Common variation in a long non-coding RNA gene modulates variation of circulating TGF-ß2 levels in metastatic colorectal cancer patients (Alliance).

BACKGROUND: Herein, we report results from a genome-wide study conducted to identify protein quantitative trait loci (pQTL) for circulating angiogenic and inflammatory protein markers in patients with metastatic colorectal cancer (mCRC). The study was conducted using genotype, protein marker, and baseline clinical and demographic data from CALGB/SWOG 80405 (Alliance), a randomized phase III study designed to assess outcomes of adding VEGF or EGFR inhibitors to systemic chemotherapy in mCRC patients. Germline DNA derived from blood was genotyped on whole-genome array platforms. The abundance of protein markers was quantified using a multiplex enzyme-linked immunosorbent assay from plasma derived from peripheral venous blood collected at baseline. A robust rank-based method was used to assess the statistical significance of each variant and protein pair against a strict genome-wide level. A given pQTL was tested for validation in two external datasets of prostate (CALGB 90401) and pancreatic cancer (CALGB 80303) patients. Bioinformatics analyses were conducted to further establish biological bases for these findings. RESULTS: The final analysis was carried out based on data from 540,021 common typed genetic variants and 23 protein markers from 869 genetically estimated European patients with mCRC. Correcting for multiple testing, the analysis discovered a novel cis-pQTL in LINC02869, a long non-coding RNA gene, for circulating TGF-ß2 levels (rs11118119; AAF = 0.11; P-value < 1.4e-14). This finding was validated in a cohort of 538 prostate cancer patients from CALGB 90401 (AAF = 0.10, P-value < 3.3e-25). The analysis also validated a cis-pQTL we had previously reported for VEGF-A in advanced pancreatic cancer, and additionally identified trans-pQTLs for VEGF-R3, and cis-pQTLs for CD73. CONCLUSIONS: This study has provided evidence of a novel cis germline genetic variant that regulates circulating TGF-ß2 levels in plasma of patients with advanced mCRC and prostate cancer. Moreover, the validation of previously identified pQTLs for VEGF-A, CD73, and VEGF-R3, potentiates the validity of these associations.

Aqueous humor cytokine levels are associated with the severity of visual field defects in patients with primary open-angle glaucoma.

BACKGROUND: To evaluate the aqueous humor (AH) levels of cytokines in primary open-angle glaucoma (POAG) patients and cataract patients. METHODS: Thirty-eight POAG patients and 26 cataract patients were recruited. Peripheral blood (PB) was collected from each subject. The POAG group was divided into 2 subgroups according to the severity of visual field defects. The cutoff point of the mean deviation (MD) of the visual field was -12 dB. AH was obtained at the time of anterior chamber puncture during cataract or glaucoma surgery by using a 27-gauge needle attached to a microsyringe. AH and PB levels of interleukin-2 (IL-2), tumor necrosis factor-alpha (TNF-α), transforming growth factor-beta2 (TGF-ß2) and IL-4 were assayed by enzyme-linked immunosorbent assay. Postoperative intraocular pressures (IOPs) of POAG patients were recorded during the follow-up period. RESULTS: TNF-α and TGF-ß2 showed significantly higher AH levels in the POAG group than in the cataract group (P < 0.001 and P = 0.001, respectively). For the POAG group, preoperative IOPs were significantly positively correlated with AH levels of TNF-α (r2 = 0.129, P = 0.027) and TGF-ß2 (r2 = 0.273, P = 0.001). AH levels of TGF-ß2 were significantly different among cataract patients, POAG patients with MD> -12 dB and POAG patients with MD≤ -12 dB (P = 0.001). AH levels of TNF-α were significantly positively associated with IOP reduction after trabeculectomy (P = 0.025). AH and PB levels of cytokines were not related to the long-term success of trabeculectomy. CONCLUSION: The levels of TNF-α and TGF-ß2 showed different profiles in POAG patients and cataract patients. AH levels of TGF-ß2 were correlated with the severity of glaucomatous neuropathy in POAG patients. The findings suggest possible roles for cytokines in the pathogenesis and development of POAG.

