A study on supereulerian digraphs and spanning trails in digraphs

A strong digraph D is eulerian if for any v ∈ V (D), d+D (v) = d−D (v). A digraph D is supereulerian if D contains a spanning eulerian subdigraph, or equivalently, a spanning closed directed trail. A digraph D is trailable if D has a spanning directed trail. This dissertation focuses on a study of trailable digraphs and supereulerian digraphs from the following aspects. 1. Strong Trail-Connected, Supereulerian and Trailable Digraphs. For a digraph D, D is trailable digraph if D has a spanning trail. A digraph D is strongly trail- connected if for any two vertices u and v of D, D posses both a spanning (u, v)-trail and a spanning (v,u)-trail. As the case when u = v is possible, every strongly trail-connected digraph is also su- pereulerian. Let D be a digraph. Let S(D) = {e ∈ A(D) : e is symmetric in D}. A digraph D is symmetric if A(D) = S(D). The symmetric core of D, denoted by J(D), has vertex set V (D) and arc set S(D). We have found a well-characterized digraph family D each of whose members does not have a spanning trail with its underlying graph spanned by a K2,n−2 such that for any strong digraph D with its matching number α′(D) and arc-strong-connectivity λ(D), if n = |V (D)| ≥ 3 and λ(D) ≥ α′(D) − 1, then each of the following holds. (i) There exists a family D of well-characterized digraphs such that for any digraph D with α′(D) ≤ 2, D has a spanning trial if and only if D is not a member in D. (ii) If α′(D) ≥ 3, then D has a spanning trail. (iii) If α′(D) ≥ 3 and n ≥ 2α′(D) + 3, then D is supereulerian. (iv) If λ(D) ≥ α′(D) ≥ 4 and n ≥ 2α′(D) + 3, then for any pair of vertices u and v of D, D contains a spanning (u, v)-trail. 2. Supereulerian Digraph Strong Products. A cycle vertex cover of a digraph D is a collection of directed cycles in D such that every vertex in D lies in at least one dicycle in this collection, and such that the union of the arc sets of these directed cycles induce a connected subdigraph of D. A subdigraph F of a digraph D is a circulation if for every vertex v in F, the indegree of v equals its outdegree, and a spanning circulation if F is a cycle factor. Define f(D) to be the smallest cardinality of a cycle vertex cover of the digraph D/F obtained from D by contracting all arcs in F , among all circulations F of D. In [International Journal of Engineering Science Invention, 8 (2019) 12-19], it is proved that if D1 and D2 are nontrivial strong digraphs such that D1 is supereulerian and D2 has a cycle vertex cover C′ with |C′| ≤ |V (D1)|, then the Cartesian product D1 and D2 is also supereulerian. We prove that for strong digraphs D1 and D2, if for some cycle factor F1 of D1, the digraph formed from D1 by contracting arcs in F1 is hamiltonian with f(D2) not bigger than |V (D1)|, then the strong product D1 and D2 is supereulerian

Interferon Lambda: A New Sword in Cancer Immunotherapy

The discovery of the interferon-lambda (IFN-λ) family has considerably contributed to our understanding of the role of interferon not only in viral infections but also in cancer. IFN-λ proteins belong to the new type III IFN group. Type III IFN is structurally similar to type II IFN (IFN-γ) but functionally identical to type I IFN (IFN-α/β). However, in contrast to type I or type II IFNs, the response to type III IFN is highly cell-type specific. Only epithelial-like cells and to a lesser extent some immune cells respond to IFN-λ. This particular pattern of response is controlled by the differential expression of the IFN-λ receptor, which, in contrast to IFN-α, should result in limited side effects in patients. Recently, we and other groups have shown in several animal models a potent antitumor role of IFN-λ that will open a new challenging era for the current IFN therapy

Double codage des niveaux de gris : Application au corrélogramme

Dans cet article, nous présentons le corrélogramme qui représente un outil de caractérisation de texture et qui prend en compte les propriétés spatiales des niveaux de gris. On lui a appliqué notre nouvelle approche de codage détaillée dans le paragraphe 2. Ces caractéristiques de texture sont extraites en utilisant les matrices du corrélogramme du fait de leur richesse en information de texture. On applique, tout d'abord, un premier codage qui réduira le nombre de niveaux de gris en passant de 256 niveaux à 9 niveaux de gris; Il est utilisé pour coder les textures originelles. Puis ensuite, on effectuera un deuxième codage qui fait augmenter les niveaux de gris à 16, mais en parallèle, fais améliorer la qualité de l'image et c'est à ce niveau que l'on va extraire les attributs de texture. Enfin, la classification par SVM sera réalisée à la fois sur le corrélogramme avec quantification et avec codage, afin de montrer l'efficacité de ce dernier par rapport à la méthode universelle de la quantification

The transcription factor RUNX2 regulates receptor tyrosine kinase expression in melanoma.

