CD27 signaling on chronic myelogenous leukemia stem cells activates Wnt target genes and promotes disease progression

Chronic myelogenous leukemia (CML) results from a chromosomal translocation in hematopoietic stem or early progenitor cells that gives rise to the oncogenic BCR/ABL fusion protein. Clinically, CML has a chronic phase that eventually evolves into an accelerated stage and blast crisis. A CML-specific immune response is thought to contribute to the control of disease. Whether the immune system can also promote disease progression is not known. In the present study, we investigated the possibility that the TNF receptor family member CD27 is present on leukemia stem cells (LSCs) and mediates effects of the immune system on CML. In a mouse model of CML, BCR/ABL+ LSCs and leukemia progenitor cells were found to express CD27. Binding of CD27 by its ligand, CD70, increased expression of Wnt target genes in LSCs by enhancing nuclear localization of active β-catenin and TRAF2- and NCK-interacting kinase (TNIK). This resulted in increased proliferation and differentiation of LSCs. Blocking CD27 signaling in LSCs delayed disease progression and prolonged survival. Furthermore, CD27 was expressed on CML stem/progenitor cells in the bone marrow of CML patients, and CD27 signaling promoted growth of BCR/ABL+ human leukemia cells by activating the Wnt pathway. Since expression of CD70 is limited to activated lymphocytes and dendritic cells, our results reveal a mechanism by which adaptive immunity contributes to leukemia progression. In addition, targeting CD27 on LSCs may represent an attractive therapeutic approach to blocking the Wnt/β-catenin pathway in CML.

Interactions between short-term and long-term plasticity: shooting for a moving target

Far from being static transmission units, synapses are highly dynamical elements that change over multiple time scales depending on the history of the neural activity of both the pre- and postsynaptic neuron. Moreover, synaptic changes on different time scales interact: long-term plasticity (LTP) can modify the properties of short-term plasticity (STP) in the same synapse. Most existing theories of synaptic plasticity focus on only one of these time scales (either STP or LTP or late-LTP) and the theoretical principles underlying their interactions are thus largely unknown. Here we develop a normative model of synaptic plasticity that combines both STP and LTP and predicts specific patterns for their interactions. Recently, it has been proposed that STP arranges for the local postsynaptic membrane potential at a synapse to behave as an optimal estimator of the presynaptic membrane potential based on the incoming spikes. Here we generalize this approach by considering an optimal estimator of a non-linear function of the membrane potential and the long-term synaptic efficacy—which itself may be subject to change on a slower time scale. We find that an increase in the long-term synaptic efficacy necessitates changes in the dynamics of STP. More precisely, for a realistic non-linear function to be estimated, our model predicts that after the induction of LTP, causing long-term synaptic efficacy to increase, a depressing synapse should become even more depressing. That is, in a protocol using trains of presynaptic stimuli, as the initial EPSP becomes stronger due to LTP, subsequent EPSPs should become weakened and this weakening should be more pronounced with LTP. This form of redistribution of synaptic efficacies agrees well with electrophysiological data on synapses connecting layer 5 pyramidal neurons.

Risk of target lesion failure in relationship to vessel angiographic geometry and stent conformability using the second generation of drug-eluting stents

Vessel angulation and large changes in vessel geometry after stent implantation have been associated with an increased risk of target lesion failure (TLF) using bare-metal stents. Second-generation drug-eluting stents (DES)offer superior conformability and inhibition of neointima. The aim of the study is to investigate the relationship between pre and post-implant vessel geometry and the occurrence of TLF at 1 year after treatment with second-generation DES; and to compare the conformability of Resolute and Xience stents.

The phosphoinositide 3-kinase signaling pathway as a therapeutic target in grade IV brain tumors

Brain tumors comprise a wide variety of neoplasia classified according to their cellular origin and their morphological and histological characteristics. The transformed phenotype of brain tumor cells has been extensively studied in the past years, achieving a significant progress in our understanding of the molecular pathways leading to tumorigenesis. It has been reported that the phosphoinositide 3-kinase (PI3K)/AKT signaling pathway is frequently altered in grade IV brain tumors resulting in uncontrolled cell growth, survival, proliferation, angiogenesis, and migration. This aberrant activation can be explained by oncogenic mutations in key components of the pathway or through abnormalities in its regulation. These alterations include overexpression and mutations of receptor tyrosine kinases (RTKs), mutations and deletions of the phosphatase and tensin homologue deleted on chromosome 10 (PTEN) tumor suppressor gene, encoding a lipid kinase that directly antagonized PI3K activity, and alterations in Ras signaling. Due to promising results of preclinical studies investigating the PI3K/AKT pathway in grade IV brain tumors like glioblastoma and medulloblastoma, the components of this pathway have emerged as promising therapeutic targets to treat these malignant brain tumors. Although an arsenal of small molecule inhibitors that target specific components of this signaling pathway is being developed, its successful application in the clinics remains a challenge. In this article we will review the molecular basis of the PI3K/AKT signaling pathway in malignant brain tumors, mainly focusing on glioblastoma and medulloblastoma, and we will further discuss the current status and potential of molecular targeted therapies.