The alterations of cerebrospinal fluid TNF-alpha and TGF-beta2 levels in early relapsing-remitting multiple sclerosis.

AIM OF THE STUDY: This study aimed to analyze serum and cerebrospinal fluid (CSF) concentrations of proinflammatory and anti-inflammatory cytokines produced by T regulatory (Treg) cells in early RRMS according to the 2017 McDonald criteria. CLINICAL RATIONALE FOR THE STUDY: Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the central nervous system (CNS) with the cytokine network playing an important role. However, there is a continual lack of data regarding the immunopathogenesis of early RRMS, especially according to the 2017 McDonald criteria. MATERIALS AND METHODS: The study groups included early RRMS patients during relapse (n = 18), remission (n = 14), and the control group. The MS diagnosis was established according to the 2017 McDonald criteria. Patients were studied up to 1 year after diagnosis was made. A quantitative test kit based on ELISA was used for cytokine measurement in the serum and CSF. Comparative and correlation analyses between the levels of TNF-α, TGF-ß2, IgG index, and relapse duration were performed. RESULTS: Significantly higher CSF concentrations of TNF-α in both RRMS-relapse and RRMS-remission groups were found compared to the controls (p < 0.01). The CSF levels of TGF-ß2 in the RRMS-relapse group were significantly lower in comparison to the control group (p = 0.01). CONCLUSIONS AND CLINICAL IMPLICATIONS: An inappropriate inflammatory response seems to occur in early RRMS and includes the production of TNF-α and a decrease in TGF-ß2 release suggesting a significant Treg cells role. Further studies on the topic may contribute to developing new disease-modifying drugs and biochemical markers of the disorder.

Caloric Restriction Impairs Regulatory T cells Within the Tumor Microenvironment After Radiation and Primes Effector T cells.

Outcomes for triple negative breast cancer (TNBC) are poor and may be improved by increasing CD8+ tumor infiltrating lymphocytes (TIL) to augment antitumor immunity. Radiation (RT) can promote immunogenic cell death with increased antitumor T cell activity but also stimulates suppressive regulatory T cells (Tregs). Because metabolic alterations affect immune homeostasis and prior studies show caloric restriction (CR) combined with RT improves preclinical TNBC outcomes, we hypothesized that CR augments RT, in part, by altering intratumoral immunity. Using an in vivo model of TNBC, we treated mice with ad libitum (AL) diet, radiation, a CR diet, or CR + RT, and demonstrated an immune suppressive environment with a significant increase in CD4+ CD25+Foxp3+ Tregs after RT but not in CR-fed mice. CD8:Treg ratio in CR + RT TIL increased 4-fold compared with AL + RT mice. In vivo CD8 depletion was performed to assess the role of effector T cells in mitigating the effects of CR, and it was found that in mice undergoing CR, depletion of CD8 T cells resulted in increased tumor progression and decreased median survival compared with isotype control-treated mice. In addition, PD-1 expression on CD3+CD8+ T cells within the tumor microenvironment was significantly increased in CR + RT versus AL + RT treated mice as per immunofluorescence. Serum from breast cancer patients undergoing RT alone or CR and RT was collected pre- and postintervention, and a cytokine array demonstrated that patients treated with CR + RT had notable decreases in immunosuppressive cytokines such as IL-2Rγ, IL-10Rß, and TGF-ß2 and 3 compared with patients receiving RT alone. In conclusion, combining CR with RT decreases intratumoral Tregs, increases CD8:Treg, and increases PD-1 expression via a process dependent on CD8 T cells in a TNBC model. Breast cancer patients undergoing CR concurrently with RT also had significant reduction in immunosuppressive cytokine levels compared with those receiving RT alone.

