Inducing and exploiting vulnerabilities for the treatment of liver cancer
西晋灭亡
干鱿鱼的做法Abstract
Liver cancer remains difficult to treat, owing to a paucity of drugs that target critical dependencies; broad-spectrum kina inhibitors such as sorafenib provide only a modest benefit to patients with hepatocellular carcinoma. The induction of nescence may reprent a strategy for the treatment of cancer, especially when combined with a cond drug that lectively eliminates nescent cancer cells (nolysis). Here, using a kinome-focud genetic screen, we show that pharmacological inhibition of the DNA-replication kina CDC7 induces nescence lectively in liver cancer cells with mutations in TP53. A follow-up chemical screen identified the antidepressant rtraline as an agent that kills hepatocellular carcinoma cells that have been rendered nescent by inhibition of CDC7. Sertraline suppresd mTOR signalling, and lective drugs that target this pathway were highly effective in causing the apoptotic cell death of hepatocellular carcinoma cells treated with a CDC7 inhibitor. The feedback reactivation of mTOR signalling after its inhibition is blo钢琴教材
cked in cells that have been treated with a CDC7 inhibitor, which leads to the sustained inhibition of mTOR and cell death. Using multiple in vivo mou models of liver cancer, we show that treatment with combined inhibition of of CDC7 and mTOR results in a marked reduction of tumour growth. Our data indicate that exploiting an induced vulnerability could be an effective treatment for liver cancer.
由于缺乏针对关键依赖性的药物，肝癌仍然难以治疗。广谱激酶抑制剂（如索拉非尼）仅对肝细胞癌患者提供适度的益处。衰老的诱导可能代表了癌症的治疗策略，特别是与第二种药物选择性地消除衰老的癌细胞（衰老）结合使用时。在这里，使用针对kinome的遗传筛选，我们表明DNA复制激酶CDC7的药理学抑制作用选择性诱导TP53突变的肝癌细胞衰老。后续化学筛查确定抗抑郁药舍曲林为杀伤因抑制CDC7而衰老的肝癌细胞的药物。舍曲林抑制mTOR信号传导，靶向该途径的选择性药物在引起用CDC7抑制剂治疗的肝癌细胞凋亡中非常有效。抑制mTOR信号后的反馈重新激活在已经用CDC7抑制剂处理过的细胞中被阻断，这导致mTOR的持续抑制和细胞死亡。使用多种肝癌的体内小鼠模型，我们显示CDC7和mTOR联合抑制的治疗导致肿瘤生长明显降低。我们的数据表明，利用诱发的脆弱性可能是治疗肝癌的有效方法。
Coordinated alterations in RNA splicing and epigenetic regulation drive leukaemogenesis
Abstract泰姬陵在哪
Transcription and pre-mRNA splicing are key steps in the control of gene expression and mutations in genes regulating each of the process are common in leukaemia. Despite the frequent overlap of mutations affecting epigenetic regulation and splicing in leukaemia, how the process influence one another to promote leukaemogenesis is not understood and, to our knowledge, there is no functional evidence that mutations in RNA splicing factors initiate leukaemia. Here, through analys of transcriptomes from 982 patients with acute myeloid leukaemia, we identified frequent overlap of mutations in IDH2 and SRSF2 that together promote leukaemogenesis through coordinated effects on the epigenome and RNA splicing. Whereas mutations in either IDH2 or SRSF2 imparted distinct splicing changes, co-expression of mutant IDH2 altered the splicing effects of mutant SRSF2 and resulted in more profound splicing changes than either mutation alone. Consistent with this, co-expression of mutant IDH2 and SRSF2 resulted in lethal m
yelodysplasia with proliferative features in vivo and enhanced lf-renewal in a manner not obrved with either mutation alone. IDH2 and SRSF2 double-mutant cells exhibited aberrant splicing and reduced expression of INTS3, a member of the integrator complex, concordant with incread stalling of RNA polymera II (RNAPII). Aberrant INTS3 splicing contributed to leukaemogenesis in concert with mutant IDH2 and was dependent on mutant SRSF2 binding to cis elements in INTS3 mRNA and incread DNA methylation of INTS3. The data identify a pathogenic crosstalk between altered epigenetic state and splicing in a subt of leukaemias, provide functional evidence that mutations in splicing factors drive myeloid malignancy development, and identify spliceosomal changes as a mediator of IDH2-mutant leukaemogenesis.
转录和mRNA剪接是控制基因表达的关键步骤，在白血病中，调节这些过程的基因突变很常见。尽管影响白血病的表观遗传调控和剪接的突变经常重叠，但尚不清楚这些过程如何相互影响以促进白血病的发生，据我们所知，没有功能证据表明RNA剪接因子中的突变会引发白血病。在这里，通过分析982例急性髓性白血病患者的转录组，我们发现IDH2和SRSF2突变的频繁重叠，通过对表观基因组和RNA剪接的协同作用共同促进白血病的发生。
尽管IDH2或SRSF2中的突变赋予明显的剪接变化，但突变体IDH2的共表达改变了突变体SRSF2的剪接效果，并导致比单独的任一突变更深刻的剪接变化。与此相一致，突变体IDH2和SRSF2的共表达导致具有体内增殖特征的致死性骨髓增生异常，并且以单独两种突变均未观察到的方式增强了自我更新。 IDH2和SRSF2双突变细胞表现出异常的剪接和INTS3的表达减少，INTS3是整合子复合体的成员，与RNA聚合酶II（RNAPII）的失速增加相一致。异常的INTS3剪接与突变IDH2协同促成白血病的发生，并且依赖于突变SRSF2与INTS3 mRNA中的顺式元素结合以及INTS3的DNA甲基化增加。这些数据确定了白血病的子集中表观遗传状态和剪接之间的致病串扰，提供了剪接因子突变驱动髓系恶性肿瘤发展的功能证据，并确定剪接体变化是IDH2突变性白细胞生成的媒介。
Host-Microbe-Drug-Nutrient Screen Identifies Bacterial Effectors of Metformin Therapy
Summary
Metformin is the first-line therapy for treating type 2 diabetes and a promising anti-aging drug. We t out to address the fundamental question of how gut microbes and nutrition, key regulators of host physiology, affect the effects of metformin. Combining two tractable
genetic models, the bacterium E. coli and the nematode C. elegans, we developed a high-throughput four-way screen to define the underlying host-microbe-drug-nutrient interactions. We show that microbes integrate cues from metformin and the diet through the phosphotransfera signaling pathway that converges on the transcriptional regulator Crp. A detailed experimental characterization of metformin effects downstream of Crp in combination with metabolic modeling of the microbiota in metformin-treated type 2 diabetic patients predicts the production of microbial agmatine, a regulator of metformin effects on host lipid metabolism and lifespan. Our high-throughput screening platform paves the way for identifying exploitable drug-nutrient-microbiome interactions to improve host health and longevity through targeted microbiome therapies.
