Dasatinib enhances anti-leukemia efficacy of chimeric antigen receptor T cells by inhibiting cell differentiation and exhaustion

Relapses of CD19-expressing leukemia in patients who achieved initial remission after CART cell treatment have been reported to correlate with poor CART cells persistence. Sustained tonic signaling or strong activation drives CART cell differentiation and exhaustion, which limit the therapeutic efficacy and persistence of CART cells. Here, we identified dasatinib as the optimal candidate to prevent or reverse both CD28/CART and 4-1BB/CART cell differentiation and exhaustion during ex vivo expansion, which profoundly enhanced the therapeutic efficacy and in vivo persistence. Moreover, strong activation-induced CART cells differentiation, exhaustion and apoptosis driven by CD3/CD28 stimulation or antigen exposure were dramatically prevented or reversed by dasatinib treatment. Mechanistically, dasatinib markedly reduced the phosphorylation of Src and Lck, and downregulated the expression of genes involved in CAR signaling pathways, which resulted in the optimization of cell differentiation, exhaustion and apoptosis-related gene expression. Our study proposes a promising pharmacological approach for optimizing CART cells manufacture, and provides an experimental basis for reinvigorating CART cells in clinical application.

Evolutionary Algorithm for Multiobjective Optimization Based on Density Estimation Ranking

In the past few decades, a number of multiobjective evolutionary algorithms (MOEAs) have been proposed in the continue study. As pointed out in some recent studies, the performance of the most existing MOEAs is not promising when solving different shapes of Pareto fronts. To address this issue, this paper proposes an MOEA based on density estimation ranking. The algorithm includes density estimation ranking to shift the reference solution position, calculating the density of candidate solutions and ranking by the estimated density value, to modify the Pareto dominance relation and for handling complicated Pareto front. The result of this ranking can be used as the second selection criterion for environmental selection, and the optimal candidate individual with distribution and diversity information is selected. Experimental results show that the proposed algorithm can solve various types of Pareto fronts, outperformance several state-of-the-art evolutionary algorithms in multiobjective optimization.

A Rationale for Drug Design Provided by Co-Crystal Structure of IC261 in Complex with Tubulin

Microtubules composed of α/β tubulin heterodimers are an essential part of the cytoskeleton of eukaryotic cells and are widely regarded as targets for cancer chemotherapy. IC261, which is discovered as an ATP-competitive inhibitor of serine/threonine-specific casein kinase 1 (CK1), has shown its inhibitory activity on microtubule polymerization in recent studies. However, the structural information of the interaction between tubulin and IC261 is still unclear. Here, we provided a high-resolution (2.85 Å) crystal structure of tubulin and IC261 complex, revealed the intermolecular interaction between tubulin and IC261, and analyzed the structure–activity relationship (SAR). Subsequently, the structure of tubulin-IC261 complex was compared with tubulin-colchicine complex to further elucidate the novelty of IC261. Furthermore, eight optimal candidate compounds of new IC261-based microtubule inhibitors were obtained through molecular docking studies. In conclusion, the co-crystal structure of tubulin-IC261 complex paves a way for the design and development of microtubule inhibitor drugs.

Selection of the Optimal Candidate to MitraClip for Secondary Mitral Regurgitation: Beyond Mitral Valve Morphology

Secondary mitral regurgitation (MR) occurs despite structurally normal valve apparatus due to an underlying disease of the myocardium leading to disruption of the balance between tethering and closing forces with ensuing failure of leaflet coaptation. In patients with heart failure (HF) and left ventricular dysfunction, secondary MR is independently associated with poor outcome, yet prognostic benefits related to the correction of MR have remained elusive. Surgery is not recommended for the correction of secondary MR outside coronary artery bypass grafting. Percutaneous mitral valve repair (PMVR) with MitraClip implantation has recently evolved as a new transcatheter treatment option of inoperable or high-risk patients with severe MR, with promising results supporting the extension of guideline recommendations. MitraClip is highly effective in reducing secondary MR in HF patients. However, the derived clinical benefit is still controversial as two randomized trials directly comparing PMVR vs. optimal medical therapy in severe secondary MR yielded virtually opposite conclusions. We reviewed current evidence to identify predictors of PMVR-related outcomes in secondary MR useful to improve the timing and the selection of patients who would derive maximal benefit from MitraClip intervention. Beyond mitral valve anatomy, optimal candidate selection should rely on a comprehensive diagnostic workup and a fine-tuned risk stratification process aimed at (i) recognizing the substantial heterogeneity of secondary MR and its complex interaction with the myocardium, (ii) foreseeing hemodynamic consequences of PMVR, (iii) anticipating futility and (iv) improving symptoms, quality of life and overall survival.

A Deep Q-Learning Network for Dynamic Constraint-Satisfied Service Composition

Traditional service composition methods usually address the constraint-satisfied service composition (CSSC) problem with static web services. Such solutions however are inapplicable to the dynamic scenarios where the services or their QoS values may change over time. Some recent studies are proposed to use reinforcement learning, especially, integrate the idea of Q-learning, to solve the dynamic CSSC problem. However, such Q-learning algorithm relies on Q-table to search for optimal candidate services. When the problem of CSSC becomes complex, the number of states in Q-table is very large and the cost of the Q-learning model will become extremely high. In this paper, the authors propose a novel solution to address this issue. By training a DQN network to replace the Q-table, this solution can effectively model the uncertainty of services with fine-grained QoS attributes and choose suitable candidate services to compose on the fly in the dynamic scenarios. Experimental results on both artificial and real datasets demonstrate the effectiveness of the method.

AN OT ACCOUNT OF PHONOTACTIC AND CODA NEUTRALIZATION OF ENGLISH LOANS IN PILIBHIT HINDI-URDU

This paper provided the basic information of the phonological processes as the Coda Neutralization and Phonotactics of English Loans in Pilibhit Hindi-Urdu within the framework of Optimality Theory (OT). The objectives of this paper were to represent the aspects of the coda neutralization in the sense of voiced obstruent segment becomes voiceless obstruent segment in the final syllable structure of the loanwords, and the consonant clusters break within the insertion of an extraneous segment in any location of the English Loans in Pilibhit Hindi-Urdu. In the another framework, this paper revealed the phenomena of devoicing features of coda consonants and the grades of the additional segments in Pilibhit Hindi-Urdu loanwords within the principles of Optimality Theory (Prince & Smolensky, 1993). The central idea of this paper was to explore the process of conflicts between the candidates at the surface level and reflects the properties of the input candidate by the observation of the constraint rankings. In this study, it was propounded the effective formalities of the hierarchy of the constraint rankings and drew one of the best candidates as an optimal candidate out of the output candidates from English loans in Pilibhit Hindi-Urdu. The groundwork of this paper was related to the significant aspects of the English loans that were adapted within the addition, insertion, or deletion of the segments in Pilibhit Hindi-Urdu. In this paper, it was also determined the facts of the coda devoicing of the speech segments in terms of neutralization at the end of the syllable structure of English loans in Pilibhit Hindi-Urdu.