Determination of neuroinflammatory biomarkers in autistic and neurotypical Saudi children.

To identify neuroinflammatory biomarkers in patients with various severity of autism spectrum disorder (ASD) increases the insight about the pathogenesis and pathophysiology of this neurodevelopmental disorder. The aim of the present study was to analyze the levels in plasma of TGFß2, Heat shock protein 70 (HSP70), and hematopoietic prostaglandin D2 synthase (H-PGDS) in Saudi ASD children and healthy age-matched neurotypical controls. Also, it was in the present study examined the correlation among these neuroinflammatory biomarkers and the sensory deficit exhibited by the ASD children. Blood samples from 38 Saudi children with ASD and 32 age-matched neurotypical controls were withdrawn after an overnight fast. For the blood taking 3 mL EDTA containing blood collection tubes was used. The samples were centrifuged for 20 min (4 °C; 3000×g) directly after the blood sampling. The harvested plasma was used for in vitro quantification of TGF-ß2, HSP70, and H-PGDS by using the sandwich enzyme immunoassay. Receiver operating characteristic (ROC) analysis and predictiveness curves showed that each of TGF-ß2, HSP70 or H-PGDS alone could not be used as a predictive neuroinflammatory biomarker for ASD. However, when TGF-ß2 and HSP70 were combined in one ROC curve, the AUC was increased to an appreciable value that makes them together robust predictors of variation between the ASD and neurotypical control groups. Overall, it was in the present study found significant differences for TGF-ß2 and HSP70 when the ASD and neurotypical control groups were compared, independently of the sensory deficit level. In conclusion, the present study highlights the usefulness of TGF-ß2, HSP70, and H-PGDS as diagnostic tools to differentiate between ASD and neurotypical control children, but not among subgroups of ASD children exhibiting different severity levels of sensory dysfunction. The presented data also suggest the effectiveness of ROC as a powerful statistical tool, which precisely can measure a combined effect of neuroinflammatory biomarkers intended for diagnostic purposes.

Association of recurrent venous thromboembolism and circulating microRNAs.

BACKGROUND: Patients with unprovoked first venous thromboembolism (VTE) are at a high risk of recurrence. Although circulating microRNAs (miRNAs) have been found to be associated with VTE and are markers of hypercoagulability, this study is the first to examine whether circulating miRNAs are associated with the risk of VTE recurrence. RESULTS: A nested case-control study design was used where plasma samples were obtained from 78 patients with unprovoked VTE from the Malmö Thrombophilia Study (MATS). A total of 39 VTE patients with recurrent VTE (cases) were matched with 39 VTE patients without recurrent VTE (controls) defined by age and sex (MATS population). Plasma levels of 179 different miRNAs were evaluated in the 78 samples (after anticoagulant treatment was stopped) using qPCR. A total of 110 miRNAs were detected in all samples. Among those, 12 miRNAs (miR-15b-5p, miR-106a-5p, miR-197-3p, miR-652-3p, miR-361-5p, miR-222-3p, miR-26b-5p, miR-532-5p, miR-27b-3p, miR-21-5p, miR-103a-3p, and miR-30c-5p) were found to be associated with recurrent VTE after multiple correction test and conditional logistic regression analysis. A further analysis showed that miR-15b-5p, miR-197-3p, miR-27b-3p, and miR-30c-5p exhibited a trend over time, with a larger difference in miRNA levels between cases and controls for earlier recurrence. Of these 12 miRNAs, 8 miRNAs significantly correlated with circulating transforming growth factor ß1/2 (TGFß1/2). Three of them correlated with platelet count. CONCLUSION: We have identified 12 plasma miRNAs that may have the potential to serve as novel, non-invasive predictive biomarkers for VTE recurrence.

Elevated TGF ß2 serum levels in Emery-Dreifuss Muscular Dystrophy: Implications for myocyte and tenocyte differentiation and fibrogenic processes.

