Search Results (1,087)

Background: Epidermal growth factor receptor (EGFR) mutations are presented in approximately 50% of East Asian populations with advanced non-small cell lung cancer (NSCLC). While EGFR-tyrosine kinase inhibitors (TKIs) are the standard treatment, patient outcomes are also influenced by host-related factors. This study aimed to investigate clinical and radiological factors associated with early mortality and develop a prognostic prediction model in advanced EGFR-mutated NSCLC. Methods: A retrospective cohort was conducted in patients with EGFR-mutated NSCLC treated with first line EGFR-TKIs from January 2012 to October 2022 at Chiang Mai University Hospital. Clinical data and radiologic findings at the initiation of treatment were analyzed. A multivariable flexible parametric survival model was used to determine the predictors of death at 18 months. The predicted survival probabilities at 6, 12, and 18 months were estimated, and the model performance was evaluated. Results: Among 189 patients, 84 (44.4%) died within 18 months. Significant predictors of mortality included body mass index <18.5 or ≥23, bone metastasis, neutrophil-to-lymphocyte ratio ≥ 5, albumin-to-globulin ratio < 1, and mean pulmonary artery diameter ≥ 29 mm. The model demonstrated good performance (Harrell’s C-statistic = 0.72; 95% CI: 0.66–0.78). Based on bootstrap internal validation, the optimism-corrected Harrell’s C-statistic was 0.71 (95% CI: 0.71–0.71), derived from an apparent C-statistic of 0.75 (95% CI: 0.74–0.75) and an estimated optimism of 0.04 (95% CI: 0.03–0.04). Estimated 18-month survival ranged from 87.1% in those without risk factors to 2.1% in those with all predictors. A web-based tool was developed for clinical use. Conclusions: The prognostic model developed from fundamental clinical and radiologic parameters demonstrated promising utility in predicting 18-month mortality in patients with advanced EGFR-mutated NSCLC receiving first-line EGFR-TKI therapy. Full article

Background/Objectives: Hepatic cancers, including hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), are major global health concerns due to rising incidence and limited therapeutic success. While traditional risk factors include chronic liver disease and environmental exposures, recent evidence underscores the significance of genetic alterations and gut microbiota in liver cancer development and progression. This review aims to integrate emerging knowledge on the interplay between host genomic changes and gut microbial dynamics in the pathogenesis and treatment of hepatic cancers. Methods: We conducted a comprehensive review of current literature on genetic and epigenetic drivers of HCC and CCA, focusing on commonly mutated genes such as TP53, CTNNB1, TERT, IDH1/2, and FGFR2. In parallel, we evaluated studies addressing the gut–liver axis, including the roles of dysbiosis, microbial metabolites, and immune modulation. Key clinical and preclinical findings were synthesized to explore how host–microbe interactions influence tumorigenesis and therapeutic response. Results: HCC and CCA exhibit distinct but overlapping genomic landscapes marked by recurrent mutations and epigenetic reprogramming. Alterations in the gut microbiota contribute to hepatic inflammation, genomic instability, and immune evasion, potentially enhancing oncogenic signaling pathways. Furthermore, microbiota composition appears to affect responses to immune checkpoint inhibitors. Emerging therapeutic strategies such as probiotics, fecal microbiota transplantation, and precision oncology based on mutational profiling demonstrate potential for personalized interventions. Conclusions: The integration of host genomics with microbial ecology provides a promising paradigm for advancing diagnostics and therapies in liver cancer. Targeting the gut–liver axis may complement genome-informed strategies to improve outcomes for patients with HCC and CCA. Full article

