Histologically Validated Myocardial Fibrosis in Relation to Left Ventricular Geometry and Its Function in Aortic Stenosis.

Background and Objectives: The combination of aortic valve stenosis (AS) and ischemic heart disease (IHD) is quite common and is associated with myocardial fibrosis (MF). The purpose of this study was to evaluate the association between the histologically verified left ventricular (LV) MF and its geometry and function in isolated AS and AS within IHD groups. Materials and Methods: In a single-center, prospective trial, 116 patients underwent aortic valve replacement (AVR) with/without concomitant surgery. The study population was divided into groups of isolated AS with/without IHD. Echocardiography was used, and LV measurements and aortic valve parameters were obtained from all patients. Myocardial tissue was procured from all study patients undergoing elective surgery. Results: There were no statistical differences between isolated AS and AS+IHD groups in LV parameters or systolic and diastolic functions during the study periods. The collagen volume fraction was significantly different between the isolated AS and AS+IHD groups and was 7.3 ± 5.6 and 8.3 ± 6.4, respectively. Correlations between MF and left ventricular end-diastolic diameter (LVEDD) (r = 0.59, p = < 0.001), left ventricular mass (LVM) (r = 0.42, p = 0.011), left ventricular ejection fraction (LVEF) (r = -0.67, p < 0.001) and an efficient orifice area (EOA) (r = 0.371, p = 0.028) were detected in isolated AS during the preoperative period; the same was observed for LVEDD (r = 0.45, p = 0.002), LVM (r = 0.36, p = 0.026), LVEF (r = -0.35, p = 0.026) and aortic annulus (r = 0.43, p = 0.018) in the early postoperative period; and LVEDD (r = 0.35, p ≤ 0.05), LVM (r = 0.43, p = 0.007) and EOA (r = 0.496, p = 0.003) in the follow-up period. In the group of AS and IHD, correlations were found only with LV posterior wall thickness (r = 0.322, p = 0.022) in the follow-up period. Conclusions: Histological MF in AS was correlated with LVM and LVEDD in all study periods. No correlations between MF and LV parameters were found in aortic stenosis in the ischemic heart disease group across all study periods.

Human Placental Mesenchymal Stem Cells and Derived Extracellular Vesicles Ameliorate Lung Injury in Acute Respiratory Distress Syndrome Murine Model.

This study investigates the therapeutic potential of human placental mesenchymal stem cells (P-MSCs) and their extracellular vesicles (EVs) in a murine model of acute respiratory distress syndrome (ARDS), a condition with growing relevance due to its association with severe COVID-19. We induced ARDS-like lung injury in mice using intranasal LPS instillation and evaluated histological changes, neutrophil accumulation via immunohistochemistry, bronchoalveolar lavage fluid cell count, total protein, and cytokine concentration, as well as lung gene expression changes at three time points: 24, 72, and 168 h. We found that both P-MSCs and EV treatments reduced the histological evidence of lung injury, decreased neutrophil infiltration, and improved alveolar barrier integrity. Analyses of cytokines and gene expression revealed that both treatments accelerated inflammation resolution in lung tissue. Biodistribution studies indicated negligible cell engraftment, suggesting that intraperitoneal P-MSC therapy functions mostly through soluble factors. Overall, both P-MSC and EV therapy ameliorated LPS-induced lung injury. Notably, at the tested dose, EV therapy was more effective than P-MSCs in reducing most aspects of lung injury.

The association of left ventricular histologically verified myocardial fibrosis with pulmonary hypertension in severe aortic stenosis.

