Search Results (426)

Hepatocellular carcinoma (HCC) is the main type of liver cancer and one of the malignancies with the highest mortality rates worldwide. HCC is associated with diverse etiological factors including alcohol use, viral infections, fatty liver disease, and liver cirrhosis (a major risk factor for HCC). Unfortunately, many patients are diagnosed at advanced stages of the disease and receive palliative treatment only. Therefore, early markers of HCC and novel therapeutic approaches are urgently needed. The endocannabinoid system is involved in various physiological processes such as motor coordination, emotional control, learning and memory, neuronal development, antinociception, and immunological processes. Interestingly, endocannabinoids modulate signaling pathways involved in cell survival, proliferation, apoptosis, autophagy, and immune response. Consistently, several cannabinoids have demonstrated potential antitumor properties in experimental models. The participation of metabotropic and ionotropic cannabinoid receptors in the biological effects of cannabinoids has been extensively described. In addition, cannabinoids interact with other targets, including several ion channels. Notably, several ion channels targeted by cannabinoids are involved in inflammation, proliferation, and apoptosis in liver diseases, including HCC. In this literature review, we describe and discuss both the endocannabinoid system and exogenous phytocannabinoids, such as cannabidiol and Δ⁹-tetrahydrocannabinol, along with their canonical receptors, as well as the cannabidiol-targeted ion channels and their role in liver cancer and its preceding liver diseases. The cannabidiol-ion channel association is an extraordinary opportunity in liver cancer prevention and therapy, with potential implications for several environments that are for the benefit of cancer patients, including sociocultural, public health, and economic systems. Full article

Introduction: The sustained global epidemic of Human Immunodeficiency Virus (HIV) necessitates comprehensive, region-specific surveillance to inform public health policy. This 30-year retrospective observational cohort study delineated the epidemiological patterns, transmission dynamics, treatment efficacy, and long-term clinical outcomes of HIV infection in Oman to strategically align preventative and therapeutic programs with Oman’s Vision 2040 framework. Methods: We analyzed the clinical and epidemiological data of 429 confirmed HIV-positive patients with a minimum follow-up period of six months, registered at a secondary care facility in North Batinah, Oman, between January 1995 and December 2024. Predictors of mortality were rigorously assessed utilizing Kaplan–Meier survival analysis and Cox proportional hazards regression models. Continuous variables were evaluated using independent sample t-tests or Mann–Whitney U tests, while categorical variables employed chi-square or Fisher’s exact tests. Results: The cohort exhibited a male predominance (70.6%) with a mean age at diagnosis of 32.8 years (SD ± 12.17). Heterosexual contact constituted the predominant mode of acquisition (56%), followed by bisexual (17%) and homosexual (12%) contacts. Although 67.1% of patients presented with early, asymptomatic disease (WHO Stage 1), opportunistic infections were evident in 28.1% of the cohort, with recurrent sepsis (8.4%) and bacterial pneumonia (3.5%) being the most frequent complications. The WHO clinical stage at presentation was confirmed as a highly significant predictor of survival (p < 0.0001). Stage 1 patients achieved excellent long-term prognosis (approximately 75% survival beyond 30 years), markedly contrasting with Stage 4 patients, whose survival declined sharply (median survival of approximately 8 years, and only 10–15% surviving past 20 years). The tenofovir/emtricitabine/efavirenz regimen showed superior efficacy, achieving 75% survival at 30 years, relative to zidovudine-based regimens, which showed significantly poorer performance (15–20% survival at 20 years). Conclusions: This investigation substantiates the shift toward predominant heterosexual transmission and emphasizes the critical prognostic significance of the clinical stage at diagnosis. Optimal long-term survival mandates prompt diagnosis, timely initiation of contemporary antiretroviral therapies, and sustained viral suppression. These findings offer crucial evidence to strengthen HIV prevention and treatment programs within Oman. Full article

