Matrix metalloproteinases in subjects with type 1 diabetes

<p>Abstract</p> <p>Background</p> <p>Nephropathy is serious complication of diabetes. We have previously shown that level of the proteoglycan syndecan-1 in blood is associated with ultrastructural kidney changes in young persons with type 1 diabetes. Dysregulation of matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) may contribute to the development of nephropathy. The aim of this study was to investigate if the levels of MMPs in blood samples are potential markers of early nephropathy in type 1 diabetes.</p> <p>Methods</p> <p>Blood samples were collected from type 1 diabetes patients after 11 years of diabetes (n = 15) and healthy volunteers (n = 12) and stored at ÷80°C until measurement. Levels and activities of serum MMP-2, MMP-9, TIMP-1 and TIMP- 2 were analyzed and compared to those of control individuals using ELISA, SDS-PAGE gelatin zymography, and Western blot analysis.</p> <p>Results</p> <p>The serum levels of both MMP-9 and MMP-2 were significantly higher in subjects with type 1 diabetes, compared to controls (p = 0.016 and p = 0.008 respectively). Western blotting revealed no differences between the two groups in the levels of TIMP-1 or TIMP-2, respectively.</p> <p>Conclusion</p> <p>Our MMP analysis of serum from a limited number of patients with type 1 diabetes suggest that such analysis is potentially useful as markers in studies of people at risk of progression to chronic kidney disease.</p

20/20 Vision - What does the next 20 years hold for citizenship education?

Citizenship is a feeling, status and practice. It is essentially about living together and working to transform society towards greater democracy and social justice. It is a curriculum space shared by educational movements for human rights, political literacy, sustainable development, peace and equalities. Implementing this synthesis of politics, philosophy, sociology, law and international relations is an adventure in curriculum development. I identify three periods of Citizenship in England, analysing opportunities and significant and severe threats now and in the future

Molards as an analogue for ejecta-ice interactions on Mars

International audience&lt;p&gt;The 125-km-diameter Hale impact crater is located in the southern hemisphere of Mars and has been dated to 1 Ga (Early to Middle Amazonian; Jones et al., 2011). It is thought to have penetrated the martian cryosphere, because it hosts landforms indicating volatile mobilisation post-impact: its ejecta are lobate and bear channels, and the interior is pervasively pitted and hosts alluvial fans (Collins-May et al. 2020; El-Maarry et al., 2013; Jones et al., 2011; Tornabene et al., 2012). Here, we test the hypothesis that conical mounds found within the ejecta are &amp;#8220;molards&amp;#8221; by comparing them to terrestrial analogues. Molards are conical mounds of debris resulting from the degradation of blocks of ice-rich material which have been mobilised by a landslide and are found in periglacial environments (Morino et al., 2019).&lt;/p&gt;&lt;p&gt;Our study area (240x180 km) is in the South-East part of the Hale impact crater ejecta (36&amp;#176;&amp;#8211;39&amp;#176;S, 36&amp;#176;&amp;#8211;31&amp;#176;W). We analyse the spatial and topographic distribution of the conical mounds using orbital images from 25 cm/pixel to 15 m/pixel and measure their height, width and slope using 1 m/pixel elevation data. We then compare them to conical mounds on the deposits of the 2010 Mount Meager debris avalanche, Canada (Roberti et al. 2017) and of the 2000 Paatuut landslide in western Greenland (Dahl-Jensen et al. 2004).&lt;/p&gt;&lt;p&gt;The conical mounds of the Hale impact crater are located at the distal boundary of the thickest part of the ejecta blanket, which reflects the spatial distribution of mounds along the distal parts of the terminal lobe of the Mount Meager debris avalanche. Furthermore, mounds in the Hale impact crater have comparable shapes and flank slopes to molards in the Mount Meager and Paatuut case studies, but are one order of magnitude bigger. This size difference is consistent with the flow-depth that transported the blocks also being one order of magnitude bigger than on Earth.&lt;/p&gt;&lt;p&gt;We infer that conical mounds near the Hale impact crater are a result of fragmented blocks of ice-cemented regolith produced by the impact and transported by the ejecta flows, and finally degraded into cones of debris (molards) by the loss of interstitial ice. Our interpretation supports the prevailing hypothesis that the Hale impact event penetrated the martian cryosphere and further provides important constraints on the rheology of martian ejecta deposits that can be tested by future studies and in other locations on Mars.&lt;/p&gt;&lt;p&gt;We acknowledge financial support for the PERMOLARDS project from French National Research Agency (ANR-19-CE01-0010).&lt;/p&gt