Among rare diseases caused by mutations in LMNA gene, Emery-Dreifuss Muscular Dystrophy type 2 and Limb-Girdle muscular Dystrophy 1B are characterized by muscle weakness and wasting, joint contractures, cardiomyopathy with conduction system disorders. Circulating biomarkers for these pathologies have not been identified. Here, we analyzed the secretome of a cohort of patients affected by these muscular laminopathies in the attempt to identify a common signature. Multiplex cytokine assay showed that transforming growth factor beta 2 (TGF ß2) and interleukin 17 serum levels are consistently elevated in the vast majority of examined patients, while interleukin 6 and basic fibroblast growth factor are altered in subgroups of patients. Levels of TGF ß2 are also increased in fibroblast and myoblast cultures established from patient biopsies as well as in serum from mice bearing the H222P Lmna mutation causing Emery-Dreifuss Muscular Dystrophy in humans. Both patient serum and fibroblast conditioned media activated a TGF ß2-dependent fibrogenic program in normal human myoblasts and tenocytes and inhibited myoblast differentiation. Consistent with these results, a TGF ß2 neutralizing antibody avoided fibrogenic marker activation and myogenesis impairment. Cell intrinsic TGF ß2-dependent mechanisms were also determined in laminopathic cells, where TGF ß2 activated AKT/mTOR phosphorylation. These data show that TGF ß2 contributes to the pathogenesis of Emery-Dreifuss Muscular Dystrophy type 2 and Limb-Girdle muscular Dystrophy 1B and can be considered a potential biomarker of those diseases. Further, the evidence of TGF ß2 pathogenetic effects in tenocytes provides the first mechanistic insight into occurrence of joint contractures in muscular laminopathies.

Changes in the cytokine profile in first-episode, drug-naïve patients with psychosis after short-term antipsychotic treatment.

An increasing body of evidence suggests that antipsychotic medication can cause immunological changes that could be attributed to the amelioration of psychotic symptoms or the metabolic side effects of the drugs. So far, the results of the studies remain controversial. Our aim was to compare the levels of interleukin (IL) IL-2, IL-6 and transforming growth factor-ß2 (TGF-ß2) in drug-naïve, first-episode patients with psychosis before and after six weeks of antipsychotic medication. Thirty-nine first-episode patients with psychosis were enrolled in the study. Serum levels of IL-2, IL-6 and TGF-ß2 were measured by enzyme linked immunosorbent assay (ELISA) before and six weeks after the initiation of antipsychotics. In addition, clinical psychopathology was assessed using Positive and Negative Syndrome Scale (PANSS) before and after treatment. Serum levels of IL-2 were significantly increased six weeks after the initiation of antipsychotic treatment (p <0.001) while TGF-ß2 levels were decreased (p <0.001). IL-6 levels were overall increased (p <0.004), but this occurred in a non-linear way. These findings, although preliminary, provide further evidence that antipsychotic treatment in patients with psychosis may be correlated with immunological changes but further research is needed.

[Study on the establishment of HMLD model and the expression of KL-6/TGF-beta in rat].

Objective: To establish an animal model of hard metal lung disease (HMLD) in rats, and to screen the indications for diagnosis of HMLD. Methods: The rats were randomly divided into 5 groups, each group included 8 rats: saline group, pure cobalt group, pure tungsten carbide group, silica group and hard metal (HM) group. 10 mg subjects were administered in each group by using the pulmonary endotracheal tube. After 8 week, the lung CT scan and lung tissue pathology were observed, the serum and bronchoalveolar lavage fluid (BALF) were collected for KL-6, TGF-beta1 and TGF-beta2. Results: The lung tissue structure of HM group was destroyed, a large number of nuclear giant cells and epithelial like cells appeared in the stroma, and uncommon CT scan images appeared in the lung. KL-6, TGF-beta1, TGF-beta2 expression in each group was not the same, the difference was statistically significant (P<0.05) . The expression of KL-6 and TGF-beta1 in serum was not identical in all the groups, the difference was statistically significant (P<0.05) . The expression of TGF-beta2 had no significant difference between the groups (P>0.05) . Conclusion: Rats can be successfully established HMLD model, rats in vivo lung CT scan images appear abnormal, which are provided with assistant diagnostic value for HMLD. The expression of KL-6 and TGF-beta2 in serum and BALF on HMLD rats are not highly specific, and TGF-beta1 has reference value in the rat HMLD auxiliary diagnosis.

