MCT1-mediated transport of a toxic molecule is an effective strategy for targeting glycolytic tumors

There is increasing evidence that oncogenic transformation modifies the metabolic program of cells. A common alteration is the upregulation of glycolysis, and efforts to target glycolytic enzymes for anticancer therapy are under way. Here, we performed a genome-wide haploid genetic screen to identify resistance mechanisms to 3-bromopyruvate (3-BrPA), a drug candidate that inhibits glycolysis in a poorly understood fashion. We identified the SLC16A1 gene product, MCT1, as the main determinant of 3-BrPA sensitivity. MCT1 is necessary and sufficient for 3-BrPA uptake by cancer cells. Additionally, SLC16A1 mRNA levels are the best predictor of 3-BrPA sensitivity and are most elevated in glycolytic cancer cells. Furthermore, forced MCT1 expression in 3-BrPA–resistant cancer cells sensitizes tumor xenografts to 3-BrPA treatment in vivo. Our results identify a potential biomarker for 3-BrPA sensitivity and provide proof of concept that the selectivity of cancer-expressed transporters can be exploited for delivering toxic molecules to tumors.National Institutes of Health (U.S.) (NIH CA103866)Jane Coffin Childs Memorial Fund for Medical Research (Fellowship)National Science Foundation (U.S.) (Fellowship)Howard Hughes Medical Institute (Investigator

A multicentre, randomised controlled trial to compare the clinical and cost-effectiveness of Lee Silverman Voice Treatment versus standard NHS Speech and Language Therapy versus control in Parkinson’s disease: a study protocol for a randomised controlled trial

Abstract: Background: Parkinson’s disease (PD) affects approximately 145,519 people in the UK. Speech impairments are common with a reported prevalence of 68%, which increase physical and mental demands during conversation, reliance on family and/or carers, and the likelihood of social withdrawal reducing quality of life. In the UK, two approaches to Speech and Language Therapy (SLT) intervention are commonly available: National Health Service (NHS) SLT or Lee Silverman Voice Treatment (LSVT LOUD®). NHS SLT is tailored to the individuals’ needs per local practice typically consisting of six to eight weekly sessions; LSVT LOUD® comprises 16 sessions of individual treatment with home-based practice over 4 weeks. The evidence-base for their effectiveness is inconclusive. Methods/design: PD COMM is a phase III, multicentre, three-arm, unblinded, randomised controlled trial. Five hundred and forty-six people with idiopathic PD, reporting speech or voice problems will be enrolled. We will exclude those with a diagnosis of dementia, laryngeal pathology or those who have received SLT for speech problems in the previous 2 years. Following informed consent and completion of baseline assessments, participants will be randomised in a 1:1:1 ratio to no-intervention control, NHS SLT or LSVT LOUD® via a central computer-generated programme, using a minimisation procedure with a random element, to ensure allocation concealment. Participants randomised to the intervention groups will start treatment within 4 (NHS SLT) or 7 (LSVT LOUD®) weeks of randomisation. Primary outcome: Voice Handicap Index (VHI) total score at 3 months. Secondary outcomes include: VHI subscales, Parkinson’s Disease Questionnaire-39; Questionnaire on Acquired Speech Disorders; EuroQol-5D-5 L; ICECAP-O; resource utilisation; adverse events and carer quality of life. Mixed-methods process and health economic evaluations will take place alongside the trial. Assessments will be completed before randomisation and at 3, 6 and 12 months after randomisation. The trial started in December 2015 and will run for 77 months. Recruitment will take place in approximately 42 sites around the UK. Discussion: The trial will test the hypothesis that SLT is effective for the treatment of speech or voice problems in people with PD compared to no SLT. It will further test whether NHS SLT or LSVT LOUD® provide greater benefit and determine the cost-effectiveness of both interventions. Trial registration: International Standard Randomised Controlled Trials Number (ISRCTN) Registry, ID: 12421382. Registered on 18 April 2016

A multicentre, randomised controlled trial to compare the clinical and cost-effectiveness of Lee Silverman Voice Treatment versus standard NHS Speech and Language Therapy versus control in Parkinson’s disease: a study protocol for a randomised controlled trial

