Search Results (89)

Azvudine (FNC) is a novel cytidine analogue that is widely used in the treatment of infectious diseases such as AIDS and COVID-19. Previous studies have demonstrated its anticancer activity in various cancer cell lines, including non-Hodgkin’s lymphomas and lung adenocarcinoma cell lines. However, its effects on hepatocellular carcinoma (HCC) and the underlying mechanisms remain unclear. This study aimed to investigate the anti-epithelial–mesenchymal transition (anti-EMT) activity of FNC and evaluate its potential application in HCC treatment. We found that FNC significantly inhibits the migration of the liver cancer cell line Huh7 by downregulating key EMT markers, such as matrix metalloproteinases (MMPs) and E-cadherin, at both the transcriptional and protein expression levels. Notably, we found that FNC inhibits HEY proteins, particularly HEY1, a transcriptional regulator of the Notch signalling pathway that is overexpressed in approximately 50% of HCC patients. To identify the primary target of FNC, microscale thermophoresis (MST) and molecular dynamics (MD) simulations were performed, revealing that FNC directly binds to Jagged1. This study provides valuable insights into the therapeutic potential of FNC in HCC treatment and elucidates its underlying mechanisms. Full article

Multimorbidity poses significant challenges for resource-constrained healthcare systems, particularly in low and middle income countries where specific combinations of chronic conditions may differentially impact function. This cross-sectional study examined multimorbidity patterns and associations with functioning among 165 adults attending semi-rural primary healthcare facilities in South Africa. Participants completed performance-based measures (handgrip strength, five-times sit-to-stand test, step test and exercise prescription tool [STEP] maximum oxygen consumption) and self-reported function (12-item WHODAS 2.0). Exploratory factor analysis identified three multimorbidity patterns: HIV-hypercholesterolaemia-obesity (Pattern 1), hypertension-anaemia-lung disease (Pattern 2), and stroke-heart disease-hypercholesterolaemia (Pattern 3). Pattern 1 was associated with reduced aerobic capacity (β = −6.41, 95% CI: −9.45, −3.36) and grip strength (β = −0.11, 95% CI: −0.14, −0.07). Pattern 2 showed associations with mild (β = 1.12, 95% CI: 0.28, 1.97) and moderate (β = 1.48, 95% CI: 0.53, 2.43) self-reported functional problems and reduced grip strength (β = −0.05, 95% CI: −0.09, −0.003). Pattern 3 was associated with all self-reported impairment levels, with the strongest association for severe impairment (β = 2.16, 95% CI: 0.32, 4.01). These findings highlight the convergence of infectious and non-communicable diseases in this setting. Simple clinical measures like grip strength and self-reported function may hold potential as screening or monitoring tools in the presence of disease patterns, warranting further research. Full article

Interstitial lung diseases (ILD) represent a diverse group of disorders that primarily affect the pulmonary interstitium and, less commonly, involve the alveolar and vascular epithelium. Overlapping clinical, radiological and histopathological features make proper classification difficult, requiring multiple complementary methodologies, including flow cytometry of bronchoalveolar lavages (BAL). This retrospective study analyzed BAL flow cytometry data from 1074 real-life patients, quantifying alveolar macrophages, CD4/CD8 lymphocytes, neutrophils, eosinophils, and CD1a+ Langerhans cells, with the aim of evaluating its diagnostic utility in ILD and pulmonary infection. Clustering and logistic regression analyses identified seven distinct leukocyte profiles: lymphocytic (associated with hypersensitivity pneumonitis, cryptogenic organizing pneumonia, and lymphocytic interstitial pneumonia), sarcoidosis, macrophagic (including nonspecific interstitial pneumonia, desquamative interstitial pneumonitis, pneumoconiosis, and unclassifiable ILD), neutrophilic (including usual interstitial pneumonia, respiratory bronchiolitis ILD, and acute interstitial pneumonia), infectious diseases, eosinophilic ILD, and Langerhans cell histiocytosis. The estimated leukocyte profiles were associated with different overall survival (OS) outcomes. Neutrophilic profiles, both infectious and non-infectious, correlated with poorer OS, particularly in patients without pulmonary fibrosis. Furthermore, corticosteroids and other immunosuppressive therapies did not show significant OS differences across leukocyte profiles. Although the gold standard in BAL cytology continues to be cytopathology, these results support BAL flow cytometry as a rapid and reliable complementary tool to aid in the classification of interstitial lung diseases based on immune cell profiles, providing valuable predictive information and contributing to personalized therapeutic approaches. Full article