Are Cytokines Useful Biomarkers to Determine Disease Severity in Neonates with Congenital Diaphragmatic Hernia?

Background This study investigates plasma cytokine levels in neonates with the more common left-sided congenital diaphragmatic hernia (CDH) and correlates them with severity of disease indicated by position of the liver. An intrathoracic part of liver is associated with higher need for extracorporeal membrane oxygenation (ECMO) and higher risk for chronic lung disease (CLD). Methods A total of 28 newborns with CDH were subdivided by their liver position in partially intrathoracic (n = 16) and only abdominal (n = 12) position. Only liver-up patients went on ECMO (n = 9) and developed severe/moderate CLD (n = 5). Controls consisted of 19 healthy matched-term neonates. Laboratory samples were extracted from umbilical cord blood and during the neonatal period. Results In umbilical cord blood, CDH patients showed decreased IL-8 values while MIP-1a (macrophage inflammatory protein-1) values were increased. Concerning the severity of CDH, we measured significantly higher levels of TGFb2 in CDH patients with liver-up than in liver-down cases and controls (p < 0.006). During the neonatal period, the concentration of IL-10 and vascular endothelial growth factor (VEGF) showed significant deviations in the liver-up group with need for ECMO (p < 0.009). Conclusion In neonates with CDH, plasma cytokine levels are already altered in utero. TGFb2 may work as an early predictor for severity of disease. VEGF and IL-10 could serve as potential biomarkers predicting the course of disease in CDH.

Fibulin-4 deficiency increases TGF-ß signalling in aortic smooth muscle cells due to elevated TGF-ß2 levels.

Fibulins are extracellular matrix proteins associated with elastic fibres. Homozygous Fibulin-4 mutations lead to life-threatening abnormalities such as aortic aneurysms. Aortic aneurysms in Fibulin-4 mutant mice were associated with upregulation of TGF-ß signalling. How Fibulin-4 deficiency leads to deregulation of the TGF-ß pathway is largely unknown. Isolated aortic smooth muscle cells (SMCs) from Fibulin-4 deficient mice showed reduced growth, which could be reversed by treatment with TGF-ß neutralizing antibodies. In Fibulin-4 deficient SMCs increased TGF-ß signalling was detected using a transcriptional reporter assay and by increased SMAD2 phosphorylation. Next, we investigated if the increased activity was due to increased levels of the three TGF-ß isoforms. These data revealed slightly increased TGF-ß1 and markedly increased TGF-ß2 levels. Significantly increased TGF-ß2 levels were also detectable in plasma from homozygous Fibulin-4(R/R) mice, not in wild type mice. TGF-ß2 levels were reduced after losartan treatment, an angiotensin-II type-1 receptor blocker, known to prevent aortic aneurysm formation. In conclusion, we have shown increased TGF-ß signalling in isolated SMCs from Fibulin-4 deficient mouse aortas, not only caused by increased levels of TGF-ß1, but especially TGF-ß2. These data provide new insights in the molecular interaction between Fibulin-4 and TGF-ß pathway regulation in the pathogenesis of aortic aneurysms.

Prognostic significance of in situ and plasma levels of transforming growth factor ß1, -2 and -3 in cutaneous melanoma.

