Androgen receptor pathway inhibitors and taxanes in metastatic prostate cancer: an outcome-adaptive randomized platform trial.

ProBio is the first outcome-adaptive platform trial in prostate cancer utilizing a Bayesian framework to evaluate efficacy within predefined biomarker signatures across systemic treatments. Prospective circulating tumor DNA and germline DNA analysis was performed in patients with metastatic castration-resistant prostate cancer before randomization to androgen receptor pathway inhibitors (ARPIs), taxanes or a physician's choice control arm. The primary endpoint was the time to no longer clinically benefitting (NLCB).

Timing of Primary Surgery for Cleft Palate.

Background: Among infants with isolated cleft palate, whether primary surgery at 6 months of age is more beneficial than surgery at 12 months of age with respect to speech outcomes, hearing outcomes, dentofacial development, and safety is unknown.

Methods: We randomly assigned infants with nonsyndromic isolated cleft palate, in a 1:1 ratio, to undergo standardized primary surgery at 6 months of age (6-month group) or at 12 months of age (12-month group) for closure of the cleft. Standardized assessments of quality-checked video and audio recordings at 1, 3, and 5 years of age were performed independently by speech and language therapists who were unaware of the trial-group assignments.

Discovery, optimization and biodistribution of an Affibody molecule for imaging of CD69.

Due to the wide scale of inflammatory processes in different types of disease, more sensitive and specific biomarkers are required to improve prevention and treatment. Cluster of differentiation 69 (CD69) is one of the earliest cell surface proteins expressed by activated leukocytes. Here we characterize and optimize potential new imaging probes, Affibody molecules targeting CD69 for imaging of activated immune cells.

Influenza Vaccination After Myocardial Infarction: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial.

Background: Observational and small, randomized studies suggest that influenza vaccine may reduce future cardiovascular events in patients with cardiovascular disease.

Methods: We conducted an investigator-initiated, randomized, double-blind trial to compare inactivated influenza vaccine with saline placebo administered shortly after myocardial infarction (MI; 99.7% of patients) or high-risk stable coronary heart disease (0.

A Multicompartment Human Kidney Proximal Tubule-on-a-Chip Replicates Cell Polarization-Dependent Cisplatin Toxicity.

Drug-induced kidney injury is a major clinical problem and causes drug attrition in the pharmaceutical industry. To better predict drug-induced kidney injury, kidney in vitro cultures with enhanced physiologic relevance are developed. To mimic the proximal tubule, the main site of adverse drug reactions in the kidney, human-derived renal proximal tubule epithelial cells (HRPTECs) were injected in one of the channels of dual-channel Nortis chips and perfused for 7 days.

The Value of a New Diagnostic Test for Prostate Cancer: A Cost-Utility Analysis in Early Stage of Development.

Background: Standard biopsy for prostate cancer diagnosis is an unpleasant and sometimes painful procedure with a detection rate as low as around 50%. Consequently, an accurate blood-based test would be highly desirable to improve the predictive accuracy. However, the clinical value of a new blood test for diagnosing prostate cancer depends on its sensitivity and specificity, in relation to the selected target population.

Assessing the Multiple Dimensions of Poverty. Data Mining Approaches to the 2004-14 Health and Demographic Surveillance System in Cuatro Santos, Nicaragua.

We identified clusters of multiple dimensions of poverty according to the capability approach theory by applying data mining approaches to the Cuatro Santos Health and Demographic Surveillance database, Nicaragua. Four municipalities in northern Nicaragua constitute the Cuatro Santos area, with 25,893 inhabitants in 5,966 households (2014). A local process analyzing poverty-related problems, prioritizing suggested actions, was initiated in 1997 and generated a community action plan 2002-2015.

The Molecular Basis for Inhibition of Stemlike Cancer Cells by Salinomycin.

Tumors are phenotypically heterogeneous and include subpopulations of cancer cells with stemlike properties. The natural product salinomycin, a K-selective ionophore, was recently found to exert selectivity against such cancer stem cells. This selective effect is thought to be due to inhibition of the Wnt signaling pathway, but the mechanistic basis remains unclear.

Diagnostic Accuracy of a Machine-Learning Approach to Coronary Computed Tomographic Angiography-Based Fractional Flow Reserve: Result From the MACHINE Consortium.

Background: Coronary computed tomographic angiography (CTA) is a reliable modality to detect coronary artery disease. However, CTA generally overestimates stenosis severity compared with invasive angiography, and angiographic stenosis does not necessarily imply hemodynamic relevance when fractional flow reserve (FFR) is used as reference. CTA-based FFR (CT-FFR), using computational fluid dynamics (CFD), improves the correlation with invasive FFR results but is computationally demanding.

Synthesis, X-ray analysis, and biological evaluation of a new class of stereopure lactam-based HIV-1 protease inhibitors.

In an effort to identify a new class of druglike HIV-1 protease inhibitors, four different stereopure β-hydroxy γ-lactam-containing inhibitors have been synthesized, biologically evaluated, and cocrystallized. The impact of the tether length of the central spacer (two or three carbons) was also investigated. A compound with a shorter tether and (3R,4S) absolute configuration exhibited high activity with a K(i) of 2.

