Discovery and pharmacological characterization of AZD3229, a potent KIT/PDGFRα inhibitor for treatment of gastrointestinal stromal tumors.

Gastrointestinal stromal tumor (GIST) is the most common human sarcoma driven by mutations in or platelet-derived growth factor α (α). Although first-line treatment, imatinib, has revolutionized GIST treatment, drug resistance due to acquisition of secondary /α mutations develops in a majority of patients. Second- and third-line treatments, sunitinib and regorafenib, lack activity against a plethora of mutations in KIT/PDGFRα in GIST, with median time to disease progression of 4 to 6 months and inhibition of vascular endothelial growth factor receptor 2 (VEGFR2) causing high-grade hypertension.

Community Knowledge of Law on End-of-life Decision-making: An Australian Telephone Survey.

The law has a clear role to play in supporting patients and their substitute decision-makers (SDMs) to be involved in end-of-life (EOL) decision-making. Although existing literature suggests that knowledge of EOL law is variable among health professionals, there is little information about the extent and sources of such knowledge within the general community. A telephone survey of a representative sample of adults in three Australian States used six case scenarios to examine the extent to which adults know their legal duties, rights and powers as patients or SDMs; the sources from which people derive relevant legal knowledge; experiences of EOL decision-making; and individual characteristics associated with levels of knowledge.

Differential Activity of ATR and WEE1 Inhibitors in a Highly Sensitive Subpopulation of DLBCL Linked to Replication Stress.

DNA damage checkpoint kinases ATR and WEE1 are among key regulators of DNA damage response pathways protecting cells from replication stress, a hallmark of cancer that has potential to be exploited for therapeutic use. ATR and WEE1 inhibitors are in early clinical trials and success will require greater understanding of both their mechanism of action and biomarkers for patient selection. Here, we report selective antitumor activity of ATR and WEE1 inhibitors in a subset of non-germinal center B-cell (GCB) diffuse large B-cell lymphoma (DLBCL) cell lines, characterized by high MYC protein expression and deletion.

Prevalence of advance care directives in the community: a telephone survey of three Australian States.

Background: The community prevalence of advance care directives (ACD) is low despite known benefits of advance care planning for patients, families and health professionals.

Aim: To determine the community prevalence of instructional and appointing ACD in New South Wales, Victoria and Queensland and factors associated with completion of these documents.

Methods: A telephone survey of adults living in New South Wales, Victoria and Queensland (n = 1175) about completion of instructional ACD (making their own decisions about future healthcare) and appointing ACD (appointing another to decide).

Pharmacological Inhibition of PARP6 Triggers Multipolar Spindle Formation and Elicits Therapeutic Effects in Breast Cancer.

: PARP proteins represent a class of post-translational modification enzymes with diverse cellular functions. Targeting PARPs has proven to be efficacious clinically, but exploration of the therapeutic potential of PARP inhibition has been limited to targeting poly(ADP-ribose) generating PARP, including PARP1/2/3 and tankyrases. The cancer-related functions of mono(ADP-ribose) generating PARP, including PARP6, remain largely uncharacterized.

Does implementation matter if comprehension is lacking? A qualitative investigation into perceptions of advance care planning in people with cancer.

Purpose: While advance care planning holds promise, uptake is variable and it is unclear how well people engage with or comprehend advance care planning. The objective of this study was to explore how people with cancer comprehended advance care plans and examine how accurately advance care planning documentation represented patient wishes.

Methods: This study used a qualitative descriptive design.

Community knowledge of law at the end of life: availability and accessibility of web-based resources.

Objective The aim of the present study was to identify online resources community members may access to inform themselves about their legal duties and rights in end-of-life decision making. Methods Resource mapping identified online resources that members of the public in New South Wales, Victoria and Queensland are likely to identify, and assessed the ease or difficulty in locating them. Resources were then critically analysed for accessibility of language and format using the Patient Education Materials Assessment Tool (PEMAT).

Using Webinars for the Education of Health Professionals and People Affected by Cancer: Processes and Evaluation.

Technology provides an opportunity to engage with a variety of audiences to provide cancer education, information and support. Webinars are one such format that allow live presentations by experts that can be accessed online, from people's homes or other convenient locations. In 2015, Cancer Council Victoria (CCV) undertook a program of work to design and evaluate the effectiveness of a suite of webinars: four designed for people affected by cancer and two for health professionals.

AZD5153: A Novel Bivalent BET Bromodomain Inhibitor Highly Active against Hematologic Malignancies.

The bromodomain and extraterminal (BET) protein BRD4 regulates gene expression via recruitment of transcriptional regulatory complexes to acetylated chromatin. Pharmacological targeting of BRD4 bromodomains by small molecule inhibitors has proven to be an effective means to disrupt aberrant transcriptional programs critical for tumor growth and/or survival. Herein, we report AZD5153, a potent, selective, and orally available BET/BRD4 bromodomain inhibitor possessing a bivalent binding mode.

