Epigenetic targeting of Hedgehog pathway transcriptional output through BET bromodomain inhibition

Hedgehog signaling drives oncogenesis in several cancers and strategies targeting this pathway have been developed, most notably through inhibition of Smoothened. However, resistance to Smoothened inhibitors occurs via genetic changes of Smoothened or other downstream Hedgehog components. Here, we overcome these resistance mechanisms by modulating GLI transcription via inhibition of BET bromodomain proteins. We show the BET bromodomain protein, BRD4, regulates GLI transcription downstream of SMO and SUFU and chromatin immunoprecipitation studies reveal BRD4 directly occupies GLI1 and GLI2 promoters, with a substantial decrease in engagement of these sites upon treatment with JQ1, a small molecule inhibitor targeting BRD4. Globally, genes associated with medulloblastoma-specific GLI1 binding sites are downregulated in response to JQ1 treatment, supporting direct regulation of GLI activity by BRD4. Notably, patient- and GEMM-derived Hedgehog-driven tumors (basal cell carcinoma, medulloblastoma and atypical teratoid/rhabdoid tumor) respond to JQ1 even when harboring genetic lesions rendering them resistant to Smoothened antagonists

Social work education, research and practice in India and Australia: an introduction

The increased interest among social work educators and practitioners from India and Australia has created many pathways for innovative and creative learning opportunities through exchange programs. Social work educators and practitioners in both the countries have proactively engaged in international short-term faculty and student exchanges and field placements, research activities and collaborative initiatives such as workshops, international conferences and joint publishing of social work texts. The authors, from Bharathidasan University (BDU) and James Cook University (JCU), noted the success of these original endeavors and particularly their potential to create momentum beyond the initial activity. They saw that focusing on collaborative social work learning in their own smaller contexts could create positive change and impact in ways they did not anticipate. This experience, replicated in other collaborative activities, provided enormous insights and learning on both sides, leading finally to the idea of documenting cross-cultural perspectives from India and Australia. In this chapter the authors present their perspective on the scenario of social work education, research and practice in India and Australia. Besides, brief summaries of all the chapters of the book are also presented

Histopathological changes in banana roots caused by Pratylenchuscoffeae, Meloidogyneincognita and Radopholussimilis and identification of RAPD markers associated with P.coffeae resistance.

Worldwide, nematodes are amongst the most important pests of banana. By damaging the root system, nematodes adversely affect the uptake of water and nutrients, the basic needs for plant growth and fruit production. Although phenolics in banana roots are formed in response to infection by various pathogens including nematodes, information on the nature of such compounds and their potential role in defence is scarce. 59 banana genotypes (10 diploids and 49 triploids) were infected with the root-lesion nematode Pratylenchus coffeae, the root-knot nematode Meloidogyne incognita and the burrowing nematode Radopholus similis in glasshouse experiments. The production of phenolic compounds in healthy and nematode-infected banana roots was investigated histochemically, and RAPD markers associated with nematode resistance were identified. Root histological studies revealed higher numbers of cells with phenols and lignified cells in resistant accessions Karthobiumtham (ABB) and Bhimkol (BB) compared to susceptible accessions Therahaw-1164 (ABB) and Jahaji (AAA). RAPD analysis using arbitrary oligonucleotide primers differentiated resistant and susceptible banana genotypes. The marker bands found in the resistant accessions could be used to study the molecular basis for resistance to nematodes. Sequencing of these bands could help to establish the mechanism responsible for nematode resistance

Mechanism of resistance in banana cultivars against root- lesion nematode, Pratylenchus coffeae

Ten diploids and forty-nine triploids comprising of wild and cultivated banana accessions collected from different parts of India were screened under pot culture for understanding the mechanism of resistance against root lesion nematode, Pratylenchus coffeae. Following inoculation of banana plantlets with the nematodes, the peroxidase activity increased in both the resistant and susceptible genotypes. However, the final enzyme concentration was the maximum in resistant diploid accessions like M. balbisiana, Kanai Bansi, Aittakola, Bhimkol and Athiakol. A critical analysis of the polyphenol oxidase activity in this study revealed that resistant accessions viz., Kechulepa, M. balbisiana, Karthobiumtham, Kachkel, Bhimkol, Athiakol, Kanai Bansi and Aittakola recorded higher polyphenol oxidase activity than the susceptible ones

Phenylalanine ammonia lyaseand total phenol content in resistant banana to Pratylenchus coffeae

The biochemical alterations in resistance banana accessions showed that relatively higher Phenylalanine Ammonia Lyase (PAL) activity than the susceptible ones indicating the inherent higher content of PAL in resistant accessions. The higher activity of this enzyme in resistant accessions viz., Karthobiumtham, M. balbisiana, Kanai Bansi, Bhimkol, Athiakol, Aittakol, Kechulepa was negatively correlated with lesion index of roots and corm. Increase in phenol content and enzyme activities were negatively related with the degree of infestation. In the present study, total phenol estimated in roots of banana genotypes showed that these compounds were higher in resistant accessions than susceptible ones

Introduction

Sharing with previous criticism an uneasiness with the use of the umbrella term ‘black’ for communities as diverse as the African, the African-Caribbean, and the black British, this introduction argues for the need to examine the increasingly visible African presence on the contemporary London stage independently from other BME theatrical productions. Chapters and interviews in this collection are contextualised on the background of previous criticism (with particular reference to black British theatre studies) and the history of African artists and companies on the London stage

Transcriptional Dependencies in Diffuse Intrinsic Pontine Glioma

Diffuse intrinsic pontine glioma (DIPG) is a fatal pediatric cancer with limited therapeutic options. The majority of cases of DIPG exhibit a mutation in histone-3 (H3K27M) that results in oncogenic transcriptional aberrancies. We show here that DIPG is vulnerable to transcriptional disruption using bromodomain inhibition or CDK7 blockade. Targeting oncogenic transcription through either of these methods synergizes with HDAC inhibition, and DIPG cells resistant to HDAC inhibitor therapy retain sensitivity to CDK7 blockade. Identification of super-enhancers in DIPG provides insights toward the cell of origin, highlighting oligodendroglial lineage genes, and reveals unexpected mechanisms mediating tumor viability and invasion, including potassium channel function and EPH receptor signaling. The findings presented demonstrate transcriptional vulnerabilities and elucidate previously unknown mechanisms of DIPG pathobiology