Deuteron and antideuteron production in Au+Au collisions at sqrt(s_NN)=200 GeV

The production of deuterons and antideuterons in the transverse momentum range 1.1 < p_T < 4.3 GeV/c at mid-rapidity in Au + Au collisions at sqrt(s_NN)=200 GeV has been studied by the PHENIX experiment at RHIC. A coalescence analysis comparing the deuteron and antideuteron spectra with those of protons and antiprotons, has been performed. The coalescence probability is equal for both deuterons and antideuterons and increases as a function of p_T, which is consistent with an expanding collision zone. Comparing (anti)proton yields p_bar/p = 0.73 +/- 0.01, with (anti)deuteron yields: d_bar/d = 0.47 +/- 0.03, we estimate that n_bar/n = 0.64 +/- 0.04.Comment: 326 authors, 6 pages text, 5 figures, 1 Table. Submitted to PRL. Plain text data tables for the points plotted in figures for this and previous PHENIX publications are (or will be) publicly available at http://www.phenix.bnl.gov/papers.htm

Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress

The folate metabolism enzyme MTHFD2 (methylenetetrahydrofolate dehydrogenase/cyclohydrolase) is consistently overexpressed in cancer but its roles are not fully characterized, and current candidate inhibitors have limited potency for clinical development. In the present study, we demonstrate a role for MTHFD2 in DNA replication and genomic stability in cancer cells, and perform a drug screen to identify potent and selective nanomolar MTHFD2 inhibitors; protein cocrystal structures demonstrated binding to the active site of MTHFD2 and target engagement. MTHFD2 inhibitors reduced replication fork speed and induced replication stress followed by S-phase arrest and apoptosis of acute myeloid leukemia cells in vitro and in vivo, with a therapeutic window spanning four orders of magnitude compared with nontumorigenic cells. Mechanistically, MTHFD2 inhibitors prevented thymidine production leading to misincorporation of uracil into DNA and replication stress. Overall, these results demonstrate a functional link between MTHFD2-dependent cancer metabolism and replication stress that can be exploited therapeutically with this new class of inhibitors

Proton scattering from excited states of atomic hydrogen

© 2018 IOP Publishing Ltd. Wavepacket continuum-discretisation approach is used to calculate excitation, ionization and electron-capture (ec) cross sections for proton collisions with n = 2 states of atomic hydrogen, where n is the principal quantum number. The approach assumes a classical motion for the projectile and is based on the solution of the three-body Schrödinger equation using the two-center expansion of the total scattering wave function. The scattering wave function is expanded in an orthonormal basis set built from negative-energy eigenstates and wavepacket pseudostates representing the continuum of both the target atom and the atom formed by the projectile after capturing the electron. With a sufficiently large basis, due to the strong coupling between channels, the method produces converged cross sections for direct-scattering, ionization and ec processes simultaneously. For the quasi-elastic transitions, where both orbital and magnetic quantum numbers change, the integrated cross section is infinite. Nevertheless, the corresponding transitions probabilities are finite at any given impact parameter, indicating that the angular differential cross sections can be measured. Calculated cross sections for scattering on the metastable 2s state are compared with other theoretical results obtained using atomic-orbital close-coupling and classical-trajectory Monte Carlo approaches. Considerable disagreement with previous calculations has been found for some transitions at various incident energies

Solution of the proton-hydrogen scattering problem using a quantum-mechanical two-center convergent close-coupling method

Details of the recently developed quantum-mechanical two-center convergent close-coupling approach (Abdurakhmanov et al 2016 J. Phys. B: At. Mol. Phys. 49 03LT01) to proton-hydrogen scattering are presented. The formulation is based on the exact (fully quantum-mechanical) three-body Schrödinger equation. The total scattering wavefunction is expanded using a two-center pseudostate basis. This allows one to include all underlying processes, namely, direct scattering and ionization, electron capture into bound and continuum states of the projectile. The off-shell integration in the coupled-channel Lippmann-Schwinger integral equations emerging from the three-body Schrödinger equation for the scattering wavefunction is taken analytically which greatly reduces computational effort. While the calculated electron capture cross sections are in a good agreement with experiment, some discrepancy exists for the ionization cross sections

Important problems in the diagnosis and treatment of primary sclerosing cholangitis (based on the Russian consensus on diagnosis and treatment autoimmune hepatitis. Moscow, 2018)

