The vascular endothelial growth factor (VEGF) family members that include VEGF-A, -B, -C, -D, and placental growth factor (PlGF), display distinct binding affinities for their receptors VEGFR-1, -2, and/or -3. In addition to their requirements in the initiation, development, and maintenance of blood and lymphatic vasculature, VEGFs and VEGFRs are upregulated during neoplasia and are involved in the remodeling of tumoral blood and lymphatic vasculature. By activating VEGFR-1 and VEGFR-2, both expressed on blood endothelial cells, VEGF-A promotes the formation of new tumoral blood vessels and thereby accelerates tumor growth. In contrast, upregulation of VEGF-C, a ligand for lymphatic endothelial VEGFR-3 as well as for VEGFR-2, induces the formation of tumor-associated lymphatic vessels and thus promotes the passive metastatic dissemination of tumor cells to regional lymph nodes. Of the VEGF family members, only VEGF-C and -D were found to be proteolytically processed by Furin-like enzymes. This processing controls the selective activation of VEGFR-2 and -3 signaling during tumor angiogenesis and lymphangiogenesis. Here, we provide an overview of angiogenesis processes and discuss the importance of VEGF-C and VEGF-D precursors processing by the proprotein convertases during the activation of VEGFR-2 and VEGFR-3 receptors and the mediation of their functions during angiogenesis, lymphangiogenesis, and tumorigenesis.

Proprotein convertases (PCs) are a family of proteases including PC1, PC2, Furin, PC4, PACE4, PC5, and PC7. These enzymes are involved in the maturation of many precursor proteins involved in the process of tumorigenesis and metastasis. Since their discovery, PCs were suggested as potential targets for anti-cancer therapy, and their activity was found to directly affect tumor cell proliferation, migration invasion, and the malignant phenotypes of tumor cells. Here, we discuss a number of previous and recent findings on the PCs features, their implication in the regulation of multiple cellular functions that impact on the invasive/metastatic potential of cancer cells, and their clinical relevance in cancer patients. Among the substrates of the proprotein convertases, various growth factors, their receptors, adhesion molecules, and proteases were identified. The PCs are inhibited by endogenous and exogenous inhibitors. To date, only pro7B2, a specific chaperone of PC2, and the granine-like precursor of neuroendocrine protein proSAAS, a selective ligand of PC1, have been identified as endogenous inhibitors of the PCs found in the regulated pathway. However, only PCs prosegments, several bioengineered inhibitors, peptides, and non-peptide compounds were found to inhibit the activity of the PCs found in the secretory pathway.

The Ca+2-dependent mammalian Proprotein Convertase Subtilisin Kexins (PCSKs) or Proprotein/ Prohormone Convertases (PCs) are a family of endoproteases that play critical roles not only in normal development and metabolism but also in various physiological and pathological conditions. These were initiated by the proteolytic processing of large inactive proproteins into their shorter bioactive mature forms by the PCSK enzymes. These events take place in a highly selective, orchestrated, and stepwise manner. Among the various proprotein substrates of PCSK enzymes, particularly important are the precursor growth factors that include proPDGF-A, B, proIGF-1, 2 and proVEGF-C because of their strong implications in neoplasia initiation, progression, and metastasis. As a result of these findings, PCSK enzymes, particularly furin or PCSK3, became a major target for possible interventions of cancer via the use of their selective inhibitors. Significant progress has been accomplished in the development of peptide and protein-based PCSK inhibitors. However, non-peptide PCSK9 inhibitors are more preferable because of their drug-like and other characteristics. So far, a few non-peptide inhibitors of PCSK enzymes of various types of chemical structures have been described in the literature. These include (i) Carbocyclic compounds of diterpene and streptamine class. (ii) Nitrogen (N)-based heterocyclic compounds of various types and chemical structures such as (a) pyrrolidine bis piperazines, (b) Cu/Zn chelating terpyridine derivatives; (iii) Oxygen (O)-based Heterocyclic compounds of varying types of chemical structures such as (a) Flavonoids, (b) Coumarins of simple and dimeric types, (c) Quinonoids, (d) Iridoids; (iv) Aromatic compounds such as (a) Aryl guanidino and amidino derivatives, (b) Naphthyl fluorescein derivative, and (c) Phenyl Arsonic acids; and (v) C2-symmetrical aromatic azo-compounds. When measured against a small peptidyl-MCA fluorogenic substrate, these inhibitors displayed IC50 values ranging from nM to ?M. A number of these inhibitors exhibited significant anti-PCSK activity when tested in ex vivo or cell culture conditions. This article provides an overall review of all non-peptide PCSK inhibitors so far reported in the literature along with those we identified recently for the first time and not yet published. The potential implications of these molecules as biochemical, therapeutical, or clinical agents will also be discussed.

An intelligent agent interacting with the real world will encounter individual people, courses, test results, drugs prescriptions, chairs, boxes, etc., and needs to reason about properties of these individuals and relations among them as well as cope with uncertainty. Uncertainty has been studied in probability theory and graphical models, and relations have been studied in logic, in particular in the predicate calculus and its extensions. This book examines the foundations of combining logic and probability into what are called relational probabilistic models. It introduces representations, inference, and learning techniques for probability, logic, and their combinations. The book focuses on two representations in detail: Markov logic networks, a relational extension of undirected graphical models and weighted first-order predicate calculus formula, and Problog, a probabilistic extension of logic programs that can also be viewed as a Turing-complete relational extension of Bayesian networks.

Many proprotein convertases (PC), especially furin and PACE4, are involved in pathological processes such as viral infection, inflammation, hypercholesterolemia, and cancer, and have been postulated as therapeutic targets for some of these diseases. In this chapter, we review mostly our work using animal models of squamous cancers that have been induced by chemical or UV carcinogenesis protocols to highlight the role of PCs in the development and progression of experimental tumors. After demonstrating in wild type mice the role of PACE4 in tumor progression as well as detecting the expression of PACE4 and furin in human non-melanoma skin cancers, we developed transgenic mice that over-express either PACE4 or furin in squamous epithelia, including the epidermis. This was accomplished by targeting the expression of the corresponding PC by using the promoter of the bovine keratin 5. Both K5-PACE4 and K5-Furin transgenic mice showed increased susceptibility to a two-stage carcinogenesis protocol of chemical carcinogenesis. Similar studies conducted in K5-PACE4 mice also showed an increased sensitivity to ultraviolet B radiation carcinogenesis. In most of these experiments, we were able to demonstrate that compared to the control wild type mice, the over-expression of the transgene in the epidermis increased the number of benign and malignant skin tumors and also had an effect on tumor progression as evidenced by the presence of less differentiated tumors and more frequent local and distant metastases in many of the transgenic lines. Interestingly, double transgenic mice in which PACE4 and furin are targeted to the epidermis did not show any additive effect, pointing to a probable in vivo overlap of functions at least in cutaneous tissues. The tumor-enhancing effects of PACE4 and furin further support their possible role as therapeutic targets. Furthermore, a proof of principle for PC inhibition as a therapeutic tool has been substantiated by an in vivo experiment in which the PC-inhibitor, decanoyl-RVKRchloromethylketone, was topically administrated to the skin of wild type and transgenic mice treated with chemical carcinogenesis protocols, resulting in a significant decrease of tumor development and progression.