Interleukin-34 promotes tumor progression and metastatic process in osteosarcoma through induction of angiogenesis and macrophage recruitment

International audienceInterleukin-34 (IL-34) was recently characterized as the M-CSF "twin" cytokine, regulating the proliferation/differentiation/survival of myeloid cells. The implication of M-CSF in oncology was initially suspected by the reduced metastatic dissemination in knock-out mice, due to angiogenesis impairment. Based on this observation, our work studied the involvement of IL-34 in the pathogenesis of osteosarcoma. The in vivo effects of IL-34 were assessed on tissue vasculature and macrophage infiltration in a murine preclinical model based on a paratibial inoculation of human osteosarcoma cells overexpressing or not IL-34 or M-CSF. In vitro investigations using endothelial cell precursors and mature HUVEC cells were performed to analyse the involvement of IL-34 in angiogenesis and myeloid cell adhesion. The data revealed that IL-34 overexpression was associated with the progression of osteosarcoma (tumor growth, lung metastases) and an increase of neo-angiogenesis. In vitro analyses demonstrated that IL-34 stimulated endothelial cell proliferation and vascular cord formation. Pre-treatment of endothelial cells by chondroitinases/heparinases reduced the formation of vascular tubes and abolished the associated cell signalling. In addition, IL-34 increased the in vivo recruitment of M2 tumor-associated macrophages into the tumor tissue. IL-34 increased in vitro monocyte/CD34(+) cell adhesion to activated HUVEC monolayers under physiological shear stress conditions. This work also demonstrates that IL-34 is expressed by osteosarcoma cells, is regulated by TNF-α, IL-1β, and contributes to osteosarcoma growth by increasing the neo-angiogenesis and the recruitment of M2 macrophages. By promoting new vessel formation and extravasation of immune cells, IL-34 may play a key role in tumor development and inflammatory diseases

MWAND: A New Early Termination Algorithm for Fast and Efficient Query Evaluation

Nowadays, current information systems are so large and maintain huge amount of data. At every time, they process millions of documents and millions of queries. In order to choose the most important responses from this amount of data, it is well to apply what is so called early termination algorithms. These ones attempt to extract the Top-K documents according to a specified increasing monotone function. The principal idea behind is to reach and score the most significant less number of documents. So, they avoid fully processing the whole documents. WAND algorithm is at the state of the art in this area. Despite it is efficient, it is missing effectiveness and precision. In this paper, we propose two contributions, the principal proposal is a new early termination algorithm based on WAND approach, we call it MWAND (Modified WAND). This one is faster and more precise than the first. It has the ability to avoid unnecessary WAND steps. In this work, we integrate a tree structure as an index into WAND and we add new levels in query processing. In the second contribution, we define new fine metrics to ameliorate the evaluation of the retrieved information. The experimental results on real datasets show that MWAND is more efficient than the WAND approach

Chemical Compositions And Antioxidant Activities Of Pepper (Capsicum Annuum L.) Varieties Of Omo Nada District, Jimma Zone, Ethiopia

Capsicum annuum L. (Solanaceae family) is one of the common peppers that are used as spices to flavor dishes and consumed as a vegetable. Peppers contain many bioactive compounds most of which are related to antioxidant activity. The major bioactive constituents as well as the major determinants of consumer attraction such as pleasant pungent taste and hotness can vary with agronomical practice, crop region, and drying conditions in addition to others. The current study focused on chemical compositions and antioxidant activities of the three Capsicum annuum varieties of Omo Nada district, Jimma zone, Ethiopia. The samples of three varieties of C. annuum (Gojeb, Kolesha, and Marako) were collected purposively from the Omo Nada district of Jimma Zone. GC-MS analysis of the n-hexane extracts of C. annuum fruits revealed the presence of 43, 47, and 42 compounds in the Marako, Kolesha, and Gojeb varieties, respectively. Meanwhile, the n-hexane extract of the Gojeb cultivar showed the highest 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity which would have been due to the highest percentage of capsaicin, dihydrocapsaicin, and vitamin E. Moreover, the total phenolic content (TPC), total flavonoid contents (TFC), and DPPH radical scavenging activity were investigated by UV-Vis spectroscopy using methanol and chloroform extracts which were independently obtained by maceration. The TPC of methanol extracts was 15.18 ± 0.03, 18.50 ± 0.42, and 22.98 ± 0.08 mgGAE/g for Kolesha, Marako, and Gojeb cultivars, respectively. In the same order, TPC was 12.03 ± 0.03, 13.85 ± 0.74, and 14.63 ± 0.09 mgGAE/g for chloroform extracts. The TFC was also the highest in methanol extracts; 5.5 ± 0.052, 5.73 ± 0.02, and 7.67 ± 0.07 mgQE/g for Kolesha, Marako, and Gojeb varieties, respectively. Chloroform extracts exhibit lower TFC, which varied from 3.72 ± 0.07 to, 4.73 ± 0.32 mgQE/g. Regarding the antioxidant activity, the IC50 values for the DPPH radical scavenging were 0.92 ± 0.01, 1.36 ± 0.06 mg/mL, 0.39 ± 0.004, 0.82 ± 0.01 mg/mL, and 1.40 ± 0.02, 1.52 ± 0.03 mg/mL for methanol and chloroform extracts of Marako, Gojeb, and Kolesha, respectively. The result of the current study showed three varieties of peppers could be considered as a source of antioxidant bioactive compounds