Background: Interstitial lung diseases (ILDs) are a heterogeneous group of conditions that can cause fibrosis of the lung interstitium, resulting in respiratory failure and death. Patients with an ILD, particularly idiopathic pulmonary fibrosis (IPF) or connective tissue disease-associated ILDs (CTD-ILDs), are prone to develop chronic pulmonary infections such as tuberculosis (TB) and non-tuberculous mycobacterial pulmonary disease (NTM-PD). Methods: This case series examines the management of three ILD patients with a usual interstitial pneumonia (UIP) pattern and concomitant NTM-PD or TB at National Institute for Infectious Diseases “Lazzaro Spallanzani” in Rome, Italy, over three years (2019–2022). Results and Conclusions: Multi-disciplinary discussion (MDD) was crucial to define the therapeutic approach due to the increased risk of side effects and drug interactions. Our work underscored how a comprehensive diagnostic evaluation, enriched by MDD, is useful for optimizing the management and reducing drug-related adverse effects and interactions in ILD patients with cavitary lesions. Full article

Hypoxia-inducible factors (HIFs) are transcription factors that enable cells to adapt to low-oxygen environments. Viruses can exploit this pathway to enhance infection, making HIF modulation a potential antiviral strategy. In previous in vitro studies, we found that respiratory syncytial virus (RSV) stabilizes HIFs under normoxic conditions with inhibition of HIF-1α reducing replication. Despite several HIF-modulating compounds being tested or approved in other non-infectious models, little is known about their efficacy against respiratory viruses in relevant animal models. This study aimed to characterize the disease-modulating properties and antiviral potential of HIF-1α (PX478) and HIF-2α PT2385 inhibitors in RSV-infected BALB/c mice. We found that the inhibition of HIF-1α worsened clinical disease parameters while simultaneously improving airway function. Blocking HIF-1α also significantly reduced peak RSV replication in the lung. In contrast, the inhibition of HIF-2α was associated with improved clinical parameters, no changes in airway function, and reduced viral replication following RSV infection. The analysis of lung cells found significant modification in the T-cell compartment that correlated with changes in lung pathology and viral titers for each HIF inhibitor. This study underscores the differential roles of HIF proteins in RSV infection and highlights the need for further characterization of compounds currently in use or under therapeutic consideration. Full article

Objectives: Predicting intensive care unit (ICU) admissions during pandemic outbreaks such as COVID-19 can assist clinicians in early intervention and the better allocation of medical resources. Artificial intelligence (AI) tools are promising for this task, but their development can be hindered by the limited availability of training data. This study aims to explore model development strategies in data-limited scenarios, specifically in detecting the need for ICU admission using chest X-rays of COVID-19 patients by leveraging transfer learning and data extension to improve model performance. Methods: We explored convolutional neural networks (CNNs) pre-trained on either natural images or chest X-rays, fine-tuning them on a relatively limited dataset (COVID-19-NY-SBU, n = 899) of lung-segmented X-ray images for ICU admission classification. To further address data scarcity, we introduced a dataset extension strategy that integrates an additional dataset (MIDRC-RICORD-1c, n = 417) with different but clinically relevant labels. Results: The TorchX-SBU-RSNA and ELIXR-SBU-RSNA models, leveraging X-ray-pre-trained models with our training data extension approach, enhanced ICU admission classification performance from a baseline AUC of 0.66 (56% sensitivity and 68% specificity) to AUCs of 0.77–0.78 (58–62% sensitivity and 78–80% specificity). The gradient-weighted class activation mapping (Grad-CAM) analysis demonstrated that the TorchX-SBU-RSNA model focused more precisely on the relevant lung regions and reduced the distractions from non-relevant areas compared to the natural image-pre-trained model without data expansion. Conclusions: This study demonstrates the benefits of medical image-specific pre-training and strategic dataset expansion in enhancing the model performance of imaging AI models. Moreover, this approach demonstrates the potential of using diverse but limited data sources to alleviate the limitations of model development for medical imaging AI. The developed AI models and training strategies may facilitate more effective and efficient patient management and resource allocation in future outbreaks of infectious respiratory diseases. Full article