AZD9150, a next-generation antisense oligonucleotide inhibitor of STAT3 with early evidence of clinical activity in lymphoma and lung cancer.

Next-generation sequencing technologies have greatly expanded our understanding of cancer genetics. Antisense technology is an attractive platform with the potential to translate these advances into improved cancer therapeutics, because antisense oligonucleotide (ASO) inhibitors can be designed on the basis of gene sequence information alone. Recent human clinical data have demonstrated the potent activity of systemically administered ASOs targeted to genes expressed in the liver.

Inhibition of platelet-derived growth factor receptor α by MEDI-575 reduces tumor growth and stromal fibroblast content in a model of non-small cell lung cancer.

Platelet-derived growth factor receptor α (PDGFRα) is a receptor tyrosine kinase that promotes cell survival and is expressed in both the tumor and the stromal components of human cancers. We have developed a fully human monoclonal antibody, MEDI-575, that selectively binds to human PDGFRα with high affinity, with no observable affinity for murine PDGFRα. To more fully characterize the role of PDGFRα in the regulation of tumor stroma, we evaluated the in vivo antitumor effects of MEDI-575 in tumor-bearing severe combined immunodeficient (SCID) mice and in genetically altered SCID mice expressing human PDGFRα in place of murine PDGFRα.

Comparisons of the efficacy of a Jak1/2 inhibitor (AZD1480) with a VEGF signaling inhibitor (cediranib) and sham treatments in mouse tumors using DCE-MRI, DW-MRI, and histology.

Jak1/2 inhibition suppresses STAT3 phosphorylation that is characteristic of many cancers. Activated STAT3 promotes the transcription of factors that enhance tumor growth, survival, and angiogenesis. AZD1480 is a novel small molecule inhibitor of Jak1/2, which is a key mediator of STAT3 activation.

The Child Attention-Deficit Hyperactivity Disorder Teacher Telephone Interview (CHATTI): reliability and validity.

Background: The ICD-10 and DSM-IV diagnostic criteria for hyperkinetic disorder and attention-deficit hyperactivity disorder (ADHD) require symptoms or impairment in two or more settings. Thus, information on children's symptoms in school is usually required. This paper presents the Child ADHD Teacher Telephone Interview (CHATTI), an instrument aimed at systematically obtaining this information.

No evidence of association between HLA-DRB1 and attention deficit hyperactivity disorder.

Objectives: There has been a recent resurgence in interest in the role of autoimmunity in childhood neuropsychiatric disorders. Significant association between HLA-DRB1 and attention deficit hyperactivity disorder (ADHD) in a case-control study of 31 subjects has been reported but there have been no other published studies following up these results. We attempted to replicate these findings.

Sodium channel beta4, a new disulfide-linked auxiliary subunit with similarity to beta2.

The principal alpha subunit of voltage-gated sodium channels is associated with auxiliary beta subunits that modify channel function and mediate protein-protein interactions. We have identified a new beta subunit termed beta4. Like the beta1-beta3 subunits, beta4 contains a cleaved signal sequence, an extracellular Ig-like fold, a transmembrane segment, and a short intracellular C-terminal tail.

No evidence of association of two 5HT transporter gene polymorphisms and attention deficit hyperactivity disorder.

Objectives: Three studies to date have found evidence (or a trend for evidence) of linkage and association between the long allele of the 44 base pair repeat insertion/deletion 5-HTT functional polymorphism (5-HTTLPR) and attention deficit hyperactivity disorder (ADHD). In an attempt to replicate these findings, we examined this polymorphism and a variable number tandem repeat in the second intron of 5-HTT for association with ADHD.

Methods: One hundred and fifty children who met diagnostic criteria for ADHD and their parents (where available) were genotyped for these polymorphisms.

Association analysis of monoamine oxidase A and attention deficit hyperactivity disorder.

Attention deficit hyperactivity disorder (ADHD) is a highly heritable disorder. Although the causes of ADHD are unknown, dopaminergic, serotonergic and nor-adrenergic pathways have been strongly implicated. Monoamine Oxidase A (MAOA) is involved in the degradation of all three of these neurotransmitters and therefore has been suggested as a strong candidate gene for ADHD.

TRPV3 is a calcium-permeable temperature-sensitive cation channel.

Transient receptor potential (TRP) proteins are cation-selective channels that function in processes as diverse as sensation and vasoregulation. Mammalian TRP channels that are gated by heat and capsaicin (>43 degrees C; TRPV1 (ref. 1)), noxious heat (>52 degrees C; TRPV2 (ref.

Elimination of fast inactivation in Kv4 A-type potassium channels by an auxiliary subunit domain.

The Kv4 A-type potassium currents contribute to controlling the frequency of slow repetitive firing and back-propagation of action potentials in neurons and shape the action potential in heart. Kv4 currents exhibit rapid activation and inactivation and are specifically modulated by K-channel interacting proteins (KChIPs). Here we report the discovery and functional characterization of a modular K-channel inactivation suppressor (KIS) domain located in the first 34 aa of an additional KChIP (KChIP4a).