nature
● Scientists reveal the pathogenesis of liver cirrhosis at the cellular level.
The research team of N. C. Henderson and P. Ramachandran from the Inflammation Research Center of the University of Edinburgh, UK, found the fibrotic niche of cirrhosis at the single cell level. Related papers were published online in Nature on 20 19- 10.
In order to obtain the directly related pathogenesis at the cellular level and provide the basis for treatment design, they analyzed the transcriptome of more than100,000 human single cells, thus obtaining the molecular definition of non-parenchymal cell types existing in healthy and cirrhotic human livers.
They found a new type of TREM2+CD9+ macrophage subgroup related to scar, which expanded in liver fibrosis, differentiated from circulating monocytes, and promoted fibrosis. They also defined new types of ACKR 1+ and PLVAP+ endothelial cells, which proliferate in liver cirrhosis, are limited by scars in morphology and structure, and enhance the transport of white blood cells.
The multi-lineage ligand-receptor model of the interaction between new scar-associated macrophages, endothelial cells and PDGFRα+ collagen-producing mesenchymal cells reveals the in-scar activity of several fiber formation pathways, including TNFRSF 12A, PDGFR and NOTCH signals.
Their work analyzes the cellular and molecular basis of accidental fibrosis of human organs at the single cell level, and provides the conceptual framework needed to find a reasonable treatment target for liver cirrhosis.
It is reported that liver cirrhosis is the main killer in the world, and there is no effective anti-fibrosis treatment at present.
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● Study and decode the hematopoietic function of fetal liver.
Sam Behjati, Elisa Laurenti, Sarah A. Teichmann of Cambridge University and Muzlifah Haniffa of Newcastle University in the United Kingdom collaborated to decode the hematopoietic function of human fetal liver. This research result was published online in Nature on October 9th, 20 19/KLOC-0.
The researchers sequenced about 140000 liver and 74000 skin, as well as kidney and yolk sac cells, and determined the composition of human blood and immune cells during development.
Researchers infer the differentiation trajectory from hematopoietic stem cells and pluripotent progenitor cells, and evaluate the influence of tissue microenvironment on the development of blood and immune cells.
This study revealed physiological erythropoiesis in fetal skin and the existence of mast cells, natural killer cells and congenital lymphocyte precursors in yolk sac.
The study also proved that the hematopoietic composition of fetal liver changed during pregnancy, far away from the main erythroid line, accompanied by the parallel change of HSC/MPPs differentiation potential, and the researchers verified this function.
The comprehensive map of fetal liver hematopoiesis revealed in this study provides a blueprint for the study of pediatric blood and immune diseases and provides a reference for the therapeutic potential of HSC/MPP.
Researchers say that decisive hematopoiesis in fetal liver supports the self-renewal and differentiation of hematopoietic stem cells and pluripotent progenitor cells, but its role in humans is still unclear.
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● The new findings can be used as a potential therapy for melanoma.
Robert K. Bradley's team from Fred Haakinson Cancer Center in Seattle, USA, cooperated with Omar Abdel-Wahab's team from Si Long-Kettering Cancer Center in new york, and found the destruction of atypical BAF complex in cancer splicing, and based on this mechanism, proposed a kind of treatment for tumor deterioration. This research result was published online in Nature on 20 19 10 9.
The researchers combined the splicing analysis of pan-cancer with the screening of positive enrichment CRISPR to optimize the splicing changes that promote tumor occurrence.
The research team reported that various mutations of SF3B 1 focused on the inhibition of BRD9, which is the core component of the recently described atypical BAF chromatin remodeling complex, and the complex also contains GLTSCR 1 and GLTSCR 1L57. Mutant SF3B 1 recognizes the abnormal and deep intron branching point in BRD9, thus inducing the encapsulation of toxic exons from endogenous retrovirus elements and the subsequent degradation of BRD9 mRNA.
The elimination of BRD9 leads to the reduction of non-classical BAF at CTCF-related sites and promotes the occurrence of melanoma. BRD9 is a powerful inhibitor of uveal melanoma. Using antisense oligonucleotide or CRISPR-mediated mutation to correct the wrong splicing of BRD9 in SF3B 1 mutant cells can inhibit tumor growth.
