Rationale: Nonalcoholic steatohepatitis (NASH), as one of the key stages in the development of nonalcoholic fatty liver disease (NAFLD), can directly progress to HCC, but the underlying mechanism is not fully understood.

Lung cancer is one of the leading causes of cancer-associated death, with the etiology largely unknown. The aim of this study was to identify key driver genes with therapeutic potentials in lung adenocarcinoma (LUAD). Transcriptome microarray data from four GEO datasets (GEO: GSE7670, GSE10072, GSE68465, and GSE43458) were jointly analyzed for differentially expressed genes (DEGs). Ontologic analysis showed that most of the upregulated DEGs enriched in collagen catabolic and fibril organization processes were regulated by matrix metalloproteinases (MMPs). Matrix metalloproteinase 11 (MMP11), the highest upregulated MMP family member in LUAD-transformed cells, acted in an autocrine manner and was significantly increased in sera of LUAD patients. MMP11 depletion severely impaired LUAD cell proliferation, migration, and invasion in vitro, in line with retarded tumor growth in xenograft models. Treatment of different human LUAD cell lines with anti-MMP11 antibody significantly retarded cell growth and migration. Administration of anti-MMP11 antibody at a dose of 1 μg/g body weight significantly suppressed tumor growth in xenograft models. These findings indicate that MMP11 is a key cancer driver gene in LUAD and is an appealing target for antibody therapy.

Mutations to the BSCL2 gene disrupt the protein seipin and cause the most severe form of congenital generalised lipodystrophy (CGL). Affected individuals exhibit a near complete loss of white adipose tissue (WAT) and suffer from metabolic disease. Seipin is critical for adipocyte development in culture and mice with germline disruption to Bscl2 recapitulate the effects of BSCL2 disruption in humans. Here we examined whether loss of Bscl2 specifically in developing adipocytes in vivo is sufficient to prevent adipose tissue development and cause all features observed with congenital BSCL2 disruption. We generated and characterised a novel mouse model of Bscl2 deficiency in developing adipocytes (Ad-B2(-/-)) using the adipose-specific Adiponectin-Cre line. We demonstrate that Ad-B2(-/-) mice display early onset lipodystrophy, in common with congenital Bscl2 null mice and CGL2 patients. However, glucose intolerance, insulin resistance, and severe hepatic steatosis are not apparent. Food intake and energy expenditure are unchanged, but Ad-B2(-/-) mice exhibit significantly altered substrate utilisation. We also find differential effects of seipin loss between specific adipose depots revealing new insights regarding their varied characteristics. When fed a high-fat diet, Ad-B2(-/-) mice entirely fail to expand adipose mass but remain glucose tolerant. Our findings demonstrate that disruption of Bscl2 specifically in developing adipocytes is sufficient to cause the early-onset generalised lipodystrophy observed in patients with mutations in BSCL2. However, this significant reduction in adipose mass does not cause the overt metabolic dysfunction seen in Bscl2 knockout mice, even following a high-fat diet challenge.

Objectives: Many cancer cells depend on G2 checkpoint mechanism regulated by WEE family kinases to maintain genomic integrity. The PKMYT1 gene, as a member of WEE family kinases, participates in G2 checkpoint surveillance and probably links with tumorigenesis, but its role in breast cancer remains largely unclear.Materials and Methods: In this study, we used a set of bioinformatic tools to jointly analyse the expression of WEE family kinases and investigate the prognostic value of PKMYT1 in breast cancer.Results: The results indicated that PKMYT1 is the only frequently overexpressed member of WEE family kinases in breast cancer. KM plotter data suggests that abnormally high expression of PKMYT1 predicts poor prognosis, especially for some subtypes, such as luminal A/B and triple‐negative (TNBC) types. Moreover, the up‐regulation of PKMYT1 was associated with HER2‐positive (HER2+), basal‐like (Basal‐like), TNBC statuses and increased classifications of Scarff, Bloom and Richardson (SBR). Co‐expression analysis showed PKMYT1 has a strong positive correlation with Polo‐like kinase 1 (PLK1), implying they may cooperate in regulating cancer cell proliferation by synchronizing rapid cell cycle with high quality of genome maintenance.Conclusions: Collectively, this study demonstrates that overexpression of PKMYT1 is always found in breast cancer and predicts unfavourable prognosis, implicating it as an appealing therapeutic target for breast carcinoma.

Protein turnover and homeostasis are regulated by the proteasomal system, which is critical for cell function and viability. Pluripotency of stem cells also relies on normal proteasomal activity that mitigates senescent phenotypes induced by intensive cell replications, as previously demonstrated in human bone marrow stromal cells. In this study, we investigated the role of proteasomes in self-renewal of neural progenitor cells (NPCs). Through bothin vivoandin vitroanalyses, we found that the expression of proteasomes was progressively decreased during aging. Likewise, proliferation and self-renewal of NPCs were also impaired in aged mice, suggesting that the down-regulation of proteasomes might be responsible for this senescent phenotype. Lowering proteasomal activity by loss-of-function manipulations mimicked the senescence of NPCs bothin vitroandin vivo; conversely, enhancing proteasomal activity restored and improved self-renewal in aged NPCs. These results collectively indicate that proteasomes work as a key regulator in promoting self-renewal of NPCs. This potentially provides a promising therapeutic target for age-dependent neurodegenerative diseases.