Permafrost molards as an analogue for ejecta-ice interactions at Hale Crater, Mars

When the Hale impact crater penetrated the martian cryosphere 1Ga, landforms indicating post-impact volatile mobilisation were generated. We have found landforms in the ejecta blanket of Hale Crater similar to ‘permafrost molards’ found in periglacial environments on Earth, and probably related to the past or present presence of volatiles at/near the surface. Permafrost molards are conical mounds of debris associated with landslide deposits, resulting from the degradation of blocks of ice-rich material mobilised by a landslide in periglacial terrains. Here we analyse the spatial and topographic distribution of conical mounds around the Hale crater at regional and local scales, and compare them to those of molards on the deposits of the Mount Meager debris avalanche in Canada. Hale Crater's conical mounds are located at the distal boundary of the thickest ejecta blanket, which is the closest to the main crater. We observe a similar spatial arrangement of molards along the distal parts of the terminal lobe of the Mount Meager debris avalanche. We then compare the morphology and morphometrics of the conical mounds on Hale Crater to those of terrestrial molards on the Paatuut and Niiortuut rock avalanches in western Greenland. We find that morphology and setting of conical mounds within Hale Crater ejecta are consistent with the formation pathway of molards on Earth. We infer that they originated from blocks of ice-cemented regolith that were produced by the Hale-crater-forming impact, transported by the ejecta flows, and finally degraded to cones of debris (molards) on loss of the interstitial ice. The similarities in distribution between the ejecta flows of Hale and Mount Meager debris avalanche on Earth suggest that the mounds resulted from the rheological separation of the ejecta flows, with a relatively fluid-poor phase that allowed the volatile-rich blocks to survive transport. This supports the prevailing hypothesis that the Hale impact event penetrated the martian cryosphere, providing important constraints on the rheology of martian ejecta deposits

Elevated tumour interleukin-1β is associated with systemic inflammation: a marker of reduced survival in gastro-oesophageal cancer

Systemic inflammation is associated with adverse prognosis cancer but its aetiology remains unclear. We investigated the expression of proinflammatory cytokines within normal mucosa from healthy controls and tumour tissue in cancer patients and related these levels with markers of systemic inflammation and with the presence of a tumour inflammatory infiltrate. Tissue was collected from 56 patients with gastro-oesophageal cancer and from 12 healthy controls. Tissue cytokine mRNA concentrations were measured by real-time PCR and tissue protein concentrations by cytometric bead array. The degree of chronic inflammatory cell infiltrate was recorded. Serum cytokine and acute phase protein concentrations (including C-reactive protein (CRP)) were measured by enzyme-linked immunosorbent assay. Proinflammatory cytokines were significantly overexpressed (interleukin (IL)-1β, IL-6, IL-8 and tumour necrosis factor-α) both at mRNA and protein levels in the cancer specimens compared with mucosa from controls. Interleukin-1β was expressed in greatest (10–100-fold) concentration and protein levels correlated significantly with systemic inflammation (CRP) (P=0.05, r=0.31). A chronic inflammatory infiltrate was observed in 75% of the cancer specimens and was associated with systemic inflammation (CRP: P=0.01). However, the presence of chronic inflammation per se was not associated with altered cytokine expression within the tumour. Both a chronic inflammatory infiltrate and systemic inflammation (CRP) were associated with reduced survival (P=0.05 and P=0.03, respectively). Tumour chronic inflammatory infiltrate and tumour tissue IL-1β overexpression are potential independent factors influencing systemic inflammation in oesophagogastric cancer patients

