New Insights into the Pathogenesis of Systemic Mastocytosis

Mastocytosis is a type of myeloid neoplasm characterized by the clonal, neoplastic proliferation of morphologically and immunophenotypically abnormal mast cells that infiltrate one or more organ systems. Systemic mastocytosis (SM) is a more aggressive variant of mastocytosis with extracutaneous involvement, which might be associated with multi-organ dysfunction or failure and shortened survival. Over 80% of patients with SM carry the KIT D816V mutation. However, the KIT D816V mutation serves as a weak oncogene and appears to be a late event in the pathogenesis of mastocytosis. The management of SM is highly individualized and was largely palliative for patients without a targeted form of therapy in past decades. Targeted therapy with midostaurin, a multiple kinase inhibitor that inhibits KIT, has demonstrated efficacy in patients with advanced SM. This led to the recent approval of midostaurin by the United States Food and Drug Administration and European Medicines Agency. However, the overall survival of patients treated with midostaurin remains unsatisfactory. The identification of genetic and epigenetic alterations and understanding their interactions and the molecular mechanisms involved in mastocytosis is necessary to develop rationally targeted therapeutic strategies. This review briefly summarizes recent developments in the understanding of SM pathogenesis and potential treatment strategies for patients with SM.     

Understanding the metabolic burden of recombinant antibody production in Saccharomyces cerevisiae using a quantitative metabolomics approach

The cellular changes induced by heterologous protein expression in the yeast Saccharomyces cerevisiae have been analysed on many levels and found to be significant. However, even though high‐level protein production poses a metabolic burden, evaluation of the expression host at the level of the metabolome has often been neglected. We present a comparison of metabolite profiles of a wild‐type strain with those of three strains producing recombinant antibody variants of increasing size and complexity: an scFv fragment, an scFv–Fc fusion protein and a full‐length IgG molecule. Under producing conditions, all three recombinant strains showed a clear decrease in growth rate compared with the wild‐type strain and the severity of the growth phenotype increased with size of the protein. The levels of 76 intracellular metabolites were determined using a targeted (semi) quantitative mass spectrometry based approach. Based on unsupervised and supervised multivariate analysis of metabolite profiles, together with pathway activity profiling, the recombinant strains were found to be significantly different from each other and from the wild‐type strain. We observed the most prominent changes in metabolite levels for metabolites involved in amino acid and redox metabolism. Induction of the unfolded protein response was detected in all producing strains and is considered to be a contributing factor to the overall metabolic burden on the cells.     

冷链仓储创新装备在河南鲁山精准扶贫中的应用分析

文章对鲁山县董周乡酥梨冷箱仓储扶贫试点应用项目的实施情况开展了专题调研,现将多功能模块化组合冷箱配套农产品市场经营策略精准促进鲁山县董周乡农村产业扶贫的实施情况做系统阐述。     

Novel strategy for encapsulation and targeted delivery of poorly water-soluble active substances

Carriers for targeted delivery and controlled release of poorly water-soluble active substances (PWSAS) are facing three challenges: (a) the encapsulation issues, (b) limitations of PWSAS water solubility, and (c) burst drug release which can be pharmacologically dangerous and economically inefficient. The present study brings a novel strategy for encapsulation and controlled release of PWSAS—caffeine in concentrations which are higher than its maximal water solubility without the possibility of burst effect. The modification of hydrophilic carrier based on poly(methacylic acid) was done using casein and liposomes. To further increase the maximal caffeine loading inside the carrier nicotinamide was used. The release study of the encapsulated PWSAS was elaborated with respect to morphology of the carriers and interactions that could be established between its structural components. The carriers swelling and the release of caffeine and nicotinamide were also investigated depending on caffeine concentration, the presence of different liposomal formulations and the volume ratio of liposomal formulation, in three media with different pH simulating the path of the carrier through the human gastrointestinal tract. The synthesized carriers are promising candidates for encapsulation of PWSAS in concentrations which are higher than its maximal water solubility and for the targeted delivery of those dosages.     

