Publications by authors named "Martin Forbes"

9 Publications

  • Page 1 of 1

Inhibiting phosphoglycerate dehydrogenase counteracts chemotherapeutic efficacy against MYCN-amplified neuroblastoma.

Int J Cancer 2021 Mar 17;148(5):1219-1232. Epub 2020 Dec 17.

Department of Pediatric Hematology and Oncology, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany.

Here we sought metabolic alterations specifically associated with MYCN amplification as nodes to indirectly target the MYCN oncogene. Liquid chromatography-mass spectrometry-based proteomics identified seven proteins consistently correlated with MYCN in proteomes from 49 neuroblastoma biopsies and 13 cell lines. Among these was phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme in de novo serine synthesis. MYCN associated with two regions in the PHGDH promoter, supporting transcriptional PHGDH regulation by MYCN. Pulsed stable isotope-resolved metabolomics utilizing C-glucose labeling demonstrated higher de novo serine synthesis in MYCN-amplified cells compared to cells with diploid MYCN. An independence of MYCN-amplified cells from exogenous serine and glycine was demonstrated by serine and glycine starvation, which attenuated nucleotide pools and proliferation only in cells with diploid MYCN but did not diminish these endpoints in MYCN-amplified cells. Proliferation was attenuated in MYCN-amplified cells by CRISPR/Cas9-mediated PHGDH knockout or treatment with PHGDH small molecule inhibitors without affecting cell viability. PHGDH inhibitors administered as single-agent therapy to NOG mice harboring patient-derived MYCN-amplified neuroblastoma xenografts slowed tumor growth. However, combining a PHGDH inhibitor with the standard-of-care chemotherapy drug, cisplatin, revealed antagonism of chemotherapy efficacy in vivo. Emergence of chemotherapy resistance was confirmed in the genetic PHGDH knockout model in vitro. Altogether, PHGDH knockout or inhibition by small molecules consistently slows proliferation, but stops short of killing the cells, which then establish resistance to classical chemotherapy. Although PHGDH inhibition with small molecules has produced encouraging results in other preclinical cancer models, this approach has limited attractiveness for patients with neuroblastoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ijc.33423DOI Listing
March 2021

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.

Trials 2020 May 27;21(1):436. Epub 2020 May 27.

Institute for Applied Health Research, University of Birmingham, Birmingham, B15 2TT, UK.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13063-020-04354-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251680PMC
May 2020

Analysing central metabolism in ultra-high resolution: At the crossroads of carbon and nitrogen.

Mol Metab 2020 03 19;33:38-47. Epub 2019 Dec 19.

Max-Delbrück-Center for Molecular Medicine (MDC), Berlin, Germany; Berlin Institute for Medical Systems Biology (BIMSB), Berlin, Germany. Electronic address:

Background: Cancer cell metabolism can be characterised by adaptive metabolic alterations, which support abnormal proliferative cell growth with high energetic demand. De novo nucleotide biosynthesis is essential for providing nucleotides for RNA and DNA synthesis, and drugs targeting this biosynthetic pathway have proven to be effective anticancer therapeutics. Nevertheless, cancers are often able to circumvent chemotherapeutic interventions and become therapy resistant. Our understanding of the changing metabolic profile of the cancer cell and the mode of action of therapeutics is dependent on technological advances in biochemical analysis.

Scope Of Review: This review begins with information about carbon- and nitrogen-donating pathways to build purine and pyrimidine moieties in the course of nucleotide biosynthesis. We discuss the application of stable isotope resolved metabolomics to investigate the dynamics of cancer cell metabolism and outline the benefits of high-resolution accurate mass spectrometry, which enables multiple tracer studies.

Conclusion: With the technological advances in mass spectrometry that allow for the analysis of the metabolome in high resolution, the application of stable isotope resolved metabolomics has become an important technique in the investigation of biological processes. The literature in the area of isotope labelling is dominated by C tracer studies. Metabolic pathways have to be considered as complex interconnected networks and should be investigated as such. Moving forward to simultaneous tracing of different stable isotopes will help elucidate the interplay between carbon and nitrogen flow and the dynamics of de novo nucleotide biosynthesis within the cell.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.molmet.2019.12.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7056925PMC
March 2020

The effects of lifelong cognitive lifestyle on executive function in older people with Parkinson's disease.

Int J Geriatr Psychiatry 2017 12 7;32(12):e157-e165. Epub 2017 Feb 7.

Centre for Research in Ageing and Cognitive Health, School of Psychology, Devon, UK.

