90 results on '"Mantripragada K"'
Search Results
2. Genome-wide common and rare variant analysis provides novel insights into clozapine-associated neutropenia
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Legge, S E, Hamshere, M L, Ripke, S, Pardinas, A F, Goldstein, J I, Rees, E, Richards, A L, Leonenko, G, Jorskog, L F, Chambert, K D, Collier, D A, Genovese, G, Giegling, I, Holmans, P, Jonasdottir, A, Kirov, G, McCarroll, S A, MacCabe, J H, Mantripragada, K, Moran, J L, Neale, B M, Stefansson, H, Rujescu, D, Daly, M J, Sullivan, P F, Owen, M J, OʼDonovan, M C, and Walters, J TR
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- 2017
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3. Replication study implicates COMT val158met polymorphism as a modulator of probabilistic reward learning
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Lancaster, T. M., Heerey, E. A., Mantripragada, K., and Linden, D. E. J.
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- 2015
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4. COMT Val158Met genotype is associated with fluctuations in working memory performance: converging evidence from behavioural and single-trial P3b measures
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Saville, C. W.N., Lancaster, T. M., Stefanou, M. E., Salunkhe, G., Lourmpa, I., Nadkarni, A., Boehm, S. G., Bender, S., Smyrnis, N., Ettinger, U., Feige, B., Biscaldi, M., Mantripragada, K. K., Linden, D. E.J., and Klein, C.
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- 2014
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5. Session Topic: Capital Management and Capital Theory: Discussion
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Mantripragada, K.
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- 1973
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6. E-136 Safety and efficacy of an accelerated deflation algorithm for patent hemostasis in transradial neurovascular procedures
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Mantripragada, K, primary, Mansour, S, additional, Echeverry, N, additional, Hospedales, E, additional, Shapiro, S, additional, and Snelling, B, additional
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- 2020
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7. Access-Site Complications in Mechanical Thrombectomy for Acute Ischemic Stroke: A Review of Prospective Trials
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Shapiro, S.Z., primary, Sabacinski, K.A., additional, Mantripragada, K., additional, Shah, S.S., additional, Stein, A.A., additional, Echeverry, N.B., additional, MacKinnon, G.A., additional, and Snelling, B.M., additional
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- 2020
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8. S02. Capturing Irish Rare Disease activity, a must for improved cross border care and research
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Coleman, A, McKinley, F, Gough, A, Wheatley, N, Xu, H, McKnight, AJ, Lambert, DM, Lynch, SA, Marron, R, Gray, D, Treacy, EP, Moore, RS, McConnell, V, Kelly, D, Das, S, Moran, B, Han, K, Mulligan, N, Barrett, C, Buckley, PG, Mc Mahon, P, McCaffrey, J, Van Essen, HF, Connor, K, Ylstra, B, Lambrechts, D, Gallagher, WM, O’Connor, DP, Kelly, CM, Dockery, A, Carrigan, M, Malone, C, Keegan, D, Stevenson, K, Silvestri, J, Green, A, McCourt, J, Humphries, P, Kenna, PF, Farrar, GJ, Smyth, LJ, Neville, CE, McKay, GJ, Maxwell, AP, Woodside, JV, McLaughlin, RL, Schijven, D, van Rheenen, W, van Eijk, KR, O’Brien, M, Kahn, R, Ophoff, RA, Goris, A, Bradley, DG, Al-Chalabi, A, van den Berg, LH, Luykx, JJ, Hardiman, O, Veldink, JH, Mackin, SJ, O’Neill, K, Irwin, R, Walsh, CP, Xu, M, Stattin, EL, Shaw, G, Heinegård, D, Sullivan, G, Wilmut, I, Colman, A, Önnerfjord, P, Khabut, A, Aspberg, A, Dockery, P, Hardingham, T, Murphy, M, Barry, F, Gilbert, E, Carmi, S, Ennis, S, Wilson, J.F., Cavalleri, G.L., McNerlan, S, Scott, J, O’Neill, T, Jager, D, Eustace-Ryan, S, Ryan, F, Barton, D, O’Dwyer, V, Neylan, D, Chemaly, M, Peace, A, Gibson, M, Clauss, M, Watterson, S, Bjourson, T, McGilligan, V, McVeigh, UM, McVeigh, TP., Owens, P, Morris, D, Miller, N, Lowery, AJ, Kerin, MJ, Goodman, R, Thompson, PD, Wingfield, B, Lapsley, CR, McDowell, A, McLafferty, M, Coleman, S, McGinnity, M, O’Neill, SM, Bjourson, Tony, Murray, EK, Rodriguez, EP, Doherty, D, O’Halloran, E, Conroy, J, Novak, M, Mulholland, C, Gallagher, L, McCormack, M, Heavin, S, Doherty, CP, Zhu, X, Heinzen, E, Goldstein, DB, Costello, D, Delanty, N, Cavalleri, GL, Stapleton, CP, Connaughton, DM, Conlon, PJ., Parton, A, O’Kane, M, Elwood, J, Sunnotel, O, Stockdale, DJ, Bjourson, AJ, Bell, AF, Sinclair, M, Lynch, SM, Ward, M, McNulty, H, Horigan, G, Strain, JJ, Purvis, J, Tackett, M, McKenna, DJ, Baldemor, S, Yankova, E, Barnard, E, McCafferty, D, Martin, L, Fairley, D, O’Rourke, D, Catherwood, M, Patrick, S, Conway, C, Stead, LS, Wood, HM, Rabbitts, PH, Maloney, DM, Chadderton, N, Millington-Ward, S, Flynn, M, Whitton, L, Cosgrove, D, Morrison, C, Walters, J, Rujescu, D, Corvin, A, Donohoe, G, Clarkson, C, Harold, D, Kendall, K, Richards, A, Mantripragada, K, Owen, MJ, O’Donovan, MC., Hartmann, A, Konte, B, Gill, M, Rea, S, Morris, DW, Harrison, A, Pentieva, K, Ozaki, M, Parle-McDermott, A, Hanlon, KS, Palfi, A, Nesbitt, H, Byrne, NM, Ming, L, Worthington, J, Errington, RJ, Patterson, LH, Smith, PJ, McKeown, SR, O’Neill, KM, McKenna, MM, Irwin, RE, Caffrey, A, Walsh, CP., Benson, KA, Sweeney, Michael, hIcí, Brónagh o, Feder, Ania, Barton, David E., Casey, Jill, Lynch, SallyAnn, McQuaid, Shirley, and McElhatton, N
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Poster Presentations ,Abstracts ,Spoken Papers - Abstract
Behcet’s disease (BD) is a complex, multifactorial rare disease, which is poorly understood. Genetic and environmental factors contribute to BD, but the process of diagnosis is challenging with inconsistent clinical manifestations. A recent survey of individuals living with rare disease(s) in Northern Ireland revealed ~50% of individuals receive ≥1 misdiagnosis with 1/20 seeing >10 doctors. Individuals with BD report a range of symptoms, which are variable in onset, severity, and frequency for this systemic vasculitis. Patients describe prolonged journeys to diagnosis with multiple healthcare professionals and medical specialties; there is no BD specialist in Northern Ireland. Using invitations via social media, voluntary groups, and direct contact we are using surveys incorporating micro-narratives, one-to-one semi-structured interviews, and focus groups to collect detailed family histories and stressor information to help characterise recurrent features in patients living with BD and their relatives in Northern Ireland. BD is most often reported in populations along the Silk Road. The highest prevalence is reported in Turkey at 20-420/100,000, compared 1.5/100,000 individuals in the UK. Mapping through general practitioners revealed a much higher than expected prevalence of 12.6/100,000 in the Northern Ireland population. Clusters were observed in Co. Down and Co. Antrim and plotted with social-demographic information. This high ‘UK’ prevalence and the identification of several families with multiple members diagnosed makes NI ideal to explore genetic and epigenetic risk factors for BD. This project involves deep phenotyping and strategies to improve recognition of Behcet’s disease, build collaborative partnerships, improve data collection, enhance training, and information sharing., The National Rare Disease Office (NRDO), initiated in June 2015, collates and disseminates Irish rare disease (RD) information. The prevalent nature of RD (1 in 16 of the population, approximately 80% of which has a genetic basis) and the burden to the health care system is under-recognised and a neglected public health issue. Awareness of rare diseases is a challenge, especially for GPs who each care for > 90 RD patients. The NRDO has made 58 presentations, lectures and publications and received numerous enquiries (58% of contacts from patients/ families, 25% from health care professionals and 4% researchers). Mapping Irish RD clinical and research expertise is developing through Orphanet Ireland. Enrolment of clinical expert centres has increased by 50%,but only, Aims To assess the tumour surveillance advice given to patients in Northern Ireland with confirmed PTEN hamartoma tumour syndrome (HTS). Methods We used the surveillance advice laid out by the Pan Thames Cancer Genetics Group in 2014 to benchmark our patients against. A coding search was carried out on our regional information management system to identify all patients with a confirmed diagnosis. The written/ electronic notes of these patients were reviewed. We adhered to the National PTEN audit inclusion criteria of including patients older than16 years, those with a pathogenic/likely pathogenic PTEN mutation or at 50% risk and those who had received advice between 01/08/10 - 01/08/2015. Results 21 patients were identified. All patients had a pathogenic PTEN mutation. 6 children were excluded. 1 adult was excluded due to lack of documented advice. 6 patients had a cancer diagnosis. 9 patients had a positive family history of cancer. Annual breast screening was recommended for 67% of patients which involved mammography in 83% and MRI in 17%. Annual thyroid USS and TFTs were recommended for 54% and 31% of patients respectively. 16% of female patients had gynaecology referrals completed. An annual dermatological review was recommended for 23% of patients. Widely variable colonoscopy and renal USS screening was recommended for 77% and 65% of patients respectively. No cases of Lhermitte-Duclos disease were identified vs 12% in the national UK audit. Conclusions There is a need for regional PTEN tumour surveillance guidelines to be produced and implemented through a regional PTEN specialist clinic., Catastrophic genomic alterations can drive unusually aggressive cancer phenotypes. We describe a diagnostically challenging rapidly fatal case of medullary thyroid carcinoma (MTC) occurring in a young, morbidly obese man presenting with diffuse bone marrow involvement and disseminated intravascular coagulation. Whole-exome sequencing and shallow whole-genome sequencing was carried out for the primary tumour and multiple metastases. We identified three germline SNP’s within the RET proto-oncogene which remained undetected using routine hospital genetic testing procedures. Indeed, one of the variants identified (L769L) has been previously reported in literature to be associated aggressive MTC presentation, yet remains untested for in the routine diagnosis of MTC. Supported by findings from shallow whole genome sequencing, we report for the first time in thyroid cancer, the occurrence of a catastrophic “chromothripsis-like pattern” (CTLP) event, which involved shattering of chromosome 4 leading to complete abrogation of normal chromosomal function, in addition to dramatic wide-spread copy number aberrations (CNA), across both primary tumour and bone marrow samples. We further describe the presence of loss-of-heterozygosity (LOH) in key genes involved in DNA repair mechanism pathways such as ATM, which possibly facilitated the CTLP event, in addition to LOH in other disease-associated genes such as ALK and NOTCH1 as key drivers of the aggressive and rapidly fatal clinical course in this patient and unresponsiveness to the standard-of-care targeted agent chosen. Given a possible rapid generation of tumor neo-antigens as a result of the CTLP event, immunotherapy may have been more suitable as a treatment option. Moreover, the presence of disease-associated SNP’s within the RET