Charles Dickens'ds child-novels

Dissertação (mestrado) - Universidade Federal de Santa Catarina, Florianópolis, 1981

Inhibition of glutaminase-1 in DLBCL potentiates venetoclax-induced antitumor activity by promoting oxidative stress

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma in adults, but first-line immunochemotherapy fails to produce a durable response in about one-third of the patients. Because tumor cells often reprogram their metabolism, we investigated the importance of glutaminolysis, a pathway converting glutamine to generate energy and various metabolites, for the growth of DLBCL cells. Glutaminase-1 (GLS1) expression was robustly detected in DLBCL biopsy samples and cell lines. Both pharmacological inhibition and genetic knockdown of GLS1 induced cell death in DLBCL cells regardless of their subtype classification, whereas primary B cells remained unaffected. Interestingly, GLS1 inhibition resulted not only in reduced levels of intermediates of the tricarboxylic acid cycle but also in a strong mitochondrial accumulation of reactive oxygen species. Supplementation of DLBCL cells with α-ketoglutarate or with the antioxidant α-tocopherol mitigated oxidative stress and abrogated cell death upon GLS1 inhibition, indicating an essential role of glutaminolysis in the protection from oxidative stress. Furthermore, the combination of the GLS1 inhibitor CB-839 with the therapeutic BCL2 inhibitor ABT-199 not only induced massive reactive oxygen species (ROS) production but also exhibited highly synergistic cytotoxicity, suggesting that simultaneous targeting of GLS1 and BCL2 could represent a novel therapeutic strategy for patients with DLBCL.ISSN:2473-9537ISSN:2473-952

Tribology of thin wetting films between bubble and moving solid surface

This work shows a successful example of coupling of theory and experiment to study the tribology of bubble rubbing on solid surface. Such kind of investigation is reported for the first time in the literature. A theory about wetting film intercalated between bubble and moving solid surface was developed, thus deriving the non-linear evolution differential equation which accounted for the friction slip coefficient at the solid surface. The stationary 3D film thickness profile, which appears to be a solution of the differential equation, for each particular speed of motion of the solid surface was derived by means of special procedure and unique interferometric experimental setup. This allowed us to determine the 3D map of the lift pressure within the wetting film, the friction force per unit area and the friction coefficient of rubbing at different speeds of motion of the solid surface. Thus, we observed interesting tribological details about the rubbing of the bubble on the solid surface like for example: 1. A regime of mixed friction between dry and lubricated friction exists in the range of 6–170µm/s, beyond which the rubbing between the bubble and solid becomes completely lubricated and passes through the maximum;2. The friction coefficient of rubbing has high values at very small speeds of solid's motion and reduces substantially with the increase of the speed of the solid motion until reaching small values, which change insignificantly with the further increase of the speed of the solid. Despite the numerous studies on the motion of bubble/droplet in close proximity to solid wall in the literature, the present investigation appears to be a step ahead in this area as far as we were able to derive 3D maps of the bubble close to the solid surface, which makes the investigation more profound

Role of Smac in cephalostatin-induced cell death.

Cephalostatin 1 is a natural compound isolated from a marine worm that induces apoptosis in tumor cells via an apoptosome-independent but caspase-9-dependent pathway and through an endoplasmic reticulum stress response that is accompanied by caspase-4 activation. Here, we show that cephalostatin evokes mitochondrial Smac (second mitochondria-derived activator of caspases) but not cytochrome c release in various carcinoma cell lines. We also show that Smac is critically involved in caspase-9 activation as evidenced by gene silencing experiments. Remarkably, caspase-2 appears to be a major target for cephalostatin-induced cytosolic Smac. Using biochemical and genetic inhibition experiments, we demonstrate that caspase-2 participates in the apoptotic machinery induced by cephalostatin. Cephalostatin-activated caspase-2 appears to act as initiator caspase and is not involved in the activation of caspase-9. Importantly, experiments immunoprecipitating PIDD (p53-induced protein with a DD), RAIDD (RIP-associated ICH-1/CED-3-homologous protein with DD) and caspase-2 identify cephalostatin as an experimental drug that induces the formation of the PIDDosome. The bis-steroid cephalostatin proves to be both a helpful tool to investigate apoptotic signaling and a promising chemotherapeutic agent.Cell Death and Differentiation advance online publication, 19 September 2008; doi:10.1038/cdd.2008.125

The marine product cephalostatin 1 activates an endoplasmic reticulum stress-specific and apoptosome-independent apoptotic signaling pathway

Cephalostatin 1, a bis-steroidal marine natural product, has been reported to induce apoptosis without the requirement of an active caspase-8 or mitochondrial cytochrome c release and apoptosome formation. Here we show that despite the absence of these events, caspase-9 activation is essential for cephalostatin 1-induced apoptosis. Cephalostatin 1 initiates a rapid endoplasmic reticulum stress response characterized by phosphorylation of eukaryotic initiation factor-2 alpha-subunit and increased expression of the chaperone immunoglobulin heavy chain-binding protein GRP78 as well as the transcription factor C/EBP homologous protein (CHOP)/GADD153. Cephalostatin 1 activates apoptosis signal-regulating kinase 1 and c-Jun N-terminal kinase (JNK). However, this pathway does not play a major role in cephalostatin 1-induced apoptosis, as assessed by stable expression of a dominant negative apoptosis signal-regulating kinase 1. Importantly, the endoplasmic reticulum-associated caspase-4 is required and as shown by biochemical and genetic inhibition experiments, acts upstream of caspase-9 in cephalostatin-induced apoptosis

Discovery of BAY-985, a Highly Selective TBK1/IKK epsilon Inhibitor

The serine/threonine kinase TBK1 (TANK-binding kinase 1) and its homologue IKKϵ are noncanonical members of the inhibitor of the nuclear factor κB (IκB) kinase family. These kinases play important roles in multiple cellular pathways and, in particular, in inflammation. Herein, we describe our investigations on a family of benzimidazoles and the identification of the potent and highly selective TBK1/IKKϵ inhibitor BAY-985. BAY-985 inhibits the cellular phosphorylation of interferon regulatory factor 3 and displays antiproliferative efficacy in the melanoma cell line SK-MEL-2 but showed only weak antitumor activity in the SK-MEL-2 human melanoma xenograft model