Methyltransferase like 3 enhances pinin mRNA stability through N6 -methyladenosine modification to augment tumourigenesis of colon adenocarcinoma.

NEW FINDINGS: What is the central question of this study? What is the role of pinin (PNN) in the malignant phenotype of colon adenocarcinoma cells and the underlying mechanism? What is the main finding and its importance? PNN mRNA can be stabilized and upregulated by methyltransferase like 3 (METTL3), which promotes glycolysis in colon adenocarcinoma and augments cell proliferation, migration and invasiveness. METTL3 and PNN might serve as potential targets for the treatment of colon adenocarcinoma. ABSTRACT: Colon adenocarcinoma (COAD) is a fatal malignancy with high morbidity and mortality rates globally. Pinin (PNN), a desmosome associated protein, has been revealed as a tumour driver in several malignancies. This study aims to probe the expression and role of PNN in COAD and the underlying mechanism. PNN was expressed at high levels in clinically collected COAD tumours and was linked to poor prognosis of patients. Downregulation of PNN reduced glucose uptake, lactate production and ATP levels in COAD cells and suppressed cell proliferation, migration and invasiveness. Methyltransferase like 3 (METTL3) was positively associated with PNN levels in COAD tumour tissues. RNA immunoprecipitation and N6 -methyladenosine (m6 A) quantification assays indicated that METTL3 enhanced PNN mRNA stability and expression in COAD through m6 A modification with the involvement of the m6 A 'reader' protein YT521-B homology domain family member 1. Downregulation of METTL3 reduced COAD cell glycolysis and proliferation in vitro and suppressed growth and metastasis of xenograft tumours in vivo, but further overexpression of PNN restored malignant behaviours of COAD cells and tumour growth. In summary, this study demonstrates that METTL3 promotes PNN mRNA stability and expression in COAD through m6 A modification, which augments glycolysis and proliferation of COAD cells and leads to the resultant tumour progression.

Retrospective Analyses of Complete Resection Combined with Systemic Chemotherapy and Targeted Therapy for Patients with Ovarian Metastases from Colorectal Cancer.

Background: The aim of the study is to evaluate clinical outcomes of patients with ovarian metastases from colorectal cancer (OM-CRC) treated with complete resection combined with chemotherapy and targeted therapy. Materials and Methods: Fifty female patients with OM-CRC who were treated in two different hospitals were categorized into three groups: 14 patients with OM-CRC received resection and chemotherapy combined with targeted therapy, 16 patients with OM-CRC only received chemotherapy combined with targeted therapy, and 20 patients with non-OM-CRC (NOM-CRC) received chemotherapy combined with targeted therapy. The primary outcomes, including overall survival (OS), the objective response rate (ORR), disease control rate (DCR), safety, and progression-free survival (PFS), were observed. Results: The ORR of OM-CRC was significantly lower compared with NOM-CRC (36.7% vs. 70.0%, p = 0.021), and the DCR of OM-CRC was also lower compared with NOM-CRC (76.7% vs. 90.0%, p = 0.229). The following chemotherapy and targeted therapy in the additional surgical resection of OM-CRC were positively associated with longer PFS and OS compared to no surgical resection (9.0 vs. 6.0 months and 21.0 vs. 15.0 months, respectively, p < 0.001), but the PFS and OS were best in patients with NOM-CRC (9.0 and 35.0 months). Improved OS was associated with R0 resection (23.0 vs. 17.0 months, p < 0.001). Multivariate analysis indicated that patients with well-differentiated pathology and unilateral ovarian metastasis had a better prognosis. Conclusion: Multidisciplinary treatment strategy, including systemic chemotherapy, targeted therapy, and complete surgery, may contribute to the prolongation of OS and be safe for treatment of OM-CRC.

Multi-Task Classification and Segmentation for Explicable Capsule Endoscopy Diagnostics.

Capsule endoscopy is a leading diagnostic tool for small bowel lesions which faces certain challenges such as time-consuming interpretation and harsh optical environment inside the small intestine. Specialists unavoidably waste lots of time on searching for a high clearness degree image for accurate diagnostics. However, current clearness degree classification methods are based on either traditional attributes or an unexplainable deep neural network. In this paper, we propose a multi-task framework, called the multi-task classification and segmentation network (MTCSN), to achieve joint learning of clearness degree (CD) and tissue semantic segmentation (TSS) for the first time. In the MTCSN, the CD helps to generate better refined TSS, while TSS provides an explicable semantic map to better classify the CD. In addition, we present a new benchmark, named the Capsule-Endoscopy Crohn's Disease dataset, which introduces the challenges faced in the real world including motion blur, excreta occlusion, reflection, and various complex alimentary scenes that are widely acknowledged in endoscopy examination. Extensive experiments and ablation studies report the significant performance gains of the MTCSN over state-of-the-art methods.

Sodium butyrate protects against lipopolysaccharide-induced liver injury partially via the GPR43/ ß-arrestin-2/NF-κB network.

