Optimized Inhibitors of MDM2 via an Attempted Protein-Templated Reductive Amination

Innovative and efficient hit-identification techniques are required to accelerate drug discovery. Protein-templated fragment ligations represent a promising strategy in early drug discovery, enabling the target to assemble and select its binders from a pool of building blocks. Development of new protein-templated reactions to access a larger structural diversity and expansion of the variety of targets to demonstrate the scope of the technique are of prime interest for medicinal chemists. Herein, we present our attempts to use a protein-templated reductive amination to target protein-protein interactions (PPIs), a challenging class of drug targets. We address a flexible pocket, which is difficult to achieve by structure-based drug design. After careful analysis we did not find one of the possible products in the kinetic target-guided synthesis (KTGS) approach, however subsequent synthesis and biochemical evaluation of each library member demonstrated that all the obtained molecules inhibit MDM2. The most potent library member (Ki=0.095 μm) identified is almost as active as Nutlin-3, a potent inhibitor of the p53-MDM2 PPI

The effect of a micronutrient powder home fortification program on anemia and cognitive outcomes among young children in rural China: a cluster randomized trial

Abstract Background Anemia early in life has been associated with delayed cognitive and motor development. The WHO recommends home fortification using multiple micronutrient powders (MNPs) containing iron as a strategy to address anemia in children under two. We evaluated the effects of a program freely distributing MNP sachets to caregivers of infants in rural China. Methods We conducted a cluster-randomized controlled trial in Shaanxi province, enrolling all children aged 6–11 months in target villages. Following a baseline survey, investigators randomly assigned each village/cluster to a control or treatment group. In the treatment group, caregivers were instructed to give MNPs daily. Follow-up was after 6, 12, and 18 months of intervention. Primary outcomes were hemoglobin concentrations and scores on the Bayley Scales of Infant Development. Results One thousand, eight hundred and-two eligible children and their caregivers were enrolled. At baseline 48% (870) of children were anemic and 29% (529) were developmentally delayed. Six hundred and-ten children (117 villages) were assigned to the control group and 1192 children (234 villages) were assigned to the treatment group. Assignment to the treatment group was associated with an improvement in hemoglobin levels (marginal effect 1.77 g/L, 95% CI 0.017–3.520, p-value = 0.048) and cognitive development (marginal effect 2.23 points, 95% CI 0.061–4.399, p-value = 0.044) after 6 months but not thereafter. There were no significant effects on motor development. Zero effects after the first 6 months were not due to low compliance, low statistical power, or changes in feeding behavior. Hemoglobin concentrations improved in both the treatment and control groups over the course of the study; however, 22% (325) of children remained anemic at endline, and 48% (721) were cognitively delayed. Conclusions Providing caregivers with MNP sachets modestly hastened improvement in hemoglobin levels that was occurring absent intervention; however, this improvement did not translate into improved developmental outcomes at endline. Trial registration ISRCTN44149146 ; prospectively registered on 15th April 2013

The combination of bilateral congenital adrenal hemorrhage and congenital hemihypertrophy

[No abstract available

A malformed fetus in a rudimentary uterine horn pregnancy

We present a case of a 13-week pregnancy with a malformed fetus in a ruptured non-communicating rudimentary horn. The patient, a 21-year-old woman with pelvic and right-sided abdominal pain, was admitted to the gynecology clinic of our institution. A ruptured rudimentary horn pregnancy was diagnosed by ultrasonography. The fetus in the gestation sac showed euisceration of the liver and intestines and an absent left femur. There was an amniotic band extending across the body of the fetus. The ruptured horn was excised by laparotomy. The factors associated with rudimentary horn pregnancy and related fetal abnormalities are discussed

Comparison of resolving time values of different scintillation detectors in the coincidence experiments

WOS: 000313713300080The resolving time values of the coincidence spectrometers composed by NaI(Tl) inorganic, BC408 type and BC418 type organic scintillation detectors were obtained in this work. For this purpose, fast-fast coincidence measurements were carried out. Best timing performance was obtained by BC418 type plastic scintillator for various source-detector distances.TUBITAK, the Scientific and Technical Research Council of TurkeyTurkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [197T087, 111T571]; EBILTEM, Center of Science and Technology, Ege UniversityEge University [99 BIL 001]; Scientific Research Foundation of Ege UniversityEge University [11 FEN 085]This work was supported by TUBITAK, the Scientific and Technical Research Council of Turkey under Project numbers 197T087 and 111T571, and by EBILTEM, Center of Science and Technology, Ege University under Project No. 99 BIL 001, and Scientific Research Foundation of Ege University under Project No. 11 FEN 085

A 22-week cervical pregnancy.

We report on a cervical pregnancy at advanced gestational age, Misdiagnosis allowed pregnancy to proceed until the 22nd week of gestation and made its management more complicated. An abdominal hysterectomy with preservation of the adnexa was performed, Copyright (C) 2000 S. Karger AG, Basel