Melanoma is an aggressive type of cutaneous malignancy. Transforming growth factor (TGF)­ß has been demonstrated to be an important mediator of tumor progression. However, to the best of our knowledge, the systemic roles of plasma TGF­ß and TGF­ß in situ have not been investigated in Han Chinese melanoma patients. The results of the present study demonstrated that the in situ and plasma levels of TGF­ß1, TGF­ß2 and TGF­ß3 protein and messenger RNA were significantly elevated in tumor tissues compared with those of normal tissues. The survival rates of the patients which were triple­positive (TGF­ß1+, TGF­ß2+ and TGF­ß3+) were found to be markedly decreased compared to those which were single­ (TGF­ß1+, TGF­ß2+ or TGF­ß3+) or double­positive (TGF­ß1+, TGF­ß2+; TGF­ß2+, TGF­ß3+; or TGF­ß1+, TGF­ß3+). These results may therefore contribute to the use of TGF­ß as a prognostic biomarker, and to the development of novel therapies for melanoma treatment.

Clinical and biochemical profiles suggest fibromuscular dysplasia is a systemic disease with altered TGF-ß expression and connective tissue features.

Fibromuscular dysplasia (FMD) is a rare, nonatherosclerotic arterial disease for which the molecular basis is unknown. We comprehensively studied 47 subjects with FMD, including physical examination, spine magnetic resonance imaging, bone densitometry, and brain magnetic resonance angiography. Inflammatory biomarkers in plasma and transforming growth factor ß (TGF-ß) cytokines in patient-derived dermal fibroblasts were measured by ELISA. Arterial pathology other than medial fibrodysplasia with multifocal stenosis included cerebral aneurysm, found in 12.8% of subjects. Extra-arterial pathology included low bone density (P<0.001); early onset degenerative spine disease (95.7%); increased incidence of Chiari I malformation (6.4%) and dural ectasia (42.6%); and physical examination findings of a mild connective tissue dysplasia (95.7%). Screening for mutations causing known genetically mediated arteriopathies was unrevealing. We found elevated plasma TGF-ß1 (P=0.009), TGF-ß2 (P=0.004) and additional inflammatory markers, and increased TGF-ß1 (P=0.0009) and TGF-ß2 (P=0.0001) secretion in dermal fibroblast cell lines from subjects with FMD compared to age- and gender-matched controls. Detailed phenotyping of patients with FMD allowed us to demonstrate that FMD is a systemic disease with alterations in common with the spectrum of genetic syndromes that involve altered TGF-ß signaling and offers TGF-ß as a marker of FMD.

Transforming growth factor-ß (TGF-ß) pathway abnormalities in tenascin-X deficiency associated with CAH-X syndrome.

Patients with congenital adrenal hyperplasia (CAH) with tenascin-X deficiency (CAH-X syndrome) have both endocrine imbalances and characteristic Ehlers Danlos syndrome phenotypes. Unlike other subtypes, tenascin-X-related Ehlers Danlos syndrome is caused by an extracellular matrix protein deficiency rather than a defect in fibrillar collagen or a collagen-modifying enzyme, and the understanding of the disease mechanisms is limited. We hypothesized that transforming growth factor-ß pathway dysregulation may, in part, be responsible for connective tissue phenotypes observed in CAH-X, due to this pathway's known role in connective tissue disorders. Fibroblasts and direct tissue from human skin biopsies from CAH-X probands and age- and sex-matched controls were screened for transforming growth factor-ß biomarkers known to be dysregulated in other hereditary disorders of connective tissue. In CAH-X fibroblast lines and dermal tissue, pSmad1/5/8 was significantly upregulated compared to controls, suggesting involvement of the bone morphogenetic protein pathway. Additionally, CAH-X samples compared to controls exhibited significant increases in fibroblast-secreted TGF-ß3, a cytokine important in secondary palatal development, and in plasma TGF-ß2, a cytokine involved in cardiac function and development, as well as palatogenesis. Finally, MMP-13, a matrix metalloproteinase important in secondary palate formation and tissue remodeling, had significantly increased mRNA and protein expression in CAH-X fibroblasts and direct tissue. Collectively, these results demonstrate that patients with CAH-X syndrome exhibit increased expression of several transforming growth factor-ß biomarkers and provide a novel link between this signaling pathway and the connective tissue dysplasia phenotypes associated with tenascin-X deficiency.