Abstract: Background: Parkinson’s disease (PD) affects approximately 145,519 people in the UK. Speech impairments are common with a reported prevalence of 68%, which increase physical and mental demands during conversation, reliance on family and/or carers, and the likelihood of social withdrawal reducing quality of life. In the UK, two approaches to Speech and Language Therapy (SLT) intervention are commonly available: National Health Service (NHS) SLT or Lee Silverman Voice Treatment (LSVT LOUD®). NHS SLT is tailored to the individuals’ needs per local practice typically consisting of six to eight weekly sessions; LSVT LOUD® comprises 16 sessions of individual treatment with home-based practice over 4 weeks. The evidence-base for their effectiveness is inconclusive. Methods/design: PD COMM is a phase III, multicentre, three-arm, unblinded, randomised controlled trial. Five hundred and forty-six people with idiopathic PD, reporting speech or voice problems will be enrolled. We will exclude those with a diagnosis of dementia, laryngeal pathology or those who have received SLT for speech problems in the previous 2 years. Following informed consent and completion of baseline assessments, participants will be randomised in a 1:1:1 ratio to no-intervention control, NHS SLT or LSVT LOUD® via a central computer-generated programme, using a minimisation procedure with a random element, to ensure allocation concealment. Participants randomised to the intervention groups will start treatment within 4 (NHS SLT) or 7 (LSVT LOUD®) weeks of randomisation. Primary outcome: Voice Handicap Index (VHI) total score at 3 months. Secondary outcomes include: VHI subscales, Parkinson’s Disease Questionnaire-39; Questionnaire on Acquired Speech Disorders; EuroQol-5D-5 L; ICECAP-O; resource utilisation; adverse events and carer quality of life. Mixed-methods process and health economic evaluations will take place alongside the trial. Assessments will be completed before randomisation and at 3, 6 and 12 months after randomisation. The trial started in December 2015 and will run for 77 months. Recruitment will take place in approximately 42 sites around the UK. Discussion: The trial will test the hypothesis that SLT is effective for the treatment of speech or voice problems in people with PD compared to no SLT. It will further test whether NHS SLT or LSVT LOUD® provide greater benefit and determine the cost-effectiveness of both interventions. Trial registration: International Standard Randomised Controlled Trials Number (ISRCTN) Registry, ID: 12421382. Registered on 18 April 2016

Evolução Orçamentária e a Efetividade de sua execução: O Caso da Esquadra Brasileira

Este estudo tem por objetivo verificar a existência de eventuais distorções e descompassos entre o orçamento planejado e o que foi efetivamente executado, atinentes aos recursos destinados à Esquadra Brasileira. Para tanto, utilizou-se o estudo de caso como estratégia de pesquisa, buscando-se apresentar os principais conceitos e características do planejamento orçamentário e a evolução dos orçamentos da organização em lide no período entre 2006 e 2011, sob a ótica do Planejamento Orçamentário Governamental. Em um segundo plano, esta pesquisa realiza um cotejamento entre os gastos em Defesa Nacional realizados pelos países componentes do bloco BRICS (Brasil, Rússia, Índia, China e África do Sul). Apresenta uma análise comparativa entre o planejamento orçamentário da Esquadra Brasileira e a sua execução nos últimos seis anos, com a coleta e análise de dados disponíveis no Sistema Integrado de Administração Financeira do Governo Federal (SIAFI) e no Sistema de Acompanhamento do Plano Diretor (SIPLAD). Os resultados alcançados no presente trabalho sugerem que, à luz da literatura existente e dos cotejamentos efetuados, no período analisado, a execução do planejamento orçamentário da Esquadra sofreu reveses, em decorrência da não contemplação da totalidade do orçamento planejado. Ainda assim, mostra-se patente a importância do bom planejamento em todas as fases do processo, alinhado à Política de Defesa Nacional (PDN), à Estratégia Nacional de Defesa (END), e, em um futuro próximo, ao Livro Branco da Defesa Nacional (LBDN), em qualquer cenário

Selecting portable ankle/toe brachial pressure index systems for a peripheral arterial disease population screening programme: A systematic review, clinical evaluation exercise, and consensus process.

Objective To provide an overview of systems available for peripheral arterial disease (PAD) screening, together with respective accuracies and a clinical evaluation to identify a system suitable for use in a community screening programme. Methods A systematic review of the diagnostic accuracy of six ankle brachial pressure index (ABPI) and toe brachial pressure index (TBPI) devices deemed to be portable, which were Conformité Européenne (CE) marked, and were automated or semi-automated was carried out compared with gold standard handheld Doppler and duplex ultrasound. The devices were MESI-ABPI-MD, Huntleigh Dopplex Ability, Huntleigh ABPI and TBPI systems, Systoe TBPI system, and BlueDop. Seven databases (MEDLINE, EMBASE, Scopus, Web of Science, Cochrane Database of Systematic Reviews, Cochrane Register of Controlled Trials (CENTRAL), and Cumulative Index to Nursing and Allied Health Literature (CINAHL)) were searched, and 11 studies were identified as eligible for review. This was followed by hands on clinical evaluation by abdominal aortic aneurysm (AAA) screening staff (n = 39). During this, devices were demonstrated to staff which they then tested on volunteers and gave feedback using pre-designed questionnaires on their suitability for use in a screening programme. Finally, accuracy data and staff preferences were combined during a consensus conference that was held between study and screening staff to determine the most appropriate device to use in a community screening programme. Results Generally, the evaluated systems have a moderate level of sensitivity and a high level of specificity: Dopplex ability sensitivity 20% – 70%, specificity 86% – 96%; MESI sensitivity 57% – 74%, specificity 85% – 99%; BlueDop sensitivity 95%, specificity 89%; and Systoe sensitivity 71%, specificity 77%. Clinical evaluation by screening staff identified a preference for the MESI system. The consensus conference concluded that the MESI device was a good candidate for use in a community PAD screening programme. Conclusion The MESI system is a good candidate to consider for community PAD screening.</p