Bone morphogenetic protein-7 is a MYC target with prosurvival functions in childhood medulloblastoma

Medulloblastoma (MB) is the most common malignant brain tumor in children. It is known that overexpression and/or amplification of the MYC oncogene is associated with poor clinical outcome, but the molecular mechanisms and the MYC downstream effectors in MB remain still elusive. Besides contributing to elucidate how progression of MB takes place, most importantly, the identification of novel MYC-target genes will suggest novel candidates for targeted therapy in MB. A group of 209 MYC-responsive genes was obtained from a complementary DNA microarray analysis of a MB-derived cell line, following MYC overexpression and silencing. Among the MYC-responsive genes, we identified the members of the bone morphogenetic protein (BMP) signaling pathway, which have a crucial role during the development of the cerebellum. In particular, the gene BMP7 was identified as a direct target of MYC. A positive correlation between MYC and BMP7 expression was documented by analyzing two distinct sets of primary MB samples. Functional studies in vitro using a small-molecule inhibitor of the BMP/SMAD signaling pathway reproduced the effect of the small interfering RNA-mediated silencing of BMP7. Both approaches led to a block of proliferation in a panel of MB cells and to inhibition of SMAD phosphorylation. Altogether, our findings indicate that high MYC levels drive BMP7 overexpression, promoting cell survival in MB cells. This observation suggests the potential relevance of targeting the BMP/SMAD pathway as a novel therapeutic approach for the treatment of childhood MB.

Approaching water stress in the Alps: Transdisciplinary co-production of systems, target and transformation knowledge

There is increasing recognition that transdisciplinary approaches are needed to create suitable knowledge for sustainable water management. However, there is no common understanding of what transdisciplinary research may be and there is very limited debate on potentials and challenges regarding its implementation. Against this background, this paper presents a conceptual framework for transdisciplinary co-production of knowledge in water management projects oriented towards more sustainable use of water. Moreover, first experiences with its implementation are discussed. In so doing, the focus lies on potentials and challenges related to the co-production of systems, target and transformation knowledge by researchers and local stakeholders.

Mitochondrial translation in trypanosomatids: a novel target for chemotherapy?

Trypanosomatids cause widespread disease in humans and animals. Treatment of many of these diseases is hampered by the lack of efficient and safe drugs. New strategies for drug development are therefore urgently needed. It has long been known that the single mitochondrion of trypanosomatids exhibits many unique features. Recently, the mitochondrial translation machinery of trypanosomatids has been the focus of several studies, which revealed interesting variations to the mammalian system. It is the aim of this article to review these unique features and to discuss them in the larger biological context. It is our opinion that some of these features represent promising novel targets for chemotherapeutic intervention that should be studied in more detail.

Seed fate and seedling dynamics after masting in two African rain forest trees

How the effects of biotic factors are moderated by abiotic factors, and their consequences for species interactions, is generally understudied in ecology. A key abiotic feature of forests is regular canopy disturbances that create temporary patches, or “gaps,” of above-average light availability. Co-occurring in lowland primary forest of Korup National Park (Cameroon), Microberlinia bisulcata and Tetraberlinia bifoliolata are locally dominant, ectomycorrhizal trees whose seeds share predator guilds in masting years. Here, we experimentally tested the impact of small mammal predators upon seedling abundance, growth, and survivorship. In 2007, we added a fixed density of seeds of each species to exclosures at 48 gap–understory locations across 82.5 ha within a large Microberlinia grove, and at 15 locations outside it. For both species, small mammals removed more seeds in gaps than in understory, whereas this was reversed for seeds killed by invertebrates. Nonetheless, Microberlinia lost twice as many seeds to small mammals, and more to invertebrates in exclosures, than Tetraberlinia, which was more prone to a pathogenic white fungus. After six weeks, both species had greater seedling establishment in gaps than understory, and in exclosures outside compared to exclosures inside the grove. In the subsequent two-year period, seedling growth and survivorship peaked in exclosures in gaps, but Microberlinia had more seedlings' stems clipped by animals than Tetraberlinia, and more than twice the percentage of leaf area damaged. Whereas Microberlinia seedling performance in gaps was inferior to Tetraberlinia inside the grove, outside it Microberlinia had reduced leaf damage, grew taller, and had many more leaves than Tetraberlinia. No evidence was found for “apparent mutualism” in the understory as seedling establishment of both species increased away from (>25 m) large stems of either species, pointing to “apparent competition” instead. In gaps, Microberlinia seedling establishment was lower near Tetraberlinia than conspecific adults because of context-dependent small mammal satiation. Stage-matrix analysis suggested that protecting Microberlinia from small mammals could increase its population growth rate by 0.06. In the light of prior research we conclude that small mammals and canopy gaps play an important role in promoting species coexistence in this forest, and that their strong interaction contributes to Microberlinia's currently very poor regeneration.

