Tigilanol tiglate is an oncolytic small molecule that induces immunogenic cell death and enhances the response of both target and non-injected tumors to immune checkpoint blockade.

Background: Tigilanol tiglate (TT) is a protein kinase C (PKC)/C1 domain activator currently being developed as an intralesional agent for the treatment of various (sub)cutaneous malignancies. Previous work has shown that intratumoral (I.T.

Cryptic Epoxytiglianes from the Kernels of the Blushwood Tree ().

The kernels of the Australian blushwood tree () are the source of the veterinary anticancer drug tigilanol tiglate (, Stelfonta) and contain a concentration of phorboids significantly higher than croton oil, the only abundant source of these compounds previously known. The oily matrix of the blushwood kernels is composed of free fatty acids and not by glycerides as found in croton oil. By active partitioning, it was therefore possible to recover and characterize for the first time a cryptic tigliane fraction, that is, the diterpenoid fraction that, because of its lipophilicity, could not be obtained by solvent partition of crude extracts.

Targeting the P2Y Receptor Suppresses IL-33 and HMGB1 Release and Ameliorates Experimental Asthma.

The alarmins IL-33 and HMGB1 (high mobility group box 1) contribute to type 2 inflammation and asthma pathogenesis. To determine whether P2Y-R (P2Y receptor), a purinergic GPCR (G protein-coupled receptor) and risk allele for asthma, regulates the release of IL-33 and HMGB1. Bronchial biopsy specimens were obtained from healthy subjects and subjects with asthma.

Murine dorsal hair type is genetically determined by polymorphisms in candidate genes that influence BMP and WNT signalling.

Mouse dorsal coat hair types, guard, awl, auchene and zigzag, develop in three consecutive waves. To date, it is unclear if these hair types are determined genetically through expression of specific factors or can change based on their mesenchymal environment. We undertook a novel approach to this question by studying individual hair type in 67 Collaborative Cross (CC) mouse lines and found significant variation in the proportion of each type between strains.

Different genetic mechanisms mediate spontaneous versus UVR-induced malignant melanoma.

Genetic variation conferring resistance and susceptibility to carcinogen-induced tumorigenesis is frequently studied in mice. We have now turned this idea to melanoma using the collaborative cross (CC), a resource of mouse strains designed to discover genes for complex diseases. We studied melanoma-prone transgenic progeny across seventy CC genetic backgrounds.

Keratinocyte Cytokine Networks Associated with Human Melanocytic Nevus Development.

Melanocytes can group together in nevi, commonly thought to form because of intrinsic somatic mutations involving MAPK pathway activation. However, the role of the microenvironment, in particular keratinocytes, in nevogenesis is rarely studied. Melanocytes proliferate during the hair follicle growth phase and in some basal cell carcinomas, allowing us to construct keratinocyte gene expression clusters correlated with melanocyte activation.

Keratinocyte Sonic Hedgehog Upregulation Drives the Development of Giant Congenital Nevi via Paracrine Endothelin-1 Secretion.

Giant congenital nevi are associated with clinical complications such as neurocutaneous melanosis and melanoma. Virtually nothing is known about why some individuals develop these lesions. We previously identified the sonic hedgehog (Shh) pathway regulator Cdon as a candidate nevus modifier gene.

A mutation in the Cdon gene potentiates congenital nevus development mediated by NRAS(Q61K).

Congenital nevi develop before birth and sometimes cover large areas of the body. They are presumed to arise from the acquisition of a gene mutation in an embryonic melanocyte that becomes trapped in the dermis during development. Mice bearing the Cdk4(R24C) ::Tyr-NRAS(Q) (61K) transgenes develop congenital nevus-like lesions by post-natal day 10, from melanocytes escaping the confines of hair follicles.

Hair follicle melanocyte precursors are awoken by ultraviolet radiation via a cell extrinsic mechanism.

Melanocyte stem cells (MCSCs) in the upper portion of the hair follicle periodically supply melanocytes (MCs) that migrate downward into the hair bulb during anagen, the growth phase of the hair cycle. However MCs can also migrate upwards. We previously observed an increase in epidermal MC density in the mouse epidermis after a single ultraviolet radiation (UVR) exposure in neonatal, but not adult mice.

Mouse models for actinic keratosis and squamous cell carcinoma.

This manuscript focuses on the use of mice to study the genetics and biology of cutaneous squamous cell carcinoma (SCC). Mice develop actinic keratosis-like lesions and SCC resembling those seen in humans. As an animal model, the mouse provides great experimental flexibility and has been useful in investigating aspects of the genetics and biology of SCC that are difficult to study in humans.

Differential effects of ultraviolet irradiation in neonatal versus adult mice are not explained by defective macrophage or neutrophil infiltration.

Epidemiological studies suggest that ultraviolet B exposure (UVR) during childhood is the most important environmental risk factor for melanoma. In accordance, neonatal, but not adult, UVR exacerbates melanoma incidence in mouse models. The inability of neonates, as opposed to adults, to mount a proper neutrophil inflammatory response in the skin upon UVR exposure has been one of the driving hypotheses explaining this observation for the past decade.

