Volume 102 Issue 10, October 2022

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 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.

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 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 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.

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.

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.

Apolipoprotein B100 (apoB100) is the structural protein of several of the lipoprotein cholesterol carriers and accumulates in extracellular deposits in the systemic disease atherosclerosis, and the neurodegenerative blinding disease, age-related macular degeneration. Herein, the authors characterized the retinal pathology of transgenic mice expressing mouse apoB100, in order to catalog their functional and morphological ocular phenotypes, as a function of age, and establish measurable endpoints for their use as a pre-clinical mouse model to test potential therapies.

Targeting Siglec-15 may be an effective alternative therapy for patients that do not respond to PD-1/PD-L1 inhibition. In this study, the authors show broad expression of this potential immune modulatory target in a wide range of cancer types. These data may inform future clinical development and show potential for future companion diagnostic tests for Siglec-15 therapeutics.

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.