© 2019 Consilium Medikum. All rights reserved. The article is published based on the results of the Russian Consensus on the diagnosis and treatment of primary sclerosing cholangitis (PSC), discussed at the 44 th annual Scientific Session of the CNIIG "Personalized Medicine in the Era of Standards" (March 1, 2018). The aim of the review is to highlight the current issues of classification of diagnosis and treatment of patients with PSC, which causes the greatest interest of specialists. The urgency of the problem is determined by the multivariate nature of the clinical manifestations, by often asymptomatic flow, severe prognosis, complexity of diagnosis and insufficient study of PSC, the natural course of which in some cases can be considered as a function with many variables in terms of the nature and speed of progression with numerous possible clinical outcomes. In addition to progression to portal hypertension, cirrhosis and its complications, PSC can be accompanied by clinical manifestations of obstructive jaundice, bacterial cholangitis, cholangiocarcinoma and colorectal cancer. Magnetic resonance cholangiography is the main method of radial diagnostics of PSC, which allows to obtain an image of bile ducts in an un-invasive way. The use of liver biopsy is best justified when there is a suspicion of small-diameter PSC, autoimmune cross-syndrome PSC-AIG, IgG4-sclerosing cholangitis. Currently, a drug registered to treat primary sclerosing cholangitis which can significantly change the course and prognosis of the disease does not exist. There is no unified view on the effectiveness and usefulness of ursodeoxycholic acid and its dosage in PSC. Early diagnosis and determination of the phenotype of PSC is of clinical importance. It allows to determine the tactics of treatment, detection and prevention of complications

Important problems in the diagnosis and treatment of primary sclerosing cholangitis (based on the Russian consensus on diagnosis and treatment autoimmune hepatitis. Moscow, 2018)

© 2019 Consilium Medikum. All rights reserved. The article is published based on the results of the Russian Consensus on the diagnosis and treatment of primary sclerosing cholangitis (PSC), discussed at the 44 th annual Scientific Session of the CNIIG "Personalized Medicine in the Era of Standards" (March 1, 2018). The aim of the review is to highlight the current issues of classification of diagnosis and treatment of patients with PSC, which causes the greatest interest of specialists. The urgency of the problem is determined by the multivariate nature of the clinical manifestations, by often asymptomatic flow, severe prognosis, complexity of diagnosis and insufficient study of PSC, the natural course of which in some cases can be considered as a function with many variables in terms of the nature and speed of progression with numerous possible clinical outcomes. In addition to progression to portal hypertension, cirrhosis and its complications, PSC can be accompanied by clinical manifestations of obstructive jaundice, bacterial cholangitis, cholangiocarcinoma and colorectal cancer. Magnetic resonance cholangiography is the main method of radial diagnostics of PSC, which allows to obtain an image of bile ducts in an un-invasive way. The use of liver biopsy is best justified when there is a suspicion of small-diameter PSC, autoimmune cross-syndrome PSC-AIG, IgG4-sclerosing cholangitis. Currently, a drug registered to treat primary sclerosing cholangitis which can significantly change the course and prognosis of the disease does not exist. There is no unified view on the effectiveness and usefulness of ursodeoxycholic acid and its dosage in PSC. Early diagnosis and determination of the phenotype of PSC is of clinical importance. It allows to determine the tactics of treatment, detection and prevention of complications

Efficacy and safety of the Russian protease inhibitor narlaprevir at treatment-naive and earlier treated noncirrhotic patients with the 1st genotype chronic hepatitis C (PIONEER study)

Aim of investigation. To estimate efficacy and safety of narlaprevir (NVR) with ritonavir (RTV), pegilated interferon (peg-IFN) and ribavirin (RBV) at treatmentnaïve and earlier treated noncirrhotic patients with chronic hepatitis C caused by the 1st virus genotype in double blind placebo-controlled 3rd phase study (PIONEER). Material and methods. The main group received NVR (200 mg od orally) in combination to RTV (100 mg) and pegIFN/RBV for 12 weeks that was followed by peg-IFN/ RBV for 12 weeks. Comparison group received pegIFN/ RBV for 48 weeks, for the first 12 weeks in combination to placebo. Results. The sustained virologic response in 24 weeks after treatment termination (SVR24) in the main group (NVR/RTV, PEG IFN/RBV)) was achieved in 89.1% (163/183) of treatment-naïve and 69.7% (69/99) of earlier treated patients. SVR24 was achieved in 86.5% (32/37) of patients with relapse after previous peg-IFN/ RBV treatment course. The viral load decreased for the mean of 5.3 log10 in 2 weeks and 5.9 log10 in 4 weeks of treatment in the main group vs 1.5 log10 in 2 weeks and 2.5 log10 in 4 weeks in comparison group. In treatment-naïve patients from the main group SVR24 was achieved in 90.8% at initial METAVIR F0-F2 liver fibrosis stage and in 75% at F3 liver fibrosis stage. In those who were previously treated by peg-IFN/RBV, in the main group SVR-24 was attained in 72.6% at liver fibrosis stage F0-F2 and in 53.3% with F3 liver fibrosis stage. NVR/RTV addition to peg-IFN/RBV treatment did not alter safety profile as compared to peg-IFN/RBV therapy. Conclusions. In PIONEER study the narlaprevir combination therapy was characterized by high efficacy, convenience of administration and favorable safety profile