Plasticity of melanoma in vivo: murine lesions resulting from Trp53, but not Cdk4 or Arf deregulation, display neural transdifferentiation.

We previously noted that melanomas developing in Cdk4(R24C/R24C) ::Tyr-NRAS, Arf(-/-) ::Tyr-NRAS and Trp53(F/F) ::Tyr-Cre(ER)::Tyr-NRAS mice exhibited differences in behaviour in vivo. We investigated this phenomenon using global gene expression profiling of lesions from the respective genotypes. While those from the Cdk4- and Arf-mutant mice exhibited similar profiles, the Trp53(F/F) ::Tyr-Cre(ER)::Tyr-NRAS melanomas were strikingly different, showing relative down-regulation of melanocyte-related genes, and up-regulation of genes related to neural differentiation.

UVB-induced melanocyte proliferation in neonatal mice driven by CCR2-independent recruitment of Ly6c(low)MHCII(hi) macrophages.

Intermittent sunburns, particularly in childhood, are the strongest environmental risk factor for malignant melanoma (MM). In mice, a single neonatal UVR exposure induces MM, whereas chronic doses to adult mice do not. Neonatal UVR alters melanocyte migration dynamics by inducing their movement upward out of hair follicles into the epidermis.

Differential roles of the pRb and Arf/p53 pathways in murine naevus and melanoma genesis.

We report on a systematic analysis of genotype-specific melanocyte (MC) UVR responses in transgenic mouse melanoma models along with tumour penetrance and comparative histopathology. pRb or p53 pathway mutations cooperated with Nras(Q61K) to transform MCs. We previously reported that MCs migrate from the follicular outer root sheath into the epidermis after neonatal UVR.

No association between neuregulin 1 and psychotic symptoms in Alzheimer's disease patients.

Alzheimer's disease (AD) patients commonly suffer from behavioral and psychological symptoms of dementia (BPSD). Variants within the neuregulin-1 (NRG1) gene have been investigated both in early onset psychiatric disorders, such as schizophrenia and recently in AD patients with psychosis. In this study, we analyzed NRG1 variants in AD patients with and without psychosis.

Association study of candidate variants from brain-derived neurotrophic factor and dystrobrevin-binding protein 1 with neuroticism, anxiety, and depression.

Objectives: Association of the valine/methionine variant at codon 66 (Val66Met) of brain derived neurotrophic factor (BDNF) has been reported inconsistently across a spectrum of psychiatric disorders. Haplotypes of six tagging single nucleotide polymorphisms (SNPs) of a 37-kb region of dystrobrevin-binding protein 1 (DTNBP1) were found to be associated with schizophrenia. These haplotypes have not been studied extensively for other psychiatric disorders but are plausible candidates for anxiety and depression disorders.

Genome-wide copy number analysis in esophageal adenocarcinoma using high-density single-nucleotide polymorphism arrays.

We applied whole-genome single-nucleotide polymorphism arrays to define a comprehensive genetic profile of 23 esophageal adenocarcinoma (EAC) primary tumor biopsies based on loss of heterozygosity (LOH) and DNA copy number changes. Alterations were common, averaging 97 (range, 23-208) per tumor. LOH and gains averaged 33 (range, 3-83) and 31 (range, 11-73) per tumor, respectively.

Association study of candidate variants of COMT with neuroticism, anxiety and depression.

The Val158Met polymorphism of the gene encoding catechol-O-methyltransferase (COMT) is one of the most widely tested variants for association with psychiatric disorders, but replication has been inconsistent including both sex limitation and heterogeneity of the associated allele. In this study we investigate the association between three SNPs from COMT and anxiety and depression disorders and neuroticism all measured within the same study sample. Participants were selected as sibling pairs (or multiples) that were either concordant or discordant for extreme neuroticism scores from a total sample of 18,742 Australian twin individuals and their siblings.

SiDCoN: a tool to aid scoring of DNA copy number changes in SNP chip data.

The recent application of genome-wide, single nucleotide polymorphism (SNP) microarrays to investigate DNA copy number aberrations in cancer has provided unparalleled sensitivity for identifying genomic changes. In some instances the complexity of these changes makes them difficult to interpret, particularly when tumour samples are contaminated with normal (stromal) tissue. Current automated scoring algorithms require considerable manual data checking and correction, especially when assessing uncultured tumour specimens.

Association study of the dystrobrevin-binding gene with schizophrenia in Australian and Indian samples.

Numerous studies have reported association between variants in the dystrobrevin binding protein 1 (dysbindin) gene (DTNBP1) and schizophrenia. However, the pattern of results is complex and to date, no specific risk marker or haplotype has been consistently identified. The number of single nucleotide polymorphisms (SNPs) tested in these studies has ranged from 5 to 20.