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The Niemann–Pick C1-like intracellular cholesterol transporter gene and a number of genes in the cholesterol synthesis pathway are transcriptionally regulated by SREBP-2. The liganded Ah receptor increases proteolytic turnover of transcriptionally active SREBP2. Thus, Ah receptor ligands are capable of attenuating cholesterol uptake into Caco-2 cells.
This study was performed to evaluate role of RORα in mouse testicular structure. Lack of RORα expression induces apoptosis, reduces germ cells differentiation, and may cause infertility. RORα is one of the essential proteins regulating testicular structure. RORα-deficient mice may be a suitable model for studying mutation-induced of human infertility.
Obesity causes complications in the treatment of asthma. This manuscript explores the role of Notch pathway in animal models. The authors found that the inhibition of the Notch pathway by a γ-secretase inhibitor suppresses Th17-associated airway hyperresponsiveness in obese asthmatic mice. This finding may provide a novel insight into asthma treatment in the clinic.
The severe immunodeficiency of NOD.Cg-PrkdcscidIl2rgtm1Wjl (NSG) mice, a widely used strain for generating patient-derived xenografts from primary tumors, impairs drug metabolism and reduces tolerability towards common cytostatic drugs. Consequently, dose finding and tolerance tests are strongly recommended prior to perform large-scale cancer precision medicine approaches.
This study investigates lipid droplet (LD) trafficking and LD velocity (LDV) in cancer. LD density correlated with prostate tumor grade and high grade tumors had significantly higher LDV when compared to low grade tumors. Acidifying conditions drove up velocities and LDV was normalized with blockade of H+ proton pump, V-ATPase.
The authors show that Muc5ac−/− mice develop spontaneous gastric antro-pyloric hyperplasia and adenomas. Interestingly, Muc5ac−/− mice have suppression of gastric corpus mucous metaplasia and key proinflammatory cytokines (Tnfα and Il-17a) in a setting of enhanced Helicobacter pylori colonization, thus implying a complex role for Muc5ac in gastric homeostasis.
The authors established and characterized a novel gastroesophageal junction (GEJ) cancer cell line derived from the malignant pleural effusion of a treated GEJ cancer patient. This cell line represents a valuable addition to the limited number of bona fide GEJ cancer cell lines for both basic and translational research.
This study shows how telomerase reverse transcriptase (TERT) assists growth differentiation factor 11 (GDF11) to rejuvenate senescent endothelial progenitor cells via the Smad2/3 and eNOS pathways. Therapeutically, it may be possible to exploit TERT mediated-GDF11 signaling to activate senescent stem cells in the myocardial ischemic microenvironment.
Transcription factor STAT3 constitutively activated in cancer promotes tumor progression. The authors detected activated STAT3 in human metastatic melanoma cells and identified new STAT3 targets. STAT3 regulates a discrete set of genes in melanoma cells and its knockdown impairs cell migration and invasion via regulation of its transcriptional target SERPINA3.
This study confirms that the depletion of Thy-1 and upregulation of integrin β3 is an essential mechanism and potential therapeutic target for PI3K-Akt-mTOR pathway-associated inhibition of lung fibroblast autophagy in lipopolysaccharide-induced pulmonary fibrosis.
The calcium signal is a regulator of the acquisition of a more mesenchymal phenotype. Our work in MDA-MB-468 breast cancer cells identifies a complex relationship between factor-specific induction of the epithelial–mesenchymal marker vimentin and the differential involvement of the canonical store-operated calcium channel ORAI1 and the calcium channel component TRPC1.
TGF-β plays a key role in fibrosis. β-catenin is common transcription factor in major TGF-β profibrotic signaling pathways and binds competitively to either TCF or Foxo transcription factors. In human kidney biopsies, the authors found that β-catenin/Foxo interaction was negatively correlated, while that of β-catenin/TCF was positively correlated with kidney fibrosis. They further identified β-catenin/Foxo-dependent protection against TGF-β-induced profibrotic changes in tubular cells and kidney fibrosis.
Wnt11 is more strongly expressed in small cell lung cancer (SCLC) than in non-SCLC. Ascl1 promotes Wnt11 expression by altering H3K27Ac levels at the enhancer region of the WNT11 gene. Ascl1-induces Wnt11 regulates neuroendocrine differentiation, cell proliferation, and E-cadherin expression in SCLC. The Ascl1-Wnt11 axis has potential as a therapeutic target and supports the clinical utility of Wnt11 as a biological marker in SCLC.
Mitotic density is part of breast cancer grading yet is hampered by interobserver variability. The authors developed a deep learning algorithm which automatically locates the mitotic hotspot in breast tumors. Counting mitoses within this predefined hotspot considerably improved interobserver agreement. Mitotic counts assessed by the algorithm were comparable to the observers’ results.
********The authors engineered and constructed a circRNA containing both miR-21 and miR-93 binding sites, then deployed it against esophageal carcinoma. This novel multi-miR circular sponge significantly inhibits endogenous miR-21 and miR-93 activities, suppresses cellular proliferation, migration and tumor growth. These findings suggest an entirely new area of research based on developing synthetic circular RNA sponges as tools for miR-directed molecular therapy.