Characterization of the Pho89 phosphate transporter by functional hyperexpression in Saccharomyces cerevisiae.

The Na(+)-coupled, high-affinity Pho89 plasma membrane phosphate transporter in Saccharomyces cerevisiae has so far been difficult to study because of its low activity and special properties. In this study, we have used a pho84Deltapho87Deltapho90Deltapho91Delta quadruple deletion strain of S. cerevisiae devoid of all transporter genes specific for inorganic phosphate, except for PHO89, to functionally characterize Pho89 under conditions where its expression is hyperstimulated.

In vitro evolution of an antibody fragment population to find high-affinity hapten binders.

Recently, we constructed a focused antibody library tailored to interact with haptens. High functionality of this library was demonstrated, as specific binders could be retrieved to a range of different haptens. In the current study we have developed a mutagenesis and selection strategy in order to further fine-tune the hapten binding properties of these antibody fragments.

A structural insight into the inhibition of human and Leishmania donovani ornithine decarboxylases by 1-amino-oxy-3-aminopropane.

The critical role of polyamines in key processes such as cell growth, differentiation and macromolecular synthesis makes the enzymes involved in their synthesis potential targets in the treatment of certain types of cancer and parasitic diseases. Here we present a study on the inhibition of human and Leishmania donovani ODC (ornithine decarboxylase), the first committed enzyme in the polyamine biosynthesis pathway, by APA (1-amino-oxy-3-aminopropane). The present study shows APA to be a potent inhibitor of both human and L.

Frequent fusion of the CRTC1 and MAML2 genes in clear cell variants of cutaneous hidradenomas.

Fusion of the CREB regulated transcription coactivator CRTC1 (a.k.a.

A promiscuous glutathione transferase transformed into a selective thiolester hydrolase.

Human glutathione transferase A1-1 (hGST A1-1) can be reengineered by rational design into a catalyst for thiolester hydrolysis with a catalytic proficiency of 1.4 x 10(7) M(-1). The thiolester hydrolase, A216H that was obtained by the introduction of a single histidine residue at position 216 catalyzed the hydrolysis of a substrate termed GSB, a thiolester of glutathione and benzoic acid.

Molecular basis for differential substrate specificity in class IV alcohol dehydrogenases: a conserved function in retinoid metabolism but not in ethanol oxidation.

Mammalian class IV alcohol dehydrogenase enzymes are characteristic of epithelial tissues, exhibit moderate to high K(m) values for ethanol, and are very active in retinol oxidation. The human enzyme shows a K(m) value for ethanol which is 2 orders of magnitude lower than that of rat class IV. The uniquely significant difference in the substrate-binding pocket between the two enzymes appears to be at position 294, Val in the human enzyme and Ala in the rat enzyme.

Arabidopsis formaldehyde dehydrogenase. Molecular properties of plant class III alcohol dehydrogenase provide further insights into the origins, structure and function of plant class p and liver class I alcohol dehydrogenases.

A glutathione-dependent formaldehyde dehydrogenase (class III alcohol dehydrogenase) has been characterized from Arabidopsis thaliana. This plant enzyme exhibits kinetic and molecular properties in common with the class III forms from mammals, with a K(m) for S-hydroxymethylglutathione of 1.4 microM, an anodic electrophoretic mobility (pI: 5.

Effects of KRN2391, a novel vasodilator acting as a nitrate and a K+ channel opener, on the rabbit lower urinary tract.

1. The relaxant effect of KRN2391, suggested to act both as a nitrate and a K+ channel opener, was investigated in the rabbit lower urinary tract and compared with the effects of the NO-donor SIN-1 and the K+ channel opener levcromakalim. 2.

Demonstration of voltage-dependent and TTX-sensitive Na(+)-channels in human melanocytes.

The electrophysiological properties of cultured human melanocytes were investigated using the whole-cell configuration of the patch-clamp technique. Depolarizations to membrane potentials more positive than -30 mV resulted in the rapid development ( < 1 ms to peak) of an inward current. The maximum peak current was observed at +10 mV and reached an average amplitude of about 270 pA.

Macula densa cell function.

Studies concerning the sensing step in the tubuloglomerular feedback (TGF) mechanism have been conflicting. To study this step, we measured macula densa (MD) cell volume and membrane potentials in the isolated perfused ascending limb of the loop of Henle with attached glomerulus with MD segments (cTAL-MD). Addition of furosemide reduced cell volume rapidly and the effect could be reversed on removal of the drug.

Calcium binding to the isolated beta-hydroxyaspartic acid-containing epidermal growth factor-like domain of bovine factor X.

Coagulation factor X is a vitamin K-dependent protein composed of discrete domains or modules. A proteolytically modified derivative of factor X that lacks the NH2-terminal gamma-carboxyglutamic acid (Gla)-containing region retains one Ca2+ binding site. To localize this Gla-independent Ca2+ binding site and to facilitate future studies aimed at elucidating structure-function relationship in the factor X molecule, we have devised a method to isolate the first beta-hydroxyaspartic acid (Hya)-containing epidermal growth factor (EGF)-like domain from proteolytic digests of bovine factor X performed under strictly controlled conditions.