proto-oncogene, support their inclusion as part of routine RET genetic testing for aggressive MTC cases. These results provide a rationale for application of comprehensive genomic analysis of cancers presenting with unusually aggressive behavior to facilitate more appropriate therapeutic options and diagnoses., The Target 5000 research project aims to provide genetic testing for the estimated 5,000 people in Ireland who have an inherited retinal condition. Many clinical trials are available for patients with sight loss, however, many such trials require patients to have their causative mutation identified in order to enter the trial. The objective of the study is to genetically characterise patients with inherited retinal degenerations (IRDs) in Ireland and in principle to make clinical trials more accessible to some Irish people suffering from sight loss. The study also seeks to identify previously undiscovered pathological mutations in a panel of known retinopathy genes evaluated utilizing target capture next generation sequencing (NGS). Thus far in the study, as part of Target 5000 roughly 10% of the Irish IRD population has been sequenced and the results obtained are encouraging. Target 5000 offers not only a chance to discover new causative mutations, but is vital in giving patients access to information regarding the pathogenesis of their disease. Over 50 novel mutations have been discovered, as well as some previously ambiguous phenotypes resolved. More precise matching of genotype with phenotype from this study and similar studies globally should start to enable clinicians to better formulate accurate future diagnoses and at times prognoses., MicroRNAs are understood to play a functional role within the establishment of epigenetic marks and are in turn under epigenetic control. Emerging evidence suggests microRNAs are vital for both kidney development and renal function. This study aimed to identify differential methylation affecting microRNAs in patients with end-stage renal disease (ESRD). Methylation status was determined for 485,577 unique CpG sites in 105 individuals with ESRD and 52 donor controls with no evidence of renal disease using the HumanMethylation450K BeadChip array (Illumina). Statistically significant associations (P, Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease characterized by rapid-onset loss of upper and lower motor neurones, resulting in progressive paralysis and death from respiratory failure. Schizophrenia is a neuropsychiatric disease with positive symptoms, negative symptoms and impairment over a range of cognitive abilities. We have recently shown that schizophrenia occurs more frequently than expected in the pedigrees of ALS patients, suggesting an aetiological relationship between both diseases. Using linkage disequilibrium score regression with summary statistics for GWAS of ALS and schizophrenia comprising over 100,000 unique individuals, we estimated the genetic correlation between ALS and schizophrenia to be 14.3% (95% CI 7.05-21.6; p = 1×10-4). Up to 0.12% of the variance in ALS was explained by schizophrenia polygenic risk scores (p = 8.4×10). We leveraged the apparent pleiotropic relationship between ALS and schizophrenia to identify five potential novel ALS-associated genomic loci at conditional false discovery rate < 0.01. Diagnostic misclassification in the schizophrenia cohort did not contribute significantly to our observations (BUHMBOX p = 0.94) and we estimated that 4.86% (2.47-7.13%) of ALS cases would need to be misdiagnosed as schizophrenia to observe our genetic correlation estimate under a true genetic correlation of 0%. Our results indicate that the lifetime risk for comorbid ALS and schizophrenia increases from 1 in 40,000 to 1 in 34,336, which would require an incident cohort of 16,488 ALS patients to observe epidemiologically. Our findings suggest shared underlying biology between ALS and schizophrenia which will direct novel approaches in research and therapeutic development., Background Imprinted genes are autosomal, but only expressed from one parental allele and are often clustered in small groups. They play an important role in the regulation of normal mammalian development. Differentially methylated regions (DMR) on each allele are important in regulating the genes, with marks being characterised as primary or secondary DMRs, depending on whether they are inherited from the germ cells or arise later, respectively. Imprinting disorders such as Prader-Willi Syndome (PWS) and Beckwith-Weidemann Syndrome (BWS) arise either from uniparental disomy or faulty DNA methylation. We wished to determine 1) which of the loci are most sensitive to loss of methylation 2) to more precisely define the sensitive regions and 3) determine what happens at primary versus secondary imprints. Methods Stable knockdowns of the maintenance methyltransferase DNMT1 were generated in hTERT-immortalised adult fibroblasts using shRNA. Genome wide methylation levels were assayed using the Illumina 450k BeadChip array and analysed using bioinformatic approaches. Results We found that 1) the imprinted loci varied extensively in their sensitivity to loss of methylation 2) the extended locus involved in PWS was particularly sensitive 3) that loss of methylation at primary DMR appears to drive gains in methylation at secondary DMR. Conclusion Our results point to a mechanistic link between primary and secondary DMR which may explain why imprints are difficult to reprogram in somatic tissues., Osteoarthritis (OA) is a degenerative joint disease that affects millions of people globally with no disease-modifying strategies yet available. Our understanding of the pathology of OA is inadequate and this impedes investigation of efficient diagnosis and treatment. To expand our understanding of the underlying cellular pathology of OA, we studied a monogenic condition, familial osteochondritis dissecans (FOCD), associated with a known mutation in the ACAN gene. Patients with FOCD develop early onset OA with multiple joint involvement. The objectives of the project were to investigate the cellular pathogenesis of FOCD by studying (a) chondrogenesis of patient-derived bone marrow-mesenchymal stem cells (BM-MSCs) and (b) induced pluripotent stem cells (iPSCs) generated from patient fibroblasts. Our findings revealed that the mutation resulted in a misfolded or unfolded aggrecan protein, which accumulated in the rough endoplasmic reticulum (rER) during protein production. The consistent accumulation resulted in ER stress throughout chondrogenesis. Moreover, the rER stress caused abnormal or disregulated global extracellular matrix (ECM) production and assembly. Importantly, ECM composition analysis indicated that the patient chondrocytes produced abundant amounts of OA-associated markers. Using patient-specific stem cell models, we have discovered a cellular pathogenesis of FOCD involving abnormal cell function and defective tissue formation, contributing to the OA phenotype., Aims The Irish Travellers are a nomadic population primarily found within Ireland and the UK. Consanguineous unions are common, and as a population they are socially and genetically isolated from the surrounding, “settled” Irish population. Previous low-resolution genetic analyses suggested a common Irish origin between the settled and the Traveller populations. It is not known, however, what is the extent of population structure within the Irish Traveller population, the time of divergence from the general Irish population, and the extent of autozygosity. Methods We recruited Irish Travellers from across Ireland and the UK. For inclusion, a participant had to have had at least three grandparents with a surname associated with the Irish Travellers. DNA was extracted from saliva samples, and genotypes were generated using the Illumina OmniExpress SNP genotyping platform. With this data, we investigated population structure using fineStructure, quantified the levels of autozygosity with PLINK, and estimated a time of divergence using a method based on Identity by Descent (IBD) segment sharing. Results We merged, cleaned, and analysed data from 42 Irish Travellers, 2232 settled Irish, 2039 British, 143 Roma Gypsies, and 931 individuals from 57 world-wide populations. We confirm an Irish origin for the Irish Travellers, demonstrate evidence for population substructure within the population, confirm high levels of autozygosity consistent with a consanguineous population, and for the first time provide estimates for a date of divergence between the Irish Travellers and settled Irish. Conclusion Our findings have implications for disease mapping within Ireland, and they additionally inform on the social history of the Irish Traveller population., Copy number variants at 16p13.11 have been described in association with a variety of neurodevelopmental disorders. While deletions of this region are perhaps better described, the clinical significance of the reciprocal duplication is less clearly defined. Phenotypes reported in association with the duplication include developmental delay, speech delay, behavioural difficulties and neurodevelopmental phenotype such as autism, schizophrenia and ADHD. However, the region appears to be subject to variable expressivity and incomplete penetrance. To date we have detected duplications of 16p13.11 in 5 probands using oligonucleotide array CGH. Of these patients 3 showed duplications within the typical ~1.5Mb duplication region while 2 patients had a larger ~2.8Mb duplication, encompassing all of the above region. The clinical phenotype of these patients will be described. Two of these patients have inherited the duplication from their mothers, one was a de novo finding and the inheritance of the others is currently unknown. One of the maternal duplication carriers are also known to have a phenotype. Our data provides further clinical information on the phenotypic features of patients with this syndrome and provides more evidence for the pathogenic nature of this duplication., Introduction Patients referred to the NI Regional Cancer Genetics Service for genetic counselling were sent a questionnaire to evaluate patient satisfaction. The questionnaire focused on satisfaction surrounding the referral process, waiting times and communication during and after the appointment. Method One hundred patients, whose episode of care was completed between November 2015 and June 2016, were sent an anonymised structured questionnaire by post. Patients were seen by a genetic counsellor for assessment of their family history of cancer, predictive testing and genetic mutation screening Results To date (23/06/2016) the questionnaire response rate is 34%. So far 91% have expressed satisfaction with the service that they received. Useful comments and observations have been feedback in the questionnaire to aid service improvement. Data collection will be completed imminently to allow for complete analysis. Discussion Useful data has been collected which reinforces the service currently being delivered by genetic counsellors whilst also highlighting areas of service development., Leber’s Hereditary Optic Neuropathy (LHON) is one of the most commonly inherited optic neuropathies and results in significant visual morbidity among young adults. 