BACKGROUND: Butyrate acts as a regulator in multiple inflammatory organ injuries. However, the role of butyrate in acute liver injury has not yet been fully explored. In the present study, we aimed to investigate the association between butyrate and lipopolysaccharide (LPS)-induced acute liver injury and the signaling pathways involved. METHODS: LPS-induced acute liver injury was induced by intraperitoneal injection of LPS (5 mg/kg) in G-protein-coupled receptor 43 (GPR43)-knockout (KO) and wild-type female C57BL/6 mice. Sodium butyrate (500mg/kg) was administered intraperitoneally 30 min prior to LPS exposure. Liver injury was detected by serum markers, tissue morphology, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL). Pro-inflammatory-factor levels were detected by enzyme-linked immunosorbent assay and real-time polymerase chain reaction (RT-PCR). Cell models were first treated with sodium butyrate (4 µmol/mL), followed by LPS (1 µg/mL) half an hour later in GPR43 small interfering RNA (siRNA)-transfected or control RAW264.7 cells. Cell-inflammation status was evaluated through detecting pro-inflammatory-factor expression by RT-PCR and also through checking toll-like receptor 4/nuclear factor-κB (TLR4/NF-κB)-element levels including TLR4, TRAF6, IKKß, IкBα, phospho-IкBα, p65, and phospho-p65 by Western blot. The interaction between GPR43 and ß-arrestin-2 was tested by co-immunoprecipitation. RESULTS: Sodium butyrate reversed the LPS-induced tissue-morphology changes and high levels of serum alanine aminotransferase, aspartate transaminase, myeloperoxidase, TUNEL, and pro-inflammatory cytokines such as tumor necrosis factor-α and interleukin-6. The ameliorating effect of sodium butyrate was weakened in GPR43-KO mice and GPR43 siRNA RAW264.7 cells, compared with those of GPR43-positive controls. Sodium butyrate downregulated some elements of the TLR4/NF-κB pathway, including phospho-IκBα and phospho-p65, in RAW264.7 cells. Increased interactions between GPR43 and ß-arrestin-2, and between ß-arrestin-2 and IкBα were observed. CONCLUSION: Sodium butyrate significantly attenuated LPS-induced liver injury by reducing the inflammatory response partially via the GPR43/ß-arrestin-2/NF-κB signaling pathway.

Predict Ki-67 Positive Cells in H&E-Stained Images Using Deep Learning Independently From IHC-Stained Images.

OBJECTIVE: To obtain molecular information in slides directly from H&E staining slides, which apparently display morphological information, to show that some differences in molecular level have already encoded in morphology. METHODS: In this paper, we selected Ki-67-expression as the representative of molecular information. We proposed a method that can predict Ki-67 positive cells directly from H&E stained slides by a deep convolutional network model. To train this model, we constructed a dataset containing Ki-67 negative or positive cell images and background images. These images were all extracted from H&E stained WSIs and the Ki-67 expression was acquired from the corresponding IHC stained WSIs. The trained model was evaluated both on classification performance and the ability to quantify Ki-67 expression in H&E stained images. RESULTS: The model achieved an average accuracy of 0.9371 in discrimination of Ki-67 negative cell images, positive cell images and background images. As for evaluation of quantification performance, the correlation coefficient between the quantification results of H&E stained images predicted by our model and that of IHC stained images obtained by color channel filtering is 0.80. CONCLUSION AND SIGNIFICANCE: Our study indicates that the deep learning model has a good performance both on prediction of Ki-67 positive cells and quantification of Ki-67 expression in cancer samples stained by H&E. More generally, this study shows that deep learning is a powerful tool in exploring the relationship between morphological information and molecular information. AVAILABILITY AND IMPLEMENTATION: The main program is available at https://github.com/liuyiqing2018/predict_Ki-67_from_HE.

ß-arrestin 2 attenuates lipopolysaccharide-induced liver injury via inhibition of TLR4/NF-κB signaling pathway-mediated inflammation in mice.

AIM: To study the role and the possible mechanism of ß-arrestin 2 in lipopolysaccharide (LPS)-induced liver injury in vivo and in vitro. METHODS: Male ß-arrestin 2+/+ and ß-arrestin 2-/- C57BL/6J mice were used for in vivo experiments, and the mouse macrophage cell line RAW264.7 was used for in vitro experiments. The animal model was established via intraperitoneal injection of LPS or physiological sodium chloride solution. Blood samples and liver tissues were collected to analyze liver injury and levels of pro-inflammatory cytokines. Cultured cell extracts were collected to analyze the production of pro-inflammatory cytokines and expression of key molecules involved in the TLR4/NF-κB signaling pathway. RESULTS: Compared with wild-type mice, the ß-arrestin 2 knockout mice displayed more severe LPS-induced liver injury and significantly higher levels of pro-inflammatory cytokines, including interleukin (IL)-1ß, IL-6, tumor necrosis factor (TNF)-α, and IL-10. Compared with the control group, pro-inflammatory cytokines (including IL-1ß, IL-6, TNF-α, and IL-10) produced by RAW264.7 cells in the ß-arrestin 2 siRNA group were significantly increased at 6 h after treatment with LPS. Further, key molecules involved in the TLR4/NF-κB signaling pathway, including phospho-IκBα and phosho-p65, were upregulated. CONCLUSION: ß-arrestin 2 can protect liver tissue from LPS-induced injury via inhibition of TLR4/NF-κB signaling pathway-mediated inflammation.