Oncogenic Deregulation of EZH2 as an Opportunity for Targeted Therapy in Lung Cancer

As a master regulator of chromatin function, the lysine methyltransferase EZH2 orchestrates transcriptional silencing of developmental gene networks. Overexpression of EZH2 is commonly observed in human epithelial cancers, such as non-small cell lung carcinoma (NSCLC), yet definitive demonstration of malignant transformation by deregulated EZH2 remains elusive. Here, we demonstrate the causal role of EZH2 overexpression in NSCLC with new genetically-engineered mouse models of lung adenocarcinoma. Deregulated EZH2 silences normal developmental pathways leading to epigenetic transformation independent from canonical growth factor pathway activation. As such, tumors feature a transcriptional program distinct from KRAS- and EGFR-mutant mouse lung cancers, but shared with human lung adenocarcinomas exhibiting high EZH2 expression. To target EZH2-dependent cancers, we developed a novel and potent EZH2 inhibitor JQEZ5 that promoted the regression of EZH2-driven tumors in vivo, confirming oncogenic addiction to EZH2 in established tumors and providing the rationale for epigenetic therapy in a subset of lung cancer

General Liquid‐Driven Coaxial Flow Focusing Preparation of Novel Microcapsules for Rechargeable Magnesium Batteries

Abstract Magnesium batteries have been considered promising candidates for next‐generation energy storage systems owing to their high energy density, good safety without dendrite formation, and low cost of magnesium resources. However, high‐performance cathodes with stable capacity, good conductivity, and fast ions transport are needed, since many conventional cathodes possess a low performance and poor preparation controllability. Herein, a liquid‐driven coaxial flow focusing (LDCFF) approach for preparing a novel microcapsule system with controllable size, high loading, and stable magnesium‐storage performance is presented. Taking the MoS2‐infilled microcapsule as a case study, the magnesium battery cathode based on the microcapsules displays a capacity of 100 mAh g−1 after 100 cycles. High capacity retention is achieved at both low and high temperatures of −10, ‒5, and 45 °C, and a stable rate‐performance is also obtained. The influences of the liquid flow rates on the size and shell thickness of the microcapsules are investigated; and electron and ion diffusion properties are also studied by first‐principle calculations. The presented LDCFF method is quite general, and the high performance of the microcapsules enables them to find broad applications for making emerging energy‐storage materials and secondary battery systems

Abnormal global functional network connectivity and its relationship to medial temporal atrophy in patients with amnestic mild cognitive impairment

<div><p>Background</p><p>Amnestic mild cognitive impairment (aMCI), which is recently considered as a high risk status for developing Alzheimer’s disease (AD), manifests with gray matter atrophy and increased focal functional activity in the medial temporal lobe (MTL). However, the abnormalities of whole-brain functional network connectivity in aMCI and its relationship to medial temporal atrophy (MTA) remain unknown.</p><p>Methods</p><p>In this study, thirty-six aMCI patients and thirty-five healthy controls (HCs) were recruited. Neuropsychological assessments and MTA visual rating scaling were carried out on all participants. Furthermore, whole brain functional network was constructed at voxel level, and functional connectivity strength (FCS) was computed as the sum of the connections for each node to capture its global integrity. General linear model was used to analyze the FCS values differences between aMCI and HCs. Then, the regions showing significant FCS differences were adopted as the imaging markers for discriminative analysis. Finally, the relationship between FCS values and clinical cognitive scores was correlated in patients with aMCI.</p><p>Results</p><p>Comparing to HCs, aMCI exhibited significant atrophy in the MTL, while higher FCS values within the bilateral MTL regions and orbitofrontal cortices. Notably, the right hippocampus had the highest classification power, with the area under receiver operating characteristics (ROC) curve (AUC) of 0.790 (confidence interval: 0.678, 0.901). Moreover, FCS values of the right hippocampus and the left temporal pole were positively correlated with the cognitive performance in aMCI.</p><p>Conclusion</p><p>This study demonstrated significantly structural atrophy and raised global functional integrity in the MTL, suggesting simultaneous disruption and compensation in prodromal AD. Increased intrinsic functional connectivity in the MTL may have the potential to discriminate subjects with tendency to develop AD.</p></div

The FCS in aMCI and HCs and the group differences.

