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"Liu, Tian"
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The Chinese Society of Clinical Oncology (CSCO): clinical guidelines for the diagnosis and treatment of gastric cancer
China is one of the countries with the highest incidence of gastric cancer. There are differences in epidemiological characteristics, clinicopathological features, tumor biological characteristics, treatment patterns, and drug selection between gastric cancer patients from the Eastern and Western countries. Non-Chinese guidelines cannot specifically reflect the diagnosis and treatment characteristics for the Chinese gastric cancer patients. The Chinese Society of Clinical Oncology (CSCO) arranged for a panel of senior experts specializing in all sub-specialties of gastric cancer to compile, discuss, and revise the guidelines on the diagnosis and treatment of gastric cancer based on the findings of evidence-based medicine in China and abroad. By referring to the opinions of industry experts, taking into account of regional differences, giving full consideration to the accessibility of diagnosis and treatment resources, these experts have conducted experts’ consensus judgement on relevant evidence and made various grades of recommendations for the clinical diagnosis and treatment of gastric cancer to reflect the value of cancer treatment and meeting health economic indexes. This guideline uses tables and is complemented by explanatory and descriptive notes covering the diagnosis, comprehensive treatment, and follow-up visits for gastric cancer.
Journal Article
Cryptic activation of an Irf8 enhancer governs cDC1 fate specification
Induction of the transcription factor
Irf8
in the common dendritic cell progenitor (CDP) is required for classical type 1 dendritic cell (cDC1) fate specification, but the mechanisms controlling this induction are unclear. In the present study
Irf8
enhancers were identified via chromatin profiling of dendritic cells and CRISPR/Cas9 genome editing was used to assess their roles in
Irf8
regulation. An enhancer 32 kilobases (kb) downstream of the
Irf8
transcriptional start site (+32-kb
Irf8
) that was active in mature cDC1s was required for the development of this lineage, but not for its specification. Instead, a +41-kb
Irf8
enhancer, previously thought to be active only in plasmacytoid dendritic cells, was found to also be transiently accessible in cDC1 progenitors, and deleting this enhancer prevented the induction of
Irf8
in CDPs and abolished cDC1 specification. Thus, cryptic activation of the +41-kb
Irf8
enhancer in dendritic cell progenitors is responsible for cDC1 fate specification.
The transcription factor IRF8 is essential for classical type 1 dendritic cell (cDC1) development. Murphy and colleagues investigate in detail the molecular control of cDC1 fate specification by systematically unpicking the IRF8 enhancer regions.
Journal Article
Theophylline Extracted from Fu Brick Tea Affects the Metabolism of Preadipocytes and Body Fat in Mice as a Pancreatic Lipase Inhibitor
The dramatic increase in obesity is putting people under increasing pressure. Lipase inhibitors, as a kind of effective anti-obesity drug, have attracted more and more researchers’ attention in recent years because of their advantages of acting on the intestinal tract and having no side effects on the central nervous system. In this study, lipase inhibitor Fu Brick Theophylline (FBT) was screened based on enzyme molecular dynamics, and the inhibition mechanism of lipase inhibitors on obesity was analyzed and discussed at the cellular level and animal model level. We found that FBT had high inhibition effects of lipase with an IC50 of 1.02~0.03 μg/mL. Firstly, the laboratory used 3T3-L1 proadipocytes as models, flow cytometry was used to detect the effects of FBT on the cycle, apoptosis and intracellular ROS activity of proadipocytes. To study the contents of triglyceride, total cholesterol, related metabolites and related gene and protein expression in adipocytes. The results showed that FBT could reduce ROS production and inflammatory factor mRNA expression during cell differentiation. Secondly, by establishing the animal model of high-fat feed ob nutritional obese mice, the morphological observation and gene expression analysis of body weight, fat rate, adipocyte and hepatocyte metabolism of FBT obese mice were further discussed. It was proven that FBT can effectively reduce the degree of fatty liver, prevent liver fibrosis and fat accumulation, and improve the damage of mitochondrial membrane structure. This study provides a theoretical basis for the screening and clinical treatment of lipase inhibitors.
Journal Article
An Nfil3–Zeb2–Id2 pathway imposes Irf8 enhancer switching during cDC1 development
Classical type 1 dendritic cells (cDC1s) are required for antiviral and antitumor immunity, which necessitates an understanding of their development. Development of the cDC1 progenitor requires an E-protein-dependent enhancer located 41 kilobases downstream of the transcription start site of the transcription factor
Irf8
(+41-kb
Irf8
enhancer), but its maturation instead requires the
Batf3
-dependent +32-kb
Irf8
enhancer. To understand this switch, we performed single-cell RNA sequencing of the common dendritic cell progenitor (CDP) and identified a cluster of cells that expressed transcription factors that influence cDC1 development, such as
Nfil3, Id2
and
Zeb2
. Genetic epistasis among these factors revealed that
Nfil3
expression is required for the transition from
Zeb2
hi
and
Id2
lo
CDPs to
Zeb2
lo
and
Id2
hi
CDPs, which represent the earliest committed cDC1 progenitors. This genetic circuit blocks E-protein activity to exclude plasmacytoid dendritic cell potential and explains the switch in
Irf8
enhancer usage during cDC1 development.
Classical type 1 dendritic cells (cDC1s) are essential for activation of antiviral and anticancer T cell responses. Murphy and colleagues describe a genetic circuit that involves the transcription factors
Nfil3
,
Id2
and
Zeb2
. This circuit imposes a molecular switch that allows cDC1 specification and development.
