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The levels of m6A and WTAP are elevated in the CD4+ T cells of tolerant kidney transplant recipients. In naïve CD4+ T cells from kidney transplant recipients with immune rejection, WTAP is highly expressed and facilitates Foxo1 transcription by enhancing m6A modification of Foxo1 mRNA in the CDS region, which enhances Foxo1-mediated Foxp3 transcription and subsequent Treg cell differentiation and function.
Idelalisib, a specific inhibitor of phosphoinositide 3-kinase (PI3K) δ, inhibits Akt activation, fibronectin expression and collagen gel contraction induced by transforming growth factor (TGF)-β2 in human RPE cells as well as in an animal model of proliferative vitroretinopathy. These results suggest that idelalisib may be useful for preventing proliferative vitroretinopathy in humans.
The present study elucidates the novel role of PIK3CD in glioblastoma (GBM) progression. Using in vitro and in vivo models of GBM, the authors show that GBM migration, invasion, proliferation and growth affect greatly when the activity of PIK3CD is disrupted by CRISPR/Cas9. Mechanistically, PIK3CD regulates the activity of p21 activated kinase (PPAK3) and plecstrin 2 (PLEK2) through axonogenesis pathway. The findings provide a novel mechanism of PIK3CD-mediated GBM development and suggest PIK3CD might be a target of GBM.
The authors show that CC chemokine receptor 2 (CCR2) overexpression is an independent prognostic marker for diffuse large B-cell lymphoma (DLBCL) and predicts overall survival and progression-free survival in these patients. Blockade of CCR2 signaling with a CCR2 antagonist inhibits tumor cell proliferation, migration, and apoptosis inhibition by activating the PI3K/Akt signaling pathway and inhibiting the p38 MAPK signaling pathway. Furthermore, administration of a CCR2 antagonist decreases tumor growth and dissemination of DLBCL cells and increases survival time in a xenograft model.
Levels of E3 ligase FBXW7 are depressed in radioresistant cells. Overexpression of FBXW7 represses proliferation and colony formation and increases γ-H2AX-positive foci in cultured cells. Overexpression of FBXW7 increases ubiquitination levels and reduces the stability of SOX9, which binds to the CDKN1A promoter to inhibit expression. The authors conclude that FBXW7 inhibits tumorigenesis and apoptosis and enhances radiosensitivity of NSCLC cells via SOX9/CDKN1A.
Lymph node metastasis (LNM) worsens the prognosis of nasopharyngeal cancer (NPC) patients. Thus, bioinformatic analysis was used to determine a key gene, the tyrosine-kinase receptor KITLG, that might play a critical rols in the LNM of NPC. The suppression of KITLG inhibits the proliferation, invasion, and metastasis of NPC cells via the JAK/STAT signaling pathway.
Lung squamous cell carcinoma (LSCC) is a common subtype of lung cancer with high malignancy. The authors show that the kinase PAK2 binds to the transcription factor SOX2 and activates the oncogene DEK, thus contributing to the malignant behavior of LSCC cells. This work provides new therapeutic targets and insightful information for enhancing targeted therapy of LSCC.
The authors developed a concise and efficient survival analysis model, named CNN-Cox. The survival prediction performance of this model on RNA-seq datasets of various cancers from The Cancer Genome Atlas cohort was discussed and compared with other state-of-the-art survival analysis methods. They also conducted protein–protein interaction network analysis to identify potential prognostic genes and analyzed the biological function of 13 hub genes for a lung adenocarcinoma dataset.
Nobiletin (NOB) has significant neuroprotective effects on retinal ganglion cells (RGCs) in glaucomatous neurodegeneration, including reducing RGC apoptosis and oxidative stress, partially restoring RGC dysfunction, further enhancing Nrf2/HO-1 pathway in RGCs, and attenuating Müller glial activation. These effects do not depend on lowering intraocular pressure. Intervention to enhance activation of Nrf2/HO-1 pathway are viable therapies for glaucoma.
PAQR3 silencing promotes skin wound healing and angiogenesis, enhanced macrophage M2 polarization and elevated expression of PPARγ in diabetic mice. PAQR3 silencing in macrophages also enhances migration of HaCaT cells and tube formation of HUVECs in vitro. The promotion of diabetic wound healing through M2 macrophage polarization and angiogenesis by PAQR3 silencing is mediated by the inhibition of STUB1-mediated PPARγ protein ubiquitination and degradation.
The authors propose a new role for ADAR1, an RNA editing enzyme, in nonalcoholic fatty liver disease (NAFLD). Overexpression of ADAR1 ameliorates high-fat diet-induced liver injury and significantly abolishes NLRP3 inflammasome activation in THP-1 cells. Inhibition of ADAR1 expression causes a dramatic enhancement in NLRP3 inflammasome activation. Therefore, ADAR1 is a potential NAFLD suppressor through regulation of NLRP3 inflammasomes.
The replacement and desmoplastic histopathological growth patterns (HGP) were studied in patients with uveal melanoma liver metastases (MUM). L1CAM and laminin vascular network were detected at the advancing front of the high-risk replacement HGP but not in the more prognostically favorable desmoplastic HGP. Any percentage of replacement HGP (rHGP), predominant rHGP, or pure rHGP in MUM had a significant adverse effect on metastasis-specific overall survival (p = 0.038; (p = 0.0058); p = 0.0064
Smurf1 is highly expressed in the livers of non-alcoholic fatty liver disease (NAFLD) patients and NAFLD mode mice. Smurf1 promotes p53 ubiquitynation via stabilizing mouse double minute 2 (MDM2). An decrease in p53 enhances lipogenesis by inducing SREBP-1c, and inhibits lipolysis via repressing malonyl-CoA decarboxylase (MCD) or Lipin1. Overall, Smurf1 deficiency attenuates liver steatosis via the MDM-p53 pathway.
The presence of visceral obesity or type 2 diabetes mellitus is a major risk factor and potential therapeutic target for non-alcoholic fatty liver disease (NAFLD). A new murine NAFLD model established in this study had obesity and insulin resistance, and rapidly develop steatohepatitis and fibrosis. This model could be useful as preclinical models for drug development of NAFLD.
Characterization of macrophage polarization into different functional phenotypes is valuable for further investigation of gout pathogenesis, as well as for a better disease management. In this study the authors found that altered macrophage polarization exists in various stages of gouty inflammation. Macrophages in acute gout were polarized into M1 at an early stage and into M2 at later stages while the macrophages in chronic gout were generally polarized towards M2. The number of M1 rose with the progression of inflammation. Early increase of M2 was observed, which might be generated directly from M0.
The antibody drug conjugate (ADC) Trastuzumab deruxtecan (T-DXd) has shown activity in breast cancer with low levels of HER2 expression. The historical/conventional assays for HER2 were designed separate high levels of HER2 from intermediate levels and show no expression in the low range. In this study, we determine the optimal dynamic range for unamplified HER2 detection in breast cancer and then design a quantitative assay to stratify HER2 expression in unamplified cases. Assessment of HER2 protein in the optimal dynamic range will ultimately help select the optimal patients for T-DXd and this work can serve as a model for other assays for ADCs where pathology reads may be less accurate that protein measurements.
