Comparative analysis of racing performance following surgical correction of epiglottic entrapment in standardbreds and thoroughbreds.

Introduction: Epiglottic entrapment (EE) is a common cause of poor performance in racing standardbreds (STBs) and thoroughbreds (TBs). There is limited information published on the condition in STB racehorses and limited information on factors associated with return to racing available for either breed.

Methods: This study investigated and compared the pre surgical findings, post-surgical complications and racing performance in STBs and TBs undergoing surgery for correction of EE.

The Surgical Repair of a Salter-Harris Type-2 Physeal Fracture of the Proximal Phalanx in a Foal.

A 6-month-old thoroughbred colt foal was referred to a private equine referral hospital for evaluation of an acute onset, left hind limb lameness. On arrival the foal was 4/5 lame on the left hind at walk and there was diffuse swelling of the left hind pastern and fetlock region. The physical exam was otherwise unremarkable.

Design of a brain-penetrant CDK4/6 inhibitor for glioblastoma.

CDK4 and CDK6 are kinases with similar sequences that regulate cell cycle progression and are validated targets in the treatment of cancer. Glioblastoma is characterized by a high frequency of CDKN2A/CCND2/CDK4/CDK6 pathway dysregulation, making dual inhibition of CDK4 and CDK6 an attractive therapeutic approach for this disease. Abemaciclib, ribociclib, and palbociclib are approved CDK4/6 inhibitors for the treatment of HR+/HER2- breast cancer, but these drugs are not expected to show strong activity in brain tumors due to poor blood brain barrier penetration.

Implementation of a Quit Smoking Programme in Community Adult Mental Health Services-A Qualitative Study.

Little is known about the experiences of people with severe mental health difficulties in smoking cessation interventions. This study aimed to review the implementation of a smoking cessation programme across 16 community mental health day services. The aim was to establish the experience from both service user and facilitator perspectives and refine implementation for future groups.

The feasibility of early pulmonary rehabilitation and activity after COPD exacerbations: external pilot randomised controlled trial, qualitative case study and exploratory economic evaluation.

Background: Chronic obstructive pulmonary disease (COPD) affects > 3 million people in the UK. Acute exacerbations of COPD (AECOPD) are the second most common reason for emergency hospital admission in the UK. Pulmonary rehabilitation is usual care for stable COPD but there is little evidence for early pulmonary rehabilitation (EPR) following AECOPD, either in hospital or immediately post discharge.

Working at the Periphery: A View of Group Psychotherapy in Australia.

Australia is a vast country with a relatively small population living in cities separated by long distances. It is a wealthy country with a highly developed mental health system in which psychotherapy has a limited, but recognized, place. Group psychotherapists are a small but active community within that mental health world.

Metabolic response of prostate cancer to nicotinamide phophoribosyltransferase inhibition in a hyperpolarized MR/PET compatible bioreactor.

Background: Metabolic shifts in disease are of great interest for the development of novel therapeutics. In cancer treatment, these therapies exploit the metabolic phenotype associated with oncogenesis and cancer progression. One recent strategy involves the depletion of the cofactors needed to maintain the high rate of glycolysis seen with the Warburg effect.

Covalent and allosteric inhibitors of the ATPase VCP/p97 induce cancer cell death.

VCP (also known as p97 or Cdc48p in yeast) is an AAA(+) ATPase regulating endoplasmic reticulum-associated degradation. After high-throughput screening, we developed compounds that inhibit VCP via different mechanisms, including covalent modification of an active site cysteine and a new allosteric mechanism. Using photoaffinity labeling, structural analysis and mutagenesis, we mapped the binding site of allosteric inhibitors to a region spanning the D1 and D2 domains of adjacent protomers encompassing elements important for nucleotide-state sensing and ATP hydrolysis.

Combination drug scheduling defines a "window of opportunity" for chemopotentiation of gemcitabine by an orally bioavailable, selective ChK1 inhibitor, GNE-900.