Objective: Active lifelong cognitive lifestyles increase cognitive reserve and have beneficial effects on global cognition, cognitive decline and dementia risk in Parkinson's disease (PD). Executive function is particularly impaired even in early PD, and this impacts on quality of life. The effects of lifelong cognitive lifestyle on executive function in PD have not been studied previously. This study examined the association between lifelong cognitive lifestyle, as a proxy measure of cognitive reserve, and executive function in people with PD.

Methods: Sixty-nine people diagnosed with early PD without dementia were recruited as part of the Bilingualism as a protective factor in Age-related Neurodegenerative Conditions study. Participants completed a battery of tests of executive function. The Lifetime of Experiences Questionnaire was completed as a comprehensive assessment of lifelong cognitive lifestyle. Non-parametric correlations compared clinical measures with executive function scores. Cross-sectional analyses of covariance were performed comparing the performance of low and high cognitive reserve groups on executive function tests.

Results: Correlational analyses showed that better executive function scores were associated with younger age, higher levodopa dose and higher Lifetime of Experiences Questionnaire scores. Higher cognitive reserve was associated with better motor function, but high and low cognitive reserve groups did not differ in executive function.

Conclusions: Cognitive reserve, although associated with global cognition, does not appear to be associated with executive function. This differential effect may reflect the specific cognitive profile of PD. The long-term effects of cognitive reserve on executive function in PD require further exploration. Copyright © 2017 John Wiley & Sons, Ltd.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/gps.4677DOI Listing
December 2017

Next-Generation Sequencing-Assisted DNA-Based Digital PCR for a Personalized Approach to the Detection and Quantification of Residual Disease in Chronic Myeloid Leukemia Patients.

J Mol Diagn 2016 Mar 5;18(2):176-89. Epub 2016 Feb 5.

Imperial Molecular Pathology, Imperial Healthcare Trust, Hammersmith Hospital, London, United Kingdom; Centre for Haematology, Faculty of Medicine, Imperial College London, London, United Kingdom.

Recent studies indicate that 40% of chronic myeloid leukemia patients who achieve sustained undetectable BCR-ABL1 transcripts on tyrosine kinase inhibitor therapy remain disease-free after drug discontinuation. In contrast, 60% experience return of detectable disease and have to restart treatment, thus highlighting the need for an improved method of identifying patients with the lowest likelihood of relapse. Here we describe the validation of a personalized DNA-based digital PCR (dPCR) approach for quantifying very low levels of residual disease, which involves the rapid identification of t(9;22) fusion junctions using targeted next-generation sequencing coupled with the use of a dPCR platform. t(9;22) genomic breakpoints were successfully mapped in samples from 32 of 32 patients with early stage disease. Disease quantification by DNA-based dPCR was performed using the Fluidigm BioMark platform on 46 follow-up samples from 6 of the 32 patients, including 36 samples that were in deep molecular remission. dPCR detected persistent disease in 81% of molecular-remission samples, outperforming both RT-dPCR (25%) and DNA-based quantitative PCR (19%). We conclude that dPCR for BCR-ABL1 DNA is the most sensitive available method of residual-disease detection in chronic myeloid leukemia and may prove useful in the management of tyrosine kinase inhibitor withdrawal.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jmoldx.2015.09.005DOI Listing
March 2016

Tracking Parkinson's: Study Design and Baseline Patient Data.

J Parkinsons Dis 2015 ;5(4):947-59

Department of Neurology, Institute of Neurological Sciences, Southern General Hospital, Glasgow, UK.

Background: There is wide variation in the phenotypic expression of Parkinson's disease (PD), which is driven by both genetic and epidemiological influences.

Objectives: To define and explain variation in the clinical phenotype of PD, in relation to genotypic variation.

Methods: Tracking Parkinson's is a multicentre prospective longitudinal epidemiologic and biomarker study of PD. Patients attending specialist clinics in the United Kingdom with recent onset (<3.5 years) and young onset (diagnosed <50 years of age) PD were enrolled. Motor, non-motor and quality of life assessments were performed using validated scales. Cases are followed up 6 monthly up to 4.5 years for recent onset PD, and up to 1 year for young onset PD. We present here baseline clinical data from this large and demographically representative cohort.

Results: 2247 PD cases were recruited (1987 recent onset, 260 young onset). Recent onset cases had a mean (standard deviation, SD) age of 67.6 years (9.3) at study entry, 65.7% males, with disease duration 1.3 years (0.9), MDS-UPDRS 3 scores 22.9 (12.3), LEDD 295 mg/day (211) and PDQ-8 score 5.9 (4.8). Young onset cases were 53.5 years old (7.8) at study entry, 66.9% male, with disease duration 10.2 years (6.7), MDS-UPDRS 3 scores 27.4 (15.3), LEDD 926 mg/day (567) and PDQ-8 score 11.6 (6.1).

