This paper presents an innovative mathematical model for assessing the dynamics and optimal control of Nipah virus (NiV) with imperfect vaccination. The model formulation considers transmissions through contaminated food and human-to-human contacts. It also incorporates the potential virus transmission through contact with a deceased body infected with NiV. Initially, the NiV model is assessed theoretically, identifying three distinct equilibrium states: the NiV-endemic equilibrium state, the NiV-free equilibrium state, and the equilibrium state involving infected flying foxes. Furthermore, the stability results of the model in the case of constant controls are thoroughly analyzed at the NiV-free equilibrium. Some of the parameters of the model are estimated based on the infected cases documented in Bangladesh from 2001 to 2017. We further perform sensitivity analysis to determine the most influential parameters and formulate effective time-dependent controls. Numerical simulations indicate the optimal course of action for eradicating the disease and provide a comparative analysis of controlling the infection under constant and time-varying interventions. The simulation confirms that the implementation of time-varying interventions is effective in minimizing disease incidence.

• MeSH
• Henipavirus Infections * transmission   prevention & control   epidemiology   MeSH
• Humans MeSH
• Computer Simulation MeSH
• Models, Theoretical MeSH
• Vaccination * MeSH
• Nipah Virus * immunology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Bangladesh MeSH

Interleukin-2-inducible T-cell kinase (ITK) and Bruton's tyrosine kinase (BTK) are two important members of the Tec family with crucial roles in immune system function. Deregulation in ITK and BTK activity is linked to several hematological malignancies, making them key targets for cancer immunotherapy. In this study, we synthesized a series of azaspirooxindolinone derivatives and evaluated their cytotoxic activity against ITK/BTK-negative and positive cancer cell lines, followed by enzymatic inhibition studies to assess the ITK/BTK kinase selectivity of two hit compounds. Several compounds demonstrated selective cytotoxicity against ITK- or BTK-expressing cells. Compound 3d exhibited high cytotoxicity in ITK-positive Jurkat (IC50 = 3.58 μM) and BTK-positive Ramos (IC50 = 3.06 μM) cells, while compound 3j showed strong cytotoxicity in Ramos (IC50 = 1.38 μM) and Jurkat (IC50 = 4.16 μM) cells. Compounds 3a and 3e were selectively cytotoxic in Jurkat cells (IC50 = 9.36 μM and 10.85 μM, respectively), while compounds 3f and 3g were highly cytotoxic in Ramos cells (IC50 = 1.82 μM and 1.42 μM, respectively). None of the active compounds exhibited cytotoxicity in non-cancer cell lines (IC50 > 50 μM), demonstrating their selectivity for malignant cells. Enzyme inhibition assay showed that 3d is a selective ITK inhibitor (IC50 = 0.91 μM) with no detectable BTK inhibition, aligning with its strong activity in ITK-positive cells. In contrast, compound 3j did not inhibit ITK or BTK enzymatically, suggesting an alternative mechanism of action. These findings highlight 3d as a promising ITK inhibitor and warrant further investigation to elucidate its mechanism of action.

• MeSH
• Protein Kinase Inhibitors * pharmacology   chemical synthesis   chemistry   MeSH
• Humans MeSH
• Molecular Structure MeSH
• Cell Line, Tumor MeSH
• Oxindoles pharmacology   chemistry   chemical synthesis   MeSH
• Cell Proliferation drug effects   MeSH
• Agammaglobulinaemia Tyrosine Kinase * antagonists & inhibitors   metabolism   MeSH
• Antineoplastic Agents * pharmacology   chemical synthesis   chemistry   MeSH
• Drug Design * MeSH
• Drug Screening Assays, Antitumor * MeSH
• Molecular Docking Simulation MeSH
• Spiro Compounds chemistry   pharmacology   chemical synthesis   MeSH
• Protein-Tyrosine Kinases * antagonists & inhibitors   metabolism   MeSH
• Dose-Response Relationship, Drug MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

