Water Sorption and Structural Properties of Human Airway Mucus in Health and Muco-Obstructive Diseases.

Muco-obstructive diseases change airway mucus properties, impairing mucociliary transport and increasing the likelihood of infections. To investigate the sorption properties and nanostructures of mucus in health and disease, we investigated mucus samples from patients and cell cultures (cc) from healthy, chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF) airways. Atomic force microscopy (AFM) revealed mucin monomers with typical barbell structures, where the globule to spacer volume ratio was the highest for CF mucin. Accordingly, synchrotron small-angle X-ray scattering (SAXS) revealed more pronounced scattering from CF mucin globules and suggested shorter carbohydrate side chains in CF mucin and longer side chains in COPD mucin. Quartz crystal microbalance with dissipation (QCM-D) analysis presented water sorption isotherms of the three types of human airway mucus, where, at high relative humidity, COPD mucus had the highest water content compared to cc-CF and healthy airway mucus (HAM). The higher hydration of the COPD mucus is consistent with the observation of longer side chains of the COPD mucins. At low humidity, no dehydration-induced glass transition was observed in healthy and diseased mucus, suggesting mucus remained in a rubbery state. However, in dialyzed cc-HAM, a sorption-desorption hysteresis (typically observed in the glassy state) appeared, suggesting that small molecules present in mucus suppress the glass transition.

Effects of endobronchial coils for endoscopic lung volume reduction on sleep in COPD patients with advanced pulmonary emphysema.

PURPOSE: Treatment of advanced pulmonary emphysema with endobronchial coils can improve clinical outcomes like quality of life (QOL). Yet, patients with chronic obstructive pulmonary disease (COPD) are also known to suffer from reduced sleep quality. The effect of coil therapy on sleep has not yet been investigated. The primary aim of this study was to investigate sleep efficiency before and after coil treatment. Secondly, we investigated the effects on nocturnal breathing pattern, QOL, and physical activity. METHODS: Polysomnography (PSG) testing was performed before (T0), 6 month after (T3), and 12 months after (T4) treatment with endobronchial coils. Further examinations included QOL by St George's Respiratory Questionnaire (SGRQ) and COPD assessment test (CAT), and physical activity using an accelerometer for 1 week after each visit. RESULTS: Of 21 patients, 14 completed the study: 6 women; mean age 58.0 ± 4.9 years; BMI 22.6 ± 4.6 kg/m2; FEV1 28.6 ± 7.1% predicted; residual volume (RV) 278.2 ± 49.4% predicted. Sleep efficiency did not vary between baseline and follow-up examinations (T0 69.0 ± 15.8%; T3 70.9 ± 16.0%; T4 66.8 ± 18.9%). Non-REM respiratory rate decreased compared to baseline (T0 19.4 ± 3.9/min; T3 17.8 ± 3.5/min; T4 17.1 ± 3.1/min (p = 0.041; p = 0.030) and QOL improved meeting the minimal clinically important difference (MCID) (SGRQ, T3 -12.8 units; T4 -7.1 units; CAT: T3 -5.6 units; T4 -3.4 units). No increase in physical activity was recorded (light activity T0 31.9 ± 9.9; T3 30.8 ± 16.9; T4 26.3 ± 10.6 h/week). CONCLUSIONS: Treatment with endobronchial coils did not influence objectively measured sleep quality or physical activity, but reduced nocturnal breathing frequency and improved QOL in severe emphysema patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02399514, First Posted: March 26, 2015.

Microvessel density correlates with lymph node metastases and prognosis in hilar cholangiocarcinoma.

BACKGROUND: Neovascularization was shown to be critically involved in the progression of multiple cancers, and treatment approaches targeting tumor-associated neovascularization provide convincing results in recent years in some tumor entities. However, little is known about the tumor-associated neovascularization in hilar cholangiocarcinoma. The present study was conducted to analyze tumor-associated neovascularization in hilar cholangiocarcinoma and to determine its influence on tumor growth, metastasis, recurrence, and prognosis. METHODS: We analyzed tissue specimens of hilar cholangiocarcinoma (n = 60) by immunohistochemistry using the endothelial-specific antibody CD31 and subsequently quantified the microvessel density (MVD). The MVD was correlated with clinicopathological characteristics and recurrence pattern of the tumors as well as survival of patients. RESULTS: Hilar cholangiocarcinoma revealed a high degree of vascularization, with a calculated mean MVD of 28.1 +/- 14.5 vessels. Tumors with a high MVD had a significant higher incidence of lymph node involvement (P = 0.009) and local recurrence (P < 0.001). Furthermore, a high MVD was identified to be a significant overall survival disadvantage (3-year, 28% vs. 93%; 5-year, 8% vs. 78%; P < 0.001) as well as disease-free survival disadvantage (3-year, 7% vs. 88%, 5-year, 7% vs. 72%; P < 0.001), with MVD representing an independent prognostic factor for survival. CONCLUSIONS: Neovascularization is associated with nodal spread as well as local recurrence and serves as an independent prognostic factor for survival after curative resection of hilar cholangiocarcinoma. Therefore, tumor-associated neovascularization seems to be critically involved in the progression of this tumor entity. In addition, neovascularization may represent a potential target in he development of new therapeutic approaches in hilar cholangiocarcinoma.

VEGF-D promotes tumor growth and lymphatic spread in a mouse model of hepatocellular carcinoma.

Lymphatic spread is an important clinical determinant for the prognosis of hepatocellular carcinoma (HCC), but little is known about the control of lymphangiogenesis in HCC. We addressed expression and biological role of the pro-(lymph), angiogenic protein VEGF-D in this tumor entity. Using immunohistochemistry and in situ hybridization on specimens of HCC, cirrhotic and normal liver we found abundant expression of VEGF-D exclusively in the tumor cells. The cognate receptor VEGFR-3 was detected on blood and lymphatic vessels. By clinicopathological analysis VEGF-D expression was correlated with pT-stage of the primary, lymph node metastasis and lymphangiosis carcinomatosa. Three out of 4 human HCC cell lines expressed and secreted VEGF-D. To approach its biological function, VEGF-D deficient SKHep-1 cells were stably transfected with VEGF-D cDNA and effects on tumor progression were determined in vivo. Compared to mock-transfected controls, subcutaneous tumors derived from VEGF-D expressing cells were larger and more frequently metastasized to regional lymph nodes. VEGF-D expressing tumors exhibited increased microvessel density and increased abundance of peri- and intratumoral lymphatics, as assessed by immunostaining for CD31 and for LYVE-1 and/or podoplanin, respectively. Furthermore, coexpression of the soluble extracellular VEGFR-3 domain blocked VEGF-D-induced tumor growth and lymphatic spread via reduction of angiogenesis and lymphangiogenesis. In the orthotopic approach, VEGF-D expression resulted in an increased rate of intra- and extrahepatic as well as lymph node metastasis. In conclusion, our study suggests that expression of VEGF-D is involved in growth and lymphatic spread of HCC. Therefore, VEGF-D might represent a therapeutic target in HCC.