Lipid raft-associated gangliosides facilitate the early stages of SARS-CoV-2 entry by triggering the exposure of the receptor-binding domain (RBD) within the trimeric spike protein, which is initially sequestered. A broad range of in silico, cryoelectron microscopy and physicochemical approaches indicate that the RBD becomes accessible after a ganglioside-induced conformational rearrangement originating in the N-terminal domain (NTD) of one protomer and propagating to the neighboring RBD. We previously identified a triad of amino acids, Q134-F135-N137, as a strictly conserved element on the NTD. In the present review, we integrate a series of structural and experimental data revealing that this triad may act as a conformational transducer connected to a chain of residues that are capable of transmitting an internal conformational wave within the NTD. This wave is generated at the triad level after physical interactions with lipid raft gangliosides of the host cell membrane. It propagates inside the NTD and collides with the RBD of a neighboring protomer, triggering its unmasking. We also identify a chain of aromatic residues that are capable of controlling electron transfer through the NTD, leading us to hypothesize the existence of a dual conformational/quantum wave. In conclusion, the complete conservation of the Q134-F135-N137 triad despite six years of extensive NTD remodeling underscores its critical role in the viral life cycle. This triad represents a potential Achilles’ heel within the hyper-variable NTD, offering a stable target for therapeutic or vaccinal interventions to disrupt the conformational wave and prevent infection. These possibilities are discussed. Full article

Background: Durvalumab, a PD-L1 inhibitor used as consolidation therapy after chemoradiation in unresectable stage III non–small cell lung cancer (NSCLC), can induce immune-related adverse events, among which immune-mediated pneumonitis represents one of the most severe. Differentiating checkpoint inhibitor pneumonitis (CIP) from infectious pneumonia is challenging due to overlapping clinical and radiologic findings. Case presentation: We describe a 67-year-old woman with stage III lung adenocarcinoma treated with chemotherapy, radiotherapy, and durvalumab, who presented with progressive dyspnea and extensive bilateral ground-glass opacities on CT imaging. Laboratory tests revealed leukopenia and elevated inflammatory markers. Despite broad-spectrum antibiotic and antiviral therapy, her condition worsened, requiring high-flow nasal cannula oxygen therapy. Multiplex molecular testing on sputum identified human metapneumovirus (HMPV), while blood cultures and urinary antigens for Streptococcus pneumoniae and Legionella pneumophila were negative. A pulmonology consultation raised suspicion for severe durvalumab-induced pneumonitis exacerbated by viral infection. High-dose methylprednisolone (2 mg/kg/day) followed by a four-week taper led to gradual clinical and radiologic resolution. Durvalumab was permanently discontinued. Discussion: To our knowledge, this is the first reported case of HMPV-associated pneumonitis in a patient receiving durvalumab. This case highlights the potential synergistic interplay between viral infection and immune checkpoint blockade, resulting in severe lung injury. Comprehensive microbiologic evaluation, including molecular diagnostics, is essential to guide therapy and distinguish infectious from immune-mediated causes. Conclusions: Early recognition of mixed infectious and immune-mediated pneumonitis, and timely corticosteroid therapy are critical to achieving favorable outcomes and preventing irreversible pulmonary damage. Full article

This paper proposes that immune delay, beyond immune evasion, is key in the propagation competence of major viral and bacterial infections, and that the dynamics of infection and immune response suggest possibilities for mitigating the ensuing infectious diseases. Recent data show a critical role of neutrophils at various stages of viral and bacterial infections, revealing how early activation of neutrophils could help mitigate infectious diseases. It could prevent the gradual overactivation of subclasses of neutrophils and probably not induce it. In respiratory virus infections, an immune delay of several days allows the development of a high viral load supporting infectivity towards further hosts when a delayed and increased immune response takes place. Virus variants will optimize immune delay towards highest infectivity, supporting pandemic potential. The influenza virus, coronavirus, and several major bacterial infections exhibit such immune delay capability. Recurrent urinary tract infections (rUTI) are common, often associated with the causative uropathogenic E. coli (UPEC) that has this capability, suggesting that immune delay is crucial in the pathogenesis of rUTI and other widespread bacterial infections. Counteracting immune delay, therefore, is a promising approach for mitigating infectious diseases with epidemic and pandemic presence or potential. Previously proven low-frequency electromagnetic field (LF-EMF)-induced neutrophil activation is such an approach. Full article