Background: Polymerase chain reaction (PCR) is highly sensitive and specific for the rapid diagnosis of invasive fungal disease (IFD) but is not yet widely implemented due to concerns regarding limited standardisation between assays, the lack of commercial options and the absence of clear guidance on interpreting results. Objectives and Methods: This review provides an update on technical and clinical aspects of PCR for the diagnosis of the most pertinent fungal pathogens, including Aspergillus, Candida, Pneumocystis jirovecii, Mucorales spp., and endemic mycoses. Summary: Recent meta-analyses have demonstrated that quantitative PCR (qPCR) offers high sensitivity for diagnosing IFD, surpassing conventional microscopy, culture and most serological tests. The reported specificity of qPCR is likely underestimated due to comparison with imperfect reference standards with variable sensitivity. Although the very low limit of detection of qPCR can generate false positive results due to procedural contamination or patient colonisation (particularly in pulmonary specimens), the rates are comparable to those observed for biomarker testing. When interpreting qPCR results, it is essential to consider the pre-test probability, determined by the patient population, host factors, clinical presentation and risk factors. For patients with low to moderate pre-test probability, the use of sensitive molecular tests, often in conjunction with serological testing or biomarkers, can effectively exclude IFD when all tests return negative results, reducing the need for empirical antifungal therapy. Conversely, for patients with high pre-test probability and clinical features of IFD, qPCR testing on invasive specimens from the site of infection (such as tissue or bronchoalveolar lavage fluid) can confidently rule in the disease. The development of next-generation sequencing methods to detect fungal infection has the potential to enhance the diagnosis of IFD, but standardisation and optimisation are essential, with improved accessibility underpinning clinical utility. Full article

Background/Objectives: Romania remains a tuberculosis (TB) hotspot in the European Union, yet host-derived factors of poor outcomes are poorly characterised. We quantified circulating pro-inflammatory cytokines and examined their interplay with behavioural risk factors, the nutritional status, and the clinical course in adults hospitalised with pulmonary TB. We analysed 80 adults with microbiologically confirmed pulmonary TB and 40 respiratory symptom controls; four TB patients (5%) died during hospitalisation, all within 10 days of admission. Methods: A retrospective analytical case–control study was conducted at the Constanța regional TB referral centre (October 2020—October 2023). Patients with smear- or culture-confirmed TB were frequency-matched by sex, 10-year age band, and BMI class to culture-negative respiratory controls at a 2:1 ratio. The patients’ serum interferon-γ (IFN-γ), interleukin-1α (IL-1α), interleukin-1β (IL-1β), and tumour-necrosis-factor-α (TNF-α) were quantified within 24 h of admission; the neutrophil/lymphocyte ratio (NLR) was extracted from full blood counts. Independent predictors of in-hospital mortality were identified by multivariable logistic regression; factors associated with the length of stay (LOS) were modelled with quasi-Poisson regression. Results: The median TNF-α (24.1 pg mL⁻¹ vs. 16.2 pg mL⁻¹; p = 0.009) and IL-1β (5.34 pg mL⁻¹ vs. 3.67 pg mL⁻¹; p = 0.008) were significantly higher in the TB cases than in controls. TNF-α was strongly correlated with IL-1β (ρ = 0.80; p < 0.001), while NLR showed weak concordance with multiplex cytokine patterns. Among the patients with TB, four early deaths (5%) exhibited a tripling of TNF-α (71.4 pg mL⁻¹) and a doubling of NLR (7.8) compared with the survivors. Each 10 pg mL⁻¹ rise in TNF-α independently increased the odds of in-hospital death by 1.8-fold (95% CI 1.1–3.0; p = 0.02). The LOS (median 29 days) was unrelated to the smoking, alcohol, or comorbidity load, but varied across BMI strata: underweight, 27 days; normal weight, 30 days; overweight, 23 days (Kruskal–Wallis p = 0.03). In a multivariable analysis, under-nutrition (BMI < 18.5 kg m⁻²) prolonged the LOS by 19% (IRR 1.19; 95% CI 1.05–1.34; p = 0.004) independently of the disease severity. Conclusions: A hyper-TNF-α/IL-1β systemic signature correlates with early mortality in Romanian pulmonary TB, while under-nutrition is the dominant modifiable determinant of prolonged hospitalisation. Admission algorithms that pair rapid TNF-α testing with systematic nutritional assessment could enable targeted host-directed therapy trials and optimise bed utilisation in high-burden settings. Full article