Attenuated Salmonella strains are promising oral vectors for vaccination against human infectious diseases. Human cytomegalovirus (CMV) is among the most common causes of disability in children, including intellectual disability and sensorineural hearing loss. Developing an anti-CMV vaccine is a major public health priority. We report in this study the construction of a new attenuated Salmonella strain to express murine cytomegalovirus (MCMV) M25 protein and its use for vaccination in mice against MCMV infection. In mice orally vaccinated with the constructed Salmonella vector carrying the M25 expression cassette, we revealed a substantial induction of anti-MCMV serum IgG and mucosal IgA humoral responses and a considerable elicitation of anti-MCMV T cell responses. When the vaccinated mice were challenged intraperitoneally and intranasally with MCMV, we observed a significant inhibition of virus infection and growth in various organs including spleens, livers, lungs, and salivary glands, compared to the non-vaccinated animals or those receiving a control vaccine without M25 protein expression. Moreover, we showed effective protection of these vaccinated mice from MCMV challenge. Our study provides the first direct evidence that an attenuated Salmonella-based vector with the MCMV M25 expression cassette can induce strong humoral and T cell responses and provide effective protection against MCMV infection. These results illustrate the feasibility of engineering Salmonella-based vectors expressing the M25 antigen for anti-CMV oral vaccine development. Full article

The pediatric common variable immunodeficiency (CVID) is the most frequent symptomatic antibody production defect characterized by infectious and non-infectious autoimmune, inflammatory, and lymphoproliferative complications. The background for CVID-related organ-specific immunopathology is associated with immune dysregulation and immunophenotypic biomarkers with expansion of CD21low B cells, and dysfunctional memory B cell, follicular T cell, and regulatory T cell compartments. The ever-increasing progress in immunogenetics shows the heterogeneity of genetic background for CVID related to the complexity of clinical phenotypes. Multiple systemic modulatory pathways are determined by variants in such genes as TACI or TNFRSF13B gene encoding for BAFF-R, CTLA-4, LRBA, NFKB1 and NFKB2, and PIK3CD or PIK3R1. The organ-specific immunopathology encompasses a spectrum of disorders associated with immune dysregulation, such as granulomatous interstitial lung disease, hepatocellular nodular regenerative hyperplasia, enteropathy, neuropathy, endocrinopathies, and dermatoses. This review is aimed to define and delineate the organ-specific immunopathology in pediatric CVID. It is also conducted to gather data facilitating a better understanding of complex and heterogeneous immunophenotypes in the context of immune dysregulation mechanisms and genetic background determining manifestations of the disease and implicating personalized targeted therapies with biological agents. Full article

Background/Objectives: Streptococcus pneumoniae (S. pneumoniae) is a major pathogen causing severe infectious diseases, with an escalating issue of antimicrobial resistance that threatens the efficacy of existing antibiotics. Given the challenges in developing traditional antibiotics, drug repurposing strategies offer a novel approach to address the resistance crisis. This study aims to evaluate the antibacterial and anti-biofilm activities of the approved non-antibiotic anticancer drug carmofur against multidrug-resistant S. pneumoniae, and investigate the mechanism of action, and assess therapeutic potential in vivo. Methods/Results: Antimicrobial tests revealed that carmofur exhibited strong antibacterial activity against multidrug-resistant S. pneumoniae strains, with minimum inhibitory concentrations (MICs) ranging from 0.25 to 1 µg/mL. In the biofilm detection experiments, carmofur not only inhibited the formation of biofilms, but also effectively removed biofilms under high concentration conditions. Mechanistic studies showed that carmofur disrupted bacterial membrane permeability and decreased intracellular ATP levels. Molecular docking and dynamics simulation assays indicated that carmofur could stably bind to thymidylate synthase through hydrogen bonding and hydrophobic interactions, thereby exerting antibacterial effects. Meanwhile, carmofur was able to repress the expression of the thyA gene at the mRNA level. In a mouse infection model, the carmofur treatment group showed a reduction of approximately two log levels in bacterial load in lung tissue and blood, a significant decrease in the levels of inflammatory cytokines TNF-α and IL-6, and an improvement in survival rate to 60%. Conclusions: In summary, carmofur demonstrated significant antibacterial and anti-biofilm activities against multidrug-resistant S. pneumoniae and showed good anti-infective effects in vivo, suggesting its potential clinical application as a therapeutic agent against drug-resistant bacteria. Full article

