Suppression of MYC by PI3K/AKT/mTOR pathway inhibition in combination with all-trans retinoic acid treatment for therapeutic gain in acute myeloid leukaemia.

Aberrant activity of the phosphatidylinositol-3 kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR [PAM]) pathway, as well as suppressed retinoic acid signalling, contribute to enhanced proliferation and the differentiation blockade of immature myeloid cells in acute myeloid leukaemia (AML). Inhibition of the PAM pathway was shown to affect especially mixed-lineage leukaemia-rearranged AML. Here, we sought to test a combined strategy using small molecule inhibitors against members of the PAM signalling pathway in conjunction with all-trans retinoic acid (ATRA) to target a larger group of different AML subtypes. We find that ATRA treatment in combination with inhibition of PI3K (ZSTK474), mTOR (WYE132) or PI3K/mTOR (BEZ235, dactolisib) drastically reduces protein levels of the proto-oncogene MYC. In combination with BEZ235, ATRA treatment led to almost complete eradication of cellular MYC, G1 arrest, loss of clonal capacity and terminal granulocytic differentiation. We demonstrate that PAM inhibitor/ATRA treatment targets MYC via independent mechanisms. While inhibition of the PAM pathway causes MYC phosphorylation at threonine 58 via glycogen synthase kinase 3 beta and subsequent degradation, ATRA reduces its expression. Here, we present an approach using a combination of known drugs to synergistically reduce aberrant MYC levels, thereby effectively blocking proliferation and enabling differentiation in various AML subtypes

Microstructural, Electrical, and Tribomechanical Properties of Mo-W-C Nanocomposite Films

This study investigates the phase composition, microstructure, and their influence on the properties of Mo-W-C nanocomposite films deposited by dual-source magnetron sputtering. The synthesised films consist of metal carbide nanograins embedded in an amorphous carbon matrix. It has been found that nanograins are composed of the hexagonal β-(Mo2 + W2)C phase at a low carbon source power. An increase in the power results in the change in the structure of the carbide nanoparticles from a single-phase to a mixture of the β-(Mo2 + W2)C and NaCl-type α-(Mo + W)C(0.65≤k≤1) solid-solution phases. The analysis of electrical properties demonstrates that the nanograin structure of the films favours the occurrence of hopping conductivity. The double-phase structure leads to a twofold increase in the relaxation time compared to the single-phase one. Films with both types of nanograin structures exhibit tunnelling conductance without the need for thermal activation. The average distance between the potential wells produced by the carbide nanograins in nanocomposite films is approximately 3.4 ± 0.2 nm. A study of tribomechanical properties showed that Mo-W-C films composed of a mixture of the β-(Mo2 + W2)C and α-(Mo + W)C(0.65≤k≤1) phases have the highest hardness (19–22 GPa) and the lowest friction coefficient (0.15–0.24) and wear volume (0.00302–0.00381 mm2). Such a combination of electrical and tribomechanical properties demonstrates the suitability of Mo-W-C nanocomposite films for various micromechanical devices and power electronics

Inhibition of CHIT1 as a novel therapeutic approach in idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive and eventually fatal lung disease with a complex etiology. Approved drugs, nintedanib and pirfenidone, modify disease progression, but IPF remains incurable and there is an urgent need for new therapies. We identified chitotriosidase (CHIT1) as new driver of fibrosis in IPF and a novel therapeutic target. We demonstrate that CHIT1 activity and expression are significantly increased in serum (3-fold) and induced sputum (4-fold) from IPF patients. In the lungs CHIT1 is expressed in a distinct subpopulation of profibrotic, disease-specific macrophages, which are only present in patients with ILDs and CHIT1 is one of the defining markers of this fibrosis-associated gene cluster. To define CHIT1 role in fibrosis, we used the therapeutic protocol of the bleomycin-induced pulmonary fibrosis mouse model. We demonstrate that in the context of chitinase induction and the macrophage-specific expression of CHIT1, this model recapitulates lung fibrosis in ILDs. Genetic inactivation of Chit1 attenuated bleomycin-induced fibrosis (decreasing the Ashcroft scoring by 28%) and decreased expression of profibrotic factors in lung tissues. Pharmacological inhibition of chitinases by OATD-01 reduced fibrosis and soluble collagen concentration. OATD-01 exhibited anti-fibrotic activity comparable to pirfenidone resulting in the reduction of the Ashcroft score by 32% and 31%, respectively. These studies provide a preclinical proof-of-concept for the antifibrotic effects of OATD-01 and establish CHIT1 as a potential new therapeutic target for IPF

Zaopatrzenie krwotoku poporodowego szwami kompresyjnymi. Globalny wpływ na śmiertelność kobiet

Artykuł przedstawia siłę empirycznego podejścia dotyczącego postępowania w krwotoku poporodowym (PPH) z użyciem szwów kompresyjnych oraz podejmuje analizę piśmiennictwa postępowania w krwotoku poporodowym na świecie w ciągu ostatnich 20 lat. Szwy kompresyjne macicy według B-Lyncha są używane w ośrodkach na całym świecie i są najpopularniejszym i najbardziej skutecznym sposobem postępowania w PPH. Dostępne dane sugerują, że ponad 2 000 000 kobiet odniosło korzyści z zastosowania szwów B-Lyncha w ciągu 20 lat od ich wprowadzenia