Transforming growth factor (TGF)-ß levels and unprovoked recurrent venous thromboembolism.

Prediction of recurrence in patients with unprovoked venous thromboembolism (VTE) remains a challenge. Studies of atherosclerosis suggest a protective role of transforming growth factor (TGF)-ß. However, the role of TGF-ß has not been studied in VTE. The aim of this study was to investigate TGF-ß as a predictive marker of recurrent VTE in patients with a first episode of unprovoked VTE. Patients in the Malmö Thrombophilia Study (MATS) were followed after the discontinuation of anticoagulant treatment until the diagnosis of recurrent VTE or the end of the study in December 2008 (mean ± SD 38.5 months ± 27). Among patients with a first episode of unprovoked VTE, we identified 42 patients with recurrent VTE during the follow-up period. Two age- and sex-matched control subjects without recurrent VTE were selected for each patient (n = 84). Plasma levels of the three isoforms of TGF-ß (TGF-ß1, TGF-ß2 and TGF-ß3) were quantified simultaneously by TGF-ß 3-plex immunoassay. Compared to controls, plasma levels of TGF-ß1 and TGF-ß2 were significantly lower in patients with recurrent VTE (p < 0.05), whereas no difference was found for TGF-ß3. In a multivariate Cox regression analyses, adjusted for inherited thrombophilia, age, sex and BMI, low levels of TGF-ß1 [hazard ratio (HR) = 2.2, 95% confidence interval (CI) 1.1-4.3; p = 0.02] and TGF-ß2 (HR = 2.4, 95% CI 1.2-4.7; p = 0.01) were independently associated with a higher risk of recurrent VTE. We propose TGF-ß1 and TGF-ß2 as potential predictive markers for recurrence in patients with unprovoked VTE.

Transforming growth factor-ß and inflammation in vascular (type IV) Ehlers-Danlos syndrome.

BACKGROUND: Vascular Ehlers-Danlos syndrome (VEDS) causes reduced life expectancy because of arterial dissections/rupture and hollow organ rupture. Although the causative gene, COL3A1, was identified >20 years ago, there has been limited progress in understanding the disease mechanisms or identifying treatments. METHODS AND RESULTS: We studied inflammatory and transforming growth factor-ß (TGF-ß) signaling biomarkers in plasma and from dermal fibroblasts from patients with VEDS. Analyses were done in terms of clinical disease severity, genotype-phenotype correlations, and body composition and fat deposition alterations. VEDS subjects had increased circulating TGF-ß1, TGF-ß2, monocyte chemotactic protein-1, C-reactive protein, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and leptin and decreased interleukin-8 versus controls. VEDS dermal fibroblasts secreted more TGF-ß2, whereas downstream canonical/noncanonical TGF-ß signaling was not different. Patients with COL3A1 exon skipping mutations had higher plasma intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, and VEDS probands had abnormally high plasma C-reactive protein versus affected patients identified through family members before any disease manifestations. Patients with VEDS had higher mean platelet volumes, suggesting increased platelet turnover because of ongoing vascular damage, as well as increased regional truncal adiposity. CONCLUSIONS: These findings suggest that VEDS is a systemic disease with a major inflammatory component. C-reactive protein is linked to disease state and may be a disease activity marker. No changes in downstream TGF-ß signaling and increased platelet turnover suggest that chronic vascular damage may partially explain increased plasma TGF-ß1. Finally, we found a novel role for dysregulated TGF-ß2, as well as adipocyte dysfunction, as demonstrated through reduced interleukin-8 and elevated leptin in VEDS.