Avian influenza viruses (AIVs) pose significant risks to occupational populations engaged in poultry farming, livestock handling, and live poultry market operations due to frequent exposure to infected animals and contaminated environments. This review synthesizes evidence on AIV exposure patterns and risk factors through a comprehensive analysis of viral characteristics, host dynamics, environmental influences, and human behaviors. The main routes of transmission include direct animal contact, respiratory contact during slaughter/milking, and environmental contamination (aerosols, raw milk, shared equipment). Risks increase as the virus adapts between species, survives longer in cold/wet conditions, and spreads through wild bird migration (long-distance transmission) and live bird trade (local transmission). Recommended control measures include integrated animal–human–environment surveillance, stringent biosecurity measures, vaccination, and education. These findings underscore the urgent need for global ‘One Health’ collaboration to assess risk and implement preventive measures against potentially pandemic strains of influenza A viruses, especially in light of undetected mild/asymptomatic cases and incomplete knowledge of viral evolution. Full article

Periodontitis is a prevalent chronic inflammatory disease with complex etiopathogenesis involving microbial dysbiosis, host immune response, environmental factors, and genetic susceptibility. Among the cytokines implicated in periodontal immunoregulation, interleukin-35 (IL-35) has emerged as a novel anti-inflammatory mediator with potential diagnostic and therapeutic relevance. This narrative review evaluates the role of IL-35 in periodontal disease by exploring its local and systemic expression, response to non-surgical periodontal therapy (NSPT), and association with clinical disease severity. Additionally, current evidence regarding IL-35 gene polymorphisms and their potential contribution to individual susceptibility and disease progression, as well as their relevance in related systemic conditions, is assessed. A comprehensive review and synthesis of recent clinical and experimental studies were conducted, focusing on IL-35 levels in saliva, serum, and gingival crevicular fluid (GCF) among patients with healthy periodontium, gingivitis, and various stages of periodontitis, both before and after NSPT. Emphasis was placed on longitudinal studies evaluating IL-35 dynamics in correlation with periodontal parameters, as well as genetic association studies investigating IL-12A and EBI3 gene polymorphisms. IL-35 levels were generally found to be higher in healthy individuals and reduced in periodontitis patients, indicating a possible protective role in maintaining periodontal homeostasis. Following NSPT, IL-35 levels significantly increased, corresponding with clinical improvement and reduced inflammatory burden. Genetic studies revealed variable associations between IL-35 polymorphisms and susceptibility to periodontitis and related systemic conditions, although further research is needed for validation. IL-35 appears to function as a modulator of immune resolution in periodontal disease, with potential utility as a non-invasive biomarker for disease activity and therapeutic response. Its upregulation during periodontal healing supports its role in promoting tissue stabilization. The integration of cytokine profiling and genetic screening may enhance personalized risk assessment and targeted interventions in periodontal care. Full article

Canine morbillivirus (CDV), the cause of canine distemper, is a pathogen affecting many hosts. While modified live virus (MLV) vaccines are crucial for controlling the disease in dogs, cases of vaccine-related infections have been found in both domestic and wild animals. Specifically, the America-1 and Rockborn-like vaccine genotypes are concerning due to their spread and ability to transmit between different species. This study conducted a review and analysis of molecular detections of these strains in various carnivores (domestic, captive, synanthropic, and wild species). This study used a conceptual model considering host ecology and the domestic–wild interface to evaluate plausible transmission connections over time using Linear Directional Mean (LDM) and Weighted Mean Centre (WMC) methods. Statistical analyses examined the relationship between how likely a strain is to spread and factors like host type and vaccination status. The findings showed that the America-1 genotype spread in a more organised way, with domestic dogs being the main source and recipient, bridging different environments. Synanthropic mesocarnivores also played this same role, with less intensity. America-1 was most concentrated in the North Atlantic and Western Europe. In contrast, the Rockborn-like strain showed a more unpredictable and restricted spread, residual circulation from past use rather than ongoing spread. Species involved in vaccine-related infections often share characteristics like generalist behaviour, social living, and a preference for areas where domestic animals and wildlife interact. We did not find a general link between a host vaccination status and the likelihood of the strain spreading. The study emphasised the ongoing risk of vaccine-derived strains moving from domestic and synanthropic animals to vulnerable wild species, supporting the need for improved vaccination approaches. Mapping these plausible transmission routes can serve as a basis for targeted surveillance, not only of vaccine-derived strains, but of any other circulating genotype. Full article

