The Roles of S100A4 and the EGF/EGFR Signaling Axis in Pulmonary Hypertension with Right Ventricular Hypertrophy.

Pulmonary hypertension (PH) is characterized by increased pulmonary arterial pressure caused by the accumulation of mesenchymal-like cells in the pulmonary vasculature. PH can lead to right ventricular hypertrophy (RVH) and, ultimately, heart failure and death. In PH etiology, endothelial-to-mesenchymal transition (EndMT) has emerged as a critical process governing the conversion of endothelial cells into mesenchymal cells, and S100A4, EGF, and EGFR are implicated in EndMT. However, a potential role of S100A4, EGF, and EGFR in PH has to date not been elucidated. We therefore quantified S100A4, EGF, and EGFR in patients suffering from chronic thromboembolic pulmonary hypertension (CTEPH) and idiopathic pulmonary arterial hypertension (iPAH). To determine specificity for unilateral heart disease, the EndMT biomarker signature was further compared between PH patients presenting with RVH and patients suffering from aortic valve stenosis (AVS) with left ventricular hypertrophy. Reduced S100A4 concentrations were found in CTEPH and iPAH patients with RVH. Systemic EGF was increased in CTEPH but not in iPAH, while AVS patients displayed slightly diminished EGF levels. EGFR was downregulated in all patient groups when compared to healthy controls. Longitudinal data analysis revealed no effect of surgical therapies on EndMT markers. Pulmonary thrombo-endarterectomized samples were devoid of S100A4, while S100A4 tissue expression positively correlated with higher grades of Heath-Edwards histopathological lesions of iPAH-derived lung tissue. Histologically, EGFR was not detectable in CTEPH lungs or in iPAH lesions. Together, our data suggest an intricate role for S100A4 and EGF/EGFR in PH with right heart pathology.

Potential novel biomarkers for chronic lung allograft dysfunction and azithromycin responsive allograft dysfunction.

Chronic Lung Allograft Dysfunction (CLAD), manifesting as Bronchiolitis Obliterans Syndrome (BOS) or Restrictive Allograft Syndrome (RAS), is the main reason for adverse long-term outcome after Lung Transplantation (LTX). Until now, no specific biomarkers exist to differentiate between CLAD phenotypes. Therefore, we sought to find suitable cytokines to distinguish between BOS, RAS and Azithromycin Responsive Allograft Dysfunction (ARAD); and reveal potential similarities or differences to end-stage fibrotic diseases. We observed significantly increased Lipocalin-2 serum concentrations in RAS compared to BOS patients. In addition, in RAS patients immunohistochemistry revealed Lipocalin-2 expression in bronchial epithelium and alveolar walls. Patients with ARAD showed significantly lower Activin-A serum concentrations compared to Stable-LTX and BOS patients. Further, increased serum concentrations of Lipocalin-2 and Activin-A were predictors of worse freedom-from-CLAD in Stable-LTX patients. These biomarkers serve as promising serum biomarkers for CLAD prediction and seem suitable for implementation in clinical practice.

Follistatin impacts Tumor Angiogenesis and Outcome in Thymic Epithelial Tumors.

Tumor angiogenesis is a key factor in the progression of thymic epithelial tumors (TETs). Activin A, a member of the TGFß family, and its antagonist Follistatin are involved in several human malignancies and angiogenesis. We investigated Activin A and Follistatin in serum and tumor tissue of patients with TETs in relation to microvessel density (MVD), WHO histology classification, tumor stage and outcome. Membranous Activin A expression was detected in all tumor tissues of TETs, while Follistatin staining was found in tumor nuclei and cytoplasm. Patients with TETs presented with significantly higher Activin A and Follistatin serum concentrations compared to healthy volunteers, respectively. Follistatin serum concentrations correlated significantly with tumor stage and decreased to physiologic values after complete tumor resection. Follistatin serum concentrations correlated further with MVD and were associated with significantly worse freedom from recurrence (FFR). Low numbers of immature tumor vessels represented even an independent worse prognostic factor for FFR at multivariable analysis. To conclude, the Activin A - Follistatin axis is involved in the pathogenesis of TETs. Further study of Follistatin and Activin A in TETs is warranted as the molecules may serve as targets to inhibit tumor angiogenesis and tumor progression.

Subarachnoid hemorrhage in rats - Visualizing blood distribution in vivo using gadolinium-enhanced magnetic resonance imaging: Technical note.

