Mechanisms of TRAIL-resistance:novel targets to enhance TRAIL sensitization for cancer therapy

TRAIL has been shown to target tumor cells but not healthy cells in vitro. In addition, clinical studies have revealed that recombinant human TRAIL is well tolerated in patients. Taken together, the safety of treatment and targeted apoptosis in human bodies render TRAIL a promising anti-tumor therapeutic. Besides inducing this apoptotic signaling pathway, TRAIL can activate non-canonical kinase pathways through the same death receptors. In this thesis, we unraveled molecular mechanisms controlling TRAIL sensitivity in tumor cells using DR4- and DR5- specific TRAIL variants (Chapter 2 and 3). Moreover, we used combined treatment with epigenetic drugs to overcome TRAIL resistance in tumor cells (Chapter 5 and 6). In Chapter 2 , we generated FUT3 or FUT6 overexpressed cell lines to investigate their sensitivities to TRAIL. Our data show that DR5-sensitivity is completely restored in FUT3 or FUT6 overexpressed cells. In Chapter 3, we firstly showed that conditioned medium (CM) derived from cancer cells inhibits TRAIL-mediated cell death. In addition, we observed only DR5 but not DR4 in CM. In Chapter 4. We summarized strategies for combination therapy to improve TRAIL sensitivity by interfering with aberrant histone modifications using inhibitors. In Chapter 5, we found that RGFP966, a HDAC3-specific inhibitor, or PCI34051, a HDAC8-specific inhibitor, largely improve TRAIL sensitivity in combination with agonistic receptor-specific. TRAIL variants. In Chapter 6, we showed that the A485-TRAIL combination synergistically increases cell death and decreases the volume of 3D spheroids of EGFR-TKI resistant cells

Rigidity for geometric ideals in uniform Roe algebras

In this paper, we investigate the rigidity problems for geometric ideals in uniform Roe algebras associated to discrete metric spaces of bounded geometry. These ideals were introduced by Chen and Wang, and can be fully characterised in terms of ideals in the associated coarse structures. Our main result is that if two geometric ideals in uniform Roe algebras are stably isomorphic, then the coarse spaces associated to these ideals are coarsely equivalent. We also discuss the case of ghostly ideals and pose some open questions

Quasi-locality for \'{e}tale groupoids

Let $\mathcal{G}$ be a locally compact \'{e}tale groupoid and $\mathscr{L}(L^2(\mathcal{G}))$ be the $C^*$-algebra of adjointable operators on the Hilbert $C^*$-module $L^2(\mathcal{G})$. In this paper, we discover a notion called quasi-locality for operators in $\mathscr{L}(L^2(\mathcal{G}))$, generalising the metric space case introduced by Roe. Our main result shows that when $\mathcal{G}$ is additionally $\sigma$-compact and amenable, an equivariant operator in $\mathscr{L}(L^2(\mathcal{G}))$ belongs to the reduced groupoid $C^*$-algebra $C^*_r(\mathcal{G})$ if and only if it is quasi-local. This provides a practical approach to describe elements in $C^*_r(\mathcal{G})$ using coarse geometry. Our main tool is a description for operators in $\mathscr{L}(L^2(\mathcal{G}))$ via their slices with the same philosophy to the computer tomography. As applications, we recover a result by \v{S}pakula and the second-named author in the metric space case, and deduce new characterisations for reduced crossed products and uniform Roe algebras for groupoids

Association between COX-2 rs2745557 polymorphism and prostate cancer risk: a systematic review and meta-analysis

<p>Abstract</p> <p>Background</p> <p>Evidence is accumulating that chronic inflammation may have an important role in prostate cancer (PCa). The COX-2 polymorphism rs2745557 (+202 C/T) has been extensively investigated as a potential risk factor for PCa, but the results have thus far been inconclusive. This meta-analysis was performed to derive a more precise estimation of the association.</p> <p>Methods</p> <p>A comprehensive search was conducted to identify all case-control studies of COX-2 rs2745557 polymorphism and PCa risk. We used odds ratios (ORs) to assess the strength of the association, and 95% confidence intervals (CIs) give a sense of the precision of the estimate. Statistical analyses were performed by Review Manage, version 5.0 and Stata 10.0.</p> <p>Results</p> <p>A total of 8 available studies were considered in the present meta-analysis, with 11356 patients and 11641 controls for rs2745557. When all groups were pooled, there was no evidence that rs2745557 had significant association with PCa under co-dominant, recessive, over-dominant, and allelic models. However, our analysis suggested that rs2745557 was associated with a lower PCa risk under dominant model in overall population (OR = 0.85, 95%CI = 0.74-0.97, P = 0.02). When stratifying for race, there was a significant association between rs2745557 polymorphism and lower PCa risk in dominant model comparison in the subgroup of Caucasians (OR = 0.86, 95%CI = 0.75-0.99, P = 0.04), but not in co-dominant, recessive, over-dominant and allelic comparisons.</p> <p>Conclusion</p> <p>Based on our meta-analysis, COX-2 rs2745557 was associated with a lower PCa risk under dominant model in Caucasians.</p