Background: Vitamin D (VD) supplementation has increased considerably in the last decade, whether for the prevention or treatment of numerous diseases, including bone, cardiovascular, endocrine, neurologic, psychological, respiratory, infectious, or oncological. The primary objective of this scoping review was to examine and synthesize the scientific evidence on the role of VD in all-type cancer patients undergoing adjuvant and neoadjuvant therapy with chemotherapy (CT) or radiotherapy (RT), namely in improving side effects. Methods: This review was conducted by selecting papers from the CINAHL, Scopus and PubMed databases based on the descriptor terms mesh and title/abstract, taking into consideration the defined inclusion and exclusion criteria, following the PRISMA-ScR (PRISMA extension for scoping reviews) statement. Results: A total of 758 papers were identified in different databases during this review. However, using the inclusion and exclusion criteria, only five publications made up the final sample of the study. The studies included heterogeneous study methodologies, objectives, cancer diagnosis, as well as methods to assess body composition, which makes it difficult to compare them. Based on the analyzed studies, associations were found between bone density and VD in patients who underwent preoperative chemoradiotherapy (CRT). In patients with non-small-cell lung cancer receiving CT, some of the side effects associated with the treatment were attenuated and reduced. In addition, another of the studies analyzed found that VD deficiency (VDD) has been associated with increased peripheral neuropathy (PN) induced by CT in the treatment of breast cancer. VD supplementation was found to be safe and effective. Conclusions: In this scoping review, VD is highlighted as a crucial factor in preventing the side effects of neoadjuvant RT or CT, as well as treating other treatment-related health conditions, such as osteoporosis, as well as ameliorating the side effects (nausea, vomiting, fatigue) associated with aggressive CT and RT. Full article

Nontuberculous mycobacterial pulmonary disease (NTM-PD), mainly caused by Mycobacterium avium complex (MAC), and pulmonary tuberculosis (TB) are emerging health problems worldwide. However, because their clinical features are often similar, it remains difficult to differentiate NTM-PD from TB when the diagnosis cannot be made by sputum culture. To investigate potential serum biomarkers, we conducted non-targeted proteome analysis on serum extracellular vesicles (EVs) collected from 10 patients with MAC pulmonary disease (MAC-PD), 7 patients with TB, and 10 healthy controls. A total of 2614 proteins were identified in the discovery cohort. The EV protein signature from patients with NTM-PD and TB reflected infectious diseases and inflammatory response pathways. Among the identified proteins, the expression of Na⁺/H⁺ exchanger regulatory factor 2 (NHERF2) was significantly elevated in patients with MAC-PD compared with healthy controls and patients with TB. Moreover, upregulation of NHERF2 was confirmed by immunoblotting of serum EVs and immunohistochemistry of lungs with mycobacterial infection. Our findings highlight that NHERF2 in serum EVs might be a potential biomarker for distinguishing MAC-PD from TB, possibly reflecting the pathogenesis of MAC-PD. Full article

Pleural thickening can be the result of inflammation or infection but can also have a neoplastic origin. Depending on the clinical context, a pleural lesion or mass is often initially suspected of malignancy. Benign pleural tumors are rare, and their appearance on ultrasound (US) is also described less frequently than pleural metastases or malignancies. There are few descriptions of contrast-enhanced Ultrasound (CEUS) in particular. This review introduces the basics of transthoracic ultrasound (TUS) of the pleura and CEUS of the pleura and lung. CEUS is recommended for pulmonary applications in the EFSUMB guidelines in non-hepatic applications. This article provides an overview of the characteristics of benign pleural thickening, tumor-like lesions, and benign pleural tumors on transthoracic B-mode US with color Doppler imaging (CDI) and CEUS. In detail, characteristics in TUS and CEUS are described for infectious/inflammatory pleural thickening (empyema, tuberculous pleuritis, hemothorax, fibrothorax), pleural thickening in various systemic diseases, in tumor-like conditions (plaques, splenosis, endometriosis, mesothelial cysts, lymphangiomatosis) and benign tumors (lipoma, benign SFT, schwannoma, solitary extramedullary/extraosseous plasmacytoma). The descriptions are illustrated by corresponding US and CEUS images. Full article