OBJECTIVES: To evaluate the association between histologically verified left ventricular (LV) myocardial fibrosis (MF) and its bio- and functional markers with pulmonary hypertension (PH) in severe aortic stenosis (AS). METHODS: About 34 patients with isolated severe AS underwent 2D echocardiography, cardiac magnetic resonance (CMR) imaging, and plasma NT-proBNP evaluation before aortic valve replacement (AVR). LV measurements were analyzed by CMR and LV strain using feature tracking software (Medis Suite QStrain 2.0). Myocardial biopsy sampled at the time of AVR was assessed by a histomorphometric analysis. PH was defined as pulmonary artery systolic pressure (PASP) ⩾ 45 mm Hg. RESULTS: Patients with severe AS and PH (mean PASP 53 ± 3.7 mm Hg) had higher extent of diffuse MF versus patients without PH (12 (10.4-12.7)% vs 6.6 (4.6-8.2)% (p = 0.00)). The extent of diffuse MF correlated with LV dilatation (r = 0.7, p = 0.02), indices of LV dysfunction (lower ejection fraction (r = -0.6, p < 0.001), global longitudinal (r = -0.5, p = 0.02) and circumferential strain (r = -0.5, p = 0.05), elevated NT-proBNP (r = 0.5, p = 0.005) and elevated PASP (r = 0.6, p < 0.001)). Histological MF > 10% (AUC 94.9%), LV global longitudinal strain > -15.5% (AUC 86.3%), and NT-proBNP > 2090 ng/l (AUC 85.1%) were independent predictors of PH in severe AS. CONCLUSIONS: The extent of diffuse myocardial fibrosis in combination with reduced longitudinal left ventricular strain and increased plasma levels of NT-proBNP relates to pulmonary hypertension in severe aortic stenosis.

MiRNA profiling of gastrointestinal stromal tumors by next-generation sequencing.

Deregulation of miRNAs has been observed virtually in all major types of cancer, whereas the miRNA signature in GIST is not well characterized yet. In this study the first high-throughput miRNA profiling of 15 paired GIST and adjacent normal tissue samples was performed using small RNA-seq approach and differentially expressed miRNAs as well as isomiRNAs were defined. Highly significantly deregulated miRNAs were selected for validation by Taq-Man low-density array in replication group of 40 paired samples. Validated miRNAs were further subjected to enrichment analysis, which revealed significantly enriched KEGG pathways in the main GIST associated pathways. Further, we used an integrated analysis of miRNA-mRNA correlations for KIT and PDGFRA target genes and found a significant correlation between all of the enriched miRNAs and their target gene KIT. Results of the phenotype analysis showed miR-509-3p to be up-regulated in epithelioid and mixed cell types compared to spindle type, whereas miR-215-5p showed negative correlation with risk grade of GIST. These data reveal a detailed miRNA profile of GIST and highlight new candidates that may be important in the development of malignant disease.

Characteristics of Expression of Matrix Metalloproteinases (MMP-2 and MMP-9) in Glottic Squamous Cell Carcinoma and Benign Vocal Fold Lesions.

OBJECTIVES: The aim of this study was to investigate expression profile of matrix metalloproteinases (MMP-2 and MMP-9) in glottic squamous cell carcinoma (SCC) and benign vocal fold lesions (BVFLs) and to correlate it with clinical and pathological features. METHODS: The immunohistochemical expression of MMP-2 and MMP-9 was investigated in specimens taken from 217 patients group, including vocal fold polyps (n=39), recurrent respiratory papillomatosis (n=30), laryngeal keratosis (n=36), glottic SCC (n=112), and the normal tissue of vocal fold (n=12, control group). The expression of MMP-2 and MMP-9, both in epithelium and stroma cells, was graded on a semiquantitative scale, ranging from 0 (no expression) to 18 points (high expression). RESULTS: Expressions of both, MMP-2 and MMP-9 were significantly higher in the glottic SCC group comparing with BVFL group. Significant higher expression of parenchymal MMP-2 (P<0.001) and stromal MMP-9 (P=0.01) was revealed in the group of moderate/poorly differentiated glottic SCC comparing with well differentiated glottic SCC group. Expression of stroma MMP-2 was found to be correlated with nodal metastasis (P=0.030). Expressions of both, MMP-2 and MMP-9 were not correlated with clinical stage, tumor T value, smoking, alcohol use, age in the glottic SSC patients group. The MMP-2 stroma value of 11.2 points was determined as the optimum point (limiting value) for separating BVFL and glottic SCC patient groups. CONCLUSION: Our results suggest that expressions of both MMP-2 and MMP-9 are up-regulated already in the development of BVFL, the next determinant step is concerned with occurrence of malignization. Limiting value of stroma MMP-2 demonstrates prognostic importance of MMP-2 in glottic SCC carcinogenesis.

Effect of Acanthopanax senticosus on the accumulation of cadmium and on the immune response of spleen cells.