Universal Projective Synchronization of Two Different Hyperchaotic Systems with Unknown Parameters

Universal projective synchronization (UPS) of two chaotic systems is defined. Based on the Lyapunov stability theory, an adaptive control method is derived such that UPS of two different hyperchaotic systems with unknown parameters is realized, which is up to a scaling function matrix and three kinds of reference systems, respectively. Numerical simulations are used to verify the effectiveness of the scheme

Tensor singular spectral analysis for 3D feature extraction in hyperspectral images.

Due to the cubic structure of a hyperspectral image (HSI), how to characterize its spectral and spatial properties in three dimensions is challenging. Conventional spectral-spatial methods usually extract spectral and spatial information separately, ignoring their intrinsic correlations. Recently, some 3D feature extraction methods are developed for the extraction of spectral and spatial features simultaneously, although they rely on local spatial-spectral regions and thus ignore the global spectral similarity and spatial consistency. Meanwhile, some of these methods contain huge model parameters which require a large number of training samples. In this paper, a novel Tensor Singular Spectral Analysis (TensorSSA) method is proposed to extract global and low-rank features of HSI. In TensorSSA, an adaptive embedding operation is first proposed to construct a trajectory tensor corresponding to the entire HSI, which takes full advantage of the spatial similarity and improves the adequate representation of the global low-rank properties of the HSI. Moreover, the obtained trajectory tensor, which contains the global and local spatial and spectral information of the HSI, is decomposed by the Tensor singular value decomposition (t-SVD) to explore its low-rank intrinsic features. Finally, the efficacy of the extracted features is evaluated using the accuracy of image classification with a support vector machine (SVM) classifier. Experimental results on three publicly available datasets have fully demonstrated the superiority of the proposed TensorSSA over a few state-of-the-art 2D/3D feature extraction and deep learning algorithms, even with a limited number of training samples

A New Hyperchaotic System and the Synchronization Using Active Variable Universe Adaptive Fuzzy Controller

This paper presents a new hyperchaotic system by introducing an additional state variable into Lorenz system. The system’s characteristics, including the dissipativity, equilibrium, and Lyapunov exponents, are studied. A controller is developed which consists of an active control term and a variable universe adaptive fuzzy system. By using this controller, the synchronization of the new hyperchaotic systems with uncertain linear part is accomplished according to Lyapunov’s direct method. Simulation results illustrate the effectiveness of the proposed method

p38α MAPK regulates proliferation and differentiation of osteoclast progenitors and bone remodeling in an aging-dependent manner.

Bone mass is determined by the balance between bone formation, carried out by mesenchymal stem cell-derived osteoblasts, and bone resorption, carried out by monocyte-derived osteoclasts. Here we investigated the potential roles of p38 MAPKs, which are activated by growth factors and cytokines including RANKL and BMPs, in osteoclastogenesis and bone resorption by ablating p38α MAPK in LysM+monocytes. p38α deficiency promoted monocyte proliferation but regulated monocyte osteoclastic differentiation in a cell-density dependent manner, with proliferating p38α-/- cultures showing increased differentiation. While young mutant mice showed minor increase in bone mass, 6-month-old mutant mice developed osteoporosis, associated with an increase in osteoclastogenesis and bone resorption and an increase in the pool of monocytes. Moreover, monocyte-specific p38α ablation resulted in a decrease in bone formation and the number of bone marrow mesenchymal stem/stromal cells, likely due to decreased expression of PDGF-AA and BMP2. The expression of PDGF-AA and BMP2 was positively regulated by the p38 MAPK-Creb axis in osteoclasts, with the promoters of PDGF-AA and BMP2 having Creb binding sites. These findings uncovered the molecular mechanisms by which p38α MAPK regulates osteoclastogenesis and coordinates osteoclastogenesis and osteoblastogenesis