OBJECTIVES: Human papillomavirus (HPV) infections are highly prevalent sexually transmitted infections, notably associated with various cancers. This study analyses the health and economic impacts of HPV-associated diseases in the Czech Republic and evaluates the cost-effectiveness of a catch-up vaccination program. METHODS: Utilizing a Markov multistate model, the study assesses the lifetime impacts and costs related to HPV infections. Cohorts of ages 15-21 were simulated to assess the impact of catch-up vaccination outside the 11-year-old age group. RESULTS: The total quality-adjusted life years (QALYs) for the female and male cohorts (together 119,362 individuals) were higher in the vaccination scenario compared to the non-vaccination scenario. The increase in QALYs was 122,246 and 200,852 respectively, when considering the actual vaccination rates. Across both cohorts, 329 cancer-related deaths were prevented. In the probabilistic sensitivity analysis for the female population, vaccination was the dominant strategy in 99.3% of iterations. In the male population, vaccination was the dominant strategy in 80.3% of iterations. The implementation of catch-up vaccination for the 15-21 age group significantly increased QALY gains and reduced life-years-lost (LYLs). In the female cohort, all analysed rates of catch-up vaccination were the dominant strategy, while in the male cohort, the incremental cost-effectiveness ratios (ICERs) remained consistently below 42,000 CZK/QALY. CONCLUSIONS: The catch-up vaccination program for 15-21-year-olds is cost-effective and can prevent a significant number of HPV-related cancers in both men and women.

• MeSH
• Cost-Effectiveness Analysis MeSH
• Cost-Benefit Analysis * MeSH
• Adult MeSH
• Papillomavirus Infections * prevention & control   economics   MeSH
• Quality-Adjusted Life Years * MeSH
• Humans MeSH
• Markov Chains * MeSH
• Adolescent MeSH
• Young Adult MeSH
• Immunization Programs economics   MeSH
• Cost of Illness MeSH
• Papillomavirus Vaccines * economics   administration & dosage   MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Czech Republic MeSH

Apolipoprotein E (APOE) is distributed across various human tissues and plays a crucial role in lipid metabolism. Recent investigations have uncovered an additional facet of APOE's functionality, revealing its role in host defense against bacterial infections. To assess the antibacterial attributes of APOE3 and APOE4, we conducted antibacterial assays using Pseudomonas aeruginosa and Escherichia coli. Exploring the interaction between APOE isoforms and lipopolysaccharides (LPSs) from E. coli, we conducted several experiments, including gel shift assays, CD, and fluorescence spectroscopy. Furthermore, the interaction between APOE isoforms and LPS was further substantiated through atomic resolution molecular dynamics simulations. The presence of LPS induced the aggregation of APOE isoforms, a phenomenon confirmed through specific amyloid staining, as well as fluorescence and electron microscopy. The scavenging effects of APOE3/4 isoforms were studied through both in vitro and in vivo experiments. In summary, our study established that APOE isoforms exhibit binding to LPS, with a more pronounced affinity and complex formation observed for APOE4 compared with APOE3. Furthermore, our data suggest that APOE isoforms neutralize LPS through aggregation, leading to a reduction of local inflammation in experimental animal models. In addition, both isoforms demonstrated inhibitory effects on the growth of P. aeruginosa and E. coli. These findings provide new insights into the multifunctionality of APOE in the human body, particularly its role in innate immunity during bacterial infections.

• MeSH
• Apolipoprotein E3 * metabolism   chemistry   pharmacology   MeSH
• Apolipoprotein E4 * metabolism   chemistry   pharmacology   MeSH
• Escherichia coli metabolism   MeSH
• Humans MeSH
• Lipopolysaccharides * metabolism   chemistry   MeSH
• Mice MeSH
• Protein Isoforms chemistry   metabolism   MeSH
• Pseudomonas aeruginosa metabolism   MeSH
• Molecular Dynamics Simulation MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

The application of lipid-based nanoparticles for COVID-19 vaccines and transthyretin-mediated amyloidosis treatment have highlighted their potential for translation to cancer therapy. However, their use in delivering drugs to solid tumors is limited by ineffective targeting, heterogeneous organ distribution, systemic inflammatory responses, and insufficient drug accumulation at the tumor. Instead, the use of lipid-based nanoparticles to remotely activate immune system responses is an emerging effective strategy. Despite this approach showing potential for treating hematological cancers, its application to treat solid tumors is hampered by the selection of eligible targets, tumor heterogeneity, and ineffective penetration of activated T cells within the tumor. Notwithstanding, the use of lipid-based nanoparticles for immunotherapy is projected to revolutionize cancer therapy, with the ultimate goal of rendering cancer a chronic disease. However, the translational success is likely to depend on the use of predictive tumor models in preclinical studies, simulating the complexity of the tumor microenvironment (e.g., the fibrotic extracellular matrix that impairs therapeutic outcomes) and stimulating tumor progression. This review compiles recent advances in the field of antitumor lipid-based nanoparticles and highlights emerging therapeutic approaches (e.g., mechanotherapy) to modulate tumor stiffness and improve T cell infiltration, and the use of organoids to better guide therapeutic outcomes.