It is reported that SF3B 1 is the most common mutant RNA splicing factor in cancer, but little is known about the mechanism of SF3B 1 mutation promoting malignant tumor.
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● High frequency mutation of splicing RNA of U 1 appears in cancer.
A study by Lincoln D. Stein, a research group of the University of Toronto in Canada, shows that U 1 spliced RNA has mutated in many cancers. The research results were published online in Nature on 20 19- 10.
They reported that Agt frequently appeared at the third base of U 1 snRNA in several tumor types. C somatic mutation. The main function of U 1 is to identify the relationship between 5C mutation and alcoholism in hepatocellular carcinoma and the non-mutant subtype of invasive IGHV gene in chronic lymphocytic leukemia through base pairing.
U 1 mutation can also make CLL patients independently accept poor prognosis. Their research proved one of the earliest noncoding drivers in splicing RNA, and revealed a new mechanism of abnormal splicing in cancer, which may represent a new therapeutic target.
Their findings also show that the discovery of drivers should be extended to a wider genomic region.
It is reported that cancer is caused by genomic changes called drivers. There are hundreds of drivers encoding genes, but despite in-depth search, only a few non-coding drivers have been found so far.
Recently, people's attention has shifted to the role of altered RNA splicing in cancer. Although the driving mutation leading to abnormal splicing of various transcription types is only found in splicing factors encoded by protein, it has been confirmed in various cancer types.
In contrast, due to the comprehensive challenge of characterizing non-coding cancer drivers and the repeatability of snRNA genes, there are few studies on cancer-related changes of non-coding components of splice and a series of small nuclear RNA.
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Non-coding RNA mutation can lead to Shh medulloblastoma.
Recently, Michael D. Taylor's research team at the Sick Children's Hospital in Canada found that the repeated non-coding mutation U 1-snRNA drives the recessive splicing of Shh-type blastoma. 20 19 10 9, the internationally renowned academic journal nature published this achievement online.
The researchers reported a highly recurrent hot spot mutation in the small nuclear RNA of splice U 1 in about 50% of Sonic hedgehog medulloblastoma, which did not exist in other medulloblastoma subtypes.
In 2442 cases of 36 other tumor types, it was found that the hot spot mutation of U 1-snRNA was less than 0. 1%. There is basically no such mutation in infant Shh-MB, but 97% adults and 25% adolescents have such mutation.
The mutation of U 1-snRNA occurred at the junction of five splicing sites, and the tumor with snRNA mutation significantly destroyed RNA splicing, with an excessive number of five recessive splicing events. Mutant U 1-snRNA-mediated alternative splicing inactivates tumor suppressor genes and activates oncogenes, which is a new therapeutic target and causes high recurrence and tissue-specific mutation of non-protein coding genes in cancer.
It is reported that recurrent somatic single nucleotide variation in cancer is largely confined to protein coding gene, which is rare in most childhood cancers.
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British medical journal
● Correlation between nonalcoholic fatty liver disease and the risk of acute myocardial infarction and stroke.
A recent study by Naveed Sattar of Erasmus University Medical Center in Rotterdam, the Netherlands, analyzed the correlation between nonalcoholic fatty liver disease and the risk of acute myocardial infarction and stroke. Related papers 20 19 10 8 were published online in the British Medical Journal.
The research team collected the population-based electronic basic health databases of four European countries before 20 15 12 3 1, including Italy 1542672, Netherlands 2225925, Spain 5488397 and Britain 12695046. 120795 patients with NAFLD or nonalcoholic steatohepatitis were followed up for an average of 2. 1-5.5 years.
After adjusting for age and smoking, compared with the matched control group, the risk ratio of AMI in NAFLD or NASH patients was 1. 17, and the comprehensive risk ratio of stroke was 1. 18.
In the group with more complete data of risk factors, after adjusting systolic blood pressure, type 2 diabetes, total cholesterol level, statin use and hypertension, the risk ratio of AMI in patients with NAFLD or NASH was 1.0 1, and the risk ratio of stroke was 1.04.
