Search Results (12,482)

Respiratory RNA viruses extensively reprogram host regulatory networks, thereby influencing viral replication, immune evasion, and disease severity. This review examines microRNAs (miRNAs) as regulatory interfaces in host–virus interactions, focusing on influenza A virus as a paradigmatic model while integrating evidence from other respiratory RNA viruses as SARS-CoV-2 and respiratory syncytial virus. After outlining canonical miRNA biogenesis and its manipulation during infection, we discuss how respiratory RNA viruses converge on shared miRNA-regulated pathways, including interferon and NF-κB signaling, apoptosis, autophagy, cellular metabolism, and redox homeostasis. Within these networks, host miRNAs can directly target viral RNAs and modulate antiviral defenses and inflammation, whereas viruses can reshape miRNA expression to facilitate replication, influencing immunopathology. The possibility that RNA viruses encode authentic miRNAs is also critically evaluated; current evidence indicates that manipulating host miRNA biogenesis machinery and remodeling miRNA networks are more prevalent than producing canonical viral miRNAs. Finally, the potential of circulating miRNAs as diagnostic and prognostic biomarkers is considered, as well as the capability of miRNA mimics and antagomiRs to function as host-directed therapeutic strategies. Their clinical translation, however, will require standardized validation, cell- and time-resolved studies, efficient delivery systems, and a careful assessment of specificity, safety, and context-dependent effects. Full article

Background: Acute renal colic is a common urological emergency characterized by substantial interindividual variability in analgesic response. Pharmacogenetic variation in OPRM1, COMT, and ABCB1 may contribute to differences in opioid efficacy and pain control. This study primarily evaluated the associations of OPRM1 A118G (rs1799971), COMT Val158Met (rs4680), and ABCB1 C3435T (rs1045642) polymorphisms with opioid analgesic response in patients with acute renal colic. As a secondary exploratory analysis, genotype and allele frequencies were compared between patients and healthy controls. Methods: This prospective case–control study included 150 patients with acute renal colic and 100 healthy controls. Genotyping was performed using TaqMan SNP Genotyping Assays based on real-time polymerase chain reaction. Genotype frequencies were compared between groups using dominant and recessive genetic models, and Hardy–Weinberg equilibrium was assessed. In addition, genotype–phenotype associations were evaluated using pain severity, early analgesic response, initial opioid dose, rescue analgesic requirement, and multivariable logistic regression analyses. Results: In the secondary exploratory case–control analysis, no statistically significant differences in genotype or allele frequencies of OPRM1 rs1799971, COMT rs4680, or ABCB1 rs1045642 were observed between patients with acute renal colic and healthy controls. Within the patient cohort, however, genotype–phenotype analyses identified differences in early analgesic outcomes. Baseline-adjusted 30 min VAS differed according to OPRM1, COMT, and ABCB1 genotype, with the most pronounced difference observed for ABCB1 rs1045642. Patients with the ABCB1 TT genotype had higher adjusted 30 min VAS scores and showed a pattern of greater opioid requirement and more frequent rescue analgesia. In exploratory multivariable analysis, the ABCB1 TT genotype was associated with higher odds of inadequate early analgesic response (adjusted OR = 2.74, 95% CI 1.18–6.37; p = 0.019). Given the limited number of outcome events, this adjusted association should be considered preliminary and hypothesis-generating. Conclusions: No significant differences in the distributions of the polymorphisms investigated were observed between patients with acute renal colic and healthy controls. Within the patient group, ABCB1 genetic variation was associated with early opioid analgesic response, although this finding should be considered preliminary and requires confirmation in larger prospective pharmacogenetic studies before clinical implementation. Any potential future pharmacogenetic application should be considered as an adjunct to established first-line renal–colic management and specifically in patients for whom opioid therapy is clinically indicated. Full article