BACKGROUND: The aims of this study were to assess the feasibility of magnetic resonance imaging (MRI) to track the in vivo distribution of autologous, injected blood in a subarachnoid hemorrhage model (SAH), and to evaluate whether this technique results in observable morphological detriment. NEW METHOD: We used an SAH model of stereotactic injection of autologous blood into the prechiasmatic cistern in Sprague Dawley rats. To visualize its in vivo distribution, a gadolinium-containing contrast agent was added to the autologous blood prior to injection. MRI was performed on a 9.4 T Bruker Biospec scanner preoperatively, as well as at variable time points between 30 min to 23 days after SAH. T1-weighted and diffusion-weighted images were acquired. The morphological examination was completed by a histopathological work-up. RESULTS: Upon injection of contrast agent-enriched autologous blood, enhancement was observed in the entire subarachnoid space within 30 min of injection. Total clearance was noted at the first postoperative day. SAH induction did not result in changes in clinical scores or on histopathological or radiological images. COMPARISON WITH EXISTING METHODS: We modified an established method to allow in vivo MRI monitoring of subarachnoid blood distribution in an SAH model. CONCLUSION: This technique could be used to evaluate the distribution of blood components during the development of novel SAH models. Since no additional morphological detriment was observed, this technique could be used as a validation tool to verify correct application and induction in preclinical SAH models.

Prognostic and diagnostic impact of fibrinogen, neutrophil-to-lymphocyte ratio, and platelet-to-lymphocyte ratio on thymic epithelial tumors outcome.

BACKGROUND: Peripheral blood-derived inflammation-based markers, such as Neutrophil-to-Lymphocyte Ratio (NLR), Platelet-to-Lymphocyte Ratio (PLR), and Fibrinogen have been identified as prognostic markers in various solid malignancies. Here we aimed to investigate the prognostic and diagnostic impact of NLR, PLR, and Fibrinogen in patients with thymic epithelial tumors (TETs). RESULTS: Pretreatment Fibrinogen serum concentrations, NLRs and PLRs were highest in patients with TCs and advanced tumor stages. High pretreatment Fibrinogen serum concentration (≥452.5 mg/dL) was significantly associated with worse cause specific survival (CSS; p = 0.001) and freedom from recurrence (FFR; p = 0.043), high NLR (≥4.0) with worse FFR (p = 0.008), and high PLR (≥136.5) with worse CSS (p = 0.032). Longitudinal analysis revealed that compared to patients without tumor recurrence, patients with tumor recurrence had significantly higher NLR (11.8 ± 4.0 vs. 4.70 ± 0.5; p = 0.001) and PLR (410.8 ± 149.1 vs. 228.3 ± 23.7; p = 0.031). CONCLUSION: Overall, Fibrinogen serum concentrations, NLRs, and PLRs were associated with higher tumor stage, more aggressive tumor behavior, recurrence, and worse outcome. Prospective multicenter studies of the diagnostic and prognostic potential of Fibrinogen, NLR, and PLR are warranted. METHODS: This retrospective analysis included 122 patients with TETs who underwent surgical resection between 1999-2015. Fibrinogen serum concentrations, NLRs, and PLRs were measured in patients preoperatively, postoperatively, and later during follow-up. These markers were analyzed for association with several clinical variables, including tumor stage, tumor subtype, FFR, and CSS and to evaluate their prognostic and diagnostic impact for detecting tumor recurrence.

Elevated CRP levels predict poor outcome and tumor recurrence in patients with thymic epithelial tumors: A pro- and retrospective analysis.

OBJECTIVE: Scarce information exists on the pathogenesis of thymic epithelial tumors (TETs), comprising thymomas, thymic carcinomas (TCs) and neuroendocrine tumors. C-reactive protein (CRP) increases during certain malignancies. We aimed to investigate the clinical relevance of CRP in patients with TETs. RESULTS: Pretreatment CRP serum concentrations were significantly elevated in patients with TETs, particularly TCs and metastatic TETs. After complete tumor resection CRP serum concentrations were decreased (p = 0.135) but increased significantly in case of tumor recurrence (p = 0.001). High pretreatment CRP was associated with significantly worse 5- and 10-year freedom-from recurrence (FFR) (p = 0.010) and was a negative prognostic factor for FFR (HR 3.30; p = 0.015). IL-6 (not IL-1ß) serum concentrations were significantly elevated in patients with TETs but we did not detect CRP tissue expression in TETs. MATERIALS AND METHODS: Pretreatment CRP serum concentrations were retrospectively analyzed from 128 surgical patients (1990-2015). In a subset of 68 patients longitudinal analysis of CRP was performed. Additionally, immunohistochemical tumor CRP expression and serum concentrations of interleukin (IL)-6 and IL-1ß were measured. CONCLUSIONS: Hence, diagnostic measurement of serum CRP might be useful to indicate highly aggressive TETs and to make doctors consider tumor recurrences during oncological follow-up.