Stromal integrin α11 regulates PDGFR-β signaling and promotes breast cancer progression

Cancer-associated fibroblasts (CAFs) are key actors in modulating the progression of many solid tumors, such as breast cancer (BC). Herein, we identify an integrin α11/PDGFRβ–positive CAF subset displaying tumor-promoting features in BC. In the preclinical MMTV-PyMT mouse model, integrin α11 deficiency led to a drastic reduction of tumor progression and metastasis. A clear association between integrin α11 and PDGFRβ was found at both transcriptional and histological levels in BC specimens. High stromal integrin α11/PDGFRβ expression was associated with high grades and poorer clinical outcome in human BC patients. Functional assays using 5 CAF subpopulations (1 murine, 4 human) revealed that integrin α11 promotes CAF invasion and CAF-induced tumor cell invasion upon PDGF-BB stimulation. Mechanistically, the proinvasive activity of integrin α11 relies on its ability to interact with PDGFRβ in a ligand-dependent manner and to promote its downstream JNK activation, leading to the production of tenascin C, a proinvasive matricellular protein. Pharmacological inhibition of PDGFRβ and JNK impaired tumor cell invasion induced by integrin α11+ CAFs. Collectively, our study uncovers an integrin α11+ subset of protumoral CAFs that exploits the PDGFRβ/JNK signaling axis to promote tumor invasiveness in BC.publishedVersio

Adipocyte extracellular matrix composition, dynamics and role in obesity

The central role of the adipose tissue in lipid metabolism places specific demands on the cell structure of adipocytes. The protein composition and dynamics of the extracellular matrix (ECM) is of crucial importance for the functioning of those cells. Adipogenesis is a bi-phasic process in which the ECM develops from a fibrillar to a laminar structure as cells move from the commitment phase to the growth phase characterized by storage of vast amounts of triglycerides. Mature adipocytes appear to spend a lot of energy on the maintenance of the ECM. ECM remodeling is mediated by a balanced complement of constructive and destructive enzymes together with their enhancers and inhibitors. ECM remodeling is an energy costing process regulated by insulin, by the energy metabolism, and by mechanical forces. In the obese, overgrowth of adipocytes may lead to instability of the ECM, possibly mediated by hypoxia

3-Bromophenyl 6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylate inhibits cancer cell invasion in vitro and tumour growth in vivo

In search for new anticancer agents, we have evaluated the antiinvasive and antimigrative properties of recently developed synthetic coumarin derivatives among which two compounds revealed important activity: 3-chlorophenyl 6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylate and 3-bromophenyl 6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylate, Both drugs were able to inhibit cell invasion markedly in a Boyden chamber assay, the bromo derivative being more potent than the reference matrix metalloprotease (MMP) inhibitor GI 129471. In vivo, tumour growth was reduced when nude mice grafted with HT 1080 or MDA-MB231 cells were treated i.p. 3 days week(-1) with the bromo coumarin derivative. These effects were not associated with the inhibition of urokinase, plasmin, MMP-2 or MMP-9. The mechanism of action of the drugs remains to be elucidated. However, these two coumarin derivatives may serve as new lead compounds of an original class of antitumour agents

Absence of an adipogenic effect of rosiglitazone on mature 3T3-L1 adipocytes: increase of lipid catabolism and reduction of adipokine expression

Aims/hypothesis: The thiazolidinedione (TZD) rosiglitazone is a peroxisome proliferator-activated receptor-¿ agonist that induces adipocyte differentiation and, hence, lipid accumulation. This is in apparent contrast to the long-term glucose-lowering, insulin-sensitising effect of rosiglitazone. We tested whether the action of rosiglitazone involves specific effects on mature adipocytes, which are different from those on preadipocytes. Materials and methods: Differentiated mature 3T3-L1 adipocytes were used as an in vitro model. Transcriptomics, proteomics and assays of metabolism were applied to assess the effect of rosiglitazone in different insulin and glucose conditions. Results: Rosiglitazone does not induce an increase, but rather a decrease in the lipid content of mature adipocytes. Analysis of transcriptome data, confirmed by quantitative RT-PCR and measurements of lipolysis, indicates that an altered energy metabolism may underlie this change. The pathway analysis shows a consistent picture dominated by lipid catabolism. In addition, we confirmed at both mRNA level and protein level that rosiglitazone represses adipokine expression and production, except for genes encoding adiponectin and apolipoprotein E. Moreover, transcriptome changes indicate that a general repression of genes encoding secreted proteins occurs. Conclusions/ interpretation: Our findings suggest that the change of adiposity as seen in vivo reflects a shift in balance between the different effects of TZDs on preadipocytes and on mature adipocytes, while the changes in circulating adipokine levels primarily result from an effect on mature adipocyte

Влияние фосфатных связующих на физико-механические свойства периклазохромитовых огнеупоров

У данній статті наведено та порівняно фізико-механічні властивості периклазо-хромітових матеріалів в залежності від різних типів фосфатних зв’язуючих та введення різних домішок. Визначено, що найбільш раціональним є введення триполіфосфату натрію.In given clause are resulted and the physycal-mechanical properties periclase-cgromite of materials are compared depending on different of types phosphate binding and introduction of the various additives. Is determined, that most rational is the introduction treepolyphosphate sodume

Role of Matrix Metalloproteinases and Therapeutic Benefits of Their Inhibition in Spinal Cord Injury

This review will focus on matrix metalloproteinases (MMPs) and their inhibitors in the context of spinal cord injury (SCI). MMPs have a specific cellular and temporal pattern of expression in the injured spinal cord. Here we consider their diverse functions in the acutely injured cord and during wound healing. Excessive activity of MMPs, and in particular gelatinase B (MMP-9), in the acutely injured cord contributes to disruption of the blood-spinal cord barrier, and the influx of leukocytes into the injured cord, as well as apoptosis. MMP-9 and MMP-2 regulate inflammation and neuropathic pain after peripheral nerve injury and may contribute to SCI-induced pain. Early pharmacologic inhibition of MMPs or the gelatinases (MMP-2 and MMP-9) results in an improvement in long-term neurological recovery and is associated with reduced glial scarring and neuropathic pain. During wound healing, gelatinase A (MMP-2) plays a critical role in limiting the formation of an inhibitory glial scar, and mice that are genetically deficient in this protease showed impaired recovery. Together, these findings illustrate complex, temporally distinct roles of MMPs in SCIs. As early gelatinase activity is detrimental, there is an emerging interest in developing gelatinase-targeted therapeutics that would be specifically tailored to the acute injured spinal cord. Thus, we focus this review on the development of selective gelatinase inhibitors

Effect of initial imperfections in numerical simulations of collapse behaviour of stiffened plates under compression

peer reviewedThe slenderness of plated structures together with a generalised use of high strength steel leads to a great importance of stability phenomena. The practical way to deal with such problems is to use rules proposed in design codes. A common alternative to design codes is the use of non linear finite element simulations. One of the most sensitive point in these simulations is the choice of the initial imperfections to be introduced in the model. The present paper discusses the effect of initial imperfections on the calculated collapse load. Several parameters are considered (shape, magnitude and direction). Results of numerical simulations are also compared with those of a design using Eurocode 3 or ECCS Recommendations. Two cases of plate geometry are studied (plate with one single stiffener and plate with multiple stiffeners)

Transversus abdominis plane block or intravenous lignocaine in open prostate surgery: a randomized controlled trial.

BACKGROUND AND OBJECTIVES: Transversus abdominis plane block (TAP) and intravenous lignocaine are two analgesic techniques frequently used after abdominal surgery. We hypothesized that these two techniques improve post-operative analgesia after open prostate surgery and sought to compare their efficacy on immediate post-operative outcome after open prostate surgery. METHODS: After ethics committee approval, 101 patients were enrolled in this prospective study and randomly allocated to receive bilateral ultrasound-guided TAP (n = 34), intravenous lignocaine (n = 33) or placebo (n = 34). In addition, intravenous paracetamol was given every 6 h. The primary endpoint was the cumulative opioid consumption during the first 48 post-operative hours (median[IQR]). Secondary endpoints included pain scores at rest and upon coughing, need for rescue tramadol, incidence of post-operative nausea and vomiting (PONV), recovery of bowel function and incidence of bladder catheter-related discomfort. RESULTS: Cumulative piritramide consumption after 48 h was 28 [23] mg in the control group, 21 [29] mg in the TAP group and 21 [31] mg in the lignocaine group (P = 0.065). There was no significant difference in post-operative pain scores between groups. The proportions of patients requiring rescue tramadol, experiencing PONV or bladder catheter-related discomfort were similar in each group. Recovery of bowel function was also similar in the three groups. CONCLUSIONS: Our study suggests that TAP block and intravenous lignocaine do not improve the post-operative analgesia provided by systematic administration of paracetamol after open prostatectomy