COMP-Angiopoietin-1 Recovers Molecular Biomarkers of Neuropathy and Improves Vascularisation in Sciatic Nerve of ob/ob Mice

mice. mice displayed regeneration of small-diameter endoneural microvessels. Effects of COMP-Ang-1 corresponded to increased phosphorylation of Akt and p38 MAPK upon Tie-2 receptor. mice suggesting COMP-Ang-1 as novel treatment option to improve morphologic and protein expression changes associated with diabetic neuropathy

Effect of COMP-Ang-1 on Cx26, Cx32, Cx43 and TNFα expression in sciatic nerves.

<p>Diabetic neuropathy is associated with increased expression of tumour necrosis factor alpha (TNFa) and connexin (Cx) 43 and with decreased expression of Cx26 and Cx32 in endo-/perineurium of sciatic nerve in <i>ob/ob</i> mice compared with ob/+ controls. COMP-Ang-1 treatment inhibited up-regulation of pro-inflammatory cytokine TNFa and Cx43 and recovered the synthesis of Cx26 and Cx32 in sciatic nerve of ob/ob mice at 7 and 21 days. (A) Representative Western blots; (B) Data of densitometrical analysis after normalization to GAPDH. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0032881#s3" target="_blank">Results</a> are presented as mean ±SEM. * p≤0.05, ** p≤0.01, *** p≤0.001, according to the one-way analysis of variance together with the Newman-Keuls test (n = 4).</p

Ang-1, Tie-2, Akt and p38 MAPK expression in sciatic nerve biopsies of <i>ob/ob</i> and <i>ob/+</i> mice.

<p>Representative Western blots (A) and corresponding densitometrical analyses (B) of Ang-1, Tie-2, Akt and p38 MAPK and in sciatic nerve of <i>ob/ob</i> and <i>ob/+</i> mice under treatment of COMP-Ang-1. A: COMP-Ang-1 led to the increase of Ang-1 expression in ob/ob mice on day 21 of application and improved the expression of phospho–Tie2, -Akt and -p38 MAPK after 60 min of the injection in both ob/ob and ob/+ mice. B: <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0032881#s3" target="_blank">Results</a> are presented as mean ±SEM. ** p≤0.01, *** p≤0.001, according to the one-way analysis of variance together with the Newman-Keuls test (n = 4).</p

Effect of COMP-Ang-1 treatment on blood glucose concentrations and body weight.

<p>Metabolic parameters and body weight of <i>ob/ob</i> mice and non-diabetic <i>ob/+</i> control mice with COMP-Ang-1 (100 ng/ml) or NaCl treatment. COMP-Ang-1 significantly decreased blood glucose level (A) in ob/ob mice compared with NaCl treatment at 21 days. After 21 days, glucose concentration was indistinguishable between COMP-Ang1 treated <i>ob/ob</i> and non-diabetic <i>ob/+</i> mice. (B) Effect of COMP-Ang-1 treatment of body weight. Data are means ±SD; n = 6 per group.</p

The number of animals used in experiments. The experimental groups: NaCl ob/+, NaCl ob/ob, COMP‐Ang‐1 ob/+ and COMP‐Ang‐1 ob/ob mice.

*<p>lipid status</p><p>°blood glucose concentrations and body weight</p

Analysis of sciatic nerve ultrastructure.

<p>a–c: Sciatic nerves with endoneural microvessels of NaCl ob/ob, COMP-Ang-1 ob/ob and NaCl ob/+ mice. d–g: The g-ratio (as axon/fiber diameter), number of myelinated/non-mylinated nerve fibers, endoneural microvessel endothelium and SC basal lamina thicknesses were examined by electron microscopy in COPM-Ang-1 or saline treated ob/ob and ob/+ mice (n = 3). d: There are no significant differences in g-ratio in the all groups. e: The number of non-myelinated nerve fibers appears to be low in saline ob/ob mice compared with ob/+ control mice and increased after 21-day long COMP-Ang-1 treatment, these data were not statistically significant. f: The ratio of endoneural microvessels endothelium thickness shows a statistically significant decrease in ob/ob mice vs. ob/+ mice. g: The thickness of Schwann cells basal lamina is increased in the ob/ob mice. The differences between COMP-Ang-1 and saline treated ob/ob mice were not apparent. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0032881#s3" target="_blank">Results</a> are presented as mean ±SEM. * p≤0.05, ** p≤0.01 according to the one-way analysis of variance together with the Newman-Keuls test.</p

COMP-Ang-1 treatment (100 ng/ml) effect of ob/ob and ob/+ mice on lipid profile after 21 days.