95% of LHON patients will present with one of three primary mitochondrial mutations; G3460A, G11778A and T14484C. We describe a novel real time diagnostic test to detect the three common mutations leading to LHON. The test uses a combination of multiplex allele specific PCR (ARMS PCR) in combination with high resolution melt curve analysis to detect the presence of the G3460A, G11778A and T14484C mutations. PCR primer sets were designed to produce a control PCR product and PCR products only in the presence of the 3460A, 11778A and 14484C mutations in a multiplex single tube format. Products produce discrete well separated melt curves allowing clear detection of the mutations. The test has proved to be robust, cost and time effective with the real time closed tube system taking approximately 1 hour to complete. This test provides a simple, robust, easy to read output that is both cost and time effective, thus providing an alternative method to individual endpoint PCR – RFLP, PCR followed by Sanger / pyrosequencing and next generation sequencing. It will also allow diagnostic laboratories to detect 95% of LHON causing mutations in a single tube assay allowing diagnostic laboratories to avoid costly NGS assays for the vast majority of LHON patients, thus allowing resources to be focussed on patients with unknown mutations requiring further analysis., Atherosclerotic coronary artery disease (CAD) is a progressive chronic inflammatory condition that can lead to Major Adverse Cardiac Events (MACE) such as heart attacks. Currently there is no definitive test to predict MACE risk. Tumour necrosis factor alpha converting enzyme (TACE), also known as A Disintegrin And Metalloproteinase 17 (ADAM17) is a membrane-anchored protein responsible for the ectodomain shedding of a variety of transmembrane proteins such as cytokines, chemokines, growth factors and their receptors. TACE has been linked to several major acute and chronic inflammatory diseases including atherosclerosis. The aim of this study was to investigate if TACE may be a valuable predictive biomarker for CAD and MACE risk. TACE levels were measured in the plasma of CAD patients including those with acute coronary syndrome (ACS) and elective patients attending the catheterisation laboratory for coronary angiogram. TACE levels were measured using ELISA and quantitative real time PCR. Levels were compared with control samples collected from apparently healthy individuals and a subset of patients with no CAD as evidenced by coronary angiogram. Other factors that might affect TACE detection were also measured including sample type and storage time. To date 207 consecutive CAD patients and 40 controls have been recruited to the study. Results demonstrate that CAD patients have higher levels of plasma TACE in comparison to controls. TACE protein levels were especially highest in those ACS and elective patients with a previous history of MACE. Results to date indicate that TACE may be a useful marker to predict disease progression and recurrent MACE in CAD patients., Introduction NRG1 (neuregulin1) is a candidate tumour suppressor gene. NRG1 encodes ligands for members of the ERBB family, and has been shown to be silenced by methylation in breast cancer1. Breast and thyroid cancers share some genetic loci (e.g. PTEN, STK11), and an increased risk of thyroid cancer has been noted in survivors of breast cancer2. A single nucleotide variant (C>G) in NRG1 (rs2439302), has been associated with increased risk of non-medullary thyroid cancer3. Aim Our aim was to investigate the association between rs2439302 in NRG1 and predisposition to thyroid and breast cancers in an Irish population. Methods A two-arm case-control study was undertaken. Patients with mutations in high-risk cancer susceptibility genes were excluded. Controls included adults with no personal or familial history of breast or thyroid cancers. Male controls were included in thyroid case- control analysis only. DNA was extracted from whole blood/buccal swabs by ethanol precipitation. Genotyping was performed using Taqman-based PCR. Results 257 patients with thyroid cancer, 518 with breast cancer and 367 unaffected controls were genotyped. Homozygous carriers of the variant were found to have an increased risk of thyroid cancer (OR1.89 (1.21-2.95), p=0.005), but risk for mono-allelic carriers was not significantly increased (OR1.27 (0.87-1.84), p=0.21). The presence of the variant was not associated significantly with breast malignancy for mono-allelic (OR1.31 (0.95-1.8), p=0.095) or biallelic mutation carriers (OR1.15 (0.76-1.73), p=0.51). Conclusion Homozygous carriers of the G allele were found to be at increased risk of thyroid cancer, but no association was observed between the variant and breast cancer., The UGT1A gene family encode (UGT) activity that facilitate the transfer of glucuronic acid to a range of xenogenous and endogenous substrates, the polar end products of which are better suited for elimination through urine and bile. UGT1A genes exhibit an inducible pattern of expression regulated through the activities of such nuclear receptors (NRs) as pregnane X receptor (PXR) farensoid X receptor (FXR) and liver X receptor (LXR) that form a complex interactive network of ‘sensors’ to facilitate the elimination of potentially harmful metabolites and exogenous toxins. We have previously reported that activation of vitamin D receptor (VDR) through both synthetic agonists and nutritionally derived ligands, can induce the expression of both phase I metabolic (CYP3A) and phase III transporter (ABCA1) genes. Little is known however, as to how activated VDR may impact upon the regulation of phase II genes such as UGT1A1. In this study we demonstrate that ligand-activated VDR can significantly enhance the expression of several members of the UGT1A gene family. With particular respect to UGT1A1, we identify within the proximal promoter region of this gene a functional vitamin D response element (VDRE) also recognized by PXR but distinct from previously established regulatory elements that mediate FXR and LXR signalling. Based upon our data, we propose a model for VDR and circulating levels of vitamin D as maintaining stable expression of phase II and functionally related genes as a means to provide baseline protection against the effects of toxic xeno and endobiotic metabolites., Depression is a complex disorder with multiple symptoms, including a persistent low mood, anhedonia and cognitive impairments, and is currently the third leading cause of global disability. The underlying pathophysiology of depression is poorly understood but a growing body of evidence supports an important role for the microbiome in the aetiology of depression and other psychiatric disorders. While much interest is currently focused on the role of the microbiome-gut-brain axis in brain physiology and neurochemistry, the importance of the oral microbiome has received little attention. The aim of this study is to characterise the oral microbiome in adults with severe depression versus matched controls with no history of the disease. To achieve this, participants were asked to complete an online validated mental health survey and to provide a saliva sample. We identified 46 individuals who met the DSM-V criteria for severe depression and 46 age and sex-matched controls with no history of depression. Bacterial DNA was extracted from the saliva samples and 16S rRNA surveys were conducted using next generation sequencing. Differences in the bacterial community composition of the oral microbiota between patients and controls were determined. Metagenomic analyses were conducted using machine learning and computational intelligence algorithms using the 16S RNA data to generate inferred metagenome feature sets. Charting the oral microbiome in depressed patients could therefore provide new insights into the development of the condition, and lead to the identification of novel diagnostic and therapeutic response biomarkers., The nuclear receptors (NRs) pregnane X receptor (PXR) and constitutive androstane receptor (CAR) modulate transcriptional networks that dictate the bioavailability of many endogenous and exogenous compounds such as steroid hormones and therapeutic drug compounds. Elucidating those factors that invoke PXR/ CAR activity has been important for understanding the genetic basis for both metabolic disease and inter-individual variations in drug response. PXR is most closely related to Vitamin D receptor (VDR) for which there is relatively little is known for how this NR may impact upon these same physiological processes. In this study, we employed enteric cell models and ex-vivo based human colon explants to examine how activated VDR may impact upon the expression of genes of a metabolism and transporter function. We find that in relation to PXR and other evaluated NRs, VDR is the most efficient and dominant receptor for induced expression of CYP2B6, CYP3A4/5 and ABCA1. We note that upon activation with the synthetic agonist EB1089, VDR will achieve striking and sustained elevated expression of CYP3A4 at mRNA, protein and enzymatic level suggesting the potential for selective metabolic gene targeting through ligand design. In addition, we report members of the UGT1A gene family to be novel VDR regulated genes, thus extending the known metabolic effects of vitamin D to also encompass expression of phase II (conjugating) genes. This study intimates that systemic vitamin D status and/or activating VDR ligands may have pharmacokinetic relevance to co-administered drug regimes., Ancient genomes are often typically analysed with regard to ancestry and physical phenotype. Less common is examination and identification of genetic diseases, primarily due to the very low numbers of samples sequenced and poor level of sequencing related to the difficulties in sequencing from ancient DNA. Here we present the results of analysing 21 ancient Irish genomes. The data were screened for a wide range of pathogenic genotypes and markers. Giving information for the potential effects and prevalence of certain conditions as well as the earliest known confirmation of their presence. Using records of the remains, we also examined if any displayed phenotypes correlated to identified diseases., Coronary Artery Disease is the largest contributor of CVD, the leading cause of death worldwide. It is caused by atherosclerosis, a build-up of cholesterol in the blood vessels and chronic inflammation. The NLRP3 inflammasome plays a critical role in the secretion of IL-1β, and there is significant evidence that it is involved in the pathogenesis of a number of inflammatory diseases including atherosclerosis. Recent studies demonstrate that particular cell surface receptors namely the scavenger receptor CD36 and the endocannabinoid receptor CB1 are involved in the activation and regulation of the NLRP3 inflammasome and they have also been implicated in the pathogenesis of atherosclerosis. The present study aimed to investigate expression and activation levels of the NLRP3 inflammasome, the CD36 and CB1 receptors in blood samples obtained from patients with atherosclerosis at very high risk of a Major Adverse Cardiac Event (MACE) such as a heart attack. The cell signalling processes involved in NLRP3 inflammasome activation were also investigated in a THP1 in vitro model of atherosclerosis. Results to date indicate increased expression of NLRP3 in patients at very high risk of MACE and also demonstrate that THP1 macrophages require both the CD36 and CB1 receptors for optimal NLRP3 expression in response to oxidized LDL. These preliminary findings provide an insight into the mechanism of action of the NLRP3 inflammasome in atherosclerosis and prompt further exploration of this protein complex and its regulatory receptors as potential targets for prognostic and or therapeutic development in the strive towards a more personalised approach to the management of coronary artery disease., Approximately 30% of patients with epilepsy are refractory to anti-epileptic drug (AED) treatment and continue to have debilitating seizures that severely impact