Checkpoint kinase 1 (ChK1) is a serine/threonine kinase that functions as a central mediator of the intra-S and G2-M cell-cycle checkpoints. Following DNA damage or replication stress, ChK1-mediated phosphorylation of downstream effectors delays cell-cycle progression so that the damaged genome can be repaired. As a therapeutic strategy, inhibition of ChK1 should potentiate the antitumor effect of chemotherapeutic agents by inactivating the postreplication checkpoint, causing premature entry into mitosis with damaged DNA resulting in mitotic catastrophe.

Alkylsulfanyl-1,2,4-triazoles, a new class of allosteric valosine containing protein inhibitors. Synthesis and structure-activity relationships.

Valosine containing protein (VCP), also known as p97, is a member of AAA ATPase family that is involved in several biological processes and plays a central role in the ubiquitin-mediated degradation of misfolded proteins. VCP is an ubiquitously expressed, highly abundant protein and has been found overexpressed in many tumor types, sometimes associated with poor prognosis. In this respect, VCP has recently received a great deal of attention as a potential new target for cancer therapy.

Targeting p21-activated kinase 1 (PAK1) to induce apoptosis of tumor cells.

p21-activated kinases (PAKs) are serine/threonine protein kinases that serve as important mediators of Rac and Cdc42 GTPase function as well as pathways required for Ras-driven tumorigenesis. PAK1 has been implicated in signaling by growth factor receptors and morphogenetic processes that control cell polarity, invasion, and actin cytoskeleton organization. To better understand the role of PAK1 in tumorigenesis, PAK1 genomic copy number and expression were determined for a large panel of breast, lung, and head and neck tumors.

The relativity of time perception produced by facial emotion stimuli.

We systematically examined the impact of emotional stimuli on time perception in a temporal reproduction paradigm where participants reproduced the duration of a facial emotion stimulus using an oval-shape stimulus or vice versa. Experiment 1 asked participants to reproduce the duration of an angry face (or the oval) presented for 2,000 ms. Experiment 2 included a range of emotional expressions (happy, sad, angry, and neutral faces as well as the oval stimulus) presented for different durations (500, 1,500, and 2,000 ms).

Converting cancer mutations into therapeutic opportunities.

While the use of synthetic lethality has been around for decades in model organism studies, it has only recently been applied to cancer therapy and judging by recent results, with great success. Following on a recent paper that demonstrates the clinical application of this strategy (Fong et al, 2009), Chris Lord and Alan Ashworth further explore the approach and show that poly(ADP-ribose) polymerase (PARP) inhibitors such as Olaparib can selectively target cancer cells defective in phosphatase and tensin homologue (PTEN, Mendes-Pereira et al, 2009) and that methotrexate is selectively lethal to MutS-homologue-2 (MSH2)-deficient tumour cells (Martin et al, 2009).

2-Aminobenzimidazoles as potent Aurora kinase inhibitors.

This Letter describes the discovery and key structure-activity relationship (SAR) of a series of 2-aminobenzimidazoles as potent Aurora kinase inhibitors. 2-Aminobenzimidazole serves as a bioisostere of the biaryl urea residue of SNS-314 (1c), which is a potent Aurora kinase inhibitor and entered clinical testing in patients with solid tumors. Compared to SNS-314, this series of compounds offers better aqueous solubility while retaining comparable in vitro potency in biochemical and cell-based assays; in particular, 6m has also demonstrated a comparable mouse iv PK profile to SNS-314.

Discovery of a potent and selective aurora kinase inhibitor.

This communication describes the discovery of a novel series of Aurora kinase inhibitors. Key SAR and critical binding elements are discussed. Some of the more advanced analogues potently inhibit cellular proliferation and induce phenotypes consistent with Aurora kinase inhibition.

Tissue levels of arsenicals and skin tumor response following administration of monomethylarsonous acid and arsenite to K6/ODC mice.

The effects of monomethylarsonous acid (MMA[III]) and arsenite, administered in drinking water on tissue levels of arsenicals, cytogenetics, and mouse skin tumorigenicity were determined. A low-methionine diet modified the pattern of arsenical tissue concentrations and decreased the tissue arsenical concentrations, particularly in kidney and urinary bladder, less so in liver, and had little effect in the lungs. In mice given 75 ppm arsenite and a low-methionine diet, the urinary bladder tissue levels were only 29%, 26%, and 38% of the inorganic arsenic (iAs), MMA, and dimethylarsinic acid (DMA) concentrations found in mice eating the control diet.