Conclusions: We have established a large clinical PD cohort, consisting of young onset and recent onset cases, which is designed to evaluate variation in clinical expression, in relation to genetic influences, and which offers a platform for future imaging and biomarker research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/JPD-150662DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4927877PMC
September 2016

Cognitive reserve in Parkinson's disease: the effects of welsh-english bilingualism on executive function.

Parkinsons Dis 2015 1;2015:943572. Epub 2015 Apr 1.

Bangor University, Gwynedd, Bangor LL57 2DG, UK ; University of Exeter, Devon, Exeter EX4 4QG, UK.

Objective. Bilingualism has been shown to benefit executive function (EF) and delay the onset of Alzheimer's disease. This study aims at examining whether a bilingual advantage applies to EF in Parkinson's disease (PD). Method. In a cross-sectional outpatient cohort of monolingual English (n = 57) and bilingual Welsh/English (n = 46) speakers with PD we evaluated the effects of bilingualism compared with monolingualism on performance on EF tasks. In bilinguals we also assessed the effects of the degree of daily usage of each language and the degree of bilingualism. Results. Monolinguals showed an advantage in performance of language tests. There were no differences in performance of EF tests in monolinguals and bilinguals. Those who used Welsh less in daily life had better performance on one test of English vocabulary. The degree of bilingualism correlated with one test of nonverbal reasoning and one of working memory but with no other tests of EF. Discussion. The reasons why the expected benefit in EF in Welsh-English bilinguals with PD was not found require further study. Future studies in PD should include other language pairs, analysis of the effects of the degree of bilingualism, and longitudinal analysis of cognitive decline or dementia together with structural or functional neuroimaging.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2015/943572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4397475PMC
April 2015

Bilingualism, executive control, and age at diagnosis among people with early-stage Alzheimer's disease in Wales.

J Neuropsychol 2016 09 25;10(2):163-85. Epub 2014 Nov 25.

Bangor University, UK.

The observation of a bilingual advantage in executive control tasks involving inhibition and management of response conflict suggests that being bilingual might contribute to increased cognitive reserve. In support of this, recent evidence indicates that bilinguals develop Alzheimer's disease (AD) later than monolinguals, and may retain an advantage in performance on executive control tasks. We compared age at the time of receiving an AD diagnosis in bilingual Welsh/English speakers (n = 37) and monolingual English speakers (n = 49), and assessed the performance of bilinguals (n = 24) and monolinguals (n = 49) on a range of executive control tasks. There was a non-significant difference in age at the time of diagnosis, with bilinguals being on average 3 years older than monolinguals, but bilinguals were also significantly more cognitively impaired at the time of diagnosis. There were no significant differences between monolinguals and bilinguals in performance on executive function tests, but bilinguals appeared to show relative strengths in the domain of inhibition and response conflict. Bilingual Welsh/English speakers with AD do not show a clear advantage in executive function over monolingual English speakers, but may retain some benefits in inhibition and management of response conflict. There may be a delay in onset of AD in Welsh/English bilinguals, but if so, it is smaller than that found in some other clinical populations. In this Welsh sample, bilinguals with AD came to the attention of services later than monolinguals, and reasons for this pattern could be explored further.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jnp.12061DOI Listing
September 2016

A randomized controlled trial of the impact of a teacher classroom management program on the classroom behavior of children with and without behavior problems.

J Sch Psychol 2013 Oct 26;51(5):571-85. Epub 2013 Aug 26.

School of Psychology, Bangor University, Gwynedd LL57 2PZ, UK. Electronic address:

This randomized controlled trial (RCT) evaluated the efficacy of the Incredible Years (IY) Teacher Classroom Management (TCM; Webster-Stratton & Reid, 2002) program to assess whether training teachers in IY-TCM principles improve teacher behavior, whether any observed improvements impact pupil behavior classroom-wide, and whether these effects can be demonstrated with children at risk of developing conduct problems. Six intervention and six control classrooms comprising 12 teachers and 107 children (aged 3 to 7years) were recruited. Children were screened for high or low behavior problems using the cut-off points of the teacher-rated Strengths and Difficulties Questionnaire (Goodman, 1997). The primary outcome measure was independent classroom observations using the Teacher-Pupil Observation Tool (Martin et al., 2010). Multilevel modeling analyses were conducted to examine the effect of the intervention on teacher, classroom, and child behavior. Results showed a significant reduction in classroom off-task behavior (d=0.53), teacher negatives to target children (d=0.36), target child negatives towards the teacher (d=0.42), and target child off-task behavior (d=0.48). These preliminary results demonstrate the potential impact of IY-TCM on both teacher and child behavior.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jsp.2013.08.001DOI Listing
October 2013