The identification of clinical candidate LY3522348 (compound 23) is described. LY3522348 is a highly selective, oral dual inhibitor of human ketohexokinase isoforms C and A (hKHK-C, hKHK-A). ...Optimization began with highly efficient (S)-2-(2-methylazetidin-1-yl)-6-(1H-pyrazol-4-yl)-4-(trifluoromethyl)nicotinonitrile (3). Efforts focused on developing absorption, distribution, metabolism, potency, and in vitro safety profiles to support oral QD dosing in patients. Structure-based design leveraged vectors for substitution of the pyrazole ring, which provided an opportunity to interact with several different proximal amino acid residues in the protein. LY3522348 displayed a robust pharmacodynamic response in a mouse model of fructose metabolism and was advanced into clinical trials.
Patients with cancer who develop small bowel obstruction are at high risk of malnutrition and morbidity following compromise of gastrointestinal tract continuity. This study aimed to characterise ...current management and outcomes following malignant small bowel obstruction.
A prospective, multicentre cohort study of patients with small bowel obstruction who presented to UK hospitals between 16th January and 13th March 2017. Patients who presented with small bowel obstruction due to primary tumours of the intestine (excluding left-sided colonic tumours) or disseminated intra-abdominal malignancy were included. Outcomes included 30-day mortality and in-hospital complications. Cox-proportional hazards models were used to generate adjusted effects estimates, which are presented as hazard ratios (HR) alongside the corresponding 95% confidence interval (95% CI). The threshold for statistical significance was set at the level of P ≤ 0.05 a-priori.
205 patients with malignant small bowel obstruction presented to emergency surgery services during the study period. Of these patients, 50 had obstruction due to right sided colon cancer, 143 due to disseminated intraabdominal malignancy, 10 had primary tumours of the small bowel and 2 patients had gastrointestinal stromal tumours. In total 100 out of 205 patients underwent a surgical intervention for obstruction. 30-day in-hospital mortality rate was 11.3% for those with primary tumours and 19.6% for those with disseminated malignancy. Severe risk of malnutrition was an independent predictor for poor mortality in this cohort (adjusted HR 16.18, 95% CI 1.86 to 140.84, p = 0.012). Patients with right-sided colon cancer had high rates of morbidity.
Mortality rates were high in patients with disseminated malignancy and in those with right sided colon cancer. Further research should identify optimal management strategy to reduce morbidity for these patient groups.
Precise neutron-energy measurements are required to probe the nuclear structure effects of neutron-rich nuclei, where a-delayed neutron emission becomes a dominant decay mode. The Neutron dEtector ...with Xn Tracking (NEXT) array has been designed and constructed to measure a-delayed neutrons with better energy resolution. The new design localizes the neutron interaction position by optically segmenting the detector along the direction of the neutron flight path, reducing the associated uncertainties in the neutron time-of-flight measurements. This significantly improves the energy resolution without losing the necessary detection efficiency. The proof-ofprinciple and efficiency measurements showed promising results. This article details the implementation of the neutron tracking capability of NEXT array in time-of-flight measurements.
Discovery of strongly-lensed gravitational wave (GW) sources will unveil binary compact objects at higher redshifts and lower intrinsic luminosities than is possible without lensing. Such systems ...will yield unprecedented constraints on the mass distribution in galaxy clusters, measurements of the polarization of GWs, tests of General Relativity, and constraints on the Hubble parameter. Excited by these prospects, and intrigued by the presence of so-called “heavy black holes” in the early detections by LIGO-Virgo, we commenced a search for strongly-lensed GWs and possible electromagnetic counterparts in the latter stages of the second LIGO observing run (O2). Here, we summarise our calculation of the detection rate of strongly-lensed GWs, describe our review of BBH detections from O1, outline our observing strategy in O2, summarize our follow-up observations of GW170814, and discuss the future prospects of detection.
Radio-frequency E1 transitions between nearly degenerate, opposite-parity levels of atomic dysprosium (Dy) were monitored over an 8-month period to search for a variation in the fine-structure ...constant {alpha}. During this time period, data were taken at different points in the gravitational potential of the Sun. The data are fitted to the variation in the gravitational potential yielding a value of (-8.7{+-}6.6)x10{sup -6} for k{sub {alpha}}, the variation of {alpha} in a changing gravitational potential. This value gives the first laboratory limit independent of assumptions regarding other fundamental constants. In addition, our value of k{sub {alpha}} combined with other experimental constraints is used to extract the first limits on k{sub e} and k{sub q}. These coefficients characterize the variation of m{sub e}/m{sub p} and m{sub q}/m{sub p} in a changing gravitational potential, where m{sub e}, m{sub p}, and m{sub q} are electron, proton, and quark masses. The results are k{sub e}=(4.9{+-}3.9)x10{sup -5} and k{sub q}=(6.6{+-}5.2)x10{sup -5}. All these results indicate the absence of significant variation at the present level of sensitivity.
Clinical development of catechol-based orthosteric agonists of the dopamine D1 receptor has thus far been unsuccessful due to multiple challenges. To address these issues, we identified LY3154207 (3) ...as a novel, potent, and subtype selective human D1 positive allosteric modulator (PAM) with minimal allosteric agonist activity. Conformational studies showed LY3154207 adopts an unusual boat conformation, and a binding pose with the human D1 receptor was proposed based on this observation. In contrast to orthosteric agonists, LY3154207 showed a distinct pharmacological profile without a bell-shaped dose-response relationship or tachyphylaxis in preclinical models. Identification of a crystalline form of free LY3154207 from the discovery lots was not successful. Instead, a novel cocrystal form with superior solubility was discovered and determined to be suitable for development. This cocrystal form was advanced to clinical development as a potential first-in-class D1 PAM and is now in phase 2 studies for Lewy body dementia.
How angiotensin (ANG) II acutely stimulates the Na-K pump in proximal tubules is only partially understood, limiting insight into how ANG II increases blood pressure. First, we tested whether ANG II ...increases the number of pumps in plasma membranes of native rat proximal tubules under conditions of rapid activation. We found that exposure to 100 pM ANG II for 2 min, which was previously shown to increase affinity of the Na-K pump for Na and stimulate activity threefold, increased the amount of the Na-K pump in plasma membranes of native tubules by 33%. Second, we tested whether previously observed increases in phosphorylation of the Na-K pump at Ser(938) were part of the stimulatory mechanism. These experiments were carried out in opossum kidney cells, cultured proximal tubules stably coexpressing the ANG type 1 (AT1) receptor, and either wild-type or a S938A mutant of rat kidney Na-K pump under conditions found by others to stimulate activity. We found that 10 min of incubation in 10 pM ANG II stimulated activity of wild-type pumps from 2.3 to 3.5 nmol K · mg protein(-1) · min(-1) and increased the amount of the pump in the plasma membrane by 80% but had no effect on cells expressing the S938A mutant. We conclude that acute stimulation of Na-K pump activity in native rat proximal tubules includes increased trafficking to the plasma membrane and that phosphorylation at Ser(938) is part of the mechanism by which ANG II directly stimulates activity and trafficking of the rat kidney Na-K pump in opossum kidney cells.
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