• MeSH
• Amyloid Neuropathies, Familial * MeSH
• Immunotherapy MeSH
• Humans MeSH
• Lipids MeSH
• Tumor Microenvironment MeSH
• Neoplasms * therapy   MeSH
• COVID-19 Vaccines MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

INTRODUCTION: This work focuses on the Dengue-viremia ABC (Atangana-Baleanu Caputo) fractional-order differential equations, accounting for both symptomatic and asymptomatic infected cases. Symptomatic cases are characterized by higher viremia levels, whereas asymptomatic cases exhibit lower viremia levels. The fractional-order model highlights memory effects and other advantages over traditional models, offering a more comprehensive representation of dengue dynamics. METHODS: The total population is divided into four compartments: susceptible, asymptomatic infected, symptomatic infected, and recovered. The model incorporates an immune-boosting factor for asymptomatic infected individuals and clinical treatment for symptomatic cases. Positivity and boundedness of the model are validated, and both local and global stability analyses are performed. The novel Adams-Bash numerical scheme is utilized for simulations to rigorously assess the impact of optimal control interventions. RESULTS: The results demonstrate the effectiveness of the proposed control strategies. The reproduction numbers must be reduced based on specific optimal control conditions to effectively mitigate disease outbreaks. Numerical simulations confirm that the optimal control measures can significantly reduce the spread of the disease. DISCUSSION: This research advances the understanding of Dengue-viremia dynamics and provides valuable insights into the application of ABC fractional-order analysis. By incorporating immune-boosting and clinical treatment into the model, the study offers practical guidelines for implementing successful disease control strategies. The findings highlight the potential of using optimal control techniques in public health interventions to manage disease outbreaks more effectively.

• MeSH
• Dengue * MeSH
• Disease Outbreaks MeSH
• Humans MeSH
• Viremia * MeSH
• Dengue Virus immunology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

Bolivian hemorrhagic fever (BHF) caused by Machupo virus (MACV) is a New World arenavirus having a reported mortality rate of 25-35%. The BHF starts with fever, followed by headache, and nausea which rapidly progresses to severe hemorrhagic phase within 7 days of disease onset. One of the key promoters for MACV viral entry into the cell followed by viral propagation is performed by the viral glycoprotein (GPC). GPC is post-transcriptionally cleaved into GP1, GP2 and a signal peptide. These proteins all take part in the viral infection in host body. Therefore, GPC protein is an ideal target for developing therapeutics against MACV infection. In this study, GPC protein was considered to design a multi-epitope, multivalent vaccine containing antigenic and immunogenic CTL and HTL epitopes. Different structural validations and physicochemical properties were analysed to validate the vaccine. Docking and molecular dynamics simulations were conducted to understand the interactions of the vaccine with various immune receptors. Finally, the vaccine was codon optimised in silico and along with which immune simulation studies was performed in order to evaluate the vaccine's effectiveness in triggering an efficacious immune response against MACV.

• MeSH
• Hemorrhagic Fever, American * immunology   prevention & control   MeSH
• Arenaviruses, New World immunology   MeSH
• Epitopes immunology   chemistry   MeSH
• Humans MeSH
• Molecular Dynamics Simulation MeSH
• Molecular Docking Simulation MeSH
• Viral Vaccines * immunology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

Globin adducts of various chemicals, persisting in organism over the whole lifetime of erythrocytes, have been used as biomarkers of cumulative exposures to parent compounds. After removal of aged erythrocytes from the bloodstream, cleavage products of these adducts are excreted with urine as alternative, non-invasively accessible biomarkers. In our biomonitoring studies on workers exposed to ethylene oxide, its adduct with globin, N-(2-hydroxyethyl)valine, and the related urinary cleavage product N-(2-hydroxyethyl)-L-valyl-L-leucine have been determined. To describe a toxicokinetic relationship between the above types of biomarkers, a general compartmental model for simulation of formation and removal of globin adducts has been constructed in the form of code in R statistical computing environment. The essential input variables include lifetime of erythrocytes, extent of adduct formation following a single defined exposure, and parameters of exposure scenario, while other possible variables are optional. It was shown that both biomarkers reflect the past exposures differently as the adduct level in globin is a mean value of adduct levels across all compartments (subpopulations of erythrocytes of the same age) while excretion of cleavage products reflects the adduct level in the oldest compartment. Application of the model to various scenarios of continuous exposure demonstrated its usefulness for human biomonitoring data interpretation.