The recent identification of early-onset mutational signatures with geographic variations by Diaz-Gay et al. is a significant finding, since early-onset colorectal cancer has emerged as an alarming public health challenge in the past two decades, and the pathomechanism remains unclear. Environmental risk factors, including lifestyle and diet, are highly suspected. The identification of colibactin from Escherichia coli as a potential pathogenic source is a major step forward in addressing this public health challenge. Therefore, the following opinion manuscript aims to outline the likely onset of the pathomechanism and the critical role of acquired Piezo2 channelopathy in early-onset colorectal cancer, which skews proton availability and proton motive force regulation toward E. coli within the microbiota–host symbiotic relationship. In addition, the colibactin produced by the pks island of E. coli induces host DNA damage, which likely interacts at the level of Wnt signaling with Piezo2 channelopathy-induced pathological remodeling. This transcriptional dysregulation eventually leads to tumorigenesis of colorectal cancer. Mechanotransduction converts external physical cues to inner chemical and biological ones. Correspondingly, the proposed quantum mechanical free-energy-stimulated ultrafast proton-coupled tunneling, initiated by Piezo2, seems to be the principal and essential underlying novel oscillatory signaling that could be lost in colorectal cancer onset. Hence, Piezo2 channelopathy not only contributes to cancer initiation and impaired circadian regulation, including the proposed hippocampal ultradian clock, but also to proliferation and metastasis. Full article

Human papillomavirus 18 (HPV18) is the second most oncogenic high-risk HPV genotype, after HPV16, and is responsible for about 15% of cervical cancer cases worldwide. The integration of high-risk HPV DNA into the host genome leads to the disruption of the E1 and/or E2 genes, which is considered a risk factor for viral-induced carcinogenesis. This study examined the disruption events of HPV18 E1 and E2 genes in precancerous cervical lesions to investigate the rates and sites of gene disruption in the Greek population. The complete E1 and E2 genes were amplified using three and four overlapping primer sets, respectively. Extensive analysis revealed that the disruption/deletion events of the E1 and E2 genes were detected in all grades of cytology-determined lesions, with high frequency. E2 gene disruption was significantly related to LSIL+ cases (Fisher’s exact test, p = 0.022). No significant association was found in the analysis of the E1 gene. Additionally, no preferential sites of E1/E2 gene disruption were detected. This is the first study to provide evidence of disruption events of the HPV18 E1 gene. The data from the current analysis suggest that disruption of the E2 gene could be a significant marker for the progression of cytology-determined cervical dysplasia. However, future studies are required to evaluate whether different geographic populations have particular profiles regarding the rates and sites of gene disruption to further determine population-specific biomarkers. Full article

Leptospirosis is a (re-)emerging and global zoonotic disease. Given the complex host-pathogen interaction and the numerous environmental risk factors related to the transmission, a One Health approach to both disease prevention and control is needed. Occurring at the human–cattle–environment interfaces, bovine leptospirosis represents a zoonotic risk for the professionals in the field, besides being a potential cause of significant economic losses due to the bovine reproductive disorders. Although climatic change is a potential factor in exacerbating the risk of leptospirosis in Europe, this disease remains largely neglected, with several knowledge gaps in research, investigations, and diagnosis of bovine genital leptospirosis syndrome across the continent. The present report describes the results of the diagnostic investigations on a case of chronic bovine leptospirosis in a breeding bull. Following the seroconversion to Leptospira Sejroe var Hardjo after the arrival of the animal in a quarantine facility, a monitoring plan including both serological/molecular analyses and a therapeutic protocol was undertaken. The bull exhibited a persistent seroconversion and a repeated positivity for Leptospira to real-time PCR in urine samples, indicative of a chronic shedder pattern. This report emphasizes the diagnostic and management challenges in the context of such a complex but frequently overlooked disease. Full article

