Articles in 2021

The authors demonstrate that carnitine palmitoyltransferase 1A (CPT1A) expression is reduced in glioma stem cells (GSCs) in comparison with non-stem tumor cells. CPT1A overexpression promotes mitochondrial fusion and GSC differentiation by increasing the phosphorylation of dynamin-related protein 1 (Drp1) at Ser-637, thus impairing GSC-derived xenograft growth and prolonging survival in tumor-bearing mice. These results suggest that CPT1A could be a molecular target for GSC differentiation therapy.

Commensal microbe effects on alveolar bone homeostasis have been attributed to the oral microbiota, yet the impact of commensal gut microbes is unknown. Studies performed with segmented filamentous bacteria (SFB) monoassociated mice revealed commensal gut microbes modulate osteoimmune responses and skeletal homeostasis in alveolar bone. This work challenges the current paradigm that alveolar bone health is strictly regulated by oral microbes.

This study reveals a novel role for the stress-response protein sirtuin 6 (SIRT6) in modulation of glucolipid metabolism disorders in the liver and pancreas under conditions of overnutrution and starvation. The authors show that SIRT6 regulates SREBP1c through the AMPKα-mTORC1 pathway, which and then affects glucolipid metabolic enzymes in an LXR-independent pathway.

Osteosarcoma is a tumour with a highly complex genome, which hampers the identification of driver genes. Using a model of murine mesenchymal stem cells (MSCs) with deficient p15^Ink4b, p16^Ink4a, or p19^Arf that transform earlier compared to wild-type MSCs, the authors demonstrated that loss of p16^Ink4a is a driver of osteosarcomagenesis. This can be exploited with a CDK4/CDK6 inhibitor, as osteosarcoma cells showed sensitivity to palbociclib which might be used as a novel therapeutic option.

Under high-glucose conditions, LECs obtain characteristics of mesenchymal cells such as high migratory capacity and invasiveness, which is the foundational basis for DC progression. The authors demonstrated that lncRNA GAS5 facilitates high glucose-induced lens epithelial cell migration and epithelial-to-mesenchymal transition by regulating the miR-204-3p/TGFBR1 axis. This study, therefore, provides novel insights into the pathogenesis of DCs.

The smoothened (SMO) receptor maintains levels of insulin-like growth factor 1 receptor (IGF1R) in several types of cancer cells, and high protein levels of both receptors correlate with poor survival in diffuse large B-cell lymphoma (DLBCL) patients. Loss of SMO favors IGF1R degradation over recycling, and IGF1R-mediated AKT/PI3K signaling, but MAPK is not significantly impaired. The preferential disruption of AKT signaling correlates with a loss of IGF1R and AKT in raft microdomains.

Cholangiocytes are the primary targets of cholangiopathies. This study elucidates the role of miR-200c in maintaining cholangiocyte homeostasis making use of cell culture and mouse models of cholestasis. MiR-200c restrains the proliferative and neuroendocrine-like activation of cholangiocytes by targeting sestrin 1(SESN1) and inhibiting the IL-6/AKT feedback loop to prevent cholestatic liver injury. The findings provide critical mechanistic insights into biliary liver fibrosis and suggest miR-200c may be a novel therapeutic target of cholangiopathies.

Thioredoxin domain containing 5 (TXNDC5) is highly expressed in patients with septic shock. It is also upregulated in mice with lipopolysaccharide (LPS)-induced sepsis and mouse macrophages subjected to LPS stimulation. Txndc5 depletion reduced inflammatory cytokine production and affected recruitment of macrophages and neutrophils in LPS-challenged mice. TXNDC5 inhibition alleviated LPS-induced sepsis by inhibiting the nuclear factor kappa B signaling pathway. These findings suggest that TXNDC5 inhibition may be a therapeutic approach for sepsis.

The authors examined 13 mismatch repair-deficient (MMRD)-associated primary brain tumors to determine molecular characteristics and biological behavior. MMRD occurred after chemotherapy and radiotherapy in two cases. The genetic profile of MMRD glioblastoma was different from that of conventional glioblastoma. Half of the MMRD-gliomas and all Lynch syndrome-associated GBMs were high in microsatellite instability. These tumors had high mutational burdens and tended to have shorter progression-free survival than glioma without MMRD.

An artificial intelligence (AI) model was developed to discriminate between fibroadenomas and phyllodes tumors on core biopsy images. It employed a two-stage architecture comprising a convolutional neural network (CNN) component for feature extraction, and a recurrent neural network (RNN) component for whole-slide classification, with an overall slide-level accuracy of 87.5%.

This study confirms the preservation of EZH2 overexpression in 22 patient-derived orthotopic xenograft models of pediatric brain tumors. The authors demonstrate the activity of an FDA-approved EZH2 inhibitor, tazemetostat, alone and in combination with radiation in a subset of the models, and identifies EZH2-negative cells as potential cause of therapy resistance.

This paper provides new insights into the potential therapeutic effects of vitamin E on COPD. The authors show that vitamin E relieves chronic obstructive pulmonary disease (COPD) by negatively regulating the EGFR/MAPK pathway and inhibiting COX2-mediated translocation of phosphorylated STAT3 to the nucleus. Moreover, overexpression of COX2 reverses the protective effect of vitamin E in a rat model of COPD.

miR-21-5p directly decreases levels of Jag1, which inhibits the Notch pathway and subsequently promotes the differentiation of adipose-derived stem cells into myelin-forming Schwann cells. Exploiting this signalling pathway may be an effective new method for the treatment of nerve injury.

Through analysis of the PD-L1 promoter, the authors describe two clear cell renal cell carcinoma (ccRCC) models that exhibit differential PD-L1 expression levels upon IFNγ and hypoxia stimulation. Mutant-VHL ccRCC cells display higher PD-L1 expression than wild-type-VHL ccRCC cells due to high basal HIF2α expression and a stronger response to IFNγ stimulation. Thus, mutant-VHL ccRCC cells are expected to respond well to immune checkpoint inhibitors.

The authors developed a deep learning model predictive of 1p/19q status from preoperative imaging in 555 lower-grade gliomas (LGG), and achieved an area under the curve (AUC) of 0.983 in the testing dataset. They reveal that developing deep learning imaging signatures could be a noninvasive tool for predicting molecular markers in LGG.

The authors barcoded glioma-initiating cells (GIC) using combinations of virally encoded fluorophores. GIC show a strong tendency to form clonal populations over as few as two passages. Combined with stem cell marker phenotyping and computational analysis, they could trace the fate of such populations. This model presents an approach for rapid assessment of newly established GIC to assess tumour-specific vulnerabilities.

This study demonstrates that lipopolysaccharide promotes activation of the JNK signaling pathway and endogenous TNF-α secretion in pulmonary macrophages, which facilitates lung fibroblast aerobic glycolysis and lactate production through PFKFB3 activation. These findings suggests that inflammation-metabolism interactions between lung macrophages and fibroblasts might play an essential role in lipopolysaccharide-induced pulmonary fibrosis.

The authors demonstrate that matrix metalloproteinase 11 (MMP11) expression in mononuclear inflammatory cells (predominantly macrophages) is an independent negative prognostic factor in breast cancer, whereas tumoral MMP11 expression is not associated with patient survival. This study also shows that MMP11-overexpressing macrophages promote the migration of HER2-positive breast cancer cells and monocyte recruitment through CCL2-CCR2 signaling, suggesting a pro-tumoral role of MMP11 in macrophages in HER2-positive breast cancer through interaction with cancer cells and other cells in the tumor microenvironment.

The authors explored the role of microRNA-155-5p (miR-155-5p) in childhood acute lymphoblastic leukemia (cALL). They found that miRNA-155-5p targets the E3 ubiquitin ligase CBL and inhibits its expression, reducing the ubiquitination and degradation of interferon regulatory factor 4, thus elevating expression of cyclin-dependent kinase 6. These findings suggest a basis for potential future therapeutic strategies for cALL.

Diabetic cardiomyopathy is a serious diabetes-related cardiovascular complication, which is closely related to myocardial metabolic disorders, but there is no specific therapy currently. Renal denervation (RDN), a novel technique to remove renal sympathetic nerves, can reduce the overexpression of renal SGLT2 in diabetic rats, thereby promoting urinary glucose excretion and maintaining systemic glucose homeostasis. On this basis, RDN ameliorated diabetes-induced cardiac metabolic disorders and mitochondrial damages, ultimately preventing diabetes-induced cardiac dysfunction and pathological remodeling.