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a severe autoimmune neurological disorder characterized by pathogenic antibodies against the NMDAR. A systematic protein profiling approach is warranted to identify biomarkers capable of predicting disease status. An Olink proximity extension assay (PEA) profiled 91 inflammation-related proteins from anti-NMDAR encephalitis patients. Disease severity or prognosis were assessed by CASE score or mRS score at 6-month follow-up. Patients were stratified into distinct molecular clusters using unsupervised clustering. Logistic regression models incorporating selected biomarkers were developed to predict disease severity and prognosis, followed by absolute quantification using ELISA. Patients were classified into four consensus clusters. Clusters 1 and 2 corresponded to the mild group, while Cluster 3 represented the severe group, consistent with CASE score above 6. Cluster 4 showed heterogeneous clinical features. Elevated serum levels of IL-10, IL-6, and SIRT2, as well as increased CSF levels of CXCL10, CXCL11, and MMP10, were positively associated with severe disease. Conversely, several proteins including LTA and CCL11, CCL8, TGFB1, CXCL6 were associated with severe disease or unfavorable 6-month outcomes. A logistic regression model combining serum CXCL6 and CCL11 with CSF MMP10 achieved an area under the curve (AUC) of 0.95 for predicting disease severity. Serum CCL11 alone showed predictive value for 6-month prognosis, with an AUC of 0.79. These findings delineate distinct protein signatures associated with clinical heterogeneity of anti-NMDAR encephalitis. Prediction models incorporating multiple biomarkers may provide an approach for disease severity stratification and prognosis forecast. Full article

Sustainable livestock production in the arid regions of Central Asia depends almost entirely on groundwater resources. However, regional groundwater quality remains insufficiently characterized from the perspective of long-term water security and sustainable pasture management. Understanding the interaction between natural hydrogeochemical evolution and anthropogenic contamination is therefore essential for developing climate-resilient groundwater management strategies. This study presents a comparative hydrogeochemical assessment based on 101 groundwater samples collected from 58 sites in the Karaganda region and 43 sites in the Ulytau region during a single dry-season campaign (June–July 2025), with field sampling conducted across 4630 km² of active pastureland within a combined regional area of 409,070 km². Groundwater in Ulytau showed substantially greater mineralization, with a median TDS of 1027 mg/L compared with 538 mg/L in Karaganda; the proportion of samples exceeding 1000 mg/L was 53.5% (23/43) and 29.3% (17/58), respectively (Fisher’s exact p = 0.023). Median NO₃⁻ concentrations were also markedly higher in Ulytau (35.0 mg/L) than in Karaganda (5.0 mg/L), with the 50 mg/L guideline exceeded in 46.5% (20/43) vs. 19.0% (11/58) of samples (p = 0.004). NO₃⁻ and TDS were not significantly correlated in Karaganda (r_s = 0.108, p = 0.418), whereas a moderate positive relationship occurred in Ulytau (r_s = 0.388, p = 0.010). These results indicate that regional salinization is predominantly controlled by geogenic hydrochemical evolution, while nitrate contamination represents a localized anthropogenic pressure associated with vulnerable water points. The pronounced quantitative contrast between the two regions highlights the need for region-specific groundwater protection and management strategies to support sustainable livestock production and long-term water security in Central Kazakhstan. Rather than providing only a regional hydrochemical description, the present study evaluates groundwater quality as a sustainability indicator for livestock production, groundwater security, and regional adaptation to increasing water stress. Groundwater quality differed significantly between the two regions, with Ulytau exhibiting consistently higher mineralization, more frequent nitrate exceedances, and higher groundwater vulnerability. Statistical analyses confirmed that groundwater quality deterioration is controlled by different combinations of geogenic processes and localized anthropogenic impacts in the two hydrogeological settings. The findings demonstrate that groundwater quality represents a critical component of sustainable livestock production in Central Kazakhstan. The proposed regional groundwater vulnerability framework provides practical guidance for groundwater protection, climate adaptation, and the sustainable management of pastoral water resources under increasing environmental pressures. Full article