upon their quality of life. Exome sequencing in encephs etc has illustrated the importance of de-novo variants in the pathogenesis of rare neurological disorders. However, the contribution of de-novo mutations to pharmacoresistance in adult epilepsy is uncertain. In this study we investigated whether a trio whole exome sequencing paradigm could be applied to identify genetic causes of chronic, refractory epilepsy. We selected adult patients (n=5) with onset of seizures after 5 years of age, had failed ≥6 AEDs and were still experiencing >4 disabling seizures per month. Patients were excluded if they had a potentially ‘explanatory’ lesion on MRI. Parents were exome sequenced to identify de-novo mutations and these were assessed bioinformatically for pathogenicity. We confirmed the presence of coding de-novo mutations that were bioinformatically predicted to be functional and damaging in 3/5 patients. One of these occurred in the gene DNM1L, which was recently implicated in pharmacoresistant epilepsy (Vanstone et al. EJHG, 2015;Nov 25). This represents a potential diagnostic yield of 20% however more data is required and more trios are currently being sequenced. We have demonstrated the potential diagnostic yield of whole exome sequencing in a small number of adult patients with chronic refractory epilepsy. Identifying genetic mutations underpinning this disorder may provide new insight into the underlying biology and offers the potential for therapeutic intervention in the form of precision medicine., IgA nephropathy (IgAN) is the most common form of glomerular nephritis worldwide1. Difference in incidences between ethnicities and familial inheritance patterns indicate this is a genetic disorder. An IgAN locus on chromosome 6q22-23 was identified via linkage analysis; however the causal gene remains elusive2. We set out to identify mutations underlying familial IgAN using whole exome sequencing. DNA was collected on 25 (unaffected and affected) individuals across 6 families with IgAN. Families were chosen on the basis of having at least 2 affected members with IgAN. We carried out full exome sequencing on 12 of the affected members from these families. Depending on the pattern of inheritance in a given family, mutations that fitted a dominant, recessive or compound heterozygote model of inheritance were screened for. These variants were then filtered based on being shared between affected individuals within a family, their minor allele frequency, region, function and predicted deleterious nature. We identified a number of potential candidate mutations in these families and including a mutation in the gene COL4A5 which was previously described as pathogenic3. Mutations in COL4A5 have previously been found in individuals with Alport syndrome, a disease which is often mistaken for IgAN. We are currently working to confirm these candidate mutations via Sanger sequencing and will be screening for segregation., Atherosclerosis is a chronic inflammatory disorder that is responsible for approximately 71% of incidents of cardiovascular disease. A mathematical model of atherosclerosis has been developed, capturing the cell types and proteins involved in atheroma formation and describing the dynamics of disease progression. This is the first model of this type to be developed using open systems biology standards. We have predicted tertiary protein structures for all the proteins involved in this atherosclerosis model and all of their recorded mutations, using phase 3 sequence data obtained from the 1000 Genomes Project. By comparing the electrostatic potentials of these tertiary structures, we predict how the dynamics of atherosclerosis stratifies across population subgroups., The aim of this pilot study was to test the feasibility of carrying out a large scale study using this design to investigate whether methylation of the oxytocin receptor (OXTR) can serve as a potential biomarker for response to oxytocin administration in women during and after labour. Background Oxytocin is a nine-amino acid peptide with hormonal and neurotransmitter functions during labour and lactation. We hypothesised that a difference in methylation levels of the oxytocin receptor (OXTR) gene may impact the woman’s ability to become established in labour and her response to oxytocin administration. Method Blood samples were taken pre-birth and postnatally from 21 women and subjected to DNA methylation analysis of the OXTR gene by pyrosequencing. Methylation status of CpG sites -924 and -934 upstream from the initiation transcription site (ITS) of the OXTR gene was determined. Expression of the OXTR gene before and after birth was measured using qPCR. Global methylation levels were examined using Luminometric Methylation Assay (LUMA). Results We found both hypo and hypermethylation of OXTR promoter at CpG sites -924 and -934 in individual samples, however we observed no profound changes in overall OXTR methylation levels within the patient cohort at these CpG sites. We found a strong correlation between OXTR promoter methylation levels found in whole blood and those found in matched PMBC samples. Global methylation analysis using Luminometric Methylation Assay (LUMA) revealed no significant differences between whole blood and PMBC. Conclusions A larger sample is required to determine whether OXTR methylation status is predictive of response to oxytocin administration. Whole blood sampling is a suitable alternative for OXTR methylation analysis in a larger cohort of women undergoing labour., Background Cardiovascular disease (CVD) is the leading cause globally of morbidity and mortality. microRNAs (miRNAs) are small, non-coding RNAs which have a fundamental role in the pathology of various diseases including CVD. Circulating serum levels of miRNAs have been proposed as potentially valuable markers of heart failure, stroke, myocardial infarction and arterial hypertension, but the specific miRNAs involved and their function remains unclear. Therefore, this pilot study aims to profile miRNA expression in premature CVD patients to identify which miRNAs correlate best with hypertension. Methods The Multiplex Circulating miRNA Assay with Firefly™ Particle Technologies was used to profile 68 miRNAs on a cardiology focus panel in serum samples from 170 premature CVD patients recruited from Altnagelvin Area Hospital and screened for the C677T polymorphism in methylenetetrahydrofolate reductase, a risk factor for hypertension. Samples were collected at baseline and following intervention with riboflavin, a co-factor for MTHFR, which significantly lowers blood pressure specifically in adults with this polymorphism. Statistical analysis was used to correlate miRNA expression with blood pressure, MTHFR genotype and other relevant clinical data. Results The assay successfully measured miRNA expression in the sample set. miRNAs which expressed differentially between MTHFR genotype groups were highlighted and the functional significance of these miRNAs was assessed using bioinformatics to identify target genes involved in CVD. Conclusions The data provides further evidence that using specific miRNAs as serum markers could aid early prediction of CVD and may lead to better diagnostic modalities and therapeutic regimes., Gene-environment interactions, particularly in genes related to regulation of serotonin and neuronal function, have been implicated in the aetiology of depression. Allelic variations in the 5’ flanking transcriptional region of the serotonin transporter gene (5-HTTLPR) and higher levels of promoter DNA methylation are associated with depression. Brain derived neurotrophic factor (BDNF) plays an important role in neuronal differentiation and survival, and is also involved in regulation of serotonin. A single nucleotide polymorphism in the BDNF gene, leading to a valine to methionine substitution at codon 66 (Val66Met), and increased methylation of the BDNF promoter have also been associated with depression. The goal of this study is to determine whether length of the 5-HTTLPR, prevalence of the Val66Met polymorphism of the BDNF gene and DNA methylation in both 5-HTT and BDNF promoter regions are associated with depression in the student population. First year students provided a saliva sample for genetic analysis and completed an online mental health survey. Presence and severity of depression was determined from survey responses based on DSM-IV criteria. Length of the 5-HTTLPR was determined by PCR and gel electrophoresis and presence of the SNP at BDNF rs6265 and examined using restriction fragment length polymorphism analysis. Bisulphite-treated DNA was amplified by PCR and pyrosequencing assays used to determine methylation patterns of BDNF and SERT. Our preliminary findings suggest that genetic and epigenetic variation in the 5HTT and BDNF genes are associated with depression in the student population and may be candidate biological markers to assist in diagnosis., BACKGROUND Prostate cancer is the most common male cancer in the UK, where it kills approximately 11,000 men annually. There has been growing interest in the role played by the anaerobic bacterium Propionibacterium acnes, an important component if the skin microflora, in the aetiology of the condition via a chronic, asymptomatic infection of the prostate leading to oncogenesis. METHODS A quantitative real-time PCR (qRT-PRC) assay for retrospective detection of P. acnes in formalin-fixed paraffin embedded sections from archived prostate samples was developed. An in vitro infection model of prostate infection with P. acnes is being optimised, which should allow us to get insight into the dysregulation P. acnes infection causes in prostate epithelial cells. RESULTS A total of 81 biopsy samples, representing one or both prostate lobes, were examined from 53 patients with prostate carcinoma, versus 111 samples from 60 patients whose biopsies were histologically normal, and the assay revealed that 35% of cancerous prostate samples were positive for the presence of P. acnes, compared with only 8% of the disease-free samples (p, Oral squamous cell carcinoma (OSCC) is one of the top ten most prevalent cancers in the world. Prognosis is poor and quality of life is commonly reduced for patients who survive. OSCC is thought to progress via a premalignant stage called dysplasia. Effective treatment of dysplasia prior to malignant transformation, or the ability to more accurately predict the 10-20% of dysplasias that will progress to OSCC, is an unmet clinical need. With the aim to better understand the biology of OSCC development, and attempt to identify potential markers of early disease and therapeutic targets, we performed parallel whole exome sequencing and total RNA sequencing on 16 micro-dissected formalin-fixed paraffin embedded dysplasia and their associated OSCC. These are the largest omic analyses on matched patient samples from the oral cavity in non-HPV infected patients where all dysplasias are associated with progression to OSCC, that has been performed to date. Whole exome analysis revealed that every OSCC and adjacent associated dysplasia sample did have a common clonal ancestor, with many shared potential drivers of progression, but that there is also considerable genomic heterogeneity between associated pre-invasive and invasive disease, as seen in a previous study1. RNAseq analysis revealed differences in the immune cell signatures present at different disease stages, distinguished early events in pathogenesis from later events and identified several novel coding and non-coding candidates with potential involvement in oral dysplasia development and malignant transformation. These findings merit further investigation in a