Association of IL4 rs2070874, FoxP3 rs3761548 Polymorphisms with Keratoconus in Algeria

Purpose: The aim of this case–control study was to determine the impact of environmental factors on the predisposition to develop keratoconus in a sample of Western Algerian population. Subsequently, we were interested in the implication of two single nucleotide polymorphisms (SNPs) IL4 rs2070874 and FOXP3 rs3761548, previously described as contributing to the occurrence of allergy, in the development of keratoconus. Methods: The study included 70 unrelated KC cases and 70 controls originating from Western Algeria. DNA genotyping was done using predesigned probe-based allelic discrimination TaqMan® assays. Allele and genotype frequencies were compared between the cases and controls by Chi-square test and odds ratios with 95% confidence intervals. Results: A significant association between risk factors such as family history, atopy, eye rubbing, and the development of keratoconus was found in our sample. Smoking would provide a protective effect against the pathology. No statistically significant differences were found in the allele and genotype frequencies between cases and controls neither for IL4 rs2070874 nor for FOXP3 rs3761548. Conclusion: Our study provides, for the first time, a clear demonstration of the absence of association of the allergy-associated IL4 and FOXP3 polymorphisms with KC in a sample from Western Algerian population

Polymorphism rs3087243 is associated with the occurrence of ankylosing spondylitis in the West Algerian population

Background: Numerous studies have shown that polymorphism rs231775 of the CTLA4 gene is strongly implicated in the development of ankylosing spondylitis (AS). Other polymorphisms of this gene are candidates that may have an additional effect in susceptibility to AS. For the first time, we searched for the association of rs3087243 polymorphism located in the 3'UTR region of the CTLA4 gene with the development of SA in the Algerian population. Methods: The study involved 200 subjects (80 AS patients recruited at the rheumatology service and 120 healthy individuals unrelated). Genotyping was performed by real-time PCR (Taqman®). Analysis of the results was carried out by IBM.SPSS.Statictis® software. Results: The distribution of allele frequencies showed a significant association between the GG genotype of the polymorphism rs3087243 and AS risk (OR= 1.77 [0.98-3.21], p=0.004). Conclusion: Our data would suggest that the 3'UTR region of the CTLA4 gene could have an impact on the development of SA in the West Algerian population. These results need to be confirmed on a larger sample

Lack of association between genetic variants in the 19q13.32 region and CHD risk in the Algerian population: a population-based nested case-control study

Background: Coronary Heart Disease (CHD) is a major cause of morbidity and mortality over the world; intermediate traits associated with CHD commonly studied can be influenced by a combination of genetic and environmental factors. Objective: We found previously significant association between three genetic polymorphisms, and the lipid profile variations in the Algerian population. Considering these findings, we therefore decided to assess the relationships between these polymorphisms and CHD risk, Methods: We performed a population-based, cross-sectional study, of 787 individuals recruited in the city of Oran, in which, a nested case-control study for MetS, T2D, HBP, obesity and CHD were performed. Subjects were genotyped for four SNP rs7412, rs429358 rs4420638 and rs439401 located in the 19q13.32 region. Results: The T allele of rs439401 confers a high risk of hypertension with an odds ratio (OR) of 1.46 (95% CI [1.12-1.9], p = 0.006) and the G allele of rs4420638 was significantly associated with a decreased risk of obesity, OR 0.48 (95% CI [0.29-0.81], p = 0.004). No associations were found for MetS, T2D and CHD. Conclusion: Although the studied genetic variants were not associated with the risk of CHD, the 19q13.32 locus was associated with some of the cardiometabolic disorders in Algerian subjects