Journal Article
The Toxicity and Polymorphism of β-Amyloid Oligomers
It is widely accepted that β-amyloid oligomers (Aβos) play a key role in the progression of Alzheimer’s disease (AD) by inducing neuron damage and cognitive impairment, but Aβos are highly heterogeneous in their size, structure and cytotoxicity, making the corresponding studies tough to carry out. Nevertheless, a number of studies have recently made remarkable progress in the describing the characteristics and pathogenicity of Aβos. We here review the mechanisms by which Aβos exert their neuropathogenesis for AD progression, including receptor binding, cell membrane destruction, mitochondrial damage, Ca2+ homeostasis dysregulation and tau pathological induction. We also summarize the characteristics and pathogenicity such as the size, morphology and cytotoxicity of dimers, trimers, Aβ*56 and spherical oligomers, and suggest that Aβos may play a different role at different phases of AD pathogenesis, resulting in differential consequences on neuronal synaptotoxicity and survival. It is warranted to investigate the temporal sequence of Aβos in AD human brain and examine the relationship between different Aβos and cognitive impairment.
Journal Article
Circles reshaping the RNA world: from waste to treasure
A new type of RNAs was identified from genes traditionally thought to express messenger or linear ncRNA (noncoding RNA) only. They were subsequently named as circRNAs (circular RNAs) due to the covalently closed structure. Accumulating studies were performed to explore the expression profile of circRNAs in different cell types and diseases, the outcomes totally changed our view of ncRNAs, which was thought to be junk by-products in the process of gene transcription, and enriched our poor understanding of its underlying functions. The expression profile of circRNAs is tissue-specific and alters across various stages of cell differentiation. The biological function of circRNAs is multi-faceted, involving five main features (sponge effect, post-transcriptional regulation, rolling circle translation, circRNA-derived pseudogenes and splicing interference) and varying differently from the locations, binding sites and acting modes of circRNAs. The regulating role of circRNAs is not isolated but through an enormous complicated network involving mRNAs, miRNAs and proteins. Although most of the potential functions still remain unclear, circRNAs have been proved to be ubiquitous and critical in regulating cellular processes and diseases, especially in cancers, from the laboratory to the clinic. Herein, we review circRNAs’ classification, biogenesis and metabolism, their well-studied and anticipated functions, the current understanding of the potential implications of circRNAs in tumorigenesis and cancer targeted therapy.
Journal Article
Theory-guided design of hydrogen-bonded cobaltoporphyrin frameworks for highly selective electrochemical H2O2 production in acid
The pursuit of selective two-electron oxygen reduction reaction to H
2
O
2
in acids is demanding and largely hampered by the lack of efficient non-precious-metal-based electrocatalysts. Metal macrocycles hold promise, but have been relatively underexplored. Efforts are called for to promote their inherent catalytic activities and/or increase the surface exposure of active sites. In this contribution, we perform the high-throughput computational screening of thirty-two different metalloporphyrins by comparing their adsorption free energies towards key reaction intermediates. Cobalt porphyrin is revealed to be the optimal candidate with a theoretical overpotential as small as 40 mV. Guided by the computational predictions, we prepare hydrogen-bonded cobaltoporphyrin frameworks in order to promote the solution accessibility of catalytically active sites for H
2
O
2
production in acids. The product features an onset potential at ~0.68 V, H
2
O
2
selectivity of >90%, turnover frequency of 10.9 s
−1
at 0.55 V and stability of ~30 h, the combination of which clearly renders it stand out from existing competitors for this challenging reaction.
Guided by high-throughput computational screening, we report the preparation of hydrogen-bonded cobaltoporphyrin frameworks and demonstrate the achievement of high activity and selectivity for electrochemical H
2
O
2
production in acid.
Journal Article
Zinc-Catalyzed Enantioselective 3 + 3 Annulation for Synthesis of Chiral Spiroindoline-3,4′-thiopyrano2,3-bindole Derivatives
With a dinuclear zinc-ProPhenol complex as a catalyst, an efficient and novel [3 + 3] annulation of indoline-2-thiones and isatylidene malononitriles has been successfully developed via the Brønsted base and Lewis acid cooperative activation model. This practical methodology gives access to a broad range of chiral spiro[indoline-3,4′-thiopyrano[2,3-b]indole] derivatives in good yields with excellent levels of enantioselectivities (up to 88% yield and 99% ee).
Journal Article
CircKDM4B suppresses breast cancer progression via the miR-675/NEDD4L axis
Increasing studies have indicated that circular RNAs (circRNAs) play pivotal roles in various cancers. Here, we aimed to explore the roles of circRNAs in breast cancer. We identified a novel circRNA circKDM4B (hsa_circ_0002926) by whole-transcriptome sequencing and validated this by Real-time quantitative polymerase chain reaction (RT-qPCR) and Sanger sequencing. It was significantly decreased in breast cancer tissues compared with adjacent non-tumor tissues. Furthermore, circKDM4B, which is mainly localized in the cytoplasm, was more resistant to actinomycin D or ribonuclease R than its linear transcript KDM4B. In addition, the overexpression of circKDM4B inhibited cell migration and invasion in vitro, while knockdown of circKDM4B induced the opposite effects. In vivo, circKDM4B suppressed tumor growth and metastasis. Additionally, circKDM4B inhibited migration and tube formation of human umbilical vein endothelial cells (HUVECs) in vitro and angiogenesis in vivo. Mechanically, circKDM4B sponged miR-675 to upregulate the expression of NEDD4-like E3 ubiquitin protein ligase (NEDD4L), which catalyzes ubiquitination of PI3KCA, thereby inhibiting PI3K/AKT and VEGFA secretion. Collectively, these findings uncovered the tumor-suppressor role of circKDM4B in breast cancer, especially in angiogenesis and tumor metastasis, indicating that circKDM4B could be a potential therapeutic target for breast cancer progression.
Journal Article