Cell signalling in survival: Natural compounds and small-molecule inhibitors provide essential insight

Effective response to treatment is still a challenge in the clinical management of many types of tumors. As result of pharmacological intervention two different fates are observed for a cancer cell: survival or death. These two cell fates are intimately related to the overall response to treatment. Survival of a cancer cell to an aggressive treatment usually means inefficacy of a determined drug and cell death means that the cells were sensitive to the treatment. In the current literature many types of cell death are suggested. Of equal importance is the understanding of the mechanisms and signal cascades of survival. Crosstalk between multiple signal transduction pathways may organize an intricate survival network with overlapping functions that together provide strong survival signals to a dying cell. Importantly, these survival signals seem to be on the background of the classic mechanism of drug resistance which holds true for a lower efficacy of determined class of molecules or structurally unrelated ones, such as drug efflux, drug uptake, drug metabolism, DNA repair and impaired drug binding to its target. Importantly, different types of tumors present different aspects of surviving, as an example the building up of a drug resistant phenotype in hematological diseases is usually a long term process, resulting in an initial response to treatment. However, relapses occur after sometime, and not always remission is achieved with the same therapeutic strategy. The development or acquisition of drug resistance is a quite remarkable aspect of hematological malignancies. On another hand, this first response to pharmacological strategies is not really achieved in tumors such as, pancreatic cancer (PDAC). Less than 10% of pat

On the uniform controllability for a family of non-viscous and viscous Burgers- α systems

In this paper we study the global controllability of families of the so called non-viscous and viscous Burgers- systems by using boundary and space independent distributed controls. In these equations, the usual convective velocity of the Burgers equation is replaced by a regularized velocity, induced by a Helmholtz lter of characteristic wavelength . First, we prove a global exact controllability result (uniform with respect to ) for the non-viscous Burgers- system, using the return method and a xed-point argument. Then, the global uniform exact controllability to constant states is deduced for the viscous equations. To this purpose, we rst prove a local exact controllability property and, then, we establish a global approximate controllability result for smooth initial and target states

On some geometric inverse problems for nonscalar elliptic systems

In this paper, we consider several geometric inverse problems for linear elliptic systems. We prove uniqueness and stability results. In particular, we show the way that the observation depends on the perturbations of the domain. In some particular situations, this provides a strategy that could be used to compute approximations to the solution of the inverse problem. In the proofs, we use techniques related to (local) Carleman estimates and differentiation with respect to the domain

PAK2 is an effector of TSC1/2 signaling independent of mTOR and a potential therapeutic target for Tuberous Sclerosis Complex

Tuberous sclerosis complex (TSC) is caused by inactivating mutations in either TSC1 or TSC2 and is characterized by uncontrolled mTORC1 activation. Drugs that reduce mTOR activity are only partially successful in the treatment of TSC, suggesting that mTOR-independent pathways play a role in disease development. Here, kinome profiles of wild-type and Tsc2-/- mouse embryonic fibroblasts (MEFs) were generated, revealing a prominent role for PAK2 in signal transduction downstream of TSC1/2. Further investigation showed that the effect of the TSC1/2 complex on PAK2 is mediated through RHEB, but is independent of mTOR and p21RAC. We also demonstrated that PAK2 over-activation is likely responsible for the migratory and cell cycle abnormalities observed in Tsc2-/- MEFs. Finally, we detected high levels of PAK2 activation in giant cells in the brains of TSC patients. These results show that PAK2 is a direct effector of TSC1-TSC2-RHEB signaling and a new target for rational drug therapy in TSC

C9ORF72 patient-derived endothelial cells drive blood-brain barrier disruption and contribute to neurotoxicity

The blood-brain barrier (BBB) serves as a highly intricate and dynamic interface connecting the brain and the bloodstream, playing a vital role in maintaining brain homeostasis. BBB dysfunction has been associated with multiple neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS); however, the role of the BBB in neurodegeneration is understudied. We developed an ALS patient-derived model of the BBB by using cells derived from 5 patient donors carrying C9ORF72 mutations. Brain microvascular endothelial-like cells (BMEC-like cells) derived from C9ORF72-ALS patients showed altered gene expression, compromised barrier integrity, and increased P-glycoprotein transporter activity. In addition, mitochondrial metabolic tests demonstrated that C9ORF72-ALS BMECs display a significant decrease in basal glycolysis accompanied by increased basal and ATP-linked respiration. Moreover, our study reveals that C9-ALS derived astrocytes can further affect BMECs function and affect the expression of the glucose transporter Glut-1. Finally, C9ORF72 patient-derived BMECs form leaky barriers through a cell-autonomous mechanism and have neurotoxic properties towards motor neurons

Building The Sugarcane Genome For Biotechnology And Identifying Evolutionary Trends

Background: Sugarcane is the source of sugar in all tropical and subtropical countries and is becoming increasingly important for bio-based fuels. However, its large (10 Gb), polyploid, complex genome has hindered genome based breeding efforts. Here we release the largest and most diverse set of sugarcane genome sequences to date, as part of an on-going initiative to provide a sugarcane genomic information resource, with the ultimate goal of producing a gold standard genome.Results: Three hundred and seventeen chiefly euchromatic BACs were sequenced. A reference set of one thousand four hundred manually-annotated protein-coding genes was generated. A small RNA collection and a RNA-seq library were used to explore expression patterns and the sRNA landscape. In the sucrose and starch metabolism pathway, 16 non-redundant enzyme-encoding genes were identified. 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Evidence of Color Coherence Effects in W+jets Events from ppbar Collisions at sqrt(s) = 1.8 TeV

We report the results of a study of color coherence effects in ppbar collisions based on data collected by the D0 detector during the 1994-1995 run of the Fermilab Tevatron Collider, at a center of mass energy sqrt(s) = 1.8 TeV. Initial-to-final state color interference effects are studied by examining particle distribution patterns in events with a W boson and at least one jet. The data are compared to Monte Carlo simulations with different color coherence implementations and to an analytic modified-leading-logarithm perturbative calculation based on the local parton-hadron duality hypothesis.Comment: 13 pages, 6 figures. Submitted to Physics Letters