This study aimed to comprehensively review surgical interventions for ocular surface diseases (OSDs), including dry eye syndrome (DES), exposure keratopathy, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and ocular graft versus host disease (oGVHD), and to highlight the indications, contraindications, outcomes, and complications of various oculoplastic procedures used in their management. A narrative review was performed based on expert-guided selection of relevant studies retrieved from PubMed, Scopus, and Web of Science. Relevant keywords included “ocular surface disease”, “dry eye syndrome”, “exposure keratopathy”, “thyroid eye disease (TED)”, “neurotrophic keratopathy (NK)”, “Stevens-Johnson syndrome”, “toxic epidermal necrolysis”, “punctal occlusion”, “tarsorrhaphy”, “botulinum toxin”, “eyelid loading”, “retractor weakening”, “corneal neurotization (CN)”, “amniotic membrane transplantation (AMT)”, “conjunctival flap”, “ocular graft versus host disease”, and “salivary gland transplantation (SGT)”. Studies addressing surgical approaches for OSDs were included. In conclusion, surgical options for OSDs offer significant benefits when non-invasive treatments fail. Surgical techniques such as punctal occlusion, eyelid fissure narrowing, AMT, and conjunctival flap procedures help stabilize the ocular surface and alleviate symptoms. Advanced methods like CN and SGT target the underlying pathology in refractory cases such as oGVHD. The outcomes vary depending on the disease severity and surgical approach. Each procedure carries specific risks and requires individualized patient selection. Therefore, a tailored approach based on clinical condition, anatomical involvement, and patient factors is essential to achieve optimal results. Ongoing innovations in reconstructive surgery and regenerative medicine are expected to further improve outcomes for patients with OSDs. Full article

Over the past three turbulent decades, research has profoundly reshaped our understanding of chronic Toxoplasma gondii infection—traditionally regarded as harmless in immunocompetent individuals—unveiling its surprising impact on human health, performance, and behavior. This review emphasizes the effects of chronic Toxoplasma infection on physical and mental health, cognitive performance, and behavioral changes, highlighting key findings from studies investigating these domains, with a particular focus on both ultimate and proximate mechanisms underlying the observed effects. To this end, the primary focus will be on human studies; however, animal model studies will also be thoroughly considered when necessary and appropriate, to provide context and additional important information. Research demonstrates that chronic Toxoplasma infection may contribute to a broad spectrum of physical health issues. Ecological studies have revealed correlations between toxoplasmosis prevalence and increased morbidity and mortality from various conditions, including cardiovascular diseases, neurological disorders, and certain cancers. Large-scale cross-sectional studies have further shown that infected individuals report a higher incidence of numerous health complaints and diagnosed diseases, suggesting a significant impact on overall physical well-being. In addition to physical health, lifelong Toxoplasma infection (subclinical toxoplasmosis) has been implicated in cognitive impairments and behavioral changes. Studies have reported associations between infection and poorer performance in areas such as reaction time, processing speed, working memory, and executive function. Many of these behavioral changes likely relate to worsened health and a shift towards a “fast life history strategy.” These cognitive deficits can have significant implications for daily functioning and performance. Furthermore, the role of Toxoplasma infection in the development or exacerbation of mental health disorders has been extensively investigated. Meta-analyses, ecological studies, and large-scale observational studies have demonstrated associations between Toxoplasma infection and an increased risk of disorders such as schizophrenia and obsessive–compulsive disorder. While the precise mechanisms underlying these associations remain under investigation, research suggests that neuroinflammation and alterations in neurotransmitter systems are likely to play a role. Far from being harmless, subclinical toxoplasmosis is increasingly recognized as a hidden factor influencing human health, behavior, and cognitive performance—with implications that extend well beyond the individual to public health at large. Further research is warranted to elucidate the complex interplay between Toxoplasma infection, host physiology, and the development of various physical, cognitive, behavioral, and mental health conditions. Full article

