp65 and gB-specific CD4⁺IFNγ⁺ T cells was significantly higher than gL/pUL128L. Additionally, pp65 and IE-1-specific CD8⁺IFNγ⁺ T-cell responses were significantly greater than those against gH and gL/pUL128L at the resolution of infection. Notably, Controllers exhibited significantly higher frequencies of monofunctional pp65-specific T cells, particularly in CD8⁺ T cells producing IFNγ and TNFα. The response to pp65, especially IFNγ production, may serve as a key marker for identifying patients capable of controlling HCMV infection. Full article

Many methods have been developed for multilevel Space Vector Modulation (SVM), but despite their inherent advantages, all of them have been more complex than the alternative option of using Pulse Width Modulation (PWM) with sinusoidal or modified references. Different axes like g-h at 60° or ja-jb-jc at 120° have been used to simplify the operations to find the three nearest vectors and their duty cycles, but the control signals of multilevel converters are the duty cycles of phases, not the duty cycles of vectors. Moreover, throughout this paper, it was found that local information is not sufficient to compute the duty cycles of the phases: global information should be taken into account to obtain full control on the common mode voltage (CMV), and the selection of the starting vector in the switching sequence is also critical to obtain a balanced CMV. The natural coordinates ab-bc-ca were used in this paper, and a straightforward method is proposed for multilevel SVM: a method that is comparable in complexity to multilevel PWM with modified references and leads to exactly the same control signals. This method can be used as an easy starting point to develop other SVM techniques for multilevel converters. Full article

Glioblastoma (GB) is a highly aggressive brain tumor with a very poor prognosis. Treatment usually consists of surgery, followed by radiotherapy and chemotherapy, but the prognosis remains poor due to its resistance to therapies and a high recurrence rate. Multiple studies have reported the presence of human cytomegalovirus (HCMV) proteins and/or nucleic acids in GB tissues, suggesting its possible implication. These findings have led to the hypothesis that HCMV may contribute to tumor progression, immune evasion, angiogenesis, and resistance to therapy. Clinical trials using anti-HCMV therapies have shown promising preliminary results, indicating a potential therapeutic benefit. This review aims to provide a comprehensive overview of the current evidence linking HCMV to GB and the therapeutic implications. A deeper understanding of this complex interaction could unveil novel strategies for GB treatment. Full article

Approximately 12% of all human cancers are caused by oncoviruses. Macrophage migration inhibitory factor (MIF) signaling activation has been found closely related to many cancer cell malignant behaviors and infectious disease progression. However, its role in virus-associated cancers or how oncoviruses may regulate MIF signaling activities remains largely unknown. In the current review, we summarize recent findings about the oncovirus activation of MIF signaling pathways, their functional roles in viral oncogenesis, and the development of MIF-targeted therapies. We also discuss future directions in this interesting field. Full article

The complex relationship between human cytomegalovirus (HCMV) and cancer has been of interest since the 1960s. As a highly prevalent human β-herpesvirus, HCMV establishes lifelong latency in CD34+ myeloid progenitor cells and has been implicated as an oncomodulatory virus in various cancers, including glioblastoma multiforme, breast, prostate, colorectal, and ovarian cancer (OC). Recently, discussions have emerged regarding the classification of HCMV as an eighth oncovirus due to the persistence of its nucleic acids and proteins in many tumour types. As one of the deadliest gynaecological cancers, OC is often characterised as the ‘silent killer’ with less than half of women surviving for 5 years, a rate that drops below 20% when detected at advanced stages. Reported effects of HCMV vary between cancers, likely due to differences in tumour type, viral strain, and disease stage. While HCMV infection has been linked to poor OC patient outcomes, its impact on the OC tumour microenvironment (TME) and immune system remains less understood. Investigating HCMV’s potential oncogenic role could provide critical insights into OC progression. This review discusses recent developments on HCMV’s multifaceted roles in OC, including strain heterogeneity, immunomodulation of the TME, dysregulation of inflammatory signalling pathways, and potential therapeutic approaches targeting HCMV in anti-cancer immunotherapies. 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