Asthma is a chronic inflammatory airway disease strongly influenced by genetic factors. Interleukin-33 (IL-33), a key mediator of type 2 immune responses, has been implicated in airway inflammation and remodeling. However, the effects of IL-33 polymorphisms on asthma susceptibility and severity remain unclear, particularly in East Asian populations. This study investigated five IL-33 polymorphisms (rs1891385, rs16924159, rs12551256, rs1929992, and rs7044343) in relation to asthma risk and severity in Taiwanese individuals. A total of 198 asthmatic patients and 453 age- and sex-matched controls were enrolled. Genotypes were determined using PCR-RFLP. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess associations with asthma susceptibility and severity. Among the five polymorphisms, only rs1929992 was significantly associated with asthma. Compared with the TT genotype, CT and CC carriers had reduced asthma risk (OR = 0.61 and 0.51, respectively). The dominant model (CT+CC) also showed a protective effect (OR = 0.58, 95%CI = 0.40–0.82, p = 0.0032), which was supported by allelic analysis (OR = 0.70, 95%CI = 0.55–0.89, p = 0.0044). Among the five polymorphisms, rs1929992 was associated with asthma susceptibility. Under the dominant model, CT + CC carriers showed lower odds of asthma than TT carriers (OR = 0.58, 95% CI = 0.40–0.82, p = 0.0032), and the association remained significant after correction for multiple testing. Exploratory stratified analyses identified associations in the younger and male subgroups, while exploratory severity analysis suggested lower odds of more severe asthma among variant genotype carriers. These secondary findings should be considered hypothesis-generating because of the reduced subgroup sample sizes. Overall, rs1929992 was associated with asthma susceptibility in this Taiwanese population; however, independent replication and functional studies are required before its biological or clinical relevance can be established. Full article

Ornamental palm pruning residues represent a locally abundant, underutilized lignocellulosic waste stream with potential as a waste-valorized epoxy reinforcement. This study investigates the flexural behavior of particulate epoxy composites reinforced with Washingtonia robusta leaf stalk residue, evaluating the influence of reinforcement granulometry on mechanical and microstructural response. Four specimen families were fabricated from a Bisphenol A/F epoxy resin cured with a cycloaliphatic amine hardener: neat resin (RS, reference) and composites reinforced with fine (RF), coarse (RG) and mixed-fraction (RM) particles at 20 vol.% loading. Flexural properties were assessed by three-point bending and fracture surfaces were characterized by SEM. The neat resin exhibited a non-monotonic, viscoelastic-dominated response with no fracture within the extended deformation range tested, whereas all reinforced systems fractured within a substantially narrower window (~8–14.5 mm). RF showed the highest observed flexural modulus (≈15.8 GPa), followed by RM (≈15.4 GPa) and RG (≈14.2 GPa). These differences were not statistically significant (one-way ANOVA, p > 0.05). Damage tolerance followed a similar descriptive trend: RG failed earliest, linked to large interfacial pull-out cavities; RF delayed fracture through crack deflection; and RM showed the most favorable overall balance, combining a modulus comparable to RF with superior crack path tortuosity. These results indicate the potential of Washingtonia robusta, particularly in mixed-granulometry form, as a candidate reinforcement for semi-structural epoxy biocomposites, pending further characterization of properties such as tensile strength, impact resistance, moisture absorption, and long-term durability. Full article