Background: Rabies is among the oldest known zoonotic viral diseases and is caused by members of the Lyssavirus genus. The prototype species, Lyssavirus rabies, effectively evades the host immune response, allowing the infection to progress unnoticed until the onset of clinical signs. At this stage, the disease is irreversible and invariably fatal, with definitive diagnosis possible only post-mortem. Given the advances in modern proteomics, this study aimed to identify potential protein biomarkers for antemortem diagnosis of rabies in dogs, which are the principal reservoir hosts of the rabies virus. Methods: Two hundred and thirty-one samples (brain tissues (BT), cerebrospinal fluids (CSF), and serum (SR) samples) were collected from apparently healthy dogs brought for slaughter for human consumption in South-East and North-Central Nigeria. All the BT were subjected to a direct fluorescent antibody test to confirm the presence of lyssavirus antigen, and 8.7% (n = 20) were positive. Protein extraction, quantification, reduction, and alkylation were followed by on-bead (HILIC) cleanup and tryptic digestion. The resulting peptides from each sample were injected into the Evosep One LC system, coupled to the timsTOF HT MS, using the standard dia-PASEF short gradient data acquisition method. Data was processed using Spectronaut^TM (v19). An unpaired t-test was performed to compare identified protein groups (proteins and their isoforms) between the rabies-infected and uninfected BT, CSF, and SR samples. Results: The study yielded 54 significantly differentially abundant proteins for the BT group, 299 for the CSF group, and 280 for the SR group. Forty-five overlapping differentially abundant proteins were identified between CSF and SR, one between BT and CSF, and two between BT and SR; none were found that overlapped all three groups. Within the BT group, 33 proteins showed increased abundance, while 21 showed decreased abundance in the rabies-positive samples. In the CSF group, 159 proteins had increased abundance and 140 had decreased abundance in the rabies-positive samples. For the SR group, 215 proteins showed increased abundance, and 65 showed decreased abundance in the rabies-positive samples. Functional enrichment analysis revealed that pathways associated with CSF, spinocerebellar ataxia, and neurodegeneration were among the significant findings. Conclusion: This study identified canonical proteins in CSF and SR that serve as candidate biomarkers for rabies infection, offering insights into neuronal dysfunction and potential tools for early diagnosis. Full article

High-grade gliomas—particularly glioblastoma (GBM)—remain refractory to standard-of-care surgery followed by chemoradiation, with a median overall survival of ~15 months. Oncolytic viruses (OVs), which selectively infect and lyse tumor cells while engaging antitumor immunity, offer a mechanistically distinct therapeutic modality. This review synthesizes clinical progress of OVs in GBM, with emphasis on oncolytic herpes simplex virus (oHSV) and coverage of other vectors (adenovirus, reovirus, Newcastle disease virus, vaccinia virus) across phase I–III trials, focusing on efficacy and safety. Key observations include the encouraging clinical trajectory of oHSV exemplars—T-VEC (approved for melanoma) and G47Δ (approved in Japan for recurrent GBM)—the multi-center exploration of the adenovirus DNX-2401 combined with programmed death-1 (PD-1) blockade, and the early-stage status of reovirus (pelareorep) and Newcastle disease virus programs. Emerging evidence indicates that oHSV therapy augments immune infiltration within the tumor microenvironment and alleviates immunosuppression, with synergy when combined with chemotherapy or immune checkpoint inhibitors. Persistent challenges include GBM’s inherently immunosuppressive milieu, limitations imposed by the blood–brain barrier, intrapatient viral delivery and biodistribution, and concerns about viral shedding. Future directions encompass programmable vector design, optimization of systemic delivery, biomarker-guided patient selection, and rational combination immunotherapy. Collectively, OVs represent a promising immunotherapeutic strategy in GBM; further gains will hinge on vector engineering and precision combinations to translate mechanistic promise into durable clinical benefit. Full article

