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Introduction: Diffuse parenchymal lung diseases (DPLD) cover heterogeneous types of lung disorders. Among many pathological phenotypes, pulmonary fibrosis is the most devastating and represents a characteristic sign of idiopathic pulmonary fibrosis (IPF). Despite a poor prognosis brought by pulmonary fibrosis, there are no specific diagnostic biomarkers for the initial development of this fatal condition. The major hallmark of lung fibrosis is uncontrolled activation of lung fibroblasts to myofibroblasts associated with extracellular matrix deposition and the loss of both lung structure and function. Methods: Here, we used this peculiar feature in order to identify specific biomarkers of pulmonary fibrosis in bronchoalveolar lavage fluids (BALF). The primary MRC-5 human fibroblasts were activated with BALF collected from patients with clinically diagnosed lung fibrosis; the activated fibroblasts were then washed rigorously, and further incubated to allow secretion. Afterwards, the secretomes were analysed by mass spectrometry. Results: In this way, the CD44 protein was identified; consequently, BALF of all DPLD patients were positively tested for the presence of CD44 by ELISA. Finally, biochemical and biophysical characterizations revealed an exosomal origin of CD44. Receiver operating characteristics curve analysis confirmed CD44 in BALF as a specific and reliable biomarker of IPF and other types of DPLD accompanied with pulmonary fibrosis. [ABSTRACT FROM AUTHOR]

Gliomas are the most common and lethal forms of malignant brain tumors. We attempted to identify the role of the aging-suppressor Klotho gene and Klotho protein in the immunopathogenesis of gliomas. We examined Klotho genetic variants by PCR-RFLP and measured serum Klotho levels using the ELISA method. We found a statistically significantly increased frequency of rs1207568A allele and rs1207568 GA genotypes in co-dominant, dominant and over-dominant models in grade IV as compared to grade II and III glioma patients. The levels of soluble α Klotho (sαKL) were significantly lower in grade III and IV glioma patients than in healthy controls (p = 0.034; 0.0083). Patients with sαKL levels above 2500 pg/mL survived significantly longer than patients with sαKL below 2500 pg/mL (p = 0.038). We also found a positive correlation of the serum levels of sαKL with seven biomarkers, like angiogenic vascular endothelial growth factor (p = 0.0008), chemokine fractalkine (p = 0.0009), interferon γ (p = 0.003), glial derived neurotrophic factor (p = 0.0268), pro-inflammatory and pro-Th1 cytokine IL-6 (p = 0.0347), anti-inflammatory, pro-Th2 cytokines IL-4 (p = 0.0037) and IL-13 (p = 0.0004). Our results suggest the impact of Klotho genetic variants and Klotho levels on advanced-grade glioma. [ABSTRACT FROM AUTHOR]

