Volume 99 Issue 1, January 2019

Defective thermogenic response to calorie overload contributes to obesity and, in foz/foz mice, to nonalcoholic steatohepatitis (NASH). Activation of brown adipose tissue function by b3AR-agonists together with moderate calorie restriction improves the obese phenotype and resolves NASH pathology. This identifies the brown adipose tissue as a target for adjuvant therapy for NASH.

The cytoskeletal GTPase SEPT6 is elevated during hepatic stellate cell (HSC) activation and in liver fibrosis. SEPT6 promotes HSC activation, proliferation, cell cycle progression, survival and migration through the TGF-β1/Smad, MAPK and PI3K/AKT signaling pathways. Adenovirus-mediated SEPT6 inhibition attenuates thioacetamide-induced liver fibrosis.

The underlying immunopathogenic mechanisms of autoimmune hepatitis (AIH) have not been well elucidated. Kruppel-like factors 14 (KLF14) may regulate Treg differentiation, but the biological functions remain unclear. In this study, the authors reveal that KLF14 plays an as yet unrecognized role in immune- mediated hepatitis via induced Treg differentiation and inflammatory cytokine suppression. These findings indicate the possibility of KLF14 as a therapeutic target in AIH patients.

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.

Bone morphogenetic protein (BMP) 9 is a potent inducer of osteogenic differentiation from mesenchymal stem cells, but the mediators of BMP9-induced osteogenesis remain elusive. Here, the authors show that inhibition of Notch1 signaling effectively diminishes BMP9-induced osteogenesis. Genetic disruption of Notch pathway severely impairs BMP9-induced bone formation. Thus, these results demonstrate that Notch signaling may play an essential role in coordinating osteogenic differentiation.

In this study, the authors show that overexpression of hypoxia-inducible factor(HIF)-1α by ERK1/2, Akt and NF-κB activation contributes to melphalan-resistance in multiple myeloma (MM) cells. Additionally, inhibition of HIF-1α resensitizes melphalan-resistant MM cells to melphalan. Therefore, HIF-1α inhibitors may be therapeutically useful as anti-multidrug resistance protein agents in MM.

Highly immunogenic tumors were implanted in mice deficient in either T cell skin homing molecules or T cell gut homing molecules. Rejection of tumors was deficient in skin or gut, respectively, but intact in unaffected tissues. The authors conclude that T cell trafficking plays an important and heretofore overlooked role in tumor immunity.

This study evaluated both innate and adaptive cell types of myeloid and lymphoid lineage from both genders of three major immunocompetent mouse strains used in pre-clinical research. Results of the study underscore that both innate and cell-mediated immune profile varies dramatically based on mouse strain and gender, which will significantly impact on interpretation of experimental outcome in a wide spectrum of studies, including cancer.

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.

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.

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.

This paper describes mini-XPerT, a multiplexed screen to simultaneously measure cellular contraction, endothelial barrier function, and cytoskeletal and cell-cell junctional changes. It is the unique combination of these measurements that has enabled the authors to unveil the distinct biophysical mechanisms of barrier defense conferred by Y-27632 and Angpt-1. Mini-XPerT is likely to be applicable across the spectrum of basic and translational science - in mechanistic studies of the endothelium across numerous diseases, and for high-throughput drug discovery.