Background/Objectives: Endovascular thrombectomy (EVT) has transformed the treatment of acute ischaemic stroke due to large-vessel occlusion, yet peri-procedural haemodynamic instability may compromise penumbral perfusion and neurological recovery. We assessed the frequency, determinants and clinical consequences of post-procedural hypotension after EVT. Methods: We retrospectively reviewed 201 consecutive adults who underwent endovascular thrombectomy for anterior-circulation large-vessel occlusion at a single tertiary centre over a period of eight years, from 1 January 2017 to 31 January 2025. Post-procedural hypotension was defined as hypotension requiring initiation of a continuous noradrenaline infusion within 24 h of the procedure. Comorbidities, anaesthetic modality (general anaesthesia [GA] or conscious sedation [CS]), National Institutes of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS) scores, and in-hospital mortality were recorded. Logistic regression identified independent predictors of hypotension. Results: Fifty-five patients (27.4%) developed post-procedural hypotension. They presented with more severe strokes (NIHSS 16.0 ± 5.0 vs. 13.7 ± 5.0; p = 0.002), had higher NIHSS scores at day 2 (14.0 ± 6.9 vs. 9.4 ± 6.7; p < 0.001) and day 7 (p = 0.003), and displayed markedly higher in-hospital mortality (50.9% vs. 20.5%; p < 0.001). In an ordinal analysis of the day 7 modified Rankin Scale with death coded as 6, hypotension was associated with a shift towards greater disability (common OR 2.57, 95% CI 1.40–4.72; p = 0.002). In an exploratory model, each additional 10 min of door-to-groin time was independently associated with hypotension (adjusted OR 1.10, 95% CI 1.03–1.18; p = 0.003). Independent predictors of hypotension were baseline NIHSS (adjusted OR 1.11 per point, 95% CI 1.04–1.19; p = 0.003) and active malignancy (adjusted OR 2.90, 95% CI 1.04–8.09; p = 0.042). Hypotension occurred with similar frequency under GA and CS (28.6% vs. 24.6%; adjusted OR 1.12, 95% CI 0.54–2.34; p = 0.766). Conclusions: Post-EVT hypotension is common and associated with poorer early neurological recovery and a more than two-fold higher in-hospital mortality rate. Its independent predictors were baseline stroke severity and active malignancy. Patients with severe stroke or active cancer may warrant intensified haemodynamic surveillance after thrombectomy. Procedural delay emerged as the only modifiable predictor identified and warrants prospective evaluation. Full article

Background/Objectives: Interleukin-6 is a key proinflammatory cytokine involved in the pathophysiology of Familial Mediterranean Fever (FMF). This study aimed to evaluate interleukin-6 levels and the interleukin-6 rs1800795 variant in pediatric FMF participants and to investigate their associations with clinical manifestations, laboratory findings, and Mediterranean fever (MEFV) mutation status. Methods: The research involved 69 pediatric FMF participants and 50 healthy children. Interleukin-6 levels, laboratory findings, and genotype distributions of the interleukin-6 rs1800795 variant were compared between FMF and control groups. Moreover, the relationship between interleukin-6 levels and clinical findings, MEFV mutation status, and laboratory parameters were evaluated in the FMF group. Results: In the FMF group, interleukin-6, serum amyloid-A (SAA), white blood cell count (WBC), neutrophil, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) levels were higher compared to the control group. In the FMF group, interleukin-6 levels showed a positive correlation with ISSF score, annual attack frequency, the number of concomitant symptoms, disease duration, SAA, CRP, and ESR. The allele and genotype distribution of the interleukin-6 rs1800795 variant was similar to those in the control and FMF groups. In the FMF group, interleukin-6 values were higher in patients with abdominal pain, fever, chest pain, or arthralgia compared to those without these symptoms. Interleukin-6 levels were higher in both homozygous and compound heterozygous subgroups compared to the heterozygous subgroup. Conclusions: Elevated interleukin-6 levels in symptomatic pediatric FMF patients and those with homozygous or compound heterozygous MEFV mutations suggest that interleukin-6 may reflect both clinical disease severity and MEFV mutation status. Full article

Progressive pulmonary fibrosis (PPF) comprises interstitial lung diseases characterized by progressive fibrosis and lung function decline. Nintedanib slows disease progression by inhibiting FGFR, VEGFR, and PDGFR signaling, but treatment response varies among patients. We investigated whether VEGFR2, PDGFRB, and TGFB1 gene variants are associated with nintedanib treatment outcomes, including changes in pulmonary function, diffusing capacity and adverse effects. This prospective study included 75 patients with PPF diagnosed according to ATS/ERS/JRS/ALAT criteria and treated with nintedanib at the Clinic of Pulmonology, University Clinical Center of Serbia. Spirometry and diffusing capacity were assessed at baseline and after 6 and 12 months. Genotyping of VEGFR2 rs2071559 and rs1870377; PDGFRB rs2302273, rs2229562, and rs246395; and TGFB1 rs1800470 was performed using TaqMan^® assays. Carriers of the PDGFRB rs2302273 A allele more frequently experienced gastrointestinal adverse events (45.2% vs. 20.5%; p = 0.022; OR 3.2, 95% CI 1.156–8.866) and diarrhea (38.7% vs. 15.9%; p = 0.026; OR 3.3, 95% CI 1.129–9.869). Patients with the PDGFRB rs246395 TT genotype more frequently had a ≥15% decline in DLCO after one year (46% vs. 22%; p = 0.038; OR 3.0, 95% CI 1.045–8.394). No significant associations were observed for the analyzed VEGFR2 or TGFB1 variants. These findings suggest that PDGFRB variants may be associated with nintedanib treatment outcomes, although confirmation in larger cohorts is needed. Full article

