紧密连接蛋白claudins应用于肿瘤治疗的进展

Claudins蛋白家族是组成紧密连接(Tight junctions,TJs)必不可少的骨架蛋白,在维持上皮和内皮细胞中的细胞极性、细胞间的粘附固定、细胞旁路的离子运输等发挥重要作用。近年来大量的研究结果证明,claudins在许多人类恶性肿瘤中异常表达。因此,claudins也被作为癌症治疗的潜在靶标。文中就claudin蛋白家族在肿瘤中的表达情况及其相关药物的研究进展进行阐述。     

Efecto positivo de la terapia de luz brillante sobre el estado de ánimo y la calidad del sueño en las personas mayores institucionalizadas

IntroductionBright light exposure during the day has a positive effect on health and its deficit can cause multiple physiological and cognitive disorders, including depression. The aim of this study was to evaluate the effect of bright light therapy (BLT) on the quality of sleep and mood emotional state; cognitive status, global deterioration and quality of life in institutionalized elderly.Material and methodsThis is a study with repeated measures design. Thirty-seven older people admitted to a nursing home. The study lasted 3 weeks. The first week, the reference values were established with the Oviedo Sleep Questionnaire, Yesavage Depression Scale, Mini-Mental, Global Scale of Impairment and European Quality of Life Questionnaire. During the second week, they were exposed to BLT (7,000-10,000 lx at eye level) between 9:30 a.m. and 11:00 a.m. During the third week, all the data were re-evaluated.ResultsAll variables improved significantly after the application of light therapy. Sleep (COS) pre-test 4.1 ± 1.49, post-test 4.9 ± 1.46, p: 0.01), mood (pre-test 3.65 ± 2.78, post-test 2.65 ± 2.9, p: 0.01), cognitive state (pre-test 22.72 ± 6.53, post-test 24 ± 5.92, p: 0.001), state of global deterioration (pre-test 3.10 ± 1.26, post-test 2.72 ± 5.92, p: 0.001) and health-related quality of life (pre-test 6.93 ± 1.86, post-test 7.82 ± 1.62, p: 0.001).ConclusionsSleep quality, mood, cognitive status, global deterioration status and quality of life significantly improved after the application of light bright therapy.     

The progress and perspectives of CAR-T cell therapy

CAR-T cell therapy has already achieved world-renowned clinical effects in the treatment of hematological malignancies. Due to the tumor heterogeneity, immunosuppressive microenvironment, and other factors, CAR-T cell therapy has still not shown obvious clinical efficacy in clinical treatment of solid tumors. However, great progress has been made in the preparation of CAR-T cells in recent years, including T cells redirected for universal cytokine mediated killing, universal CAR -T cells, non-viral vector CAR-T cells, SynNotch technology, SUPRA CAR technology, regulated CAR-T cells, and bi-specific CAR-T cells, etc. Future research and development of CAR-T cell therapy will be focused on these following aspects: the combined application of CAR-T cells with different targets, known as "Cocktail CAR-T cells", is expected to increase efficiency toward solid tumors; based on systemic biology/synthetic biology theories, CAR-T cells are likely to be transformed to robot or intelligent system by introducing sensors, logic gates, and logic circuits. This article mainly comments on research progress and perspectives on CAR-T cell therapy in solid tumor treatment.     

Metabolic effects of anti-angiogenic therapy in tumors

Anti-angiogenic therapy has recently been added to the panel of cancer therapeutics, but predictive biomarkers of response are still not available. In animal models, anti-angiogenic therapy causes tumor starvation by increasing hypoxia and impairing nutrients supply. It is thus conceivable that angiogenesis inhibition causes remarkable metabolic perturbations in tumors, although they remain largely uncharted. We review here recent acquisitions about metabolic effects of angiogenesis blockade in tumors and discuss the possibility that some metabolic features of tumor cells - i.e. their dependency from glucose as primary energy substrate - might affect tumor responses to anti-VEGF treatment.     

增强型肿瘤特异性启动子介导CDTK治疗肝癌的体内外研究

目的:探讨运用增强子上调肿瘤特异性启动子h TERT转录活性后,调控自杀融合基因CDTK对人肝癌细胞系Bel-7402的体内外杀伤作用。方法:将CMV增强子、h TERT启动子及CDTK自杀融合基因克隆入核糖体基因区打靶载体p Hrn,构建p Hr-Ce Tp CDTK-GFP治疗载体并转染Bel-7402细胞,经RT-PCR、HPLC、MTT检测CDTK基因的表达和对肝癌细胞的体外杀伤效果。再将Bel-7402细胞接种到裸鼠皮下致瘤,以肿瘤杀伤载体p Hr-Ce Tp CDTK-GFP进行瘤内转染并检测其抑瘤效果,此外将转染后的细胞接种致瘤,检测其成瘤时间及肿瘤生长曲线等,从两方面检测其体内杀伤效果。结果:成功构建了肿瘤特异性治疗载体,体外转染肝癌细胞后,经RTPCR、HPLC证明CDTK基因能在肝癌中表达,且治疗载体在体外对肝癌细胞有明显毒性。动物实验结果发现裸鼠致瘤后治疗组血清中5-Fu浓度为7.694μg/ml,治疗组肿瘤体积与对照组相比减小6.5倍。而细胞转染治疗载体后致瘤,治疗组成瘤时间比对照组晚8天,且治疗组裸鼠的平均生存期较对照组延长16天。结论:p Hr-Ce Tp CDTK-GFP载体能在体内外高效靶向杀伤肝癌细胞,为肝癌基因治疗提供了一种新的途径。     

Chitosan nanoparticle as gene therapy vector via gastrointestinal mucosa administration: results of an in vitro and in vivo study

This study was designed to investigate the in vitro and in vivo transfection efficiency of chitosan nanoparticles used as vectors for gene therapy. Three types of chitosan nanoparticles [quaternized chitosan -60% trimethylated chitosan oligomer (TMCO-60%), C(43-45 KDa, 87%), and C(230 KDa, 90%)] were used to encapsulate plasmid DNA (pDNA) encoding green fluorescent protein (GFP) using the complex coacervation technique. The morphology, optimal chitosan-pDNA binding ratio and conditions for maximal in vitro transfection were studied. The in vivo transfection was conducted by feeding the chitosan/pDNA nanoparticles to 12 BALB/C-nu/nu nude mice. Both conventional and TMCO-60% could form stable nanoparticles with pDNA. The in vitro study showed the transfection efficiency to be in the following descending order: TMCO-60%>C(43-45 KDa, 87%)>C(230 KDa, 90%). TMCO-60% proved to be the most efficient and the optimal chitosan/pDNA ratio being 3.2:1. In vivo study showed most prominent GPF expression in the gastric and upper intestinal mucosa. GFP expression in the mucosa of the stomach and duodenum, jejunum, ileum, and large intestine were found, respectively, in 100%, 88.9%, 77.8% and 66.7% of the nude mice examined. TMCO-60%/pDNA nanoparticles had better in vitro and in vivo transfection activity than the other two, and with minimal toxicity, which made it a desirable non-viral vector for gene therapy via oral administration.     

HER2+ mCRC patients with exon 20 R784G substitution mutation do not respond to the cetuximab therapy

The human epidermal growth factor 2 (HER2) gene undergoes various mutations that could alter its activity or respond to the antibody therapies. Cetuximab, a known anti-EGFR monoclonal antibody (mAB), is widely administered in metastatic colorectal cancer (mCRC) cases. Here we identified mCRC patients who did not respond to cetuximab (500 mg/m², q2w) after fluoropyrimidine/oxaliplatin regimen failure. Tumor samples were examined with immunohistochemistry for protein distribution, polymerase chain reaction (PCR) sequencing for mutation detection and real-time PCR for mRNA expression pattern analysis between cetuximab sensitive and resistance patients. The conformational differences of normal and mutated protein structures were predicted by bioinformatics analysis. The 5-year survival rates of target groups were estimated using the Kaplan–Meier method. Immunohistochemistry showed that all cases had high level of HER2 protein. No K-Ras or B-Raf mutation was observed among the study population; however, cetuximab resistance patients harbored a somatic mutation R784G at the exon 20 region of HER2 coding sequence. According to bioinformatics analysis, this mutation caused a notable misfold in protein conformation. Meanwhile, survival analysis showed R784G mutated mCRC patients had shortened survival rate compared with the mCRC cases with wild-type HER2. Collectively, these data report a new mechanism of resistance to cetuximab and might be applicable in modifying new therapeutic strategies for HER2 involved cancers.     

核酸适配体介导的多药耐药性肿瘤的治疗

化疗是目前肿瘤治疗最常见的方法。然而,肿瘤细胞的多药耐药（multidrug resistance,MDR）常导致临床化疗失败及患者的死亡。因此,干预和逆转肿瘤多药耐药,提高化疗效果,对于肿瘤的治疗具有重要的意义。核酸适配体是一种短的单链寡核苷酸,通过折叠形成特定空间结构从而与靶标特异性结合。靶向肿瘤的核酸适配体可以选择性地将治疗性物质（抗癌药物,siRNA,miRNA）和药物载体递送至肿瘤中,对肿瘤进行靶向杀伤。利用核酸适配体靶向多药耐药性肿瘤,能够特异性干预甚至逆转肿瘤的多药耐药性。本文概述了核酸适配体介导的干预与逆转肿瘤多药耐药性的研究进展。     

Bone marrow microenvironment: The guardian of leukemia stem cells

Bone marrow microenvironment(BMM) is the main sanctuary of leukemic stem cells(LSCs) and protects these cells against conventional therapies. However, it may open up an opportunity to target LSCs by breaking the close connection between LSCs and the BMM. The elimination of LSCs is of high importance, since they follow cancer stem cell theory as a part of this population. Based on cancer stem cell theory, a cell with stem cell-like features stands at the apex of the hierarchy and produces a heterogeneous population and governs the disease.Secretion of cytokines, chemokines, and extracellular vesicles, whether through autocrine or paracrine mechanisms by activation of downstream signaling pathways in LSCs, favors their persistence and makes the BMM less hospitable for normal stem cells. While all details about the interactions of the BMM and LSCs remain to be elucidated, some clinical trials have been designed to limit these reciprocal interactions to cure leukemia more effectively. In this review, we focus on chronic myeloid leukemia and acute myeloid leukemia LSCs and their milieu in the bone marrow, how to segregate them from the normal compartment, and finally the possible ways to eliminate these cells.