In short,17.7 million patients received routine care. After excluding cardiovascular risk factors, the diagnosis of NAFLD has nothing to do with AMI or stroke risk. Adult cardiovascular risk assessment of patients with nonalcoholic fatty liver disease is very important, but it does not need to be carried out in a special way.
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● China scientists systematically evaluated the efficacy of first-line treatment for non-small cell lung cancer.
The research team of Professor Jianxing He from the First Affiliated Hospital of Guangzhou Medical University conducted a systematic evaluation and network meta-analysis on the effectiveness and safety of first-line treatment of advanced non-small cell lung cancer with epidermal growth factor receptor mutation. This research result was published online in the British Medical Journal on October 7th, 20 19/KLOC-0.
The research team searched the well-known databases such as PubMed, Embase, Cochrane Central Controlled Trial Registration Center and ClnicalTrials.gov for documents that met the standards before May 20th, 201September.
All the selected studies compared more than two kinds of first-line treatments for patients with advanced EGFR mutation non-small cell lung cancer, and reported at least one of the following clinical outcome indicators: progression-free survival, overall survival, objective remission rate and grade 3 or above adverse reactions.
18 eligible trials included 4628 patients and 12 treatments: EGFR tyrosine kinase inhibitor, pemetrexed-based chemotherapy, pemetrexed free chemotherapy and combination therapy.
Compared with gefitinib+pemetrexed chemotherapy, oxitinib showed the most favorable progression-free survival, which was significantly better than dactinib, afatinib, erlotinib, gefitinib, ectinib, pemetrexed-based chemotherapy, pemetrexed free chemotherapy, afatinib+cetuximab and gefitinib+pemetrexed.
Oxytinib and gefitinib combined with pemetrexed-based chemotherapy are similar in providing the best overall survival benefits.
However, the combined therapy is more toxic, especially erlotinib+bevacizumab, which may easily lead to serious adverse events above grade 3.
Different EGFR-TKIs show different toxicity spectra. Subgroup analysis of the two most common EGFR mutation types showed that in patients with exon 19 deletion, oxitinib was associated with the best progression-free survival, while in patients with Leu858Arg mutation, gefitinib+pemetrexed chemotherapy was associated with the best progression-free survival.
In short, compared with other first-line treatments, the chemotherapy regimen of osetinib and gefitinib combined with pemetrexed can significantly improve the progression-free survival and overall survival of patients with advanced EGFR mutation non-small cell lung cancer.
For patients with exon 19 deletion and mutation of Leu858Arg, the progression-free survival time of chemotherapy with osetinib and gefitinib+pemetrexed is the best.
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● Systematic review of prognosis model for patients with chronic obstructive pulmonary disease.
Evanger Evangelou, a research team from Aninat University School of Medicine, systematically analyzed and critically evaluated the prognosis prediction model of patients with chronic obstructive pulmonary disease. The research results were published online in the British Medical Journal on 20 19 10 4.
The research group systematically searched 228 eligible literatures, describing the development of 408 prognostic models, the external verification of 38 models, and the verification of 20 prognostic models of diseases other than COPD.
408 prognostic models were established in three clinical environments: 239 outpatients, 0/55 inpatients and 0/4 emergency patients.
Among these 408 prognostic models, the most common end points are mortality, acute exacerbation of COPD and risk of re-hospitalization.
Generally speaking, the most commonly used predictors are age, one-second forced expiratory volume, gender, body mass index and smoking. Of the 408 prediction models, 100 has been verified internally, and 9 1 has tested the calibrated development model.
286 models cannot be displayed, and the complete equation can only display 56 models. C statistical model can distinguish 3 1 1 models.
38 models were verified externally, but only 12 models were verified by a completely independent team. Only 7 prognostic models have a low risk of overall bias.
In a word, this study describes and evaluates the prognosis prediction model of COPD patients in detail, and finds that there are some methodological defects in its development process, and the external verification rate is low.
Future research should focus on improving these existing models through updating and external verification, and evaluate their safety, clinical effectiveness and cost-effectiveness in clinical practice.
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