Background/Objectives: Rapid surveillance tools are needed to monitor antimicrobial-resistant bacteria in the food chain. This study evaluated whether qPCR-based quantification of tetracycline resistance genes could replace culture-based quantification of tetracycline-resistant Escherichia coli in pig caecal content and carcass skin swabs. Methods: Caecal content (n = 89) and skin swab samples (n = 68) were collected across four Danish abattoirs and analysed by both qPCR and Petrifilm cultivation. Method comparisons were restricted to samples within the quantifiable range of Petrifilm. E. coli concentrations (uidA gene) and tetA/tetB gene concentrations were compared with Petrifilm counts of E. coli and culturable tetracycline-resistant E. coli. Method agreement was evaluated using paired t-tests, Bland–Altman analysis, and Spearman correlation. Results: In caecal samples (n = 84), no significant difference in mean log E. coli concentration was observed between uidA qPCR and Petrifilm counts (p = 0.33). However, Bland–Altman analysis showed poor agreement at the individual-sample level, with limits of agreement ranging from −1.09 to 1.21 log₁₀ CFU/g. In skin swab samples (n = 43), qPCR systematically overestimated E. coli counts compared with cultivation, with a significant bias of 0.75 log₁₀ CFU/1400 cm² (p < 0.001). No significant correlation was observed between tetA/tetB and culturable tetracycline-resistant E. coli in caecal (r_s = 0.091, p = 0.44) or skin swab samples (r_s = 0.13, p = 0.48). Conclusions: qPCR may be useful for population-level surveillance of tetracycline resistance genes in pig caecal samples but cannot replace culture-based methods for accurate quantification of tetracycline-resistant E. coli in individual samples. Full article

Carboxylesterases (CXEs) participate in diverse plant metabolic processes, including isoflavone biosynthesis. However, the soybean GmCXE subfamily remains poorly characterized, especially in relation to root isoflavone accumulation and the response to Fusarium oxysporum. Here, fifty-six putative GmCXE genes were identified in the soybean genome and classified into three major phylogenetic clades. Analyses of gene structure, conserved motifs, protein domains, and promoter cis-elements revealed conserved features as well as potential functional divergence among subfamily members. Collinearity and duplication analyses indicated that segmental duplication was the main driver of GmCXE subfamily expansion. Tissue-specific expression profiling and RT-qPCR validation selected five root-expressed genes as candidates associated with isoflavone accumulation. SNP variation analysis and allelic group analysis of 209 soybean accessions further prioritized GmCXE54 as a candidate gene for root isoflavone accumulation. Allelic groups defined by a putative promoter SNP, Chr.20-rs39215413, showed significant differences in root daidzein and total isoflavone contents, with accessions carrying the C allele exhibiting higher levels of both traits than those carrying the T allele. Functional analysis in soybean hairy roots showed that GmCXE54 overexpression increased daidzein and total isoflavone accumulation. At 3 h after F. oxysporum inoculation, GmCXE2, GmCXE39, and GmCXE54 were induced, with GmCXE54 showing the strongest response in the resistant accession ZD27. These findings clarify GmCXE subfamily evolution and identify GmCXE54 as a candidate gene associated with root isoflavone accumulation and early F. oxysporum response, offering new perspectives for improving soybean isoflavone-related traits and investigating root response mechanisms. Full article

Atmospheric water vapor is a major driver of Earth’s climate, yet despite its vital role in driving extreme weather and informing Numerical Weather Prediction (NWP) models, precise quantification of Precipitable Water Vapor (PWV) remains a challenge due to its high spatial and temporal variability. To provide an upgraded evaluation reflecting the most recent data and next-generation instrumentation, this study evaluates the accuracy, relative to radiosonde measurements, in calculating PWV values across six different instruments: Microwave Radiometer (MWR), NOAA-21, TROPOMI, Pandora spectrometer, AERONET sun-photometer, and GNSS/GPS against the bias-corrected Vaisala RS-92 and RS-41 radiosondes over Beltsville, Maryland, utilizing an updated 2024–2025 database. As a certified GRUAN site, HUBC adheres to strict international observation standards designed specifically to provide reference-quality data and comprehensive corrections for systematic errors. This rigorous framework justifies their application as the definitive ‘referent truth’ benchmark for remote sensing validation. RMSE and bias were the primary metrics used to assess relative accuracy. GPS measurements provided the highest level of relative accuracy, yielding the lowest RMSE (1.50 mm) and a near-unity linear fit (y = 0.98x). NOAA-21 and TROPOMI exhibit higher random noise when compared to ground-based instrumentation, yet both obtain high relative accuracy retrievals with negligible biases. AERONET and Pandora also showed strong performance with low RMSEs and R² values of 0.986 and 0.988, respectively, while slightly underestimating PWV. In contrast, the Radiometer performed with the lowest relative accuracy, characterized by the highest RMSE (6.19 mm) and a significant negative bias (−5.55 mm). Although all instruments maintained high correlation coefficients (R² ≥ 0.904), these results indicate that satellite and ground-based remote sensing provide reliable PWV retrievals, while GPS presents the most robust benchmark for high-accuracy PWV retrievals relative to radiosonde measurements. The findings also underscore the need for instrument-specific calibration constants to better align remote sensing retrievals with in situ observations. Full article

Background: Research in behavioral genetics has demonstrated that genetic factors significantly contribute to individual differences in behavior, while environmental exposures shape gene expression through epigenetic mechanisms. This interaction is also relevant to the development of antisocial behavior and psychopathic traits. One of the first evidence of gene–environment interaction was the association between low-activity variants of the MAOA gene, childhood maltreatment, and increased risk of antisocial behavior [¹]. Similarly, our research in incarcerated populations showed that adverse paternal parenting is associated with higher levels of psychopathy and the HTR1B rs13212041 TT genotype appears to modulate the individual susceptibility to negative experiences [²]. Single genetic variants, however, exert only modest effects and current evidence supports a polygenic model in which multiple genetic factors interact with environmental adversity to influence neurodevelopment and behavioral outcomes. Using a genome-wide/endophenotype informed analysis, for example, we identified novel gene–environment interactions as risk factors for psychopathy, involving three independent genetic loci in interaction with paternal maltreatment, which were previously associated with disruptive behavior, temperament, and neuroticism [³]. More recently, we also evaluated whether machine-learning models, integrating behavioral, environmental, and genetic variables, could be helpful to predict psychopathic traits. Methods: We compared logistic regression, random forest, support vector machine, XGBoost, and multilayer perceptron. Results: Support vector machine showed the highest accuracy for predicting Psychopathy Check List-Revised (PCL-R) Factor 2 (antisocial lifestyle). Feature-importance analyses identified impulsivity (BIS-11), empathy (IRI), childhood maltreatment (MOPS), and 12 SNPs as the most informative predictors. Notably, removing genetic variables or MOPS scores substantially reduced the model accuracy, indicating that both genetic and environmental information meaningfully contributed to prediction of antisocial behavior. Conclusions: These findings confirm that genetic influences are neither deterministic nor sufficient to explain criminal behavior but may contribute to interindividual differences in vulnerability, particularly through their interaction with environmental and psychosocial factors. In forensic psychiatry, the integration of genetic and environmental information into behavioral assessment may provide additional objective correlates that complement, rather than replace, traditional clinical and psychosocial evaluations. Such an integrated approach could potentially contribute to a more comprehensive understanding of individual vulnerability and behavioral trajectories. However, the use of genetic information in assessments of criminal responsibility should be approached with caution and proven expertise, given the complex, multifactorial nature of antisocial and criminal behavior. Full article

Background/Objectives: This study assessed the impact of variations in autophagy-related genes (ATG) on baseline characteristics of cutaneous melanoma, laboratory parameters (including inflammatory biomarkers), response to therapy, and survival in patients treated with immune checkpoint inhibitors (ICIs) as first-line therapy. Methods: DNA was extracted from blood samples of 144 melanoma patients. Genotyping of ATG5 (rs2245214 and rs510432), ATG10 (rs1864183 and rs1864182), and ATG16L1 (rs2241880) was performed using an allelic discrimination method on the StepOnePlus^TM Real-Time PCR System. Correlations with laboratory parameters, response to therapy, and survival were assessed only in the subgroup of patients who received ICIs in first-line treatment (n = 74). Statistical significance was calculated, and p values were adjusted for multiple testing using the Benjamini–Hochberg False Discovery Rate (FDR). Results: Considering baseline characteristics of 144 patients, ATG5 rs2245214 showed a trend with regression (p = 0.042) and lymphovascular invasion (p = 0.05), while ATG16L1 rs2241880 was associated with lymphovascular invasion (p = 0.056), with corrected FDR q value for all histopathological characteristics of 0.076. In patients who received ICIs in first-line, ATG5 rs2245214 genotypes were associated with LDH (p = 0.001, q = 0.004) and the number of metastatic sites (p < 0.001, q = 0.004). Also, ATG5 rs2245214 was associated with neutrophil-to-lymphocyte ratio (NLR) (p = 0.036, q = 0.045) systemic immune-inflammation (SII) index (p = 0.038, q = 0.048) and pan-immune-inflammation value (PIV) (p = 0.031,q = 0.041), while ATG10 rs1864183 was associated with PIV (p = 0.047, q = 0.047). The association of ATG genotypes with disease control rate (DCR) was demonstrated for ATG5 rs2245214 (p = 0.013, q = 0.029) and ATG16L1 rs2241880 (p = 0.032,q = 0.032). Progression-free survival (PFS) was significantly associated with ATG10 rs1864183 (p = 0.023, q = 0.046). The significance of the ATG10 rs1864183 C/T genotype as a prognostic marker for progression was confirmed in both univariate and multivariate Cox proportional hazards regression analyses (p = 0.025, q = 0.028 and p = 0.022, respectively). Conclusions: This study shows that ATG5 rs2245214, ATG10 rs1864183, and ATG16L1 rs2241880 correlate with systemic inflammation, response to ICIs, and had a trend toward melanoma characteristics. However, these findings should be confirmed in larger patient cohorts. Full article

Exosomes have emerged as key mediators of intercellular and inter-organ communication. Although substantial advances have expanded the understanding of the biology of extracellular vesicles, exosome biogenesis and their role in the disease progression of systemic diseases have not yet been fully elucidated. In this review, we present a comprehensive overview of the molecular pathways responsible for exosome biogenesis, emphasizing how the selective incorporation of proteins, lipids, metabolites, messenger RNAs, and microRNAs (miRs) determines the composition and biological activity of exosomes. We also discuss how exosome-mediated inter-organ communication functions as an integrated biological network that connects the kidney, the cardiovascular system, the brain, the liver, the immune system, and tumors, thereby coordinating the pathological responses underlying the progression of chronic diseases. Additionally, we demonstrate the recent advances in the potential of exosomes as minimally invasive biomarkers and clinical translational implantation. Finally, we discussed the methodological and biological challenges that limit the clinical application of exosomes. Overall, this review presents an integrated framework for understanding exosome biology and supports the concept that exosomes function as dynamic platforms for systemic signaling that link molecular mechanisms to disease pathogenesis and translational medicine. Full article