Stress responses can impact bladder cancer (BC) outcomes via immune–inflammatory pathway modulation. This study explores heart rate variability (HRV) associations with serum immune–inflammatory biomarkers, blood count inflammatory markers, and psychosocial self-report measures in patients versus healthy controls. The TREM-1 and TREM-2 expressions on peripheral blood monocytes were analysed via flow cytometry; serum inflammatory biomarkers by ELISA; HRV (5-min ECG) pre-tumour resection; blood counts by haematology analyser; and psychosocial factors by validated questionnaires. Patients exhibited altered immune–inflammatory profiles with increased TREM-1/TREM-2, sTREM-1, sTREM-1/sTREM-2 ratio, BDNF, MCP-1, and NLR, and reduced IFN-γ, IL-10, LMR, and PMR. HRV analysis indicated sympathetic dominance (SNS, Stress indices, ACmod) and reduced parasympathetic modulation (PNS index, SDNN, RMSSD, 2UV%, DCmod, SD1). Sympathetic HRV indices correlated positively with sTREM-1, sTREM-1/sTREM-2 ratio, fractalkine, and inflammatory markers (SII, NLR, PLR) and negatively with parasympathetic HRV indices—correlations absent in controls. Only in patients, reduced physical function and social support, and higher anxiety, depression, and fatigue, associated positively with sympathetic HRV indices and inflammatory markers. This study links immune–inflammatory markers, HRV parameters, and psychosocial factors in BC, suggesting that immune and autonomic variations may relate to unfavourable outcomes. Incorporating these assessments could help tailor more personalised treatment strategies for BC patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Human leukocyte antigen G (HLA-G) is an immunosuppressive molecule that is often found at higher levels in various cancers, including bladder cancer (BC). We looked at 89 BC patients and 74 control subjects to understand how HLA-G is linked to BC progression. We examined specific genetic variations and measured HLA-G levels in urine and blood samples, also considering factors such as tumor stage, body mass index, and heart rate variability (HRV). We found that a particular genetic variation was associated with lower HLA-G mRNA levels in the urine of BC patients. Conversely, higher HLA-G mRNA levels were found in patients with advanced stages of cancer. Moreover, patients with higher blood levels of HLA-G had shorter disease-free survival. HRV was linked to HLA-G levels differently in healthy people compared to those with BC. These results suggest that HLA-G plays a role in BC progression and may be influenced by genetic factors and the body's stress response. Background: Human leukocyte antigen G (HLA-G) is an immune checkpoint molecule with immunosuppressive and anti-inflammatory activities. It belongs to class I non-classical major histocompatibility complex molecules and has been upregulated in various cancer types. In bladder cancer (BC) tumors, the association of HLA-G with cancer progression has to be explained. Methods: A total of 89 BC patients and 74 control subjects were genotyped for the HLA-G 14 bp ins/del polymorphism. In urine cell samples, HLA-G mRNA expression was analyzed using real-time PCR. Soluble HLA-G (sHLA-G) serum levels were measured by ELISA. The associations between the HLA-G 14 bp ins/del polymorphism, HLA-G mRNA expression, and/or sHLA-G levels and selected variables including tumor grade, disease stage, body mass index, and heart rate variability (HRV) parameters were evaluated. Results: The protective HLA-G 14 bp ins/ins genotype under the recessive genetic model was associated with lower HLA-G mRNA expression in the BC group (p = 0.049). Significantly higher HLA-G mRNA expression was detected in patients with pT2 + pT3 as compared to those with pTa + pT1 stages (p = 0.0436). Furthermore, higher HLA-G mRNA expression was observed in high-grade muscle-infiltrating BC (MIBC) than in the low-grade non-MIBC group (p = 0.0365). Patients with a level of sHLA-G above 29 U/mL had shorter disease-free survival than patients with lower sHLA-G levels. Furthermore, the opposite HRV correlations with sHLA-G levels in BC patients as compared to controls probably reflect the different roles of HLA-G in health and cancer. Conclusions: Our results suggest the impact of the HLA-G 14 bp ins/del variant, HLA-G expression, and autonomic nervous system imbalance on advanced stages of BC. [ABSTRACT FROM AUTHOR]

HLA-G is the checkpoint molecule involved in the suppression of the immune response. Increased expression of HLA-G and its ILTs receptors have been correlated with tumor progression in various cancer types. In head and neck squamous cell carcinoma (HNSCC) tumors, the effect of HLA-G, ILT2 and ILT4 expression on cancer development has to be explained. The 34 HNSCC patients and 98 controls were genotyped for the HLA-G 14 bp ins/del polymorphism. In HNSCC lesions, HLA-G, ILT2 and ILT4 mRNA expression was analysed using real-time PCR. The association between HLA-G, ILT2 and ILT4 mRNA expression and clinical variables (age at onset, TNM staging system and p16 positivity) was also evaluated. No genetic association between the HLA-G 14 bp ins/del and HNSCC risk was detected (p > 0.05). However, in the non-metastatic HNSCC group, a significantly higher HLA-G mRNA expression was noted in tumors in the T4 stage compared to those in the T1 and T2 stages (p = 0.0289). ILT2 mRNA expression was significantly increased in non-metastatic vs. metastatic tumors (p = 0.0269). Furthermore, a significantly higher ILT4 mRNA expression was noted in tumors in the T1+T2 stage compared to those in the T3 stage (p = 0.0495). Our results suggest that the HLA-G molecule creates an immunological microenvironment involved in HNSCC development. [ABSTRACT FROM AUTHOR]

Human leukocyte antigen G (HLA-G) belongs to non-classical MHC class I molecules that is involved in the suppression of immune response. As HLA-G plays important role in the maintenance of fetal tolerance, its overexpression has been associated with tumor progression. For the regulation of HLA-G levels, genetic variants within the 5′ upstream regulatory region (5′URR) are of crucial importance. Our study aimed to analyze the association between 16 HLA-G 5′URR variants, sHLA-G level and clinical variables in glioma patients. We investigated 59 patients with gliomas (mean age 54.70 ± 15.10 years) and 131 healthy controls (mean age 41.45 ± 9.75 years). Patient's blood was obtained on the day of surgical treatment. The HLA-G 5′URR polymorphisms were typed by direct sequencing and the plasma level of sHLA-G assessed by ELISA. Haploblock within HLA-G 5′URR consisting of −762T, −716G, −689G, −666T, −633A, followed by −486C and −201A alleles were significantly more frequent in patients with gliomas than in the controls (p < 0.05). No correlation of HLA-G 5′URR variants with sHLA-G plasma level was found. Analysis of HLA-G 5′URR variants with main clinical variables in patients with grade IV gliomas revealed that haploblock carriers of −762CT, −716TG, −689AG, −666GT, −633GA, −486AC, −477GC, −201GA followed by −369AC carriers tend to have lower age at onset as compared to other genotype carriers (p = 0.04). Our results suggest genetic association of HLA-G 5′URR variants with risk of developing gliomas and possible contribution of HLA-G to disease pathology. [ABSTRACT FROM AUTHOR]