Upper airway cough syndrome in children and two inflammatory factors: TRPV1 and TGF-ß2.

OBJECTIVES: The aim of the study was to investigate upper airway cough syndrome (UACS) in children and to determine alternative methods to explore the relationships among TRPV1, TGF-ß2, and UACS. METHODS: In 2012, 104 children with adenoid hypertrophy aged 2-13 years who were admitted to the otolaryngology department, Capital Institute of Pediatrics-affiliated children's hospital, were included in this study. Enzyme-linked immunosorbent assay (ELISA) and immunohistochemical (IHC) studies for TRPV1 and TGF-ß2 were performed to understand the relationship between the two inflammatory factors, and the correlations among the indices and UACS. The research was divided into three stages. In stage 1, 72 children (24 UACS and 48 controls) were enrolled in the study, and ELISAs for TRPV1 and TGF-ß2 were performed. In stage 2, 32 children (16 UACS and 16 controls) were enrolled in the study and both ELISA and IHC for TRPV1 and TGF-ß2 were performed. In stage 3, 41 children were enrolled in this research who had thick mucus secretions in the posterior nasal apertures in stage 1 and 2 (23 cases with chief complaint (or history) of chronic cough and 18 cases without). The difference between the TRPV1 and TGF-ß2 serum values and the clinical factors was determined. RESULTS: The levels of TRPV1 and TGF-ß2 were significantly increased in the UACS cases. OSAHS and thick mucus secretions correlated with a diagnosis of UACS. A history of asthma and thick mucus secretions correlated with elevation of the two inflammatory factors. There was no statistical correlation between ELISA and IHC testing. Among the children with thick mucus secretions, some had a higher possibility of chronic coughing including those who had higher levels of the two indices, larger tonsils and a history of chronic tonsillitis. CONCLUSION: The detections of TRPV1 and TGF-ß2 from serum and adenoid body specimens are valuable for UACS auxiliary diagnosis. Tonsil hypertrophy and chronic tonsillitis history are independent risk factors of UACS.

Relationships between age-related biochemical markers of bone turnover and OPG, TGF-ß1 and TGF-ß2 in native Chinese women.

Osteoprotegerin (OPG), transforming growth factor-ß1 (TGF-ß1) and TGF-ß2 are cytokines closely associated with bone metabolism. However, their association with bone turnover markers in native Chinese women remains unknown. The study aims to investigate the relationship between bone metabolism related cytokines including OPG, TGF-ß1, TGF-ß2 and bone turnover markers in native Chinese women. The cross-sectional study was conducted on 691 healthy Chinese women (20-80 years old). Levels of OPG, TGF-ß1, TGF-ß2, serum bone-specific alkaline phosphatase (BAP), osteocalcin (OC), cross-linked N-terminal telopeptides of type I collagen (sNTX), cross-linked C-terminal telopeptides of type I collagen (sCTX), urinary NTX (uNTX), urinary CTX (uCTX) and total urinary deoxypyridinoline (uDPD) were determined. The present study showed that OPG and TGF-ß2 had positive correlation with BAP, OC, uNTX, uCTX and uDPD, while TGF-ß1 showed negative correlation with BAP, OC, sCTX, uNTX and uCTX, and most of the coefficients of partial correlation remained significant after adjustments for age and body mass index (BMI). Multiple linear regression stepwise analysis showed that OPG and TGF-ß2 were positive determinative factors for BAP, sCTX, uNTX and uCTX, which could explain 0.6-16.6% of the variation in these markers. TGF-ß1 was a negative determinative factor for BAP, OC, sCTX and uCTX, which could explain 0.7-7.3% of the variation in these markers. This study suggested that measuring bone turnover indicators and serum cytokines simultaneously might help evaluating changes in bone turnover rate caused by aging or menopause in women.