Receptor tyrosine kinases-based autocrine loops largely contribute to activate the MAPK and PI3K/AKT pathways in melanoma. However, the molecular mechanisms involved in generating these autocrine loops are still largely unknown. In the present study, we examine the role of the transcription factor RUNX2 in the regulation of receptor tyrosine kinase (RTK) expression in melanoma. We have demonstrated that RUNX2-deficient melanoma cells display a significant decrease in three receptor tyrosine kinases, EGFR, IGF-1R and PDGFRβ. In addition, we found co-expression of RUNX2 and another RTK, AXL, in both melanoma cells and melanoma patient samples. We observed a decrease in phosphoAKT2 (S474) and phosphoAKT (T308) levels when RUNX2 knock down resulted in significant RTK down regulation. Finally, we showed a dramatic up regulation of RUNX2 expression with concomitant up-regulation of EGFR, IGF-1R and AXL in melanoma cells resistant to the BRAF V600E inhibitor PLX4720. Taken together, our results strongly suggest that RUNX2 might be a key player in RTK-based autocrine loops and a mediator of resistance to BRAF V600E inhibitors involving RTK up regulation in melanoma

Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead.

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology

IFN-Lambda (IFN-λ) Is Expressed in a Tissue-Dependent Fashion and Primarily Acts on Epithelial Cells In Vivo

Interferons (IFN) exert antiviral, immunomodulatory and cytostatic activities. IFN-α/β (type I IFN) and IFN-λ (type III IFN) bind distinct receptors, but regulate similar sets of genes and exhibit strikingly similar biological activities. We analyzed to what extent the IFN-α/β and IFN-λ systems overlap in vivo in terms of expression and response. We observed a certain degree of tissue specificity in the production of IFN-λ. In the brain, IFN-α/β was readily produced after infection with various RNA viruses, whereas expression of IFN-λ was low in this organ. In the liver, virus infection induced the expression of both IFN-α/β and IFN-λ genes. Plasmid electrotransfer-mediated in vivo expression of individual IFN genes allowed the tissue and cell specificities of the responses to systemic IFN-α/β and IFN-λ to be compared. The response to IFN-λ correlated with expression of the α subunit of the IFN-λ receptor (IL-28Rα). The IFN-λ response was prominent in the stomach, intestine and lungs, but very low in the central nervous system and spleen. At the cellular level, the response to IFN-λ in kidney and brain was restricted to epithelial cells. In contrast, the response to IFN-α/β was observed in various cell types in these organs, and was most prominent in endothelial cells. Thus, the IFN-λ system probably evolved to specifically protect epithelia. IFN-λ might contribute to the prevention of viral invasion through skin and mucosal surfaces

Targeting the hedgehog transcription factors GLI1 and GLI2 restores sensitivity to vemurafenib-resistant human melanoma cells

BRAF inhibitor (BRAFi) therapy for melanoma patients harboring the V600E mutation is initially highly effective, but almost all patients relapse within a few months. Understanding the molecular mechanisms underpinning BRAFi-based therapy is therefore an important issue. Here we identified a previously unsuspected mechanism of BRAFi resistance driven by elevated Hedgehog (Hh) pathway activation that is observed in a cohort of melanoma patients after vemurafenib treatment. Specifically, we demonstrate that melanoma cell lines, with acquired in vitro-induced vemurafenib resistance, show increased levels of glioma-associated oncogene homolog 1 and 2 (GLI1/GLI2) compared with naive cells. We also observed these findings in clinical melanoma specimens. Moreover, the increased expression of the transcription factors GLI1/GLI2 was independent of canonical Hh signaling and was instead correlated with the noncanonical Hh pathway, involving TGF beta/SMAD (transforming growth factor-beta/Sma- and Mad-related family) signaling. Knockdown of GLI1 and GLI2 restored sensitivity to vemurafenib-resistant cells, an effect associated with both growth arrest and senescence. Treatment of vemurafenib-resistant cells with the GLI1/GLI2 inhibitor Gant61 led to decreased invasion of the melanoma cells in a three-dimensional skin reconstruct model and was associated with a decrease in metalloproteinase (MMP2/MMP9) expression and microphthalmia transcription factor upregulation. Gant61 monotherapy did not alter the drug sensitivity of naive cells, but could reverse the resistance of melanoma cells chronically treated with vemurafenib. We further noted that alternating dosing schedules of Gant61 and vemurafenib prevented the onset of BRAFi resistance, suggesting that this could be a potential therapeutic strategy for the prevention of therapeutic escape. Our results suggest that targeting the Hh pathway in BRAFi-resistant melanoma may represent a viable therapeutic strategy to restore vemurafenib sensitivity, reducing or even inhibiting the acquired chemoresistance in melanoma patients.Fapesp-grant number 2012/04194-1, 2013/05172-4, 2014/24400-0 and 2015/10821-7, CNPq-grant number 150447/2013-2 and 471512/2013-3 and PRODOC-grant no 3193-32/2010. Work in the lab of KS Smalley was supported by the National Institutes of Health grants R01 CA161107, R21 CA198550, and Skin SPORE grant P50 CA168536info:eu-repo/semantics/publishedVersio