Exosomal miR-146a-5p and miR-155-5p promote CXCL12/CXCR7-induced metastasis of colorectal cancer by crosstalk with cancer-associated fibroblasts

C-X-C motif chemokine receptor 7 (CXCR7) is a newly discovered atypical chemokine receptor that binds to C-X-C motif chemokine ligand 12 (CXCL12) with higher affinity than CXCR4 and is associated with the metastasis of colorectal cancer (CRC). Cancer-associated fibroblasts (CAFs) have been known to promote tumor progression. However, whether CAFs are involved in CXCR7-mediated metastasis of CRC remains elusive. We found a significant positive correlation between CXCR7 expression and CAF activation markers in colonic tissues from clinical specimens and in villin-CXCR7 transgenic mice. RNA sequencing revealed a coordinated increase in the levels of miR-146a-5p and miR-155-5p in CXCR7-overexpressing CRC cells and their exosomes. Importantly, these CRC cell-derived miR-146a-5p and miR-155-5p could be uptaken by CAFs via exosomes and promote the activation of CAFs through JAK2–STAT3/NF-κB signaling by targeting suppressor of cytokine signaling 1 (SOCS1) and zinc finger and BTB domain containing 2 (ZBTB2). Reciprocally, activated CAFs further potently enhanced the invasive capacity of CRC cells. Mechanistically, CAFs transfected with miR-146a-5p and miR-155-5p exhibited a robust increase in the levels of inflammatory cytokines interleukin-6, tumor necrosis factor-α, transforming growth factor-β, and CXCL12, which trigger the epithelial–mesenchymal transition and pro-metastatic switch of CRC cells. More importantly, the activation of CAFs by miR-146a-5p and miR-155-5p facilitated tumor formation and lung metastasis of CRC in vivo using tumor xenograft models. Our work provides novel insights into CXCR7-mediated CRC metastasis from tumor–stroma interaction and serum exosomal miR-146a-5p and miR-155-5p could serve as potential biomarkers and therapeutic targets for inhibiting CRC metastasis.Subject terms: Cancer microenvironment, Colon cancer     

TNFAIP8 protein functions as a tumor suppressor in inflammation-associated colorectal tumorigenesis

Tumor necrosis factor-α-induced protein 8 (TNFAIP8 or TIPE) is a member of the TNFAIP8 family. While TIPE was broadly considered to be pro-cancerous, its precise roles in carcinogenesis especially those of the intestinal tract are not clear. Here, we show that genetic deletion of TIPE in mice exacerbated chemical-induced colitis and colitis-associated colon cancer. Loss of TIPE exacerbated inflammatory responses and inflammation-associated dysbiosis, leading to the activation of NF-κB and STAT3, and it also accelerated dysplasia, DNA damage and proliferation of intestinal epithelial cells. We further show that colon microbiota were essential for increased tumor growth and progression in Tipe^−/− mice. The tumor suppressive function of TIPE originated primarily from the non-hematopoietic compartment. Importantly, TIPE was downregulated in human colorectal cancers, and patients with low levels of Tipe mRNA were associated with reduced survival. These results indicate that TIPE serves as an important modulator of colitis and colitis-associated colon cancer.Subject terms: Cancer microenvironment, Chronic inflammation     

暗色真菌威尼克何德霉浅部皮肤及附属器感染的特征分析

目的分析暗色真菌威尼克何德霉菌浅部皮肤及附属器感染的特征。方法收集2016年5月至2020年5月期间我科就诊的威尼克何德霉感染病例7例。总结威尼克何德霉菌的特点,分析皮肤及附属器感染病例的临床特征及诊断。结果其中4例为掌黑癣病例,临床表现均为手部单个扁平、暗棕色斑片,无明显鳞屑,界限清楚。另外3例与掌黑癣的临床表现不同,分别表现为手部湿疹样改变、指甲损害及足癣样变。结论威尼克何德霉除了可引起掌黑癣外,还可能引起手部湿疹样改变、甲真菌病及足癣样变等非掌黑癣表现,掌黑癣可通过临床表现及真菌学检查诊断。若以非掌黑癣为临床表现的威尼克何德霉感染,容易误诊漏诊,应引起临床重视。     