Helicobacter pylori infection is the strongest known risk factor for the development of gastric cancer. The bacterium leverages several unique virulence factors to its advantage in order to colonize the human host. Among these, T4SS-delivered cytotoxin-associated gene A (CagA) has the most well-established links to severe forms of disease. To explore the effect of lactobacilli in disrupting CagA functions within host cells, we expressed HA-tagged humanized cagA in the human gastric epithelial AGS cell line and studied both the phosphorylation levels of CagA and its downstream binding partners. We found that gastric-specific Lactobacillus gasseri Kx110 A1 suppressed the phosphorylation of CagA and inhibited phosphorylation-dependent downstream signaling, resulting in the suppression of CagA-induced cell elongation of AGS cells, commonly known as the hummingbird phenotype. Surprisingly, phosphorylation-independent signaling was unaffected by L. gasseri. Furthermore, our confocal microscopy analysis revealed that CagA was mislocalized to the cytoplasm, suggesting that L. gasseri interferes with its membrane localization and thereby hinders its phosphorylation. Live L. gasseri that had direct contact with host cells was found to be necessary to suppress the hummingbird phenotype. In summary, the data suggest that a L. gasseri strain can inhibit CagA phosphorylation and suppress cell elongation. Full article

Long- or post-COVID-19 syndrome, which is also designated by WHO as Post COVID-19 Condition (PCC), is characterized by the persistent symptoms that remain after recovery from SARS-CoV-2 infection. A worldwide consortium of Long COVID-19 Host Genetics Initiative (Long COVID-19 HGI) identified an SNP rs9367106 (G>C; chr6:41,515,652, GRCh38, p = 1.76 × 10⁻¹⁰, OR = 1.63, 95% CI: 1.40–1.89) that is associated with PCC. Unraveling the functional significance of this SNP is of prime importance to understanding the development of the PCC phenotypes and their therapy. Here, in Silico, I explored how the risk allele of this SNP alters the functional mechanisms and molecular pathways leading to the development of PCC phenotypes. Bioinformatic methods include physical interactions using HI-C and Chia-PET analysis, Transcription Factors (TFs) binding ability, RNA structure modeling, epigenetic, and pathway analysis. This SNP resides within two long RNA genes, LINC01276 and FOXP4-AS1, and is located at ~31 kb upstream of a transcription factor FOXP4. This DNA region, including this SNP, physically interacts with FOXP4-AS1 and FOXP4, implying that this regulatory SNP could alter the normal cellular function of FOXP4-AS1 and FOXP4. Furthermore, rs9367106 is in eQTL with the FOXP4 gene in lung tissue. rs9367106 carrying DNA sequences act as distant enhancers and bind with several transcription factors (TFs) including YY1, PPAR-α, IK-1, GR-α, and AP2αA. The G>C transition extensively modifies the RNA structure that may affect the TF bindings and enhancer functions to alter the interactions and functions of these RNA molecules. This SNP also includes an ALU/SINE sequence and alteration of which by the G>C transition may prevent IFIH1/MDA5 activation, leading to suppression of host innate immune responses. LINC01276 targets the MED20 gene that expresses mostly in brain tissues, associated with sleep disorders and basal ganglia abnormalities similar to some of the symptoms of PCC phenotypes. Taken together, G>C transition of rs9367601 may likely alter the function of all three genes to explain the molecular basis of developing the long-term symptomatic abnormalities in the lungs and brain observed after COVID-19 recovery. Full article

P. aeruginosa strain NL201 was cultured from an urban water drain in a populated subway underpass as an environmental isolate for the ST111 global high-risk P. aeruginosa clone. In addition to carrying generally present intrinsic P. aeruginosa antibiotic resistance genes, this serotype O4 isolate also carries a set of additional acquired resistance determinants, including aadA2, bla_OXA-10, sul1, and an aac(6′)-Ib family gene. The NL201 isolate features the bla_PDC-3 allele, which was found to confer significantly higher catalytic efficiency against cefepime and imipenem compared to bla_PDC-1, as well as the potent P. aeruginosa virulence factors exoS, exoT, and algD. Serotype O4 isolates of the ST111 global high-risk P. aeruginosa clone have been reported from clinical samples in Canada and the USA, human stool samples in France, and environmental samples (such as cosmetic, hospital drains, and urban water drain) from various European countries. These observations underscore the effective dissemination of the ST111 global high-risk P. aeruginosa clone between different hosts, environments, and habitats, and they warrant targeted investigations from a One Health perspective on the possible routes of its spread and molecular evolution. Full article