The combination of CHK1 inhibitor with G-CSF overrides cytarabine resistance in human acute myeloid leukaemia

Cytarabine (AraC) represents the most effective single agent treatment for AML. Nevertheless, overriding AraC resistance in AML remains an unmet medical need. Here we show that the CHK1 inhibitor (CHK1i) GDC-0575 enhances AraC-mediated killing of AML cells both in vitro and in vivo, thus abrogating any potential chemoresistance mechanisms involving DNA repair. Importantly, this combination of drugs does not affect normal long-term hematopoietic stem/progenitors. Moreover, the addition of CHK1i to AraC does not generate de novo mutations and in patients' samples where AraC is mutagenic, addition of CHK1i appears to eliminate the generation of mutant clones. Finally, we observe that persistent residual leukemic cells are quiescent and can become responsive to the treatment when forced into cycle via granulocyte colony-stimulating factor (G-CSF) administration. This drug combination (AraC+CHK1i+G-CSF) will open the doors for a more efficient treatment of AML in the clinic

Wplyw podawania zwiazkow selenu na tkankowe stezenie magnezu u szczurow

Magnesium and selenium belong to important bioelements. Magnesium is the second most abundant intracellular macroelement, which takes part in the metabolism of carbohydrates, nucleic acids, protein and lipids. Selenium is an essential microelement, whose deficit has been stated in many different pathological states. Much research on safe and effective selenium supplementation has been performed for the last fifty years but the results still remain unsatisfactory. The aim of our study was to investigate the influence of inorganic sodium selenite Na2SeO3 and two selenoorganic compounds synthetized at our chair on magnesium concentration in tissues of adolescent male Wistar rats. Inorganic selenite was administered as a water solution, whereas organic compounds: 4-(o-tolilo)-selenosemikarbazyd of 2-chlorobenzoic acid of a chain structure (ORG-C) and 3-(o-chlorobenzoylamino)-2-(o-tolylimino)-4- -methyl-4-selenazoline of a ring structure (ORG-R) were suspended in emulsion (oil, arabic gum and water). Selenium compounds were given to rats at a dose of 5⋅10–4 mg Se g–1 b.w. once a day for a period of 10 days. The control group was treated with saline. The administration was performed with use of a stomach tube. In comparison to the control group, selenium supplementation caused decrease in magnesium concentration in kidney and lung tissues, but did not cause any changes in the brain and heart muscle. In the liver and spleen it was only ring selenazoline that affected magnesium concentration, increasing it in the liver and decreasing in the spleen. In the femoral muscle it was only the selenosemicarbazide chain that exerted the significant effect causing a decrease in Mg concentration vs the control group. Selenium supplementation influences the tissue magnesium concentrations depending on tissue and structure of the supplement. Irrespective of the administered compound, it lowered magnesium in kidneys and lungs but caused no changes in the brain and heart muscle. In the liver, spleen and femoral muscle, alterations in the magnesium concentration were dependent on the provided supplement.Magnez i selen należą do biopierwiastków bardzo ważnych dla prawidłowego funkcjonowania organizmu. Magnez jest drugim co do ilości makropierwiastkiem wewnątrzkomórkowym, który odgrywa istotną rolę w metabolizmie węglowodanów, kwasów nukleinowych białek i lipidów. Selen jest niezbędnym mikroelementem, którego deficyt został stwierdzony w różnych stanach patologicznych. Przez ostatnie 50 lat prowadzono rozległe badania nad skuteczną i bezpieczną suplementacją tego pierwiastka, ale uzyskane wyniki nie są do końca satysfakcjonujące. Celem pracy było zbadanie wpływu nieorganicznego selenianu(IV) sodu Na2SeO3 i dwóch organicznych związków selenu o różnej budowie na stężenie magnezu w tkankach młodych samców szczurów rasy Wistar. Nieorganiczny selenian(IV) sodu podawano w postaci wodnego roztworu, natomiast organiczne związki selenu: 4-(o-tolilo)-selenosemikarbazyd kwasu 2-chlorobenzesowego (ORG-C, budowa łańcuchowa) i 3-(2-chlorobenzoiloamino- )-2-(o-toliloimino-)-4-metylo-4-selenazolina (ORG-R, budowa pierścieniowa) w formie emulsji złożonej z oleju, gumy arabskiej i wody. Grupa kontrolna otrzymywała sól fizjologiczną. Związki podawano sondą dożołądkowo w dawce 5⋅10–4 mg Se g–1 m.c. 1 raz dziennie przez okres 10 dni. W porównaniu z grupą kontrolną nieotrzymującą selenu, suplementacja związkami Se wpłynęła na statystyczny spadek stężenia magnezu w tkankach nerki i płuca, natomiast nie spowodowała żadnych zmian w tkance mózgu i mięśnia serca. W tkance wątroby i śledziony jedynie cykliczna selenazolina wpłynęła na stężenie magnezu – w wątrobie zaobserwowano wzrost, a w śledzionie spadek. W tkance mięśnia uda jedynie łańcuchowy selenosemikarbazyd wywarł istotny wpływ, powodując obniżenie stężenia Mg w stosunku do grupy kontrolnej. Suplementacja selenu wpływa na tkankowe stężenie magnezu w sposób zależny od rodzaju tkanki i struktury zastosowanego suplementu. Niezależnie od budowy podawanego związku, zaobserwowano obniżenie stężenia magnezu w tkance nerki i płuca, natomiast nie zauważono żadnych zmian w mózgu i mięśniu serca. W tkankach wątroby, śledziony i mięśnia uda zmiany stężenia magnezu były zależne od rodzaju podawanego związku

Cleidocranial dysplasia and RUNX2-clinical phenotype-genotype correlation

Runt-related transcription factor 2 (RUNX2/Cbfa1) is the main regulatory gene controlling skeletal development and morphogenesis in vertebrates. It is located on chromosome 6p21 and has two functional isoforms (type I and type II) under control of two alternate promoters (P1 and P2). Mutations within RUNX2 are linked to Cleidocranial dysplasia syndrome (CCD) in humans. CCD is an autosomal skeletal disorder characterized by several features such as delayed closure of fontanels, dental abnormalities and hypoplastic clavicles. Here, we summarize recent knowledge about RUNX2 function, mutations and their phenotypic consequences in patients.status: publishe

Genotype-phenotype correlation in clubfoot (talipes equinovarus)

Clubfoot (talipes equinovarus) is a congenital malformation affecting muscles, bones, connective tissue and vascular or neurological structures in limbs. It has a complex aetiology, both genetic and environmental. To date, the most important findings in clubfoot genetics involve PITX1 variants, which were linked to clubfoot phenotype in mice and humans. Additionally, copy number variations encompassing TBX4 or single nucleotide variants in HOXC11, the molecular targets of the PITX1 transcription factor, were linked to the clubfoot phenotype. In general, genes of cytoskeleton and muscle contractile apparatus, as well as components of the extracellular matrix and connective tissue, are frequently linked with clubfoot aetiology. Last but not least, an equally important element, that brings us closer to a better understanding of the clubfoot genotype/phenotype correlation, are studies on the two known animal models of clubfoot-the pma or EphA4 mice. This review will summarise the current state of knowledge of the molecular basis of this congenital malformation. © Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