Endocrine disrupting compounds: can they target the immune system of fish?

Endocrine disruption, in particular disruption by estrogen-active compounds, has been identified as an important ecotoxicological hazard in the aquatic environment. Research on the impact of endocrine disrupting compounds (EDCs) on wildlife has focused on disturbances of the reproductive system. However, there is increasing evidence that EDCs affect a variety of physiological systems other than the reproductive system. Here, we discuss if EDCs may be able to affect the immune system of fish, as this would have direct implications for individual fitness and population growth. Evidence suggesting an immunomodulatory role of estrogens in fish comes from the following findings: (a) estrogen receptors are expressed in piscine immune organs, (b) immune gene expression is modulated by estrogen exposure, and (c) pathogen susceptibility of fish increases under estrogen exposure.

Identification of a host cell target for the thiazolide class of broad-spectrum anti-parasitic drugs

The thiazolide nitazoxanide (NTZ) and some derivatives exhibit considerable in vitro activities against a broad range of parasites, including the apicomplexans Neospora caninum and Toxoplasma gondii tachyzoites. In order to identify potential molecular targets for this compound in both parasites, RM4847 was coupled to epoxy-agarose and affinity chromatography was performed. A protein of approximately 35 kDa was eluted upon RM4847-affinity-chromatography from extracts of N. caninum-infected human foreskin fibroblasts (HFF) and non-infected HFF, but no protein was eluted when affinity chromatography was performed with T. gondii or N. caninum tachyzoite extracts. Mass spectrometry analysis identified the 35 kDa protein as human quinone reductase NQO1 (P15559; QR). Within 8h after infection of HFF with N. caninum tachyzoites, QR transcript expression levels were notably increased, but no such increase was observed upon infection with T. gondii tachyzoites. Treatment of non-infected HFF with RM4847 did also lead to an increase of QR transcript levels. The enzymatic activity of 6-histidine-tagged recombinant QR (recQR) was assayed using menadione as a substrate. The thiazolides NTZ, tizoxanide and RM4847 inhibited recQR activity on menadione in a concentration-dependent manner. Moreover, a small residual reducing activity was observed when these thiazolides were offered as substrates.

Drug target identification in intracellular and extracellular protozoan parasites

The increasing demand for novel anti-parasitic drugs due to resistance formation to well-established chemotherapeutically important compounds has increased the demands for a better understanding of the mechanism(s) of action of existing drugs and of drugs in development. While different approaches have been developed to identify the targets and thus mode of action of anti-parasitic compounds, it has become clear that many drugs act not only on one, but possibly several parasite molecules or even pathways. Ideally, these targets are not present in any cells of the host. In the case of apicomplexan parasites, the unique apicoplast, provides a suitable target for compounds binding to DNA or ribosomal RNA of prokaryotic origin. In the case of intracellular pathogens, a given drug might not only affect the pathogen by directly acting on parasite-associated targets, but also indirectly, by altering the host cell physiology. This in turn could affect the parasite development and lead to parasite death. In this review, we provide an overview of strategies for target identification, and present examples of selected drug targets, ranging from proteins to nucleic acids to intermediary metabolism.

Icatibant , the bradykinin B2 receptor antagonist with target to the interconnected kinin systems

INTRODUCTION: HOE-140/ Icatibant is a selective, competitive antagonist to bradykinin (BK) against its binding to the kinin B2 receptor. Substitution of five non-proteogeneic amino acid analogues makes icatibant resistant to degradation by metalloproteases of kinin catabolism. Icatibant has clinical applications in inflammatory and vascular leakage conditions caused by an acute (non-controlled) production of kinins and their accumulation at the endothelium B2 receptor. The clinical manifestation of vascular leakage, called angioedema (AE), is characterized by edematous attacks of subcutaneous and submucosal tissues, which can cause painful intestinal consequences, and life-threatening complications if affecting the larynx. Icatibant is registered for the treatment of acute attacks of the hereditary BK-mediated AE, i.e., AE due to C1 inhibitor deficiency. AREAS COVERED: This review discusses emerging knowledge on the kinin system: kinin pharmacological properties, biochemical characteristics of the contact phase and kinin catabolism proteases. It underlines the responsibility of the kinins in AE initiation and the potency of icatibant to inhibit AE formation by kinin-receptor interactions. EXPERT OPINION: Icatibant antagonist properties protect BK-mediated AE patients against severe attacks, and could be developed for use in inflammatory conditions. More studies are required to confirm whether or not prolonged and frequent applications of icatibant could result in the impairment of the cardioprotective effect of BK.