AXL Receptor in Breast Cancer: Molecular Involvement and Therapeutic Limitations

Breast cancer was one of the first malignancies to benefit from targeted therapy, i.e., treatments directed against specific markers. Inhibitors against HER2 are a significant example and they improved the life expectancy of a large cohort of patients. Research on new biomarkers, therefore, is always current and important. AXL, a member of the TYRO-3, AXL and MER (TAM) subfamily, is, today, considered a predictive and prognostic biomarker in many tumor contexts, primarily breast cancer. Its oncogenic implications make it an ideal target for the development of new pharmacological agents; moreover, its recent role as immune-modulator makes AXL particularly attractive to researchers involved in the study of interactions between cancer and the tumor microenvironment (TME). All these peculiarities characterize AXL as compared to other members of the TAM family. In this review, we will illustrate the biological role played by AXL in breast tumor cells, highlighting its molecular and biological features, its involvement in tumor progression and its implication as a target in ongoing clinical trials.     

结合公钥加密和关键字可搜索加密的加密方案

带关键字搜索的公钥加密(PEKS)是一种有用的加密原语，它允许用户将在加密数据上搜索的功能委托给不可信的第三方服务器，而不影响原始数据的安全性和隐私性。但是，由于缺乏对于数据的加密以及解密能力，PEKS方案不能单独进行使用，必须与标准的公钥加密方案(PKE)相结合。因此，Baek等人在2006年引入了一种新的加密原语，称为结合PKE和PEKS的加密方案(PKE+PEKS)，它同时提供了PKE和PEKS的功能。目前，已有文献提出了几种PKE+PEKS方案。然而，他们都没有考虑关键字猜测攻击的问题。本文提出一个新的高效且能够抵抗关键字猜测攻击的PKE+PEKS方案，与已有方案相比，该方案在性能上有很大的提升，并且在生成关键字和数据密文时，不需要使用双线性对，极大地降低了计算和存储成本。安全性分析表明，本文中所提出的方案能够满足密文隐私安全性、陷门不可区分性和抗关键字猜测攻击的安全性。效率分析表明，本分提出的方案更加高效。     

A nanosystem of copper(II)-disulfiram for cancer treatment with high efficacy and few side effects

Developing chemotherapy drugs with high efficacy and few side effects has been a bottleneck problem that requires an efficient solution. The active cancer treatment ingredient disulfiram (DSF), inspired by the copper(II) diethyldithiocarbamate complex (CuET), can be used in a one-pot synthesis method to construct a CuET delivery nanosystem (CuET-ZIF_Cu@HA). Due to the high biocompatibility, targeting of CD44 overexpressed cancer cells, and acid response of zeolitic imidazolate framework (ZIF) materials of hyaluronic acid (HA), we realized that CuET-ZIF_Cu@HA could become an effective and highly selective cancer treatment. Both in vivo and in vitro experiments have demonstrated that CuET-ZIF_Cu@HA has robust anti-tumor properties without evident side effects. This research provided a promising strategy for DSF nanosystems that involves simple preparation and high efficacy, both of which are key to reusing DSF in cancer treatment.     

适用于无线体域网的动态口令认证协议

无线体域网中传输的是与生命高度相关的敏感数据，身份认证是信息安全保护的第一道防线。现有的基于人体生物信息的身份认证方案存在信息难提取、偶然性大和误差性大的问题，基于传统密码学的认证方案需较大计算资源和能量消耗，并不适用于无线体域网环境。为此，在动态口令和非对称加密机制基础上，提出一种适用于无线体域网的动态口令双向认证轻量协议，并对其进行形式化分析。通过理论证明、SVO逻辑推理及SPIN模型检测得出：该协议满足双向认证，且能够抵御重放攻击、伪装攻击、拒绝服务器攻击和口令离线攻击，具有较高安全性。     

胆汁酸代谢调节炎症性肠病的作用机制及药物研发

炎症性肠病（IBD）是一种慢性复发性肠道炎症性疾病，发病率及非致死性疾病负担在全世界都有累加的趋势，其病因复杂，发病机制目前还未完全明确。胆汁酸（BAs）是胆汁的主要成份，其可通过与胆汁酸受体结合、调节肠道菌群等参与IBD的发生发展。本文着重讨论BAs代谢在IBD发病中的作用机制，以及基于BAs及其相关靶点的药物研发进展，为今后IBD的预防、治疗和预后研究奠定基础。