Articles in 2018

This study was designed to investigate the role of polymerase delta interacting protein 2 (Poldip2) in vascular smooth muscle proliferation and neointimal formation. Neointimal formation and proliferating cell nuclear antigen expression were inhibited in Poldip2+/- mice, in part due to induction of the cell cycle inhibitor p21.

Cellular senescence induced by replication and an AKT inhibitor in ex-vivo spheroid leiomyomas was examined in this work. Several dysregulated genes in the ROS, hypoxic and AKT pathways were identified, including WIPI1 and SLITKR4. Induced senescence in spheroids can be reversed by ABT263, a BH3 mimetic, which may be therapeutic modality for treatment of leiomyoma.

S3I-201, a chemical inhibitor of the transcription factor STAT3, suppresses liver fibrogenesis and angiogenesis through multiple mechanisms both in vitro and in vivo. Moreover, S3I-201 and sorafenib, an FDA-approved multikinase inhibitor, function synergistically in suppressing fibrogenesis and angiogenesis of human hepatic stellate cells, indicating high potential for liver fibrosis treatment.

This study outlines the trends in human-genomic deposits in the gene expression omnibus (GEO). The authors found that there were significant increases in the use of high-throughput sequencing, protein array and multiple-platforms, and in the proportion of North-American deposits. Unclassified diseases, cancer and immunological diseases dominated GEO deposits. There was also geographic disparity in the trends of GEO deposit characteristics.

In this study, a novel epidermal growth factor receptor (EGFR)-targeted, human β-defensin 1-tailored fusion protein, Ec-LDP-DF, and its enediyne-integrated analogue, Ec-LDP(AE)-DF, have been prepared by genetic engineering and molecular reconstitution. The fusion protein Ec-LDP(AE)-DF displays extremely potent cytotoxicity and might be highly effective for non-small cell lung cancer therapy and useful for other EGFR-targeted therapeutics.

Applying histological/histomorphometrical analyses on femora and/or lumbar vertebrae, as well as spectrometric and molecular methodologies on bone-marrow mesenchymal stem cells form APOE knock out and wild-type mice, the authors demonstrate that APOE deficient mice fed a Western-type diet have remarkably augmented bone-marrow adiposity and significantly reduced bone mass due to enhanced osteoclastic and impaired osteoblastic function.

Vitamin D insufficiency is associated with the severity of oxidative stress in vitiligo patients. This study provides new insights into the mechanism of vitamin D as a treatment for vitiligo; it protects melanocytes against oxidative stress by activating Wnt/β-catenin signaling. Targeting this signaling could be a useful approach to improve treatment for vitiligo.

This study shows excellent reproducibility among 3 different digital image (DIA) analysis platforms in Ki67 scoring. An outstanding concordance was found among four operators using the same calibrated DIA platform suggesting a highly reproducible Ki67 scoring method. Finally, the authors also found that all three DIA platforms were essentially indistinguishable with respect to prediction of breast cancer patient outcome.

DNA ligase I (LIG1), an essential enzyme implicated in DNA recombination and DNA repair, is modulated by the oncoprotein SRSF1. In non-small cell lung cancer (NSCLC) cells, LIG1 inhibition is associated with reduced proliferation and increased apoptosis. LIG1 expression is therefore a poor prognosis factor in NSCLC.

Wnt/β-catenin signaling pathway activation is frequent event in the development of neoplasms. In this study, the authors defined an immunohistochemical approach to dissect CTNNB1 (β-catenin) mutations in formalin-fixed and paraffin-embedded primary neoplasms. They validated an immunohistochemical mutation detection algorithm in colon adenomas, carcinomas and various non-colonic Wnt pathway activated tumors.

Tumor cell-endothelial adhesion is one of the key steps for invasion and metastasis. The authors show that Gal-3 promotes cancer cell adhesion to vascular endothelial cells by increasing the expression of N-cadherin and CD44 via an increase of β-catenin nuclear accumulation. This new molecular mechanism of Gal-3-mediated cell adhesion may aid in the development of new strategies to prevent metastasis.

The bile acid rsodeoxycholic acid (UDCA) is the choice of treatment for primary biliary cholangitis patients with abnormal liver enzymes; however, its mechanism is not clear, and is the focus of this investigation. Bile acids alter mast cell (MC) histamine release. Following liver injury, such as that seen in primary sclerosing cholangitis, MCs infiltrate the liver. MC-derived histamine increases biliary damage, fibrosis, and inflammation. UDCA treatment decreases these parameters via reduced MC activation.

Collagen XVII directly binds to collagen IV at the basement membrane zone in both skin and oral mucosa. Mucous membrane pemphigoid autoantibodies targeting the C-terminus of collagen XVII hinder this binding and induce the detachment of basal cells in the oral mucosa. This mechanism leads to oral lesions that show less inflammation than the skin lesions show.

Human ischemic cardiomyopathy is defined by DNA hypermethylation, methyltransferase EZH2 induction, and transcription factor KLF15 suppression. Together these changes may mediate a gene expression pattern reflecting decreased oxidative phosphorylation and increased cellular remodeling. This study therefore identifies a novel mechanism through which coronary heart disease may be regulated.

In normal rats and a human hepatic cell line, the authors demonstrate that remifentanil upregulates IL-18BP expression in hepatocytes, and that the underlying mechanism involves activation of the transcription factors STAT1 and C/EBP β. These findings expand our understanding of the pharmacological effects of remifentanil and suggest its potential treatment benefits for IL-18 dysfunction-mediated hepatic diseases.

In this study, the authors found that interferon-γ mediates the protective effects of soluble receptor for advanced glycation end-product (SRAGE) on myocardial ischemia/reperfusion (MI/R) injuries in heart, which might be associated with the increasing expression of proteasome β5i. In addition, the increased β5i in cardiomyocytes promoted the p53 degradation which contributed to the anti-apoptosis effects of sRAGE in MI/R injuries.

Damage to the airway epithelium can be caused by numerous environmental factors. This study describes the development and characterization of a wound healing model from nasal epithelial cells grown at the air-liquid interface. It also identifies the rate of wound closure from healthy donors and the effect epidermal growth factor receptor inhibition has on wound healing.

As a central regulator of self-renewal and pluripotency maintenance in normal and neoplastic stem cells, transcription factor SOX2 expression is tightly controlled. The authors found that the histone-lysine N-methyltransferase MLL1/WDR5 complex methylates SOX2 at K42 and promotes its degradation. Conversely, the protein PHF20L1 recognizes methylated SOX2 through its MBT domain and blocks the degradation of SOX2.