Human cytomegalovirus (HCMV) is a herpesvirus (family) belonging to the beta herpesvirus subfamily that causes significant morbidity both in immunocompromised hosts (horizontal transmission) and during vertical transmission from mother to child. HCMV has the ability to establish a permanent latent infection with its host (even for decades), in which the DNA remains as a silent nuclear episome (latent phase) until reactivation after the appropriate conditions have occurred (lytic phase). The transition between the two phases (latent/lytic) is largely determined by the type of infected cell and the health status of the host, which ultimately corresponds to the epigenetic state of the infected cells. Lytic infection of the virus normally occurs in epithelial cells, endothelial cells, fibroblasts or macrophages, whereas the latent phase occurs when undifferentiated cells of the myeloid lineage, such as CD34+ hematopoietic progenitor cells, are infected. Epigenetic regulation of the viral genome begins with the formation of chromatin in the viral DNA just 30 min after infection and then evolves towards the latent or lytic phase. DNA viruses, including members of the herpesvirus family, are currently the subject of intense study regarding the role that epigenetics plays in controlling the viral life cycle, focusing primarily on the role of post-translational modifications (PTMs) of histones, as well as DNA methylation. Within the viral genome, nucleosomes are organized for the spatial/temporal expression of appropriate genes due to epigenetic modifications. Therefore, during the infection cycle, DNA chromatinization and chromatin modifications influence the expression of genes in the HCMV genome. This process is mediated by (i) enzymes called “writers”, which catalyze PTMs by adding chemical groups to proteins (acetylation, methylation, etc.); (ii) recruitment of specific transcription factors called “readers”, that bind to modified amino acid residues of proteins and act as interpreters of the PTM code; and (iii) “erasers”, enzymes that remove these modifications (e.g., HDACs). Indeed, recent advances in understanding the chromatin-based mechanisms of viral infections offer some promising strategies for therapeutic intervention that could be particularly useful in immunosuppressed recipients of transplants to avoid allograft rejection and infection by other opportunistic pathogens. In this review, we comprehensively examine the epigenetic regulation of the HCMV genome across distinct phases of viral infection, with particular attention to recent studies that significantly enriched the current knowledge about molecular mechanisms and future therapeutic perspectives. Full article

With an emphasis on common-mode voltage (CMV) and leakage current suppression, this research offers a thorough examination of three-phase, two-level buck inverter topologies for transformerless (TL) grid-tied photovoltaic (PV) systems. A comprehensive classification and comparative evaluation of modern voltage-source inverter (VSI) and current-source inverter (CSI) topologies, such as H6, H7, H8, H10, and hybrid setups, constitute the paper’s main contribution. The main conclusions show that CSIs naturally offer better leakage current suppression, albeit at the expense of cost and complexity, while sophisticated VSIs (such as specific H8 and H10 topologies) in conjunction with specialized modulation techniques (like modified discontinuous PWM) provide balanced performance. The study finds intriguing research possibilities for further work in this area and indicates that the ideal topology depends on the specific application. Full article

The emergence of drug-resistant cytomegalovirus (CMV) complicates viral response to therapy. We present two cases of solid organ transplant (SOT) recipients, highlighting the reversion of UL97 mutations associated with val(ganciclovir) resistance. Patient 1, a heart transplant recipient, initially received pre-emptive treatment with val(ganciclovir), followed by foscarnet for recurrent CMV episodes. Mutations A594V in the UL97-kinase gene and V715M in the UL54-polymerase gene were detected. He developed CMV colitis and was then treated with maribavir. After discontinuing val(ganciclovir), genotyping revealed no resistance mutations. Following CMV DNA suppression, secondary prophylaxis with letermovir and val(ganciclovir) was initiated. Patient 2, a double-lung transplant recipient, experienced several CMV episodes. Initially treated with val(ganciclovir), he developed the L595S mutation in the UL97 kinase gene, conferring resistance. Therapy was then switched to foscarnet, which was suspended due to renal failure, and then to maribavir. Subsequently, the H411Y mutation in the UL97 was detected, conferring maribavir resistance, while val(ganciclovir) mutation was no longer detectable. He was then treated with val(ganciclovir) and letermovir, achieving undetectable CMV DNA, and then continued letermovir alone as prophylaxis. Detecting gene mutations that confer drug resistance is crucial for managing antiviral therapy when virological response is lacking. In our cases, the reversion of (va)ganciclovir-resistance mutations occurred after drug withdrawal, a previously unreported finding. Full article