Background and objectives: Common variable immunodeficiency (CVID) is a primary immunodeficiency characterized by decreased immunoglobulins and recurrent infections, with non-infectious complications such as granulomatous–lymphocytic interstitial lung disease (GLILD) affecting up to 30% of patients. Methods: Using high-throughput 16S rRNA gene sequencing, salivary, sputum, and fecal microbiome from CVID patients with GLILD, comparing them to CVID patients without GLILD—with immune dysregulation (dCVID) and only infections (iCVID)—and healthy controls was analyzed. Results: A total of 41 CVID patients, 7 with GLILD, and 15 healthy donors were included. Global fecal biodiversity was significantly lower in GLILD patients compared to CVID subgroups and controls. GLILD patients harbored different specific bacterial communities in all niches, with some keystone species common to dCVID. Conchiformibius, Micrococcales, and Capnocytophaga are more frequent in the sputum of GLILD patients. Saliva in GLILD shows higher frequencies of Conchiformibius and Haemophilusparainfluenzae. Fecal samples from GLILD patients have higher levels of Gemella morbilorum, Lacticaseibacillus, and Cellulosimicrobium. A non-assigned Conchiformibius spp. is consistently associated with GLILD across different niches and could be a potential pathobiont or relevant microbiological marker for GLILD. Cluster network and correlation analyses show profound dysbiosis in the sputum, saliva, and feces of GLILD patients. Conclusions: These findings highlight significant microbiome alterations in CVID patients with GLILD, particularly in the respiratory tract, suggesting a possible link to both local and systemic immune dysregulation. Full article

Analysis of tracheal breathing sounds (TBS) is a significant area of study in medical diagnostics and monitoring for respiratory diseases and obstructive sleep apnea (OSA). Recorded at the suprasternal notch, TBS can provide detailed insights into the respiratory system’s functioning and health. This method has been particularly useful for non-invasive assessments and is used in various clinical settings, such as OSA, asthma, respiratory infectious diseases, lung function, and detection during either wakefulness or sleep. One of the challenges and limitations of TBS recording is the background noise, including speech sound, movement, and even non-tracheal breathing sounds propagating in the air. The breathing sounds captured from the nose or mouth can interfere with the tracheal breathing sounds, making it difficult to isolate the sounds necessary for accurate diagnostics. In this study, two surface microphones are proposed to accurately record TBS acquired solely from the trachea. The frequency response of each microphone is compared with a reference microphone. Additionally, this study evaluates the tracheal and lung breathing sounds of six participants recorded using the proposed microphones versus a commercial omnidirectional microphone, both in environments with and without background white noise. The proposed microphones demonstrated reduced susceptibility to background noise particularly in the frequency ranges (1800–2199) Hz and (2200–2599) Hz with maximum deviation of 2 dB and 2.1 dB, respectively, compared to 9 dB observed in the commercial microphone. The findings of this study have potential implications for improving the accuracy and reliability of respiratory diagnostics in clinical practice. Full article

Furin, a serine protease enzyme located in the Golgi apparatus of animal cells, plays a crucial role in cleaving precursor proteins into their mature, active forms. It is ubiquitously expressed across various tissues, including the brain, lungs, gastrointestinal tract, liver, pancreas, and reproductive organs. Since its discovery in 1990, furin has been recognized as a significant therapeutic target, leading to the active development of furin inhibitors for potential use in antiviral, antibacterial, anticancer, and other therapeutic applications. This review provides a comprehensive overview of the progress in the development and characterization of furin inhibitors, encompassing peptides, linear and macrocyclic peptidomimetics, and non-peptide compounds, highlighting their potential in the treatment of both infectious and non-infectious diseases. Full article