<p>The COMP-Ang-1 dependent decrease of plasma cholesterol and increase of triglyceride were noted in ob/ob mice. Data are means ± SD; n = 6 per group.</p

Analysis of macrophages and T cells distribution in cross sections of sciatic nerves from <i>ob/ob</i> and <i>ob/+</i> mice under treatment of COMP-Ang-1 at 21 days.

<p>Quantification of Iba-1+ macrophages (A) and CD3+ T-cells (C) activation in sciatic nerves (n = 5). B, D: Double immunofluorescence staining against Iba1 (green, macrophages) or CD3 (green, T cells) and neurofilament 200 (red). Immunoreactivity (arrows) for macrophages and T-cells was higher in nerves of non-treated ob/ob mice compared to COMP-Ang-1 treated ob/ob or ob/+ mice. E: Double immunofluorescence staining against Iba1 (green, macrophages) and TNFα (red). Note that TNFα immunoreactivity co-localizes with macrophages (arrows). Cell nuclei were stained with DAPI (blue). Bar represents 100 µm (B, D) and 30 µm (E) respectively. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0032881#s3" target="_blank">Results</a> are presented as mean ±SEM. * p≤0.05, ** p≤0.01, *** p≤0.001, according to the one-way analysis of variance together with the Newman-Keuls test.</p

Three-Year Follow-Up of a Randomized Phase II Trial on Refinement of Early-Stage NSCLC Adjuvant Chemotherapy with Cisplatin and Pemetrexed versus Cisplatin and Vinorelbine (the TREAT Study)

Adjuvant chemotherapy in non-small cell lung cancer (NSCLC) improves survival but is associated with significant toxicity. The Randomized Phase II Trial on Refinement of Early-Stage NSCLC Adjuvant Chemotherapy with Cisplatin and Pemetrexed versus Cisplatin and Vinorelbine (TREAT study) was designed to test the hypothesis that a protocol with reduced toxicity might improve feasibility of postoperative delivery of adjuvant chemotherapy drugs to patients with NSCLC, thereby improving compliance and, potentially, survival.publisher: Elsevier articletitle: Three-Year Follow-Up of a Randomized Phase II Trial on Refinement of Early-Stage NSCLC Adjuvant Chemotherapy with Cisplatin and Pemetrexed versus Cisplatin and Vinorelbine (the TREAT Study) journaltitle: Journal of Thoracic Oncology articlelink: http://dx.doi.org/10.1016/j.jtho.2015.09.014 content_type: article copyright: Copyright © 2015 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.status: publishe

Clinicopathological Characteristics of RET Rearranged Lung Cancer in European Patients

Introduction: Rearrangements of RET are rare oncogenic events in patients with non-small cell lung cancer (NSCLC). While the characterization of Asian patients suggests a predominance of nonsmokers of young age in this genetically defined lung cancer subgroup, little is known about the characteristics of non-Asian patients. We present the results of an analysis of a European cohort of patients with RET rearranged NSCLC. Methods: Nine hundred ninety-seven patients with KRAS/EGFR/ALK wildtype lung adenocarcinomas were analyzed using fluorescence in situ hybridization for RET fusions. Tumor specimens were molecularly profiled and clinicopathological characteristics of the patients were collected. Results: Rearrangements of RET were identified in 22 patients, with a prevalence of 2.2% in the KRAS/EGFR/ALK wildtype subgroup. Co-occurring genetic aberrations were detected in 10 patients, and the majority had mutations in TP53. The median age at diagnosis was 62 years (range, 39-80 years; mean +/- SD, 61 +/- 11.7 years) with a higher proportion of men (59% versus 41%). There was only a slight predominance of nonsmokers (54.5%) compared to current or former smokers (45.5%). Conclusions: Patients with RET rearranged adenocarcinomas represent a rare and heterogeneous NSCLC sub-group. In some contrast to published data, we see a high prevalence of current and former smokers in our white RET cohort. The significance of co-occurring aberrations, so far, is unclear. (C) 2015 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved