Noncoding RNAs in cancer and cancer stem cells

In recent years, it has become increasingly apparent that noncoding RNAs(ncRNA) are of crucial importance for human cancer. The functional relevance of ncRNAs is particularly evident for microRNAs(miRNAs) and long noncoding RNAs(lncRNAs). miRNAs are endogenously expressed small RNA sequences that act as post-transcriptional regulators of gene expression and have been extensively studied for their roles in cancers, whereas lncRNAs are emerging as important players in the cancer paradigm in recent years. These noncoding genes are often aberrantly expressed in a variety of human cancers. However, the biological functions of most ncRNAs remain largely unknown. Recently, evidence has begun to accumulate describing how ncRNAs are dysregulated in cancer and cancer stem cells, a subset of cancer cells harboring self-renewal and differentiation capacities. These studies provide insight into the functional roles that ncRNAs play in tumor initiation, progression, and resistance to therapies, and they suggest ncRNAs as attractive therapeutic targets and potentially useful diagnostic tools.

Reciprocal effects of alpha-synuclein aggregation and lysosomal homeostasis in synucleinopathy models

Background Lysosomal dysfunction has been implicated in a number of neurodegenerative diseases such as Parkinson’s disease(PD).Various molecular,clinical and genetic studies have highlighted a central role of lysosomal pathways and proteins in the pathogenesis of PD.Within PD pathology the synaptic protein alpha-synuclein(αSyn)converts from a soluble monomer to oligomeric structures and insoluble amyloid fibrils.The aim of this study was to unravel the effect ofαSyn aggregates on lysosomal turnover,particularly focusing on lysosomal homeostasis and cathepsins.Since these enzymes have been shown to be directly involved in the lysosomal degradation ofαSyn,impairment of their enzymatic capacity has extensive consequences.Methods We used patient-derived induced pluripotent stem cells and a transgenic mouse model of PD to examine the effect of intracellularαSyn conformers on cell homeostasis and lysosomal function in dopaminergic(DA)neurons by biochemical analyses.Results We found impaired lysosomal trafficking of cathepsins in patient-derived DA neurons and mouse models withαSyn aggregation,resulting in reduced proteolytic activity of cathepsins in the lysosome.Using a farnesyltransferase inhibitor,which boosts hydrolase transport via activation of the SNARE protein ykt6,we enhanced the maturation and proteolytic activity of cathepsins and thereby decreasedαSyn protein levels.Conclusions Our findings demonstrate a strong interplay betweenαSyn aggregation pathways and function of lysosomal cathepsins.It appears thatαSyn directly interferes with the enzymatic function of cathepsins,which might lead to a vicious cycle of impairedαSyn degradation.

DNA damage and metabolic mechanisms of cancer drug resistance

Cancer drug resistance is one of the main barriers to overcome to ensure durable treatment responses.While many pivotal advances have been made in first combination therapies,then targeted therapies,and now broadening out to immunomodulatory drugs or metabolic targeting compounds,drug resistance is still ultimately universally fatal.In this brief review,we will discuss different strategies that have been used to fight drug resistance from synthetic lethality to tumor microenvironment modulation,focusing on the DNA damage response and tumor metabolism both within tumor cells and their surrounding microenvironment.In this way,with a better understanding of both targetable mutations in combination with the metabolism,smarter drugs may be designed to combat cancer drug resistance.

Tumor microenvironment signaling and therapeutics in cancer progression

Tumor development and metastasis are facilitated by the complex interactions between cancer cells and theirmicroenvironment,which comprises stromal cells and extracellular matrix(ECM)components,among other factors.Stromal cells can adopt new phenotypes to promote tumor cell invasion.Adeep understanding of the signaling pathways involved in cell-to-cell and cell-to-ECM interactions is needed to design effective intervention strategies that might interrupt these interactions.In this review,we describe the tumor microenvironment(TME)components and associated therapeutics.We discuss the clinical advances in the prevalent and newly discovered signaling pathways in the TME,the immune checkpoints and immunosuppressive chemokines,and currently used inhibitors targeting these pathways.These include both intrinsic and non-autonomous tumor cell signaling pathways in the TME:protein kinase C(PKC)signaling,Notch,and transforming growth factor(TGF-β)signaling,Endoplasmic Reticulum(ER)stress response,lactate signaling,Metabolic reprogramming,cyclic GMP–AMP synthase(cGAS)–stimulator of interferon genes(STING)and Siglec signaling pathways.We also discuss the recent advances in Programmed Cell Death Protein 1(PD-1),Cytotoxic T-Lymphocyte Associated Protein 4(CTLA4),T-cell immunoglobulin mucin-3(TIM-3)and Lymphocyte Activating Gene 3(LAG3)immune checkpoint inhibitors along with the C-C chemokine receptor 4(CCR4)-C-C class chemokines 22(CCL22)/and 17(CCL17),C-C chemokine receptor type 2(CCR2)-chemokine(C-Cmotif)ligand 2(CCL2),C-C chemokine receptor type 5(CCR5)-chemokine(C-C motif)ligand 3(CCL3)chemokine signaling axis in the TME.In addition,this review provides a holistic understanding of the TME as we discuss the three-dimensional and microfluidic models of the TME,which are believed to recapitulate the original characteristics of the patient tumor and hence may be used as a platform to study new mechanisms and screen for various anti-cancer therapies.We further discuss the systemic influences of gut microbiota in TME reprogramming and treatment response.Overall,this review provides a comprehensive analysis of the diverse and most critical signaling pathways in the TME,highlighting the associated newest and critical preclinical and clinical studies along with their underlying biology.We highlight the importance of the most recent technologies of microfluidics and lab-on-chip models for TME research and also present an overview of extrinsic factors,such as the inhabitant human microbiome,which have the potential to modulate TME biology and drug responses.

隐源性卒中的心电监测策略：2015年卒中诊断和监测专题组的报告

卒中是一个重要的全球性公共卫生问题。2010年全世界总共发生3300万例卒中，其中1690万为首发卒中。卒中是仅次于心脏病的第二大全球人口死亡原因，占全部死亡的10％以上。卒中是一类异质性疾病，其病因可以是血管破裂（出血性）或血管闭塞（缺血性）。缺血性卒中约占全部卒中的85％，可根据发病机制进行分类。