Exposure to cadmium (Cd) is known to alter immune responses. Acanthopanax senticosus (Rupr. et Maxim.) Harms (AS) extract, an antioxidant-containing complex of phenolic compounds, tetracyclic triterpenoids/steroids, and polysaccharides, is known to produce Cd mobilization and excretion in vivo. Building upon earlier findings, the aim of the study was to evaluate the effects of an AS extract on Cd accumulation and changes in the presence of splenic immune cells in hosts during a chronic metal exposure. Chronic Cd exposure of BALB/c mice was induced by providing them solutions containing different levels of CdCl2 (25 or 250 mg/L) in double-distilled water, with/without a concurrent presence of AS root extract (approximately 151 g material/L), for 8 wk. At the study end, Cd levels in spleen were measured. Levels of key splenic immune cells, including macrophages, T-lymphocytes, and B-lymphocytes, were determined by immunohistochemistry using, respectively, CD68, CD3, and CD20 antibodies. The results indicated that chronic consumption of AS extract in the presence of the high dose of CdCl2 led to a significant decrease in Cd levels in mouse spleen. The effects of AS on the lower CdCl2 dose were less apparent. In addition, the presence of AS and Cd increased the amount of macrophages and both B and T lymphocytes in mouse spleen relative to concentrations that were lowered as a result of chronic metal only intake.

Expression of matrix metalloproteinases (MMP-2 and MMP-9) in recurrent respiratory papillomas and laryngeal carcinoma: clinical and morphological parallels.

The task of the present study was to investigate the expression of MMP-2 and MMP-9 in recurrent respiratory papillomas (RRP) and accomplish a comparative analysis with those in laryngeal squamous cell carcinoma (LSCC). The immunohistochemical expression of MMP-2 and MMP-9 was investigated in specimens taken from RRP (n = 38) and LSCC (n = 39) patient groups, and the normal tissue of vocal fold (n = 12, control group). The expression of MMP-2 and MMP-9, both in epithelium and stroma cells, was graded on a semiquantitative scale, ranging from 0 (no expression) to 18 points (high expression). Statistically significant differences in the expression of MMP-2 and MMP-9, both in epithelium and stroma among the RRP, LSCC patients and control group (epithelium) with the LSCC group having the highest MMPs expression scores were revealed. However, no statistically significant correlations among expression of MMPs and clinical and/or morphological features were found in the group of RRP patients. The MMP-2 stroma value of 10.4 points was determined as the optimum point (limiting value) for separating RRP and LSCC patient groups. Results of the present study indicate that the expression of both MMP-2 and MMP-9 are up-regulated early in development of laryngeal papillomas, when the benign neoplastic lesion begins and the next determinant step is concerned with the occurrence of malignization. These results seem promising, as they may improve our understanding of the molecular events leading to the papilloma formation and development, however, further research is needed.

Matrix metalloproteinase-9 is a prognostic marker to predict survival of patients who underwent surgery due to rectal carcinoma.

Common prognostic factors do not fully predict clinical outcomes in colorectal cancer, one of the most common malignancies in developed countries. Therefore, biological prognostic markers are under investigation. We investigated the prognostic value of expression of matrix metalloproteinases (MMP-2 and MMP-9) and their inhibitors (TIMP-2 and TIMP-3) in rectal carcinoma to predict survival of the patients. Retrospective analysis of clinicopathological findings of 64 patients who underwent rectal resection due to carcinoma and were followed-up from 2 to 96 months (median 48) was performed. Semi-quantitative scoring was used to assess the expression levels of MMP-2, MMP-9, TIMP-2 and TIMP-3 in rectal carcinoma. During the follow-up, 28 patients died. The deceased patients demonstrated significantly higher expression of MMP-9 and lower expression of TIMP-3 in parenchyma of carcinoma and lower expression of TIMP-2 in stroma of carcinoma, compared to survivors. Moreover, the deceased patients were associated with advanced tumor, metastases in lymph nodes and distant metastases. According to univariate analysis longer survival was predicted by lower expression of MMP-9 in parenchymal cells (p = 0.03), tumor size (early tumor) (p = 0.026), absence of metastases in lymph nodes (p = 0.02) or distant metastases (p = 0.04). Multivariate analysis revealed that metastases in lymph nodes, higher expression of MMP-9 in parenchyma, and lower expression of MMP-9 in stromal cells significantly increased mortality. Expression of MMP-9 in rectal carcinoma is a prognostic marker for overall survival. It is important to identify the origin of MMP-9 to predict better overall survival of the patients.

Matrix metalloproteinase-3 gene polymorphism and dilatative pathology of ascending thoracic aorta.

