Histone Deacetylase Inhibitors in Malignant Pleural Mesothelioma: Preclinical Rationale and Clinical Trials

AbstractMalignant pleural mesothelioma (MPM) is a rare and aggressive cancer of the mesothelium with only a limited range of treatment options that are largely ineffective in improving survival. Recent efforts have turned toward the analysis of specific, dysregulated biologic pathways for insight into new treatment targets. Epigenetic regulation of tumor suppressor genes through chromatin condensation and decondensation has emerged as an important mechanism that leads to tumorogenesis. A family of histone acetyltransferases and deacetylases regulates this balance, with the latter facilitating chromatin condensation, thus preventing gene transcription, resulting in the loss of heterozygosity of tumor suppressors. Inhibition of this process, coupled with a similar inhibition of nonhistone protein deacetylation, ultimately leads to the promotion of apoptosis, cell cycle arrest, and inhibition of angiogenesis. An increasing amount of preclinical data highlighting the effectiveness of histone deacetylase inhibition in MPM cell lines and mouse xenograft models has led to a number of early phase clinical trials in patients with MPM. The results of these efforts have led to a multicenter, randomized, placebo-controlled phase III study of the histone deacetylase inhibitor vorinostat in patients with advanced MPM, offering hope for a new and effective therapy in patients with this disease

Exploration strategies for articulatory synthesis of complex syllable onsets

High-quality articulatory speech synthesis has many potential applications in speech science and technology. However, developing appropriate mappings from linguistic specification to articulatory gestures is difficult and time consuming. In this paper we construct an optimisation-based framework as a first step towards learning these mappings without manual intervention. We demonstrate the production of CCV syllables and discuss the quality of the articulatory gestures with reference to coarticulation

Self-Supervised Solution to the Control Problem of Articulatory Synthesis

Given an articulatory-to-acoustic forward model, it is a priori unknown how its motor control must be operated to achieve a desired acoustic result. This control problem is a fundamental issue of articulatory speech synthesis and the cradle of acousticto-articulatory inversion, a discipline which attempts to address the issue by the means of various methods. This work presents an end-to-end solution to the articulatory control problem, in which synthetic motor trajectories of Monte-Carlo-generated artificial speech are linked to input modalities (such as natural speech recordings or phoneme sequence input) via speakerindependent latent representations of a vector-quantized variational autoencoder. The proposed method is self-supervised and thus, in principle, synthesizer and speaker model independent

Simulating vocal learning of spoken language: Beyond imitation

Computational approaches have an important role to play in understanding the complex process of speech acquisition, in general, and have recently been popular in studies of vocal learning in particular. In this article we suggest that two significant problems associated with imitative vocal learning of spoken language, the speaker normalisation and phonological correspondence problems, can be addressed by linguistically grounded auditory perception. In particular, we show how the articulation of consonant-vowel syllables may be learnt from auditory percepts that can represent either individual utterances by speakers with different vocal tract characteristics or ideal phonetic realisations. The result is an optimisation-based implementation of vocal exploration – incorporating semantic, auditory, and articulatory signals – that can serve as a basis for simulating vocal learning beyond imitation

Applying refinement to the use of mice and rats in rheumatoid arthritis research

Rheumatoid arthritis (RA) is a painful, chronic disorder and there is currently an unmet need for effective therapies that will benefit a wide range of patients. The research and development process for therapies and treatments currently involves in vivo studies, which have the potential to cause discomfort, pain or distress. This Working Group report focuses on identifying causes of suffering within commonly used mouse and rat ‘models’ of RA, describing practical refinements to help reduce suffering and improve welfare without compromising the scientific objectives. The report also discusses other, relevant topics including identifying and minimising sources of variation within in vivo RA studies, the potential to provide pain relief including analgesia, welfare assessment, humane endpoints, reporting standards and the potential to replace animals in RA research