In this paper, we develop a mathematical model to investigate HIV infection dynamics, where we focus on the virus’s dual-target mechanism involving both CD$4^{+}$ T cells and macrophages. Our model is structured as a system of seven nonlinear ordinary differential equations describing the interactions between susceptible, latent, and infected cells, alongside free virus particles. We derive the basic reproduction number, ${\mathcal{R}}_0$, as two components, ${\mathcal{R}}_{01}$ and ${\mathcal{R}}_{02}$, which quantify the respective contributions of CD$4^{+}$ T cells and macrophages to viral spread. It is deduced that the infection-free steady state is globally asymptotically stable once ${\mathcal{R}}_0\le 1$, ensuring viral eradication. For ${\mathcal{R}}_0>1$, a stable endemic steady state emerges, indicating the persistence of the infection. Later, we develop an optimal control strategy to study the impact of reverse transcriptase and protease inhibitors. This analysis identifies a critical drug efficacy threshold, ${ϵ}^{\ast }=1-{\displaystyle \frac{1}{{\mathcal{R}}_0}}$, necessary for viral eradication. The numerical simulations and the sensitivity analysis provide key parameters that drive viral dynamics, offering practical insights for designing targeted therapies, particularly during the early stages of infection. Full article

Orthoebolavirus zairense is the species name for Zaire Ebola virus (EBOV) within Filoviridae. This group of viruses can cause severe disease in humans, characterized by hemorrhagic shock, coagulation abnormalities, and severe inflammation. While tissue macrophages are critical targets early during EBOV infection, other cell types support viral replication as disease progresses. At late stages of infection, infectious EBOV is found on the surface of the skin, which may be a critical source of infectious virus transmitted between individuals during outbreaks. Human skin contains a number of cellular targets of EBOV, including keratinocytes. Here, we demonstrate EBOV infection of telomerase-immortalized normal human skin keratinocytes (NHSK-1), as well as EBOVΔVP30 infection of NHSK-1 cells that were stably complemented with EBOV transcription factor VP30. Infection with EBOVΔVP30 did not elicit detectable endogenous interferon responses; however, exogenous pre-treatment of NHSK-1 cells with type I, II, and III interferon (IFN) inhibited EBOVΔVP30 infection and infection of an additional low-containment model of EBOV, rVSV/EBOV GP, in a dose-dependent manner. Analysis of the transcriptome of IFN-treated keratinocytes identified multiple genes unique to each IFN and a subset of ISGs upregulated by all three IFNs. Our results indicate that ISGs induced by IFN pre-treatment of keratinocytes can reduce infection, underlining that ISGs may serve as EBOV-targeting therapeutics. Full article