High tumour islet macrophage infiltration correlates with improved patient survival but not with EGFR mutations, gene copy number or protein expression in resected non-small cell lung cancer

The purpose of this study was to investigate the prognostic value of tumour-associated macrophages with a focus on micro-anatomical localisation and determine whether molecular changes of the epidermal growth factor receptor (EGFR) are related to macrophage infiltration in resected non-small cell lung cancer (NSCLC). One hundred and forty-four patients were included in this study. Immunohistochemistry was used to identify CD68+ macrophages in the tumour islet and surrounding stroma. Epidermal growth factor receptor mutations were studied by direct sequencing. The EGFR gene copy number and protein expression were analysed by fluorescence in situ hybridisation and immunohistochemistry. Patients with a high tumour islet macrophage density survived longer than did the patient with a low tumour islet macrophage density (5-year overall survival rate was 63.9 vs 38.9%, P=0.0002). A multivariate Cox proportional hazard analysis revealed that the tumour islet macrophage count was an independent prognostic factor for survival (hazard ratio 0.471, 95% confidence interval 0.300–0.740). However, EGFR mutations, gene copy number, and protein expression were not related to the macrophage infiltration. In conclusion, tumour islet macrophage infiltration was identified as a strong favourable independent prognostic marker for survival but not correlated with the molecular changes of the EGFR in patients with resected NSCLC

Characterization of Rhodamine-123 as a Tracer Dye for Use In In vitro Drug Transport Assays

Fluorescent tracer dyes represent an important class of sub-cellular probes and allow the examination of cellular processes in real-time with minimal impact upon these processes. Such tracer dyes are becoming increasingly used for the examination of membrane transport processes, as they are easy-to-use, cost effective probe substrates for a number of membrane protein transporters. Rhodamine 123, a member of the rhodamine family of flurone dyes, has been used to examine membrane transport by the ABCB1 gene product, MDR1. MDR1 is viewed as the archetypal drug transport protein, and is able to efflux a large number of clinically relevant drugs. In addition, ectopic activity of MDR1 has been associated with the development of multiple drug resistance phenotype, which results in a poor patient response to therapeutic intervention. It is thus important to be able to examine the potential for novel compounds to be MDR1 substrates. Given the increasing use rhodamine 123 as a tracer dye for MDR1, a full characterisation of its spectral properties in a range of in vitro assay-relevant media is warranted. Herein, we determine λmax for excitation and emission or rhodamine 123 and its metabolite rhodamine 110 in commonly used solvents and extraction buffers, demonstrating that fluorescence is highly dependent on the chemical environment: Optimal parameters are 1% (v/v) methanol in HBSS, with λex = 505 nm, λem = 525 nm. We characterise the uptake of rhodamine 123 into cells, via both passive and active processes, and demonstrate that this occurs primarily through OATP1A2-mediated facilitated transport at concentrations below 2 µM, and via micelle-mediated passive diffusion above this. Finally, we quantify the intracellular sequestration and metabolism of rhodamine 123, demonstrating that these are both cell line-dependent factors that may influence the interpretation of transport assays

The prognostic impact of anti-cancer immune response: a novel classification of cancer patients

Until now, the anatomic extent of tumor (TNM classification) has been, by far, the most important factor to predict the prognosis of colorectal cancer patients. However, in recent years, data collected from large cohorts of human cancers demonstrated that the immune contexture of the primary tumors is an essential prognostic factor for patients' disease-free and overall survival. Global analysis of tumor microenvironment showed that the nature, the functional orientation, the density, and the location of adaptive immune cells within distinct tumor regions influence the risk of relapse events. An immune classification of the patients was proposed based on the density and the immune cell location within the tumor. The immune classification has a prognostic value that is superior to the TNM classification, and tumor invasion is statistically dependent on the host immune reaction. Tumor and immunological markers predicted by systems biology methods are involved in the shaping of an efficient immune reaction and can serve as targets for novel therapeutic approaches. Thus, the strength of the immune reaction could advance our understanding of cancer evolution and have important consequences in clinical practice