<p>(A) and (B) These two pictures showed the mean FCS both in aMCI and HCs. The color bar represents the FCS value for each group and the warm color means higher FCS value. (C) This picture indicated the group differences between aMCI patients and HCs on FCS value. The color bar at the bottom represents <i>T</i> value (<i>p</i> < 0.05, Cluster > 309 voxels). FCS, functional connectivity strength; aMCI, amnestic mild cognitive impairments; HC, healthy controls.</p

Demographic and clinical assessment of all the participants.

<p>Demographic and clinical assessment of all the participants.</p

Validation of FCS-based classification analysis for different FCS thresholds.

<p>The ROC of FCS in the right hippocampus (red), the left hippocampus (blue), and the bilateral cuneus (green) in distinguishing individuals with aMCI from HCs under FCS threshold of 0.1 (A) and 0.3 (B). FCS, functional connectivity strength.</p

Oncogenic Deregulation of EZH2 as an Opportunity for Targeted Therapy in Lung Cancer

As a master regulator of chromatin function, the lysine methyltransferase EZH2 orchestrates transcriptional silencing of developmental gene networks. Overexpression of EZH2 is commonly observed in human epithelial cancers, such as non-small cell lung carcinoma (NSCLC), yet definitive demonstration of malignant transformation by deregulated EZH2 remains elusive. Here, we demonstrate the causal role of EZH2 overexpression in NSCLC with new genetically-engineered mouse models of lung adenocarcinoma. Deregulated EZH2 silences normal developmental pathways leading to epigenetic transformation independent from canonical growth factor pathway activation. As such, tumors feature a transcriptional program distinct from KRAS- and EGFR-mutant mouse lung cancers, but shared with human lung adenocarcinomas exhibiting high EZH2 expression. To target EZH2-dependent cancers, we developed a novel and potent EZH2 inhibitor JQEZ5 that promoted the regression of EZH2-driven tumors in vivo, confirming oncogenic addiction to EZH2 in established tumors and providing the rationale for epigenetic therapy in a subset of lung cancer

STK11/LKB1 Deficiency Promotes Neutrophil Recruitment and Proinflammatory Cytokine Production to Suppress T-cell Activity in the Lung Tumor Microenvironment

STK11/LKB1 is among the most commonly inactivated tumor suppressors in non-small cell lung cancer (NSCLC), especially in tumors harboring KRAS mutations. Many oncogenes promote immune escape, undermining the effectiveness of immunotherapies, but it is unclear whether the inactivation of tumor suppressor genes, such as STK11/LKB1, exerts similar effects. In this study, we investigated the consequences of STK11/LKB1 loss on the immune microenvironment in a mouse model of KRAS-driven NSCLC. Genetic ablation of STK11/LKB1 resulted in accumulation of neutrophils with T-cell-suppressive effects, along with a corresponding increase in the expression of T-cell exhaustion markers and tumor-promoting cytokines. The number of tumor-infiltrating lymphocytes was also reduced in LKB1-deficient mouse and human tumors. Furthermore, STK11/LKB1-inactivating mutations were associated with reduced expression of PD-1 ligand PD-L1 in mouse and patient tumors as well as in tumor-derived cell lines. Consistent with these results, PD-1-targeting antibodies were ineffective against Lkb1-deficient tumors. In contrast, treating Lkb1-deficient mice with an IL6-neutralizing antibody or a neutrophil-depleting antibody yielded therapeutic benefits associated with reduced neutrophil accumulation and proinflammatory cytokine expression. Our findings illustrate how tumor suppressor mutations can modulate the immune milieu of the tumor microenvironment, and they offer specific implications for addressing STK11/LKB1-mutated tumors with PD-1-targeting antibody therapies