PI3K Isoform Immunotherapy for Solid Tumours.

Improving the anti-tumour T cell response as a consequence of immunotherapy can result in eradication of tumour burden, however, the majority of patients fail with current treatment regimens and so novel immunotherapies with greater efficacy and improved tolerability are needed. The phosphoinositide-3-kinase (PI3K) family members that are directly involved in cell signalling comprise PI3Kα, PI3Kß, PI3Kδ and PI3Kγ, with the latter two isoforms expressed primarily by leukocytes. The survival and optimal function of regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSCs) is dependent on PI3Kδ, whereas tumour-associated macrophages (TAMs), use PI3Kγ. Blocking these signalling isoforms can boost development of effective anti-cancer immune responses and result in control of tumour burden. The dependence on different PI3K isoforms in immune cells makes targeting this pathway an attractive approach for tumour immunotherapy. Herein, we discuss how inhibiting specific PI3K isoforms in pro-tumoural Tregs, MDSCS and TAMs can unleash a powerful anti-tumour immune response, driven by CD8+ T cells, capable of controlling tumour burden and consider how the immune response to therapy needs careful investigation, to identify both the correlates of successful treatment and those that impede the generation of robust anti-tumour responses. Furthermore, we review how combination immunotherapy approaches with both PI3K inhibitors and subsequent immune checkpoint blockade can potentiate the efficacy of monotherapy. Finally, we discuss the recent advances in the use of PI3K isoform-specific inhibitors as an immunotherapy for solid tumours in clinical trials.

Orthographically sensitive treatment for dysprosody in children with childhood apraxia of speech using ReST intervention.

OBJECTIVE: Impaired prosody is a core diagnostic feature of Childhood Apraxia of Speech (CAS) but there is limited evidence of effective prosodic intervention. This study reports the efficacy of the ReST intervention used in conjunction with bisyllabic pseudo word stimuli containing orthographic cues that are strongly associated with either strong-weak or weak-strong patterns of lexical stress. METHODS: Using a single case AB design with one follow-up and replication, four children with CAS received treatment of four one-hour sessions per week for three weeks. Sessions contained 100 randomized trials of pseudo word treatment stimuli. Baseline measures were taken of treated and untreated behaviors; retention was measured at one day and four weeks post-treatment. RESULTS: Children's production of lexical stress improved from pre to post-treatment. Treatment effects and maintenance varied among participants. CONCLUSIONS: This study provides support for the treatment of prosodic deficits in CAS.

Training production of lexical stress in typically developing children using orthographically biased stimuli and principles of motor learning.

PURPOSE: Impaired lexical stress production characterizes multiple pediatric speech disorders. Effective remediation strategies are not available, and little is known about the normal process of learning to assign and produce lexical stress. This study examined whether typically developing (TD) children can be trained to produce lexical stress on bisyllabic pseudowords that are orthographically biased to a strong-weak or weak-strong pattern (e.g., MAMbey or beDOON), in combination with the principles of motor learning (PML). METHOD: Fourteen TD children ages 5;0 (years;months) to 13;0 were randomly assigned to a training or control group using concealed allocation within blocks. A pre- to posttraining group design was used to examine the acquisition, retention, and generalization of lexical stress production. RESULTS: The training group learned to produce appropriate lexical stress for the pseudowords with strong maintenance and generalization to related untrained stimuli. Accuracy of stress production did not change in the control group. CONCLUSION: TD children can learn to produce lexical stress patterns for orthographically biased pseudowords via explicit training methods. Findings have relevance for the study of languages other than English and for a range of prosodic disorders.