Towards a developmental framework of consumer and carer participation in child and adolescent mental health services.

Objective: This paper examines the concept of consumer participation in the context of developmental changes in parent/child relationships and associated differences in the utilization of child and adolescent mental health services.

Method: Existing definitions and characteristics of mental health service delivery for children and young people are examined to answer the question,"Who is the consumer in the context of clinical services for young clients and their parents, and does this change with the child or young person's developmental stage?".

Results: As children, young people and parents utilize services in this area of mental health, the roles of consumer and carer need redefinition to accommodate both young clients and parents as consumers, and parents also as carers.

Mouse Aurora A: expression in Escherichia coli and purification.

Aurora kinases have recently become some of the most intensely pursued oncology targets for the design of small-molecule inhibitors. Most of the active Aurora-A protein variants are currently being expressed from baculoviruses in insect cells, while catalytically impaired proteins can also be generated in and purified from Escherichia coli. In this study we present a method of expressing large quantities of active mouse Aurora-A kinase domain as an N-terminal glutathione-S-transferase fusion protein in bacteria and outline a simple purification method that produces greater than 99% pure protein samples suitable for enzymatic assays and X-ray crystallography.

Structural analysis of caspase-1 inhibitors derived from Tethering.

Caspase-1 is a key endopeptidase responsible for the post-translational processing of the IL-1beta and IL-18 cytokines and small-molecule inhibitors that modulate the activity of this enzyme are predicted to be important therapeutic treatments for many inflammatory diseases. A fragment-assembly approach, accompanied by structural analysis, was employed to generate caspase-1 inhibitors. With the aid of Tethering with extenders (small molecules that bind to the active-site cysteine and contain a free thiol), two novel fragments that bound to the active site and made a disulfide bond with the extender were identified by mass spectrometry.

Influence of number of CAG repeats on local control in the RTOG 86-10 protocol.

Objectives: The number of CAG repeats on the androgen receptor (AR) gene is inversely proportional to transcriptional activity. The purpose of this study was to determine if short-term androgen deprivation therapy (RT + HT) can improve outcome in patients with tumors with short CAG repeats (<19).

Materials And Methods: Prostate cancer patients were randomized to receive either radiotherapy (RT) alone or (RT + HT) in the RTOG 86-10 study.

Tethering identifies fragment that yields potent inhibitors of human caspase-1.

Disulfide Tethering was applied to the active site of human caspase-1, resulting in the discovery of a novel, tricyclic molecular fragment that selectively binds in S4. This fragment was developed into a class of potent inhibitors of human caspase-1. Several key analogues determined the optimal distance of the tricycle from the catalytic residues, the relative importance of various features of the tricycle, and the importance of the linker.

Discovery of an allosteric site in the caspases.

Allosteric regulation of proteins by conformational change is a primary means of biological control. Traditionally it has been difficult to identify and characterize novel allosteric sites and ligands that freeze these conformational states. We present a site-directed approach using Tethering for trapping inhibitory small molecules at sites away from the active site by reversible disulfide bond formation.

Crystal structures of a ligand-free and malonate-bound human caspase-1: implications for the mechanism of substrate binding.

Caspase-1, a mediator of the posttranslational processing of IL-1beta and IL-18, requires an aspartic acid in the P1 position of its substrates. The mechanisms of caspase-1 activation remain poorly understood despite numerous structures of the enzyme complexed with aspartate-based inhibitors. Here we report a crystal structure of ligand-free caspase-1 that displays dramatic rearrangements of loops defining the active site to generate a closed conformation that is incompatible with substrate binding.

Prospects for caspase inhibitors.

Programmed cell death, or apoptosis, is executed by a series of Cysteine Aspartyl Proteases (Caspases) that form a proteolytic cascade. Each caspase functions either to activate downstream caspases by proteolytic cleavage and/or to proteolytically cleave cellular substrates. Increased levels of apoptosis and caspase activity are frequently observed at sites of cellular damage in both acute (e.