Patient contrastive learning: A performant,expressive, and practical approach to electrocardiogram modeling

Supervised machine learning applications in health care are often limited due to a scarcity of labeled training data. To mitigate the effect of small sample size, we introduce a pre-training approach, Patient Contrastive Learning of Representations (PCLR), which creates latent representations of electrocardiograms (ECGs) from a large number of unlabeled examples using contrastive learning. The resulting representations are expressive, performant, and practical across a wide spectrum of clinical tasks. We develop PCLR using a large health care system with over 3.2 million 12-lead ECGs and demonstrate that training linear models on PCLR representations achieves a 51% performance increase, on average, over six training set sizes and four tasks (sex classification, age regression, and the detection of left ventricular hypertrophy and atrial fibrillation), relative to training neural network models from scratch. We also compared PCLR to three other ECG pre-training approaches (supervised pre-training, unsupervised pre-training with an autoencoder, and pre-training using a contrastive multi ECG-segment approach), and show significant performance benefits in three out of four tasks. We found an average performance benefit of 47% over the other models and an average of a 9% performance benefit compared to best model for each task. We release PCLR to enable others to extract ECG representations at https://github.com/broadinstitute/ml4h/tree/master/model_zoo/PCLR.     

基于转录组的肝豆状核变性调控网络的构建和分析

本研究旨在利用生物信息学方法构建经铜诱导的ATP7B基因敲除HepG2细胞系的转录调控网络。探讨关键转录因子在肝豆状核变性发生、发展中的潜在作用机制。收集公共基因表达数据库(gene expression omnibus, GEO)中包含野生型、ATP7B基因敲除型、铜诱导的野生型和铜诱导的ATP7B基因敲除型HepG2细胞系数据。筛选由铜诱导产生的差异表达基因(differentially expressed genes,DEGs)后进行基因本体论(gene ontology,GO)、京都基因和基因组百科全书(Kyoto encyclopedia of genes and genomes, KEGG)富集分析。基于蛋白相互作用网络,识别疾病关键基因和功能模块,并对关键功能模块中的基因进行富集分析。最后,构建转录调控网络,筛选核心转录因子。共筛选出1 034个差异表达基因,其中上调525个,下调509个。上、下调关键功能模块分别包括了3785个和3931个基因。关键功能模块中的基因主要定位于细胞-基质连接、染色体、剪接复合体、核糖体等区域,共同参与了mRNA加工、组蛋白修饰、RNA剪切...     

Recombinant protein subunit vaccine booster following two-dose inactivated vaccines dramatically enhanced anti-RBD responses and neutralizing titers against SARS-CoV-2 and Variants of Concern

Dear Editor, As of October,2021,SARS-CoV-2 has infected more than 230 million people;promoting roll-out vaccinations could help build herd immunity for the pand...     

Intraspecific trait variation of woody species reduced in a savanna community,southwest China

Plants deploy various ecological strategies in response to environmental heterogeneity. In many forest ecosystems, plants have been reported to have notable inter- and intra-specific trait variation, as well as clear phylogenetic signals, indicating that these species possess a degree of phenotypic plasticity to cope with habitat variation in the community. Savanna communities, however, grow in an open canopy structure and exhibit little species diversification, likely as a result of strong environmental stress. In this study, we hypothesized that the phylogenetic signals of savanna species would be weak, the intraspecific trait variation (ITV) would be low, and the contribution of intraspecific variation to total trait variance would be reduced, owing to low species richness, multiple stresses and relatively homogenous community structure. To test these hypotheses, we sampled dominant woody species in a dry-hot savanna in southwestern China, focusing on leaf traits related to adaptability of plants to harsh conditions (year-round intense radiation, low soil fertility and seasonal droughts). We found weak phylogenetic signals in leaf traits and low ITV (at both individual and canopy-layer levels). Intraspecific variation (including leaf-, layer- and individual-scales) contributed little to the total trait variance, whereas interspecific variation and variation in leaf phenology explained substantial variance. Our study suggests that intraspecific trait variation is reduced in savanna community. Furthermore, our findings indicate that classifying species by leaf phenology may help better understand how species coexist under similar habitats with strong stresses.