larger retrospective longitudinal study of patients with oral dysplasia., Many disorders involving tissues, which have significant energy requirements, involve mitochondrial dysfunction often due to mutations affecting the mitochondrial genome. Some such mutations can involve genes coding for subunits of complex I of the electron transport chain leading to a complex I deficiency in disorders such as Leber Hereditary Optic Neuropathy (LHON) amongst others. Mitochondrial dysfunction leads to a lack of energy production and ultimately the death of the cell. In disorders such as LHON, retinal ganglion cells (RGCs) are affected, leading to retinal dysfunction. These observations have prompted interest in exploring innovative therapeutics to modulate mitochondrial disorders involving complex I deficiency. The Farrar laboratory has explored candidate gene therapies for complex I deficiency using Ndi1, a yeast gene which is a complex I homologue. In order to test the efficacy of candidate therapies, we have developed a robust, empirical assay of mitochondrial function. Previous assays measured the level of NADH oxidation in a sample, both before and after rotenone as a measure of complex I activity. To optimally distinguish between the activity of complex I and the potential therapeutic, the assay was modified with the addition of a second inhibitor which allowed specific measurement of the therapeutic, such as Ndi1. Given that this is an in vitro assay, it enables large-scale screening of potential therapeutics and ensures only those that show strong evidence of efficacy are then tested in vivo. In combination with other quantitative assays such as Reactive Oxygen Species (ROS) generation this allows detailed evaluation of the health of mitochondria within a sample., Schizophrenia is an adult-onset mental illness with that impacts cognitive function. The largest GWAS has revealed 108 loci associated with schizophrenia risk but how variation affects genes and impacts brain function to increase risk is largely unknown. The centrosome is the microtubule organising centre of the cell and seeds the growth of the primary cilium. The disproportionate number of brain disorders associated with centrosomal genes suggests the organelle underlies normal brain and cognitive development. Schizophrenia is neurodevelopmental and cognitive deficits are a core element of the disorder. We hypothesise that some of the newly identified risk genes for schizophrenia will function in the centrosome and variants in these genes will be associated with cognitive deficits. Cross-referencing genes with centrosomal functions with genes from schizophrenia GWAS, identified six candidate genes; SDCCAG8, MAD1L1, GIGYF2, MPHOSPH9, PRKD1 and MAPK3. The effect of risk SNPs on cognition was examined using an Irish dataset of psychosis cases and controls (n=1,236) using linear regression. Among the associations identified, the SDCCAG8 risk SNP was shown to affect attribution style, a measure of social cognition (P=0.001). The MAD1L1 risk SNP was associated with poorer performance on episodic memory tasks (P=0.003). A suitable replication dataset was not available for social cognition measures. We attempted replication for episodic memory results in UK and German samples but results were non-significant. Overall, we have identified a number of schizophrenia risk genes that function in the centrosome but further larger datasets are required to establish a role for these genes in cognition., Epigenetic mechanisms are an important heritable and dynamic means of regulating various genomic functions, including gene expression to orchestrate brain development. These processes when perturbed are thought to contribute to schizophrenia (SZ). A core feature of SZ is cognitive dysfunction. GWAS have identified 108 genomic loci associated with SZ risk, containing 350 genes. My aim was to identify genes that have epigenetic functions which map to loci associated with SZ, and to test the associated SNPs for association with cognitive deficits. Risk SNPs in 8 genes: BCL11B, CHD7, EP300, EPC2, GATAD2A, KDM3B, RERE and SATB2 were analysed using an Irish dataset of psychosis cases and controls (n=1235) who had completed tests across 5 cognitive domains. Five of the eight variants had significant associations with at least one cognitive task. Strongest associations were for CHD7 (rs6984242) for IQ (p=0.001) and episodic memory (p=0.007). These results did not replicate in independent samples. We link rs6984242 to CHD7 via a long range expression quantitative trait loci (eQTL) and CHD7 has not been previously reported as a candidate risk gene for SZ. To further explore its novel association with SZ, we identified a set of 45 interacting genes and used SNPs across these genes to develop a polygenic risk score for SZ, independent of CHD7 itself. This score was tested for association with cognitive function. Significant associations(p, The relevance of nutrition and other environmental influences on epigenetic modifications including DNA methylation is a topic of considerable interest. Folate One Carbon Metabolism (FOCM) is the principal supplier of the methyl groups required for DNA methylation, giving folate status a strong biological plausibility of having an impact on an individual’s and an offspring’s DNA methylation profile at both the mitotic and meiotic level. We sought to identify DNA methylation sites in the human genome that are sensitive to folate status i.e., Folate-sensitive Differentially Methylated Regions (FS-DMR) using a folic acid intervention trial in pregnant women known as FASSTT (Folic Acid Supplementation in the Second and Third Trimesters). To minimize the amount of DNA methylation ‘noise’ due to non-folate related factors such as other environmental stimuli and individual genetic variation, we compared the DNA methylation profile of the same individual pre- and post- intervention to identify putative FS-DMR. We selected six healthy pregnant women, three from the folic acid intervention arm and three from the placebo arm of the trial. We performed MeDIP (Methylated DNA Immunoprecipitation) on all 12 samples and hybridized to a Roche Nimblegen Delux 2.1M promoter array. While we observed DNA methylation changes pre- and post- folic acid intervention in each individual, the actual DNA methylation sites were not consistent across all three individuals. Of course, it is possible that a more in-depth Next Generation Sequencing approach might yield our elusive FS-DMRs. However, the published literature to date does not appear to support such a promise., The loss of retinal ganglion cells (RGCs) is a hallmark of a number of retinopathies. There are a number of gene therapies being developed that have shown efficacy in preserving RGCs when administered using an AAV vector. Localising expression of any therapeutic to the target cell type (ganglion cell layer, GCL) would represent a significant optimisation of the approach. The packaging capacity of AAV (4.7kb) imposes a limit on the size of promoters and genes relevant for AAV-mediated gene delivery. Few GCL-specific promoter sequences have been defined of a size suitable for use in AAV-guided gene expression. Exploring this, a panel of genes was chosen with GCL-limited expression profiles. A pipeline program was developed that analysed regions upstream of these genes for sequence conservation across placental mammals (as a proxy for putative promoter function), weighted by enriched GCL expression levels. Adopting this strategy, ganglion cell promoter 1 (GCP1), demonstrating the key features outlined above, was identified. To test its function, GCP1 (2.2kb in size) was engineered into an AAV2 virus expressing EGFP. Here we demonstrate the effectiveness of GCP1 in localising EGFP expression to the GCL when administered via intravitreal injection. Furthermore, absence of EGFP expression was demonstrated when targeted towards photoreceptors via subretinal injection, verifying GCP1 tissue-specificity. Expression of AAV2.GCP1-EGFP was compared to expression from a non-specific promoter construct, AAV2.CMV-EGFP. GCP1-EGFP was shown to provide equivalent expression to CMV-EGFP in the GCL. GCP1 thus offers a tissue-specific promoter option, suitable for deployment within AAV vectors without compromising functionality., Purpose Hypoxia is a common hallmark of the tumour microenvironment. Recently we have shown the anti-androgen bicalutamide induces profound hypoxia in prostate tumours in vivo. This resulted in the promotion of epithelial to mesenchymal transition. Here we target tumour hypoxia using a novel unidirectional hypoxia-activated prodrug OCT1002 to enhance the anti-tumour effect of bicalutamide. Experimental Design The effect of OCT1002 treatment on LNCaP-luc cells was measured in normoxia and hypoxia in vitro. In vivo, tumour growth and lung metastases were measured in mice treated with bicalutamide, OCT1002 or a combination. Dorsal skin fold chambers were used to image tumour vasculature in vivo. Longitudinal genetic changes in tumours were analysed using PCR. Results Reduction of OCT1002 to its active form (OCT1001) decreased LNCaP-luc cell viability. In LNCaP-luc spheroids, OCT1002 caused increased apoptosis and decreased clonogenicity. In vivo, treatment with OCT1002 alone or with bicalutamide, showed significantly greater tumour growth control and reduced lung metastases compared to controls. Re-establishment of the tumour vasculature following bicalutamide-induced vascular collapse is inhibited by OCT1002. Significantly, the up-regulation of RUNX2 and its targets caused by bicalutamide alone were also blocked by OCT1002. Conclusions OCT1002 selectively targets hypoxic tumour cells and enhances the anti-tumour efficacy of bicalutamide. Furthermore, bicalutamide causes changing genetic profiles during treatment, with development of a more malignant genotype; OCT1002 can block this effect. This study indicates that more attention should be attached to understanding genetic changes that may occur during treatment. Early targeting of hypoxic cells with OCT1002 can provide a means of inhibiting prostate tumour growth and malignant progression., Background In prostate cancer (PCa), abnormal expression of several microRNAs (miRNAs) has been previously reported. Increasing evidence shows that aberrant epigenetic regulation is a contributing factor to their altered expression in cancer. In this study we investigate whether expression of miR-200c and miR-141 in PCa is related to the DNA methylation status of their promoter. Methods PCR analysis of miR-200c and miR-141, and CpG methylation analysis of their common promoter, was performed in PCa cell-lines and in FFPE prostate biopsy specimens. The functionality of miR-200c and miR-141 expression in prostate cancer cells was assessed by a series of in vitro bioassays. Results miR-200c and miR-141 expression correlates inversely with the methylation status of the miR-200c/miR-141 promoter in PCa cells. In PC3 cells, miR-200c and miR-141 expression is elevated by treatment with the demethylating agents suggesting their expression is linked to methylation. Expression of miR-200c and miR-141 in prostate biopsy tissue was inversely correlated with methylation in CpG sites closest to the miR-200c/miR-141 loci. Over-expression of miR-200c in PC3 cells inhibited growth and clonogenic potential, as well as inducing apoptosis. Expression of the genes DNMT3A and TET1/TET3 were down-regulated by miR-200c and miR-141 respectively. Finally, treatment with the soy isoflavone genistein caused demethylation of the promoter CpG sites closest to the miR-200c/miR-141 loci resulting in increased miR-200c expression. Conclusions Our findings provide evidence that miR-200c and miR-141 are under epigenetic regulation in PCa cells. Profiling their expression and methylation status may have potential in the improved diagnosis and prognosis of PCa., Increasingly accurate surveys of human health throughout the life course has led experts to propose that stresses on the child while still in the mother’s womb can affect the individual’s health much later in life. Such long-term effects on health are thought to be mediated by a semi-permanent trace on the genes of the affected person called an epigenetic mark. Epigenetic mechanisms, such as DNA methylation, are dynamic during pregnancy whereby epigenetic marks are seeded which persist throughout the lifetime of the developing child. It has been suggested that these patterns may be altered by the mother’s diet, particularly folate – a key component in the DNA methylation cycle. Currently, mothers are universally recommended to supplement their diet with 400μg folic acid/day as a preventative measure against neural tube defects in the offspring prior to and during the first trimester. However, there remains no clinical recommendation as to whether mothers should continue supplementation during the final two trimesters and the potentially heritable effects on DNA methylation. Observational studies have suggested that folate-rich maternal diets are associated with changes in DNA methylation of the child during this period of gestation. We present here the results of a randomised control trial (FASSTT study) examining the effects of folic acid supplementation in late gestation (week 12 onwards) on DNA methylation of several gene classes in offspring cord blood samples. We report small but significant sex-specific differences between the two intervention groups. These preliminary results indicate that folic acid supplementation throughout pregnancy may exert significant effects on cord blood DNA methylation., Introduction New-onset diabetes after transplantation (NODAT) is a common complication of kidney transplantation which increases risk of subsequent graft failure, cardiovascular complications and death. NODAT is defined as the new requirement for oral hypoglycaemic agents or insulin as a result of hyperglycaemia after renal transplant. The first genome wide association study (GWAS) for NODAT was published by our group in 2014; seven of the eight top-ranked, common SNPs are implicated in β-cell apoptosis. Methods To further understand the genetic architecture of the NODAT phenotype we used whole exome sequencing for 134renal transplant recipients from a Northern Ireland renal transplant cohort. We sequenced 53 individuals with NODAT (cases)and 81 transplant recipients without NODAT (controls). Library preparation was performed using the Ion TargetSeq™ Exome Kit with samples sequenced on an Ion Torrent Proton sequencer. TheIon OneTouch 2 for emulsion PCR and Ion Enrichment System were used. Association analysis was performed using PLINK Version 1.9 to identify variants associated with NODAT (with age and weight at transplant included in the regression model). Results Following appropriate quality control, initial analysis identified 6 variants nominally associated with NODAT (Ptrend, The Irish Traveller community has a high incidence of autosomal recessive (AR) disorders due to consanguinity. The Division of Molecular Genetics at the DCG offers genetic testing, primarily to members of this community, for five specific pathogenic mutations found in five AR disorders. The pathogenic mutations are detected by bi-directional Sanger sequencing and the service includes: Gene Disorder/ Disease Phenotype LARS (leucyl-tRNA synthetase) Infantile Liver Failure Syndrome 1 (ILFS1) Infantile hepatopathy with failure to thrive (FTT) and developmental delay. MCM4 (minichromosome maintenance 4) Natural Killer Cell & Glucocorticoid Deficiency with DNA Repair Defect (NKGCD) FTT, adrenocorticotropin hormone (ACTH) resistance, familial glucocorticoid deficiency (FGD), mosaic Fanconi anaemia and recurrent infections due to NK cell deficiency. STRA6 (stimulated by retinoic acid 6 gene) Autosomal recessive isolated colobomatous microanopthalmia (MCOPS9) Microphthalmia, anophthalmia, coloboma.Specific STRA6 mutation can also cause the Matthew-Wood syndrome [anophthalmia/ severe microphthalmia, with pulmonary hypoplasia/ aplasia] LEPRE1 (Leucine-and proline-enriched proteoglycan 1)syn. PH31(prolyl-3-hydroxylase-1) Type VIII Osteogenesis Imperfecta, Variable phenoptype of bone fragility, susceptibility to fracture, short stature, bowing of the long bones and can be perinatally lethal. ATP8B1 (ATPase, Class I, Type 8B, Member1) Progressive Familial Intrahepatic Cholestasis type 1 (PFIC1) syn. Byler disease Hepatic and systemic accumulation of bile acids, hepatic fibrosis, end-stage liver disease and growth retardation. This study will detail (1) the service offered to users, (2) an audit of the test requests received over the last two years, (3) the challenges encountered in offering this unique service and (4) some interesting family pedigrees., Background Hypoxia in prostate tumours has been linked with promotion of disease progression and metastasis. miR-210 is a microRNA which is apparently affected by hypoxia, but this relationship has not been extensively studied in a prostate cancer setting. Therefore, in this study, we investigate the link between hypoxia and miR-210 in prostate cancer cells. Methods We have used 2D and 3D cell prostate cell models of hypoxia to investigate the functionality of miR-210. Expression levels of miR-210 have been measured by qPCR and functional bioassays used to examine its effect on prostate cell behaviour. Target genes have been identified and bioinformatic analysis has been employed to investigate a clinical significance for miR-210 in prostate cancer. Results miR-210 is induced by hypoxia in prostate cancer cell-lines. Over-expression of miR-210 impacts upon target genes, including SP1 and TPD52, which in turns affects cell proliferation. Data-mining of online repositories of clinical data and bioinformatic analysis of miR-210 cellular networks reveal that miR-210 plays a key role in a number of important cell processes, the dysregulation of which can lead to development of prostate cancer. Conclusions We propose that miR-210 could be an important microRNA in the pathogenesis of prostate cancer and has potential as a biomarker in this disease.
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- 2017
9. Germline and Somatic NF1 Gene Mutation Spectrum in NF1-Associated Malignant Peripheral Nerve Sheath Tumors (MPNSTs)
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Upadhyaya, M., Kluwe, Lan, Spurlock, G., Monem, Bisma, Majounie, E., Mantripragada, K., Ruggieri, Martino, Chuzhanova, N., Evans, D. G., Ferner, R., Thomas, N., Guha, A., and Mautner, V.
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- 2008
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10. Detection of copy number changes at the NF1 locus with improved high-resolution array CGH
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Shen, M H, Mantripragada, K, Dumanski, J P, Frayling, I, and Upadhyaya, M
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- 2007
11. Identification of novel deletion breakpoints bordered by segmental duplications in the NF1 locus using high resolution array-CGH
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Mantripragada, K K, Thuresson, A-C, Piotrowski, A, Díaz de Ståhl, T, Menzel, U, Grigelionis, G, Ferner, R E, Griffiths, S, Bolund, L, Mautner, V, Nordling, M, Legius, E, Vetrie, D, Dahl, N, Messiaen, L, Upadhyaya, M, Bruder, C E G, and Dumanski, J P
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- 2006
12. Associations between polygenic risk for schizophrenia and brain function during probabilistic learning in healthy individuals
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Lancaster, T.M., Ihssen, N., Brindley, L.M., Tansey, K.E., Mantripragada, K., O'Donovan, M.C., Owen, M.J., and Linden, D.E.J.
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mental disorders ,behavioral disciplines and activities - Abstract
A substantial proportion of schizophrenia liability can be explained by additive genetic factors. Risk profile scores (RPS) directly index risk using a summated total of common risk variants weighted by their effect. Previous studies suggest that schizophrenia RPS predict alterations to neural networks that support working memory and verbal fluency. In this study, we apply schizophrenia RPS to fMRI data to elucidate the effects of polygenic risk on functional brain networks during a probabilistic-learning neuroimaging paradigm. The neural networks recruited during this paradigm have previously been shown to be altered to unmedicated schizophrenia patients and relatives of schizophrenia patients, which may reflect genetic susceptibility. We created schizophrenia RPS using summary data from the Psychiatric Genetic Consortium (Schizophrenia Working Group) for 83 healthy individuals and explore associations between schizophrenia RPS and blood oxygen level dependency (BOLD) during periods of choice behavior (switch–stay) and reflection upon choice outcome (reward–punishment). We show that schizophrenia RPS is associated with alterations in the frontal pole (PWHOLE-BRAIN-CORRECTED = 0.048) and the ventral striatum (PROI-CORRECTED = 0.036), during choice behavior, but not choice outcome. We suggest that the common risk variants that increase susceptibility to schizophrenia can be associated with alterations in the neural circuitry that support the processing of changing reward contingencies.
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- 2016
13. DISCUSSION.
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MANTRIPRAGADA, K.
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RISK assessment ,RISK management in business ,FINANCIAL leverage ,FINANCIAL planning ,CORPORATE finance ,RESEARCH evaluation ,FINANCE - Abstract
The article presents commentary and criticism on the financial reports "The Effect of Leverage on the Cost of Equity Capital of Electric Utility Firms," by Alexander A. Robichek, Robert C. Higgins, and Michael Kinsman; "Corporate Financial Strategies and Market Measures of Risk and Return," by William J. Breen and Eugene M. Lerner; and "An Operational Approach to Risk-Screening," by Richard S. Bower and Donald R. Lessard, all included within the issue and addressing risk analysis within various corporate financial contexts. Criticism is given regarding certain conclusions and methodologies used by the reports.
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- 1973
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14. Nonengraftment donor lymphocyte infusions for refractory acute myeloid leukemia
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Reagan, J L, primary, Fast, L D, additional, Nevola, M, additional, Mantripragada, K, additional, Mulder, A, additional, Claas, F H J, additional, Rosati, K, additional, Schumacher, A, additional, Safran, H, additional, Young, C T, additional, Quesenberry, M I, additional, Winer, E S, additional, Butera, J N, additional, and Quesenberry, P J, additional
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- 2015
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15. Genetically predicted complement component 4A expression: effects on memory function and middle temporal lobe activation.
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Donohoe, G., Holland, J., Mothersill, D., McCarthy-Jones, S., Cosgrove, D., Harold, D., Richards, A., Mantripragada, K., Owen, M. J., O'Donovan, M. C., Gill, M., Corvin, A., and Morris, D. W.
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COGNITION ,GENE expression ,NEUROPSYCHOLOGICAL tests ,MEMORY ,SCHIZOAFFECTIVE disorders ,SCHIZOPHRENIA ,DATA analysis software ,DESCRIPTIVE statistics - Abstract
Background: The longstanding association between the major histocompatibility complex (MHC) locus and schizophrenia (SZ) risk has recently been accounted for, partially, by structural variation at the complement component 4 (
C4 ) gene. This structural variation generates varying levels ofC4 RNA expression, and genetic information from the MHC region can now be used to predictC4 RNA expression in the brain. Increased predictedC4A RNA expression is associated with the risk of SZ, andC4 is reported to influence synaptic pruning in animal models. Methods: Based on our previous studies associating MHC SZ risk variants with poorer memory performance, we tested whether increased predictedC4A RNA expression was associated with reduced memory function in a large (n = 1238) dataset of psychosis cases and healthy participants, and with altered task-dependent cortical activation in a subset of these samples. Results: We observed that increased predictedC4A RNA expression predicted poorer performance on measures of memory recall (p = 0.016, corrected). Furthermore, in healthy participants, we found that increased predictedC4A RNA expression was associated with a pattern of reduced cortical activity in middle temporal cortex during a measure of visual processing (p < 0.05, corrected). Conclusions: These data suggest that the effects ofC4 on cognition were observable at both a cortical and behavioural level, and may represent one mechanism by which illness risk is mediated. As such, deficits in learning and memory may represent a therapeutic target for new molecular developments aimed at alteringC4 ’s developmental role. [ABSTRACT FROM AUTHOR]- Published
- 2018
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16. Replication study implicatesCOMTval158met polymorphism as a modulator of probabilistic reward learning
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Lancaster, T. M., primary, Heerey, E. A., additional, Mantripragada, K., additional, and Linden, D. E. J., additional
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- 2015
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17. Supporting the Scheduling over Local HPC and Cloud Platforms: An FWI Case Study
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Binotto, A.P.D., primary, Tizzei, L.P., additional, Mantripragada, K., additional, and Netto, M.A.S., additional
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- 2015
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18. CACNA1C risk variant affects reward responsiveness in healthy individuals
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Lancaster, T M, primary, Heerey, E A, additional, Mantripragada, K, additional, and Linden, D E J, additional
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- 2014
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19. Enabling high-resolution forecasting of severe weather and flooding events in Rio de Janeiro
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Treinish, L. A., primary, Praino, A. P., additional, Cipriani, J. P., additional, Mello, U. T., additional, Mantripragada, K., additional, Villa Real, L. C., additional, Sesini, P. A., additional, Saxena, V., additional, George, T., additional, and Mittal, R., additional
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- 2013
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20. Germline and somaticNF1 gene mutation spectrum in NF1-associated malignant peripheral nerve sheath tumors (MPNSTs)
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Upadhyaya, M., primary, Kluwe, Lan, additional, Spurlock, G., additional, Monem, Bisma, additional, Majounie, E., additional, Mantripragada, K., additional, Ruggieri, Martino, additional, Chuzhanova, N., additional, Evans, D.G., additional, Ferner, R., additional, Thomas, N., additional, Guha, A., additional, and Mautner, V., additional
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- 2007
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21. Copy-number polymorphisms: mining the tip of an iceberg
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BUCKLEY, P, primary, MANTRIPRAGADA, K, additional, PIOTROWSKI, A, additional, DIAZDESTAHL, T, additional, and DUMANSKI, J, additional
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- 2005
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22. Identification of novel deletion breakpoints bordered by segmental duplications in the NF1 locus using high resolution array-CGH
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Mantripragada, K K, primary
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- 2005
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23. Capital Management and Capital Theory: Discussion
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Mantripragada, K
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- 1973
24. Deletions at 22q11.2 in idiopathic Parkinson's disease: A combined analysis of GWAS data
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Mok, K. Y., Sheerin, U., Simon-Sanchez, J., Salaka, A., Chester, L., Escott-Price, V., Mantripragada, K., Doherty, K. M., Noyce, A. J., Mencacci, N. E., Lubbe, S. J., Williams-Gray, C. H., Barker, R. A., Dijk, K. D., Berendse, H. W., Heutink, P., Corvol, J. -C, Cormier, F., Lesage, S., Alexis Brice, Brockmann, K., Schulte, C., Gasser, T., Foltynie, T., Limousin, P., Morrison, K. E., Clarke, C. E., Sawcer, S., Warner, T. T., Lees, A. J., Morris, H. R., Nalls, M. A., Singleton, A. B., Hardy, J., Abramov, A. Y., Plagnol, V., Williams, N. M., and Wood, N. W.
25. Advances in cellular therapy for the treatment of leukemia
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Mantripragada K, John Reagan, Pj, Quesenberry, and Ld, Fast
26. Erratum: Genome-wide common and rare variant analysis provides novel insights into clozapine-associated neutropenia
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Legge, S E, Hamshere, M L, Ripke, S, Pardinas, A F, Goldstein, J I, Rees, E, Richards, A L, Leonenko, G, Jorskog, L F, Chambert, K D, Collier, D A, Genovese, G, Giegling, I, Holmans, P, Jonasdottir, A, Kirov, G, McCarroll, S A, MacCabe, J H, Mantripragada, K, Moran, J L, Neale, B M, Stefansson, H, Rujescu, D, Daly, M J, Sullivan, P F, Owen, M J, O'Donovan, M C, and Walters, J T R
- Abstract
Correction to: Molecular Psychiatry (2017) 22: 1502-1508; advance online publication, 12 July 2017; doi: 10.1038/mp.2016.97 In the first paragraph of the Results section and Figure 1, the authors incorrectly referred to the finding of SNP rs77897117. The correct SNP is rs77897177. The corrected figure appears in previous page.
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- 2018
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27. DISCUSSION
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Elton, Edwin J., primary and Mantripragada, K., additional
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- 1973
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28. MiR-137-derived polygenic risk: effects on cognitive performance in patients with schizophrenia and controls.
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Cosgrove, D, Harold, D, Mothersill, O, Anney, R, Hill, M J, Bray, N J, Blokland, G, Petryshen, T, Richards, A, Mantripragada, K, Owen, M, O'Donovan, M C, Gill, M, Corvin, A, Morris, D W, and Donohoe, G
- Published
- 2017
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29. Erratum: Genome-wide common and rare variant analysis provides novel insights into clozapine-associated neutropenia
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Legge, S E, Hamshere, M L, Ripke, S, Pardinas, A F, Goldstein, J I, Rees, E, Richards, A L, Leonenko, G, Jorskog, L F, Chambert, K D, Collier, D A, Genovese, G, Giegling, I, Holmans, P, Jonasdottir, A, Kirov, G, McCarroll, S A, MacCabe, J H, Mantripragada, K, Moran, J L, Neale, B M, Stefansson, H, Rujescu, D, Daly, M J, Sullivan, P F, Owen, M J, O'Donovan, M C, and Walters, J T R
- Abstract
Correction to: Molecular Psychiatry advance online publication, 12 July 2016; doi:10.1038/mp.2016.97 The ninth author’s name was presented incorrectly. It should have been listed as LF Jarskog.
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- 2017
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30. Comprehensive genetic and epigenetic analysis of sporadic meningioma for macro-mutations on 22q and micro-mutations within the NF2 locus
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Jarbo Caroline, Mantripragada Kiran, Hellström Anders R, Piotrowski Arkadiusz, Grigelioniene Giedre, Buckley Patrick G, Hansson Caisa M, Mathiesen Tiit, and Dumanski Jan P
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Biotechnology ,TP248.13-248.65 ,Genetics ,QH426-470 - Abstract
Abstract Background Meningiomas are the most common intracranial neoplasias, representing a clinically and histopathologically heterogeneous group of tumors. The neurofibromatosis type 2 (NF2) tumor suppressor is the only gene known to be frequently involved in early development of meningiomas. The objective of this study was to identify genetic and/or epigenetic factors contributing to the development of these tumors. A large set of sporadic meningiomas were analyzed for presence of 22q macro-mutations using array-CGH in order to identify tumors carrying gene dosage aberrations not encompassing NF2. The NF2 locus was also comprehensively studied for point mutations within coding and conserved non-coding sequences. Furthermore, CpG methylation within the NF2 promoter region was thoroughly analyzed. Results Monosomy 22 was the predominant finding, detected in 47% of meningiomas. Thirteen percent of the tumors contained interstitial/terminal deletions and gains, present singly or in combinations. We defined at least two minimal overlapping regions outside the NF2 locus that are small enough (~550 kb and ~250 kb) to allow analysis of a limited number of candidate genes. Bialleinactivationo the NF2 gne was detected in 36% of meningiomas. Among the monosomy 22 cases, no additional NF2 mutations could be identified in 35% (17 out of 49) of tumors. Furthermore, the majority of tumors (9 out of 12) with interstitial/terminal deletions did not have any detectable NF2 mutations. Methylation within the NF2 promoter region was only identified at a single CpG site in one tumor sample. Conclusion We confirmed previous findings of pronounced differences in mutation frequency between different histopathological subtypes. There is a higher frequency of biallelic NF2 inactivation in fibroblastic (52%) compared to meningothelial (18%) tumors. The presence of macro-mutations on 22q also shows marked differences between fibroblastic (86%) and meningothelial (39%) subtypes. Thus, inactivation of NF2, often combined with the presence of macro-mutation on 22q, is likely not as important for the development of the meningothelial subtype, as opposed to the fibroblastic form. Analysis of 40 CpG sites distributed within 750 bp of the promoter region suggests that NF2 promoter methylation does not play a major role in meningioma development.
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- 2007
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31. Array-CGH and multipoint FISH to decode complex chromosomal rearrangements
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Dumanski Jan, Klein George, Mantripragada Kiran, Sandlund Agneta, de Ståhl Teresita, Darai-Ramqvist Eva, Imreh Stefan, and Kost-Alimova Maria
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Biotechnology ,TP248.13-248.65 ,Genetics ,QH426-470 - Abstract
Abstract Background Recently, several high-resolution methods of chromosome analysis have been developed. It is important to compare these methods and to select reliable combinations of techniques to analyze complex chromosomal rearrangements in tumours. In this study we have compared array-CGH (comparative genomic hybridization) and multipoint FISH (mpFISH) for their ability to characterize complex rearrangements on human chromosome 3 (chr3) in tumour cell lines. We have used 179 BAC/PAC clones covering chr3 with an approximately 1 Mb resolution to analyze nine carcinoma lines. Chr3 was chosen for analysis, because of its frequent rearrangements in human solid tumours. Results The ploidy of the tumour cell lines ranged from near-diploid to near-pentaploid. Chr3 locus copy number was assessed by interphase and metaphase mpFISH. Totally 53 chr3 fragments were identified having copy numbers from 0 to 14. MpFISH results from the BAC/PAC clones and array-CGH gave mainly corresponding results. Each copy number change on the array profile could be related to a specific chromosome aberration detected by metaphase mpFISH. The analysis of the correlation between real copy number from mpFISH and the average normalized inter-locus fluorescence ratio (ANILFR) value detected by array-CGH demonstrated that copy number is a linear function of parameters that include the variable, ANILFR, and two constants, ploidy and background normalized fluorescence ratio. Conclusion In most cases, the changes in copy number seen on array-CGH profiles reflected cumulative chromosome rearrangements. Most of them stemmed from unbalanced translocations. Although our chr3 BAC/PAC array could identify single copy number changes even in pentaploid cells, mpFISH provided a more accurate analysis in the dissection of complex karyotypes at high ploidy levels.
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- 2006
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32. Novel Mitochondrial Cytopathy Causing Mitochondrial Encephalomyopathy With Lactic Acidosis and Stroke-Like Episodes Syndrome and Tubulointerstitial Nephropathy.