二甲双胍是治疗2型糖尿病的一线疗法，也是一种有前途的抗衰老药物。我们着手解决一个基本问题，即肠道微生物和营养（宿主生理的关键调节剂）如何影响二甲双胍的作用。结合了两个易于处理的遗传模型，即细菌大肠杆菌和线虫秀丽隐杆线虫，我们开发了一种高通量的四向筛选技术，以定义潜在的宿主-微生物-药物-营养相互作用。我们表明，微生物通过聚合在转录调节因子Crp上的磷酸转移酶信号通路整合了来自二甲双胍和饮食的线索。春节横幅
Crp下游的二甲双胍作用的详细实验表征，结合二甲双胍治疗的2型糖尿病患者的微生物群代谢模型，预测了微生物胍丁胺的产生，胍丁胺是二甲双胍对宿主脂质代谢和寿命影响的调节剂。我们的高通量筛选平台为确定可利用的药物-营养物-微生物组之间的相互作用铺平了道路，从而可以通过针对性的微生物组疗法改善宿主的健康状况和寿命。
Tau-Mediated Disruption of the Spliceosome Triggers Cryptic RNA Splicing and Neurodegeneration in Alzheimer’s Dia
Summary
In Alzheimer’s dia (AD), spliceosomal proteins with critical roles in RNA processing aberrantly aggregate and mislocalize to Tau neurofibrillary tangles. We test the hypothesis that Tau-spliceosome interactions disrupt pre-mRNA splicing in AD. In human postmortem brain with AD pathology, Tau coimmunoprecipitates with spliceosomal components. In Drosophila, pan-neuronal Tau expression triggers reductions in multiple core and U1-specific spliceosomal proteins, and genetic disruption of the factors, including SmB, U1-70K, and U1A, enhances Tau-mediated neurodegeneration. We furthe
r show that loss of function in SmB, encoding a core spliceosomal protein, caus decread survival, progressive locomotor impairment, and neuronal loss, independent of Tau toxicity. Lastly, RNA quencing reveals a similar profile of mRNA splicing errors in SmB mutant and Tau transgenic flies, including intron retention and non-annotated cryptic splice junctions. In human brains, we confirm cryptic splicing errors in association with neurofibrillary tangle burden. Our results implicate spliceosome disruption and the resulting transcriptome perturbation in Tau-mediated neurodegeneration in AD.
在阿尔茨海默氏病（AD）中，在RNA处理中起关键作用的剪接体蛋白异常聚集并错位到Tau神经原纤维缠结中。我们测试Tau剪接体相互作用破坏AD中的前mRNA剪接的假设。在具有AD病理的人类死后大脑中，Tau与剪接体成分共免疫沉淀。在果蝇中，泛神经元Tau的表达触发了多个核心和U1特异性剪接体蛋白的减少，而这些基因（包括SmB，U1-70K和U1A）的遗传破坏增强了Tau介导的神经变性。我们进一步表明，编码核心剪接体蛋白的SmB功能丧失会导致存活率降低，进行性运动障碍和神经元丧失，而与Tau毒性无关。最后，RNA测序揭示了SmB突变体和Tau转基因果蝇中mRNA剪接错误的相似情况，包括内含子保留和未注释的隐性剪接。在人的大脑中，我们确认了与神经原纤维缠结负担相关的
隐秘剪接错误。我们的结果暗示了AD中Tau介导的神经变性中的剪接体破坏和转录组扰动。
翁的组词和拼音Integrated genomic profiling expands clinical options for patients with cancer文彦博
Abstract
Genomic analysis of paired tumor–normal samples and clinical data can be ud to match patients to cancer therapies or clinical trials. We analyzed 500 patient samples across diver tumor types using the Tempus xT platform by DNA-q, RNA-q and immunological biomarkers. The u of a tumor and germline datat led to substantial improvements in mutation identification and a reduction in fal-positive rates. RNA-q enhanced gene fusion detection and cancer type classifications. With DNA-q alone, 29.6% of patients matched to precision therapies supported by high levels of evidence or by well-powered studies. This proportion incread to 43.4% with the addition of RNA-q and immunotherapy biomarker results. Combining the data with clinical criteria, 76.8% of patients were matched to at least one relevant clinical trial on the basis of biom
arkers measured by the xT assay. The results indicate that extensive molecular profiling combined with clinical data identifies personalized therapies and clinical trials for a large proportion of patients with cancer and that paired tumor–normal plus transcriptome quencing outperforms tumor-only DNA panel testing.
