Decision making in clinical trials: Interim analyses, innovative design, and biomarkers.

The efficient and accurate execution of clinical trials testing novel treatments for Alzheimer's disease (AD) is a critical component of the field's collective efforts to develop effective disease-modifying treatments for AD. The lengthy and heterogeneous nature of clinical progression in AD contributes to the challenges inherent in demonstrating a clinically meaningful benefit of any potential new AD therapy. The failure of many large and expensive clinical trials to date has prompted a focus on optimizing all aspects of decision making, to not only expedite the development of new treatments, but also maximize the value of the information that each clinical trial yields, so that all future clinical trials (including those that are negative) will contribute toward advancing the field.

The brassinosteroid-responsive protein OCTOPUS is a novel regulator of immune signaling.

Phloem is a critical tissue for transport of photosynthates and extracellular signals in vascular plants. However, it also represents an ideal environment for pathogens seeking access to valuable host nutrients. Although many vascular pathogens induce economically relevant crop damage, there is still little known about the mechanisms by which immune signaling operates through the phloem.

Early-stage Triple-negative Breast Cancer: Time to Optimize Personalized Strategies.

Triple-negative breast cancer (TNBC) accounts for approximately 15%-20% of breast cancers diagnosed worldwide, which amounts to almost 200 000 cases each year. Although historically TNBC is considered difficult to treat with a poor prognosis, there is emerging evidence showing excellent response rates in a subset of TNBC patients. Attempts to de-escalate chemotherapy in hormone-receptor-positive (HR+) and HER2-neu amplified breast cancer subtypes have been successful.

Mapping the genetic architecture of human traits to cell types in the kidney identifies mechanisms of disease and potential treatments.

The functional interpretation of genome-wide association studies (GWAS) is challenging due to the cell-type-dependent influences of genetic variants. Here, we generated comprehensive maps of expression quantitative trait loci (eQTLs) for 659 microdissected human kidney samples and identified cell-type-eQTLs by mapping interactions between cell type abundances and genotypes. By partitioning heritability using stratified linkage disequilibrium score regression to integrate GWAS with single-cell RNA sequencing and single-nucleus assay for transposase-accessible chromatin with high-throughput sequencing data, we prioritized proximal tubules for kidney function and endothelial cells and distal tubule segments for blood pressure pathogenesis.

TransCelerate's Clinical Quality Management System: Issue Management.

Issue management is one of the elements of the TransCelerate clinical quality management (QMS) conceptual framework. Effective issue management benefits clinical development organizations by allowing them to focus efforts on those issues that materially impact patient safety, rights, and well-being; data integrity and/or scientific rigor; compliance with regulatory requirements; or trust in the clinical research enterprise, which have been defined as "Issues that Matter." Issue management begins with a triage of issues to identify those issues that materially impact as defined above, which are then handled by an end-to-end corrective and preventive action (CAPA) process.

The association of single nucleotide polymorphisms in the catechol-O-methyltransferase gene and pain scores in female patients with major depressive disorder.

Unlabelled: We tested the hypothesis that single nucleotide polymorphisms (SNPs) in the catechol-O-methyltransferase (COMT) gene are associated with baseline pain levels in patients with major depressive disorder (MDD). Pain levels were quantified using a visual analog scale (VAS) for pain. Data from 159 female and 93 male self-reported white patients with MDD were analyzed.

15 Modification of phycobiliproteins at asparagine residues.

Side-chain amide methylation of asparagine was described in a special complement of photosynthesis accessory pigment-protein complexes called phycobiliproteins nearly 20 years ago. Since that report, several investigations have assigned this posttranslational modification a functional role in tuning the spectroscopic properties of the phycobiliprotein chromophores. Asparagine methylation has not been reported in other systems and is restricted to the broader phycobiliprotein family.

Parathyroid hormone as a therapeutic agent.

Recent advances in the use of parathyroid hormone as a therapeutic agent include a controlled trial that assessed vertebral and non-vertebral fracture risk reduction in women, trials in men, and assessment of treatment on cortical and trabecular bone structure. The occurrence of osteosarcoma in long-term toxicology studies in rats is briefly reviewed.

Managing laboratory automation in a changing pharmaceutical industry.

The health care reform movement in the USA and increased requirements by regulatory agencies continue to have a major impact on the pharmaceutical industry and the laboratory. Laboratory management is expected to improve effciency by providing more analytical results at a lower cost, increasing customer service, reducing cycle time, while ensuring accurate results and more effective use of their staff. To achieve these expectations, many laboratories are using robotics and automated work stations.

Countershock strength-duration relationship for myocardial refractory period extension.

Objectives: To determine the strength-duration relationship for refractory period extension (RPE) in order to understand better the influence of shock waveform on RPE.

Methods: In six open-chest pentobarbital-anesthetized dogs, the RPE was measured by rectangular transcardiac shocks that produced 2- to 32-V/cm local voltage gradients at the measurement site. At each intensity, measurements were made for shocks with 2- to 32-msec durations delivered 30 msec before the end of the tissue refractory period.

Expression of potentially amyloidogenic derivatives of the Alzheimer amyloid precursor protein in cultured 293 cells.

The expression of the carboxyl-terminal 100 (C-100) residues of the amyloid precursor protein (APP) may provide a model for studying the processing of APP to the 42-43 residue beta-amyloid peptide (beta A4) implicated in Alzheimer's disease. Expression of human C-100 in mammalian cells reportedly causes 'toxicity' and amyloid-like fibrils. We have expressed the C-100 fragment in human embryonic kidney cells (293 cells) in a transient assay and compared it to the expression of transfected wild type and mutant (Swedish familial Alzheimer's disease) full length APP.

Positioning laboratory automation for today's dynamic climate.

Laboratory automation has existed and matured at Eli Lilly and Company for well over a decade. The author's section serves as a developer of laboratory automation systems for customers within Lilly and embodies 'robotic friendly' laboratories with highly technical and experienced personnel. With several systems showing signs of age, second generation 'smart systems' have been developed and delivered during the last three years.

Therapeutic defibrination with ancrod does not protect canine myocardium from reperfusion injury.

The purpose of this study was to determine whether normal fibrinogen contributes to the development of myocardial reperfusion injury by acting as a substrate in vivo for neutrophil adhesion. This was tested in a dog model of acute myocardial infarction that used pentobarbital anesthetized dogs subjected to 90 min regional myocardial ischemia and 5 h reperfusion. Dogs were treated with 1 unit/kg Ancrod (venom from the Malayan pit viper, Agkistrodon rhodostoma) or vehicle i.

Further characterization of tolerance to the corticosterone-elevating effect of pergolide in rats.

Four daily injections of pergolide, an ergoline dopamine agonist, made male rats tolerant to the corticosterone-elevating effects of an acute injection of pergolide on the fifth day. This tolerance occurred not only to acute treatment with pergolide, but also to other dopamine agonists differing in structure, potency and receptor subtype selectivity. Plasma corticosterone was elevated following administration of opioid or serotonin agonists in both vehicle- and pergolide-pretreated rats.