This review aims to discuss the apparent reduction in pulmonary cancer incidence in the general population during and shortly after the COVID-19 pandemic from a biological and pathophysiological mechanistic point of view. While the epidemiological evidence points to a disruption in the early- and mid-stage diagnostic process, which causes a shift to late-stage lung cancer discovery with no impact on its actual prevalence, an alternative hypothesis based on the intersection of viral and cancer biology could have a real effect on lung carcinogenesis as an independent phenomenon. By weaving together population-level trends, mechanistic insights, and translational oncology, we discuss whether the pandemic-associated decline in lung cancer diagnoses reflects primarily a temporary diagnostic artifact or whether it also reveals biologically relevant intersections between SARS-CoV-2 and pulmonary oncogenesis. The COVID-19 pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has exerted profound and multifaceted effects on global healthcare systems, altering patterns of disease detection, management, and outcomes across nearly all medical disciplines. These disruptions generated what has been termed a “diagnostic deficit”, producing a backlog of undetected cancers that have only partially been recovered in subsequent years. This phenomenon, sometimes described as a “COVID-19 debt” in oncology, is thought to contribute to excess late-stage diagnoses and potentially worse medium-term survival outcomes. Beyond the disruption of medical systems, the pandemic also raised a more speculative but biologically intriguing question: could SARS-CoV-2 infection itself, through direct or indirect mechanisms, influence lung cancer biology? Our review aims to critically synthesize the evidence across seven domains to address this dual hypothesis. (1) We examine the observed effects of the pandemic on cancer incidence, highlighting global registry and health-system data; (2) we review SARS-CoV-2 infection biology, including viral entry, replication, protein functions, and treatment implications; (3) we summarize the pathogenesis of lung cancer; (4) we explore the role of immune checkpoints in tumor immune evasion, followed by (5) analyses of immune dysregulation in acute infection and (6) in long COVID; and (7) finally, we evaluate proposed oncogenic mechanisms of SARS-CoV-2, integrating molecular virology with cancer immunology. We conclude that the “diagnostic deficit” phenomenon was a reality during and immediately post-pandemic. However, a definitive answer to the questions related to the impact of the infection as an independent phenomenon would require advanced research information covering the biology of the viral infection and lung cancer oncogenesis: processes that are not currently implemented in routine clinical laboratory investigations. Full article

Neurodegenerative diseases are widely viewed as brain-centric disorders defined by neuronal loss and protein aggregation. Yet decades of failed disease-modifying trials and mounting evidence of early peripheral symptoms suggest that this view is incomplete. This perspective review uses α-synucleinopathies as an illustrative example to outline how organ–brain axes, exosomal signaling, and strain competition shape disease trajectory, proposing a new clinical model: precision ecosystem medicine. This paradigm shift conceptualizes neurodegeneration as the late-stage manifestation of systemic ecosystem collapse: a progressive breakdown in inter-organ homeostasis driven by microbial imbalance, immune dysfunction, viral reactivation, co-infections, environmental stressors, and toxicant accumulation, when protective systems become saturated. Misfolded proteins such as α-synuclein act as prion-like mediators of this collapse, with distinct conformational “strains” emerging in different organ environments and may propagate to the brain via exosomes and neural pathways. Analyses suggest that understanding these systemic interactions could reveal new therapeutic windows before significant neurodegeneration occurs. This integrative approach establishes a conceptual foundation for regenerative therapies that address the complexity of neurodegenerative diseases beyond symptom management, offering promising directions for revolutionizing patient care with precise, multi-targeted strategies. Reframing neurodegeneration as a multi-organ, ecosystem-level disorder opens new paths for prevention, prediction, and potentially disease-modifying therapies, laying the theoretical foundation for a field of precision ecosystem medicine. Full article

Arboviruses such as dengue (DENV), Zika (ZIKV), and chikungunya (CHIKV) remain major global health threats, especially in tropical regions, with no effective antiviral treatments available. Recent research highlights progress in identifying antiviral compounds from natural sources against arboviruses belonging to the flavivirus genus, such as DENV and ZIKV. These compounds, derived from plants, marine organisms, and microorganisms, fall into several key chemical classes: quinones, flavonoids, phenolics, terpenoids, and alkaloids. Quinones inhibit viral entry and replication by targeting envelope proteins and proteases. Flavonoids disrupt RNA synthesis and show virucidal activity. Phenolic compounds reduce expression of non-structural proteins and inhibit enzyme function. Terpenoids demonstrate broad-spectrum activity against multiple arboviruses, while alkaloids interfere with early infection stages or viral enzymes. To support the reviewed literature, we performed molecular docking analyses of selected natural compounds and some arboviral proteins included as illustrative examples. These analyses support the structure–activity relationships reported for some natural compounds and highlight their potential interactions with essential viral targets such as the NS2B-NS3 protease and NS5 polymerase. Together, these literature and computational insights highlight the potential of natural products as scaffolds for antiviral drug development. Full article