Matrix metalloproteinase-3 (MMP-3) degrades extracellular matrix and may lead to development of dilatative pathology of ascending thoracic aorta. Expression of MMP-3 depends upon the 5A/6A polymorphism in the promoter region. An increased number of 5A alleles leads to high expression of MMP-3. Thus, objective of the study was to determine whether the 5A/6A polymorphism in the promoter region of MMP-3 gene is associated with the development of dilatative pathology of ascending thoracic aorta. We studied 76 patients (age ranged from 31 to 81 years; median age, 64 years) who underwent aortic reconstruction surgery due to dilatative pathology of ascending thoracic aorta and a random sample of the population (n=604) aged 25-64 years, all from Lithuania. DNA was analyzed by using real-time polymerase chain reaction to genotype polymorphism 5A/6A at a position -1171 of the MMP3 gene promoter. The prevalence of MMP-3 genotypes was similar in the group of dilatative pathology of ascending thoracic aorta and random sample of population. The frequency of 5A allele did not differ significantly between both groups and was 0.506 and 0.514, respectively. Male carriers of 5A/5A genotype were significantly younger compared with those with the 6A/6A genotype. In conclusion, the frequency of MMP-3 promoter 5A/6A genotypes did not differ between the group of patients with dilatative pathology of ascending thoracic aorta and the random sample of population, but the males with dilatative pathology of ascending thoracic aorta and 5A/5A genotype required aortic reconstruction surgery at the younger age than the males carrying 6A/6A genotype in the MMP-3 promoter region.

Expression of matrix metalloproteinases (MMP-2 and MMP-9) in vocal fold polyps.

OBJECTIVE: Vocal fold polyps are the most common benign laryngeal lesions. Matrix metalloproteinases (MMP) play an important role in the physiological and pathological remodeling of tissues. The most important subgroup of MMP family consists of gelatinases A and B (MMP-2 and MMP-9). The objective of this study was investigation of the expression of MMP-2 and MMP-9 in vocal fold polyps and normal tissue of vocal folds. MATERIAL AND METHODS: The immunohistochemical expression of MMP-2 and MMP-9 was investigated in specimens taken by endolaryngeal microsurgery from vocal fold polyps (n=30) and normal tissue of vocal fold (n=13, control group). Expression of MMP-2 and MMP-9, both in epithelium and stroma cells, was graded on a semiquantitative scale, ranging from 0 (no expression) to 6 points (high expression). RESULTS: A statistically significant increase was observed in the expression of MMP-2 in stroma cells (P=0.0176) of vocal fold polyps compared to control vocal fold group, whereas no significant difference in the expression of MMP-2 was found in epithelium cells (P=0.1487). Comparison of expression of MMP-2 and MMP-9 in epithelium cells revealed a statistically significant increase in MMP-9 expression (P<0.01) in both groups. However, there was no statistically significant difference in the expression of MMP-9 between groups of vocal fold polyps and control vocal folds. CONCLUSION: Expression of MMP-2 in stroma was significantly higher in polyps than in normal tissue of vocal folds. Our data draw attention to the role of MMP-2 in the development of vocal fold polyps and necessity of further investigations to define its function in morphogenesis of laryngeal benign, premalignant, and malignant lesions.

[Reliability of data of death causes: comparison of premortem and verified by autopsy postmortem diagnoses]. / Mirties priezasciu duomenu tikrumas: priesmirtines ir pomirtines, verifikuotos autopsija, diagnoziu palyginimas.

OBJECTIVE: The goal of the investigation was to evaluate the accuracy of medical diagnostics of death causes. MATERIAL AND METHODS: In the framework of population-based postmortem examination program the latest premortem and postmortem diagnoses of the underlying (principal disease), direct (lethal complication) and contributory (contributory pathology) causes of death of 1030 deceased and autopsied people of local randomized unit (Jonava district) autopsy study were compared. RESULTS: The discrepancy between premortem and postmortem diagnoses was 35.3% in the category "circulatory system diseases", 26.5% in the category "malignant neoplasms", 41.1% in the category "lethal complications", and more than 50% in the category "contributory pathology". CONCLUSIONS: The accuracy of data on underlying death cause is significantly limited due to overstating of circulatory system diseases, especially ischemic heart disease and understating of malignancies. Among mismatches in lethal complication cases more significant for outcome of disease were pneumonia and embolism of lung arteries, in contributory pathology--chronic bronchitis and ischemic heart disease.