Recent study in a group of German patients with SSc has implicated the SNP in the MCP-1 gene (-2518 A to G) as a factor of susceptibility to SSc. Reflecting the need for replication of genetic association studies, we investigated if this SNP is associated with SSc in another Caucasian population. MCP-1 -2518 A/G genotypes were determined using PCR-SSP in 46 SSc patients and in 449 healthy subjects, all unrelated and of Slovak (Slavonic) origin. The distribution of MCP-1 -2518 A/G genotypes complied with the Hardy-Weinberg equilibrium both in patient and healthy control groups. There was no difference in MCP-1 -2518*G allele frequency between SSc patients and healthy subjects (patients: 0.23; controls: 0.24; P > .05). Furthermore, MCP-1 -2518 GG homozygotes were similarly represented among SSc patients and healthy subjects (P > .05). The association of MCP-1 -2518 A/G SNP with SSc observed originally in German population was not replicated in the Slovak population. [ABSTRACT FROM AUTHOR]

Objectives: Analysis of new markers in bronchoalveolar lavage fluid (BALF) provides new insights into the immunopathogenesis and may be helpful in differential diagnosis of lung diseases. High mobility group box 1 protein (HMGB1) is a non-histone nuclear protein and its release into the extracellular environment may be associated with the inflammatory response. The aim of the study is the analysis of HMGB1 in BALF, correlations with other markers of inflammation and differences in extracellular HMGB1 levels in various lung diagnoses. Methods: The concentration of HMGB1 was tested by an Elisa test. We calculated correlations with other inflammatory markers (leukocytes, total protein, albumin, IgG, IgA, IgM, C3 complement component, alpha-2macroglobuline, CD3, CD4, CD8, TREM-1 and TREM-2) and specified HMGB1 level in various diagnoses. Results: A positive correlation was found between the level of HMGB1 and total protein levels (p=0.0001), albumin (p=0.0058), IgA (p=0.011), IgM (0.0439) and TREM-2 (p=0.0188). Conversely, a negative correlation was revealed between HMGB1 and TREM-1 (p=0.0009). HMGB1 level varied in different diagnoses: the highest level was detected in QuantiFERON TB-positive subjects (median: 30.2) and hypersensitivity pneumonitis (median: 33.2), followed by pulmonary sarcoidosis (median: 16.8) and idiopathic pulmonary fibrosis (median: 8.8). Conclusion: HMGB1 correlates with other inflammatory markers tested in BALF. Its level varies in different lung diagnoses. (Sarcoidosis Vasc Diffuse Lung Dis 2018; 35: 268-275) ., (Copyright: © 2018.)

Objective: Ischemic heart disease (IHD) is associated with decreased exercise tolerance and it is subjectively reported as angina pectoris or dyspnea. Inflammation and pro- inflammatory cytokines are related to progression of IHD, but their level is seldom analyzed in association with self reported exercise tolerance., Methods: Women aged 35-75 years with stable IHD from Homocysteine Slovakia study (N=175) were analyzed for monocyte chemoatractant protein-1 (MCP-1), interleukin 6 (IL-6), transforming growth factor β1 (TGF β1), Mannan binding lectin (MBL), heat shock proteins 60 (HSP60), carbonyl protein (CP), high sensitivity C-reactive protein (hsCRP) and oxidized glutathione (GSSG) in relation to exercise induced dyspnea or angina pectoris (AP) (≤200 m)., Results: Patients with dyspnea had higher HSP60 (77.3±107.2 vs 43.7±48.9 ng/ml; p=0.014) and IL-6 (2.9±1.3 vs 1.9±0.6 pg/ml; p=0.04) levels. IL-6 and HSP60 demonstrated direct correlation with dyspnea (rho=0.39; p=0.02 resp. rho=0.22; p=0.01). AP≤200 m patients showed only decreased protein carbonyl a marker of protein oxidation and increased oxidative stress (CP 61.7±27.3 vs. 72.1±23.1 pg/ml; p=0.001). CP indirectly correlates with AP≤200 m (rho=-0.25; p=0.001)., Conclusions: We have found associations of pro-inflammatory cytokines and inflammation markers with dyspnea or angina pectoris, but the relationship was not consistent in our patients with stable ischemic heart disease.