Cohort Profile:Health and Wellbeing of People with Intellectual Disability in New South Wales, Australia – A data linkage cohort

Purpose People with intellectual disability (ID) experience high rates of physical and mental health problems, while access to appropriate healthcare is often poor. This cohort was established to develop an epidemiological profile related to the health, health service use, disability services, mortality and corrective services records of people with ID. Participants The cohort contains 92 542 people with ID (40% females) with a median age of 23 years (IQR: 12–43 years) and 2 004 475 people with a neuropsychiatric or developmental disorder diagnosis (50% females) with a median age of 51 years (IQR: 29–73 years) from New South Wales, Australia. The whole sample contains records for 2 097 017 individuals with most data sets spanning financial years 1 July 2001 to 30 June 2016. A wide range of data from linked population data sets are included in the areas of disability, health, corrective services and targeted specialist support services in public schools, Public Guardian and Ombudsman services. Findings to date This study includes one of the largest cohorts of people with ID internationally. Our data have shown that the presence of ID is significantly associated with emergency department presentations and psychiatric readmissions after the first psychiatric admission based on a subcohort of people with a psychiatric admission. Adults with ID experience premature mortality and over-representation of potentially avoidable deaths compared with the general population. Future plans Within the health service system, we will examine different components, that is, inpatient, emergency adult services, children and younger people services and costs associated with healthcare as well as mortality, cause and predictors of death. The neuropsychiatric and developmental disorders comparison cohort allows comparisons of the physical health, mental health and service use profiles of people with ID and those with other neuropsychiatric disorders

Differential activity of MEK and ERK inhibitors in BRAF inhibitor resistant melanoma

Acquired resistance to BRAF inhibitors often involves MAPK re-activation, yet the MEK inhibitor trametinib showed minimal clinical activity in melanoma patients that had progressed on BRAF-inhibitor therapy. Selective ERK inhibitors have been proposed as alternative salvage therapies. We show that ERK inhibition is more potent than MEK inhibition at suppressing MAPK activity and inhibiting the proliferation of multiple BRAF inhibitor resistant melanoma cell models. Nevertheless, melanoma cells often failed to undergo apoptosis in response to ERK inhibition, because the relief of ERK-dependent negative feedback activated RAS and PI3K signalling. Consequently, the combination of ERK and PI3K/mTOR inhibition was effective at promoting cell death in all resistant melanoma cell models, and was substantially more potent than the MEK/PI3K/mTOR inhibitor combination. Our data indicate that a broader targeting strategy concurrently inhibiting ERK, rather than MEK, and PI3K/mTOR may circumvent BRAF inhibitor resistance, and should be considered during the clinical development of ERK inhibitors.11 page(s

Mutant B-RAF-Mcl-1 survival signaling depends on the STAT3 transcription factor

Approximately 50% of melanomas depend on mutant B-RAF for proliferation, metastasis and survival. The inhibition of oncogenic B-RAF with highly targeted compounds has produced remarkable albeit short-lived clinical responses in B-RAF mutant melanoma patients. Reactivation of signaling downstream of B-RAF is frequently associated with acquired resistance to B-RAF inhibitors, and the identification of B-RAF targets may provide new strategies for managing melanoma. Oncogenic B-RAF^V600E is known to promote the stabilizing phosphorylation of the anti-apoptotic protein Mcl-1, implicated in melanoma survival and chemoresistance. We now show that B-RAF^V600E signaling also induces the transcription of Mcl-1 in melanocytes and melanoma. We demonstrate that activation of STAT3 serine-727 and tyrosine-705 phosphorylations is promoted by B-RAF^V600E activity and that the Mcl-1 promoter is dependent on a STAT consensus-site for B-RAF-mediated activation. Consequently, suppression of STAT3 activity disrupted B-RAF^V600E-mediated induction of Mcl-1 and reduced melanoma cell survival. We propose that STAT3 has a central role in the survival and contributes to chemoresistance of B-RAF^V600E melanoma

Antiproliferative effects of continued mitogen-activated protein kinase pathway inhibition following acquired resistance to BRAF and/or MEK inhibition in melanoma

Inhibitors of the mitogen-activated protein kinases (MAPK), BRAF, and MAP-ERK kinase (MEK) induce tumor regression in the majority of patients with BRAF-mutant metastatic melanoma. The clinical benefit of MAPK inhibitors is restricted by the development of acquired resistance with half of those who benefit having progressed by 6 to 7 months and long-term responders uncommon. There remains no agreed treatment strategy on disease progression in these patients. Without published evidence, fears of accelerated disease progression on inhibitor withdrawal have led to the continuation of drugs beyond formal disease progression. We now show that treatment with MAPK inhibitors beyond disease progression can provide significant clinical benefit, and the withdrawal of these inhibitors led to a marked increase in the rate of disease progression in two patients. We also show that MAPK inhibitors retain partial activity in acquired resistant melanoma by examining drug-resistant clones generated to dabrafenib, trametinib, or the combination of these drugs. All resistant sublines displayed a markedly slower rate of proliferation when exposed to MAPK inhibitors, and this coincided with a reduction in MAPK signaling, decrease in bromodeoxyuridine incorporation, and S-phase inhibition. This cytostatic effect was also associated with diminished levels of cyclin D1 and p-pRb. Two shortterm melanoma cultures generated from resistant tumor biopsies also responded to MAPK inhibition, with comparable inhibitory changes in proliferation and MAPK signaling. These data provide a rationale for the continuation of BRAF and MEK inhibitors after disease progression and support the development of clinical trials to examine this strategy