BK polyomavirus (BKPyV) causes severe urinary tract diseases, including BKPyV-associated nephropathy (BKPyVN) and ureteric stenosis, in immunocompromised individuals such as renal transplant recipients. Effective antiviral therapies for BKPyV infection remain an unmet clinical need. While the interferon-stimulated gene 20 (ISG20) exhibits broad-spectrum antiviral activity against RNA viruses, its role and mechanisms against DNA viruses are poorly defined. This study demonstrates, for the first time, potent antiviral activity of ISG20 against BKPyV. This restriction was observed with both endogenous levels of ISG20 and upon overexpression, and this effect was confirmed by ISG20 knockout and immunofluorescence imaging. We observed that ISG20 expression is dynamically regulated during BKPyV infection: it is upregulated both during early infection and by expression of the viral large T antigen (LT) alone. However, endogenous ISG20 expression becomes significantly suppressed during later stages of infection, coinciding with declining LT levels. The physical interaction between LT and both wild-type and mutant ISG20 suggests a potential viral strategy to sequester this restriction factor. These findings establish ISG20 as a novel host restriction factor against BKPyV and suggest that BKPyV employs LT-mediated mechanisms to evade or counteract ISG20’s antiviral effects. Our results elucidate a complex biphasic interplay between BKPyV and host innate immunity, identifying ISG20 as a potential therapeutic target for BKPyV-associated diseases. Full article

Rapid, simple, and robust diagnostics are essential for effectively controlling the spread of plant viruses and mitigating their impact. Although recombinase polymerase amplification-lateral flow test (RPA-LFT) diagnostics currently offer high sensitivity and specificity, they rely on the Nfo endonuclease enzyme and require an expensive heat block. In this study, we present the development of a molecular diagnostic test for cucurbit leaf crumple virus (CuLCrV) using an RPA-LFT assay that employs an alternative endonuclease enzyme instead of Nfo. This alternative endonuclease demonstrates comparable functionality to Nfo and achieves a detection limit of 10 viral copies in plant samples and whiteflies. The assay can be performed using a battery-powered mini heat block, ensuring scalability and cost-effectiveness. Notably, the unavailability of commercially accessible Nfo endonuclease enzymes underscores the necessity for an alternative enzyme for RPA-LFT assay development. The RPA-LFT assay eliminates the need for nucleic acid purification and provides results within approximately 30 min from sample collection. The integration of this new endonuclease into the RPA-LFT assay represents an advancement towards on-site detection of plant viruses, enabling early-stage management of viral infections. Full article

Viral infections represent a critical threat to cultivated plant species. In papaya cultivation, two viral diseases—papaya mosaic (caused by papaya ringspot virus type P—PRSV-P) and papaya sticky disease (caused by a virus complex of papaya meleira virus—PMeV, and papaya meleira virus—PMeV2)—are prevalent and capable of devastating entire plantations, incurring substantial economic losses. Current diagnostic practices rely on visual identification of symptoms and elimination of infected plants (roguing). Monitoring photosynthetic efficiency in orchards prone to PRSV-P and PMeV2 coinfection may allow early intervention, mitigating productivity losses and reducing fruit quality. This study aimed to evaluate chlorophyll a fluorescence as a biomarker for photosynthetic impairment and symptom severity in papaya infected with PRSV-P and/or PMeV2 and to explore the feasibility of early detection of the infection by these dual pathogens, as an exploratory study under field conditions. Chlorophyll a fluorescence revealed details about the physiology of plants coinfected with the complex of PMeV2 and PRSV-P: the electron motive force within PSII decreases in infected plants and in those without visual symptoms of infection, being proportional to the age and developmental stage of the plants. A slowdown in the multiple electron transfer turnover of PSII and a decrease in the efficiency of the redox reactions of photosystem I were observed in plants with or without visual detection of infection. The evidence generated suggests that the chlorophyll a fluorescence technique can be used to monitor the pathophysiological state of plants under biotic stress. Full article