• MeSH
• Biomarkers * urine   blood   MeSH
• Models, Biological MeSH
• Biological Monitoring * MeSH
• Erythrocytes * metabolism   drug effects   MeSH
• Ethylene Oxide toxicity   pharmacokinetics   urine   MeSH
• Globins metabolism   MeSH
• Humans MeSH
• Computer Simulation MeSH
• Occupational Exposure * MeSH
• Toxicokinetics MeSH
• Valine analogs & derivatives   pharmacokinetics   urine   blood   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

The PD-1/PD-L1 complex is an immune checkpoint responsible for regulating the natural immune response, but also allows tumors to escape immune surveillance. Inhibition of the PD-1/PD-L1 axis positively contributes to the efficacy of cancer treatment. The only available therapeutics targeting PD-1/PD-L1 are monoclonal antibody-based drugs, which have several limitations. Therefore, small molecule compounds are emerging as an attractive alternative that can potentially overcome the drawbacks of mAb-based therapy. In this article, we present a novel class of small molecule compounds based on the terphenyl scaffold that bind to PD-L1. The general architecture of the presented structures is characterized by axial symmetry and consists of three elements: an m-terphenyl core, an additional aromatic ring, and a solubilizing agent. Using molecular docking, we designed a series of final compounds, which were subsequently synthesized and tested in HTRF assay and NMR binding assay to evaluate their activity. In addition, we performed an in-depth analysis of the mutual arrangement of the phenyl rings of the terphenyl core within the binding pocket of PD-L1 and found several correlations between the plane angle values and the affinity of the compounds towards the protein.

• MeSH
• B7-H1 Antigen * antagonists & inhibitors   metabolism   chemistry   MeSH
• Programmed Cell Death 1 Receptor * antagonists & inhibitors   metabolism   chemistry   MeSH
• Immune Checkpoint Inhibitors chemistry   pharmacology   MeSH
• Small Molecule Libraries pharmacology   chemistry   MeSH
• Humans MeSH
• Molecular Structure MeSH
• Molecular Docking Simulation * MeSH
• Terphenyl Compounds * chemistry   pharmacology   MeSH
• Protein Binding * MeSH
• Binding Sites MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

INTRODUCTION: While radiotherapy has long been recognized for its ability to directly ablate cancer cells through necrosis or apoptosis, radiotherapy-induced abscopal effect suggests that its impact extends beyond local tumor destruction thanks to immune response. Cellular proliferation and necrosis have been extensively studied using mathematical models that simulate tumor growth, such as Gompertz law, and the radiation effects, such as the linear-quadratic model. However, the effectiveness of radiotherapy-induced immune responses may vary among patients due to individual differences in radiation sensitivity and other factors. METHODS: We present a novel macroscopic approach designed to quantitatively analyze the intricate dynamics governing the interactions among the immune system, radiotherapy, and tumor progression. Building upon previous research demonstrating the synergistic effects of radiotherapy and immunotherapy in cancer treatment, we provide a comprehensive mathematical framework for understanding the underlying mechanisms driving these interactions. RESULTS: Our method leverages macroscopic observations and mathematical modeling to capture the overarching dynamics of this interplay, offering valuable insights for optimizing cancer treatment strategies. One shows that Gompertz law can describe therapy effects with two effective parameters. This result permits quantitative data analyses, which give useful indications for the disease progression and clinical decisions. DISCUSSION: Through validation against diverse data sets from the literature, we demonstrate the reliability and versatility of our approach in predicting the time evolution of the disease and assessing the potential efficacy of radiotherapy-immunotherapy combinations. This further supports the promising potential of the abscopal effect, suggesting that in select cases, depending on tumor size, it may confer full efficacy to radiotherapy.

• MeSH
• Immunotherapy * methods   MeSH
• Combined Modality Therapy MeSH
• Humans MeSH
• Neoplasms * therapy   immunology   radiotherapy   MeSH
• Radiotherapy methods   MeSH
• Models, Theoretical MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH