Biomedicines最新文献

Background/Objectives: Ulcerative colitis (UC) and Crohn's disease (CD) are the usual clinical forms of inflammatory bowel disease (IBD). Changes in the oral microbiota, especially the presence of emerging fungi and herpesviruses, have been shown to worsen the clinical aspects of IBD. The aim of this study was to screen for emerging pathogens in the oral yeast microbiota and the presence of herpesvirus in IBD patients. Methods: Oral swabs of seven UC or CD patients were collected. The samples were plated on Sabouraud Dextrose Agar and subcultured on CHROMagar Candida and CHROMagar Candida Plus. Polyphasic taxonomy was applied and identified using molecular tools, such as MALDI-TOF MS and ITS partial sequencing. Multiplex qPCR was used to identify the herpesvirus. Results: The mean age was 38.67 ± 14.06 years, 57.14% were female, and two had diabetes. The CD patients presented with Rhodotorula mucilaginosa, Candida orthopsilosis and Kodamaea jinghongensis, while the UC patients presented with Cutaneotrichosporon dermatis, Candida glabrata, Candida lusitanea and Candida tropicalis. Two UC individuals had at least one herpesvirus. In the first individual, a co-detection of Herpes Simplex Virus 1 (HSV-1) and C. lusitaniae was observed. The second presented with co-infections of Epstein-Barr virus (EBV), Human Herpesvirus 7 (HHV-7) and C. tropicalis. Conclusions: We identified rarely described yeasts and co-infections in IBD patients, highlighting the need to identify emerging pathogens in the oral microbiota, as they may contribute to opportunistic infections.

Objectives: The aim of the present study was to test whether a parameter reflecting tumor dissemination (Dmax), derived from basal 18F-FDG PET/CT, may predict clinical outcome in patients with advanced non-small-cell lung cancer (NSCLC). Methods: A total of 78 patients (55 men, 23 women) with stage III and IV NSCLC who had undergone whole-body 18F-FDG PET/CT scan at diagnosis were included in this study. Imaging parameters of primary lung tumors along with total MTV (MTV_TOT) and whole-body TLG (TLG_WB) of all malignant lesions were determined. Moreover, the largest distance between two 18F-FDG avid lesions (Dmax) in each patient was measured. Univariate and multivariate analyses of clinical and imaging variables were performed followed by overall survival (OS) curves. Results: A total of 441 lesions were analyzed, including 78 primary tumors, 174 metastatic lymph nodes, and 189 distant metastases. In primary tumors, the average values of SUVmax, SUVmean, MTV, and TLG were 11.80 ± 5.73, 5.37 ± 2.09, 60.61 ± 102.57 mL, and 340.36 ± 558.40 g, respectively. The mean value of Dmax was 29.98 ± 20.98 cm, whereas the average values of MTV_TOT and TLG_WB were 155.90 ± 176.94 mL and 851.08 ± 1032.17 g, respectively. In the univariate analysis, OS was predicted by MTV_TOT (p = 0.0145), TLG_WB (p = 0.0518), Dmax (p = 0.0031), and stage (p = 0.0130), whereas in the multivariate analysis, only Dmax was retained in the model (χ² = 7.3130, p = 0.0068). In particular, a high Dmax value indicates a worse prognosis. Moreover, the combination of Dmax with MTV_TOT was able to improve the prognostic stratification of patients with advanced stages of NSCLC. Conclusions: Dmax, by reflecting tumor dissemination throughout the body, can predict overall survival in NSCLC patients.

Background/Objectives: A bidirectional association between inflammatory bowel disease (IBD) and periodontitis has been observed, yet their causal relationship remains unclear. This study aimed to investigate the potential causal links between these two inflammatory conditions through comprehensive genetic and molecular analyses. Methods: We conducted a bidirectional Mendelian randomization (MR) analysis integrated with bioinformatics approaches. The causal relationships were primarily evaluated using inverse variance weighting (IVW), complemented by multiple sensitivity analyses to assess the robustness of the findings. Additionally, we performed differential gene expression analysis using RNA sequencing data to identify co-expressed genes and shared inflammatory mediators between IBD and periodontitis, followed by pathway enrichment analysis. Results: Bidirectional MR analysis revealed significant causal associations between IBD and periodontitis (p-value < 0.05). Sensitivity analyses demonstrated the consistency of these findings, with no evidence of significant heterogeneity or horizontal pleiotropy (p-value > 0.05). Integrated bioinformatics analysis identified key immune regulators, particularly interleukin 1 beta (IL1B) and C-X-C motif chemokine receptor 4 (CXCR4), and inflammatory signaling pathways, including tumor necrosis factor (TNF-α) and interleukin 17 (IL17), as potential molecular mechanisms underlying the bidirectional relationship between these conditions. Conclusions: Our findings provide genetic evidence supporting a bidirectional causal relationship between IBD and periodontitis. Transcriptomic analysis revealed shared pathological mechanisms and identified crucial immune regulatory factors common to both diseases. These insights enhance our understanding of the molecular interplay between IBD and periodontitis, potentially informing new therapeutic strategies for both conditions.

Background: Sorting nexin 19 (SNX19) is important in the localization and trafficking of the dopamine D₁ receptor (D₁R) to lipid raft microdomains. However, the interaction between SNX19 and the lipid raft components caveolin-1 or flotillin-1 and, in particular, their roles in the cellular endocytosis and cell membrane trafficking of the D₁R have not been determined. Methods: Caveolin-1 and flotillin-1 motifs were analyzed by in silico analysis; colocalization was observed by confocal immunofluorescence microscopy; protein-protein interaction was determined by co-immunoprecipitation. Results: In silico analysis revealed the presence of putative caveolin-1 and flotillin-1 binding motifs within SNX19. In mouse and human renal proximal tubule cells (RPTCs), SNX19 was localized mainly in lipid rafts. In mouse RPTCs transfected with wild-type (WT) Snx19, fenoldopam (FEN), a D₁-like receptor agonist, increased the colocalization of SNX19 with caveolin-1 and flotillin-1. FEN also increased the co-immunoprecipitation of SNX19 with caveolin-1 and flotillin-1, effects that were prevented by SCH39166, a D₁-like receptor antagonist. The FEN-mediated increase in the residence of SNX19 in lipid rafts and the colocalization of the D₁R with caveolin-1 and flotilin-1 were attenuated by the deletion of a caveolin-1 (YHTVNRRYREF) (ΔCav1) or a flotillin-1 (EEGPGTETETGLPVS) (ΔFlot1) binding motif. The FEN-mediated increase in intracellular cAMP production was also impaired by the deletion of either the flotillin-1 or caveolin-1 binding motif. Nocodazole, a microtubule depolymerization inhibitor, interfered with the FEN-mediated increase in the colocalization between SNX19 and D₁R. Conclusion: SNX19 contains caveolin-1 and flotillin-1 binding motifs, which play an important role in D₁R endocytosis and signaling.

Hepatic mesenchymal tumors (HMTs) are non-epithelial benign and malignant tumors with or without specific mesenchymal cell differentiation. They are relatively uncommon. Except for mesenchymal hamartoma, calcified nested stromal-epithelial tumor, and embryonal sarcoma, most mesenchymal lesions are not specific to the liver. Pathologists face challenges in diagnosing HMTs due to their diverse morphologies and phenotypic variations. Accurate diagnosis is critical for directing appropriate patient care and predicting outcomes. This review focuses on mesenchymal tumors with a relative predilection for the liver, including vascular and non-vascular mesenchymal neoplasms. It provides a thorough and up-to-date overview, concentrating on clinical and pathological features, differential diagnosis, and diagnostic approaches.

Background/Objectives: Coronary microvascular dysfunction (CMD) is emerging as a critical factor in patients presenting with anginal symptoms without obstructive coronary artery disease (CAD). This study aims to investigate the relationship between invasive measurements of coronary flow reserve (CFR) and the index of microcirculatory resistance (IMR) using thermodilution techniques, compared to non-invasive assessments of CFR with transthoracic Doppler echocardiography (TDE). Methods: In this observational prospective cross-sectional study, a total of 49 patients, clinically characterized as having angina with no obstructive CAD (ANOCA) or ischemia with no obstructive CAD (INOCA), underwent both TDE and invasive coronary angiography (ICA) followed by thermodilution assessment of CFR and IMR. Results: It was found that there is a statistically significant negative correlation between both non-invasive and invasive CFR measurements and IMR. Specifically, a negative moderate correlation was observed between non-invasive CFR and IMR (r_s = -0.477, p < 0.01), as well as a high negative correlation between invasive CFR and IMR (r = -0.541, p < 0.01). Receiver operating characteristic (ROC) analysis indicated that both non-invasive and invasive CFRs are effective predictors of CMD, defined as IMR > 25. Conclusions: Both noninvasive and invasive CFR measurements are significant independent predictors of CMD. Our results indicate that noninvasive TDE CFR can be a reliable tool for assessing CMD in patients with ANOCA, potentially facilitating earlier diagnosis and management strategies for this patient population.

Background/Objectives: Cardiac resynchronization therapy (CRT) is one of the interventional methods of heart failure (HF) treatment, with the criteria for CRT device implantation based on the value of the left ventricular ejection fraction, New York Heart Association functional class, QRS complex duration, and electrocardiographic morphology. Pulmonary hypertension is an important factor influencing the prognosis of patients with HF, but its influence on CRT is not fully understood. Aim: The main aim of the study was to determine the prognostic value of baseline right heart catheterization-derived parameters on the response to CRT. Methods: It was a single-centre study with retrospective analysis of data of 39 non-ischemic HF patients. Clinical, biochemical, echocardiographic, electrocardiographic, and hemodynamic data were obtained before the CRT device implantation, and after 6 months of follow-up, non-invasive re-assessment was performed. Various criteria for the response to CRT were assessed along with the correlation between the baseline parameters. Results: After follow-up, a significant difference was found in the reduction in symptoms associated with HF, an increase achieved in the six-minute walk test distance, and a reduction in N-terminal pro-brain natriuretic peptide concentration as well as improvement of LV function assessed in echocardiographic examination. Among all parameters assessed, the baseline higher value of the transpulmonary gradient and pulmonary vascular resistance most often had a significant negative impact on meeting the criteria of response to CRT. Conclusions: The results of the analyses show that the initial assessment of pulmonary hemodynamics may be crucial in predicting the response to CRT in patients with non-ischemic cardiomyopathy.

Background: The extracellular matrix (ECM) plays a critical role in the proper regeneration of skeletal muscle. ECM remodeling has been reported in the skeletal muscle of chronic obstructive pulmonary disease (COPD), while the mechanisms remain poorly understood. Methods: In this study, we examined the dynamic interplay between ECM components and ECM enzymes in COPD skeletal muscle and cigarette smoke (CS) extract-treated C2C12 cells. C2C12 cells were further used to evaluate the role of a disintegrin and metalloproteinase with thrombospondin motif 4 (ADAMTS4) in ECM remodeling and myogenesis. Results: Chronic CS exposure induced the development of COPD and comorbid sarcopenia in C57BL/6J mice. Muscle fibrosis was observed in the gastrocnemius muscle of CS-exposed mice, accompanied by an upregulation of protein expression but a downregulation of mRNA levels of fibronectin and versican. We found that the discrepancy of mRNA and protein expression was attributed to the aberrant secretion of some ECM enzymes belonging to matrix metalloproteinases and ADAMTS proteases, especially ADAMTS4. CS exposure reduced ADAMTS4 expression in gastrocnemius muscles and C2C12 cells, and Adamts4 knockdown induced fibronectin and versican accumulation and impeded myogenic process. Conclusions: Considering that recent studies have indicated an impaired skeletal muscle regeneration in COPD, we suggested that the restrained production of ADAMTS4 in response to CS could be involved in the damaged muscle regeneration through regulating skeletal muscle ECM in COPD. Targeting ECM enzymes may benefit the rehabilitation of COPD-related sarcopenia.

Background/Objectives: Hypermobile Ehlers-Danlos Syndrome (hEDS) is a complex connective tissue disorder with multi-systemic manifestations that significantly impact quality of life. This case report investigates the clinical course and molecular mechanisms of advanced hEDS through an in-depth case study and post-mortem findings. Methods: The clinical history of a 24-year-old patient with advanced hEDS was analyzed, focusing on progressive complications across multiple systems. Post-mortem examination and genetic analysis were performed to elucidate the underlying pathophysiology. Results: The patient's clinical course was marked by gastrointestinal, neurological, and immune complications requiring numerous surgical interventions. Post-mortem findings revealed severe gastrointestinal dysmotility and Alzheimer's Type II astrocytes. Genetic analysis identified variants in mtDNA genes ATP6, CYB, and ND, suggesting a potential role of impaired mitochondrial function in hEDS pathogenesis but requiring further validation through functional studies. Conclusions: This case report provides valuable insights into the potential role of mitochondrial dysfunction in advanced hEDS and highlights the need for further research in this area. Future studies should include comprehensive functional assays, longitudinal tissue sampling, family genetic analyses, and muscle biopsies to better understand the complex interplay between genetic factors, mitochondrial function, and clinical manifestations in hEDS. Establishing genetic bases and developing targeted therapies addressing both structural and metabolic aspects are crucial. The patient's legacy offers invaluable information that could significantly contribute to enhancing diagnostic accuracy and developing personalized treatment strategies for this challenging disorder, potentially leading to better care for individuals living with hEDS.

Tyrosine kinase inhibitors (TKIs) have transformed the treatment of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer. However, treatment resistance remains a major challenge in clinical practice. The tumor microenvironment (TME) is a complex system composed of tumor cells, immune and non-immune cells, and non-cellular components. Evidence indicates that dynamic changes in TME during TKI treatment are associated with the development of resistance. Research has focused on identifying how each component of the TME interacts with tumors and TKIs to understand therapeutic targets that could address TKI resistance. In this review, we describe how TME components, such as immune cells, fibroblasts, blood vessels, immune checkpoint proteins, and cytokines, interact with EGFR-mutant tumors and how they can promote resistance to TKIs. Furthermore, we discuss potential strategies targeting TME as a novel therapeutic approach.