Circulating Endothelial Progenitor Cells in Kidney Transplant Patients

Background: Kidney transplantation (RTx) leads to amelioration of endothelial function in patients with advanced renal failure. Endothelial progenitor cells (EPCs) may play a key role in this repair process. The aim of this study was to determine the impact of RTx and immunosuppressive therapy on the number of circulating EPCs. Methods: We analyzed 52 RTx patients (58613 years; 33 males, mean 6 SD) and 16 age- and gender-matched subjects with normal kidney function (57617; 10 males). RTx patients received a calcineurin inhibitor (CNI)-based (65%) or a CNI-free therapy (35%) and steroids. EPC number was determined by double positive staining for CD133/VEGFR2 and CD34/VEGFR2 by flow cytometry. Stromal cell-derived factor 1 alpha (SDF-1) levels were assessed by ELISA. Experimentally, to dissociate the impact of RTx from the impact of immunosuppressants, we used the 5/6 nephrectomy model. The animals were treated with a CNI-based or a CNI-free therapy, and EPCs (Sca+cKit+) and CD26+ cells were determined by flow cytometry. Results: Compared to controls, circulating number of CD34+/VEGFR2+ and CD133+/VEGFR2+ EPCs increased in RTx patients. There were no correlations between EPC levels and statin, erythropoietin or use of renin angiotensin system blockers in our study. Indeed, multivariate analysis showed that SDF-1 – a cytokine responsible for EPC mobilization – is independently associated with the EPC number. 5/6 rats presented decreased EPC counts in comparison to control animals. Immunosuppressive therapy was able to restore normal EPC values in 5/6 rats. These effects on EPC number were associated with reduced number of CD26+ cells, which might be related to consequent accumulation of SDF-1. Conclusions: We conclude that kidney transplantation and its associated use of immunosuppressive drugs increases the number of circulating EPCs via the manipulation of the CD26/SDF-1 axis. Increased EPC count may be associated to endothelial repair and function in these patients.

Agent-Based Model of Therapeutic Adipose-Derived Stromal Cell Trafficking during Ischemia Predicts Ability To Roll on P-Selectin

Intravenous delivery of human adipose-derived stromal cells (hASCs) is a promising option for the treatment of ischemia. After delivery, hASCs that reside and persist in the injured extravascular space have been shown to aid recovery of tissue perfusion and function, although low rates of incorporation currently limit the safety and efficacy of these therapies. We submit that a better understanding of the trafficking of therapeutic hASCs through the microcirculation is needed to address this and that selective control over their homing (organ- and injury-specific) may be possible by targeting bottlenecks in the homing process. This process, however, is incredibly complex, which merited the use of computational techniques to speed the rate of discovery. We developed a multicell agent-based model (ABM) of hASC trafficking during acute skeletal muscle ischemia, based on over 150 literature-based rules instituted in Netlogo and MatLab software programs. In silico, trafficking phenomena within cell populations emerged as a result of the dynamic interactions between adhesion molecule expression, chemokine secretion, integrin affinity states, hemodynamics and microvascular network architectures. As verification, the model reasonably reproduced key aspects of ischemia and trafficking behavior including increases in wall shear stress, upregulation of key cellular adhesion molecules expressed on injured endothelium, increased secretion of inflammatory chemokines and cytokines, quantified levels of monocyte extravasation in selectin knockouts, and circulating monocyte rolling distances. Successful ABM verification prompted us to conduct a series of systematic knockouts in silico aimed at identifying the most critical parameters mediating hASC trafficking. Simulations predicted the necessity of an unknown selectin-binding molecule to achieve hASC extravasation, in addition to any rolling behavior mediated by hASC surface expression of CD15s, CD34, CD62e, CD62p, or CD65. In vitro experiments confirmed this prediction; a subpopulation of hASCs slowly rolled on immobilized P-selectin at speeds as low as 2 µm/s. Thus, our work led to a fundamentally new understanding of hASC biology, which may have important therapeutic implications