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Dhawan S, Musa AH, and Mantripragada K
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Mitochondrial cytopathies, predominantly MT-TL1 mutations and, to a lesser extent, MT-ND5, have been associated with mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), manifesting as multi-organ dysfunction. This is just the second instance of MELAS secondary to the pathogenic novel m.13091T>C variant of MT-ND5. Moreover, nephropathy associated with MT-ND5 mutation has only been reported in nine cases so far. A middle-aged man presented in a state of acute confusion with speech difficulty with both receptive and expressive aphasia. He had a background of refractory seizures, chronic atypical migraine, childhood-onset optic neuropathy, and end-stage renal disease requiring renal transplant. During admission, he had episodes of aggression and paranoid beliefs. Magnetic resonance (MR) imaging of the head showed multiple areas of cortical abnormality, unusual for age, including a large frontal infarct crossing arterial boundaries. Cerebrospinal fluid (CSF) protein and lactate were high, whereas, the electroencephalography (EEG) result was normal. Muscle biopsy mitochondrial DNA gene sequencing derived novel MT-ND5 gene variant m.13091T>C p.(Met252Thr). Kidney biopsy previously had shown interstitial fibrosis and tubular atrophy. He was managed as acute ischaemic stroke along with a combination of clobazam, levetiracetam, and eslicarbazepine for seizures. MELAS typically presents with seizures, stroke-like episodes, cortical visual loss, and recurrent migraine headaches. The previous reported case of m.13091T>C mutation followed a similar progression, however, there was no associated nephropathy and normal visual acuity. Kidney transplants in affected patients of MELAS have been associated with a high survival rate. MT-ND5 mutation-associated nephropathy has shown a variable manifestation, either as focal segmental glomerular sclerosis (FSGS) or tubulo-interstitial disease., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Dhawan et al.)
- Published
- 2024
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33. Pain Reduction Using Ropivacaine in Tumescent Solution following Lipoaspiration.
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Mantripragada K, Yerke Hansen P, Vazquez OA, Pires G, and Becker H
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Tumescent solution utilizing dilute epinephrine and a local anesthetic agent injected into a fat compartment has been shown to effectively minimize blood loss and postoperative pain in liposuction. Ropivacaine has a longer duration of action compared to lidocaine and is a potential analgesic in tumescent solution. We sought to explore the effect of using ropivacaine in a tumescent technique with a focus on its efficacy for pain control postoperatively. The formula for the tumescent technique used combined 1 mL of epinephrine with 30 mL of ropivacaine into 500 mL of injectable saline. Tumescent solution was injected manually into fat donor sites of 10 consecutive patients followed by a 20-minute waiting period before beginning fat aspiration with liposuction cannula. Patients were seen immediately following their surgery and on postoperative day 1 and reported their pain using a numerical scale. Data gathered included the amount of ropivacaine used, average pain rating, and the average amount of fat removed. On average, participants reported little to no pain at the donor sites immediately following surgery and on postoperative day 1. Based on the low need for pain medication, we believe that ropivacaine may be successfully used in tumescent solution to reduce postoperative pain., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.)
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- 2023
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34. The effects of spectral dimensionality reduction on hyperspectral pixel classification: A case study.
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Mantripragada K, Dao PD, He Y, and Qureshi FZ
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- Forests, Physical Phenomena, Data Compression methods, Ecosystem
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This paper presents a systematic study of the effects of hyperspectral pixel dimensionality reduction on the pixel classification task. We use five dimensionality reduction methods-PCA, KPCA, ICA, AE, and DAE-to compress 301-dimensional hyperspectral pixels. Compressed pixels are subsequently used to perform pixel classifications. Pixel classification accuracies together with compression method, compression rates, and reconstruction errors provide a new lens to study the suitability of a compression method for the task of pixel classification. We use three high-resolution hyperspectral image datasets, representing three common landscape types (i.e. urban, transitional suburban, and forests) collected by the Remote Sensing and Spatial Ecosystem Modeling laboratory of the University of Toronto. We found that PCA, KPCA, and ICA post greater signal reconstruction capability; however, when compression rates are more than 90% these methods show lower classification scores. AE and DAE methods post better classification accuracy at 95% compression rate, however their performance drops as compression rate approaches 97%. Our results suggest that both the compression method and the compression rate are important considerations when designing a hyperspectral pixel classification pipeline., Competing Interests: The authors have declared that no competing interests.
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- 2022
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35. Transbrachial Access Site Complications in Endovascular Interventions: A Systematic Review of the Literature.
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Mantripragada K, Abadi K, Echeverry N, Shah S, and Snelling B
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The transfemoral approach (TFA) or transradial approach (TRA) serves as the primary technique for most endovascular cases; however, the transbrachial (TBA) route is an alternative access site used when TFA and TRA are contraindicated. Although TBA has advantages over TRA, such as the ability to accommodate large guide catheters and devices, there is some apprehension in implementing TBA due to perceived access site complication rates. This article aims to glean the rate of access site complication from current literature. Relevant studies were identified using the following search terms: ((access site complications) AND ((endovascular AND brachial) OR (percutaneous brachial access) OR (brachial))) OR (endovascular AND (percutaneous brachial access)); endovascular + brachial artery; endovascular + brachial artery + access site; and endovascular + brachial artery + access site complications. Articles published after 2008 addressing major complication rates from percutaneous TBA interventions were included. Fifteen studies out of 992 total articles met the inclusion criteria. The major access site complication rate was 75/1,424 (5.27%). Patients who underwent hemostasis with a vascular closure device (VCD) had a major complication rate of 13/309 (4.21%) compared to a major complication rate of 65/1122 (5.79%) for patients who underwent hemostasis with manual compression (MC). The major access site complication rate associated with TBA was 5.27%, which is relatively high compared to the complication rate in TFA or TRA. More prospective trials are needed to fully understand the access site complication rate in TBA interventions., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Mantripragada et al.)
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- 2022
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36. Low Anterior Cervical Approach Without Sternotomy or Clavicle Resection for Upper Thoracic Vertebra Corpectomy.
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Babici D, Johansen PM, Echeverry N, Mantripragada K, Miller T, and Snelling B
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The spine is the third most common site for metastatic disease following the lung and the liver. Approximately 60-70% of patients with metastatic cancer will have metastasis to the spine, but only 10% of these will be symptomatic. Metastases to the spine may involve the bone, epidural space, or the spinal cord. While chemotherapy and radiation therapy are the primary treatments for metastatic disease, spinal cord compression is an indication for surgical intervention. For vertebral body lesions, anterior vertebral reconstruction and stabilization also have the advantage of providing immediate stability to the vertebral column, but this anterior surgical approach to the upper thoracic spine is fraught with complications. The approach typically involves some combination of thoracotomy, sternotomy, or clavicle resection with anterior dissection into the superior mediastinum. To avoid unnecessary sternotomy and its associated complications, surgical access without sternotomy can be performed in certain cases. A sagittal MRI scan of the spine can be used to evaluate the level of the sternal notch in relation to the upper thoracic spine. If a tangential line can be drawn superior to the sternal notch and inferior to the level of the involved vertebra, surgical access without sternotomy can be performed. We present a case of a 52-year-old female with metastases to the upper thoracic vertebrae who underwent successful T2 corpectomy and T1-3 anterior fusion via a low anterior cervical approach, without sternotomy or clavicle resection., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Babici et al.)
- Published
- 2021
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37. Use of My Health Record by Clinicians in the Emergency Department: An Analysis of Log Data.
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Mullins AK, Morris H, Enticott J, Ben-Meir M, Rankin D, Mantripragada K, and Skouteris H
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Objectives: Leverage log data to explore access to My Health Record (MHR), the national electronic health record of Australia, by clinicians in the emergency department. Materials and Methods: A retrospective analysis was conducted using secondary routinely-collected data. Log data pertaining to all patients who presented to the emergency department between 2019 and 2021 of a not-for-profit hospital (that annually observes 23,000 emergency department presentations) were included in this research. Attendance data and human resources data were linked with MHR log data. The primary outcome was a dichotomous variable that indicated whether the MHR of a patient was accessed. Logistic regression facilitated the exploration of factors (user role, day of the week, and month) associated with access. Results: My Health Record was accessed by a pharmacist, doctor, or nurse in 19.60% ( n = 9,262) of all emergency department presentations. Access was dominated by pharmacists (18.31%, n = 8,656). All users demonstrated a small, yet significant, increase in access every month (odds ratio = 1.07, 95% Confidence interval: 1.06-1.07, p ≤ 0.001). Discussion: Doctors, pharmacists, and nurses are increasingly accessing MHR. Based on this research, substantially more pharmacists appear to be accessing MHR, compared to other user groups. However, only one in every five patients who present to the emergency department have their MHR accessed, thereby indicating a need to accelerate and encourage the adoption and access of MHR by clinicians., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Mullins, Morris, Enticott, Ben-Meir, Rankin, Mantripragada and Skouteris.)
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- 2021
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38. Treatment of Bilateral Giant Fusiform Petrocavernous Aneurysms.
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Mantripragada K, Echeverry N, Mansour S, Peterson EC, and Snelling B
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Aneurysms of the petrous segment of the internal carotid artery (ICA) are exceedingly rare. They are thought to arise from traumatic, mycotic, or congenital etiologies. We present a case of bilateral giant fusiform aneurysms of the petrocavernous ICA treated with bilateral flow-diverting stent placement. An 18-year-old male presented to our institution with headaches, nausea, vomiting and blurry vision that had been present since the day prior. Visual exam revealed decreased visual acuity bilaterally and a temporal field cut superiorly and inferiorly of the left eye. CT and MR imaging revealed bilateral lesions of the petrous segment of the ICA bilaterally. Catheter angiography demonstrated bilateral giant fusiform aneurysm of the petrocavernous ICA. The patient was treated with aspirin 325 mg and clopidogrel 75 mg orally daily for one week prior to the exam. VerifyNow (Accriva; San Diego, CA) confirmed adequate platelet inhibition. The right ICA was treated first, with a multiple flow-diverting stent construct. No complications were noted and the patient was discharged to home two days later. He was brought back three weeks later, and the left ICA was treated with a multiple flow-diverting stent construct. Again, no complications were noted and the patient was discharged uneventfully. The patient returned for his six-month follow-up angiogram with improvement of his visual acuity and resolution of headaches. However, the patient had ceased taking both anti-platelet medications six weeks prior. Angiography revealed no filling of the aneurysm in the right ICA, however, the left ICA was occluded at the origin. The patient was resumed on daily aspirin 325 mg orally and will have follow-up catheter angiography at 12 months. Petrous segment ICA aneurysms are rare. Most are thought to arise from trauma, infection, or congenital etiologies. These aneurysms are typically fusiform in nature, and can extend into the cavernous segment of the ICA. The natural history of these aneurysms is not well understood given their rarity. Current literature advocates for asymptomatic patients to be treated conservatively given that the natural history is not well known. Treatment is recommended in symptomatic patients, who may present with symptoms of local mass effect or ischemic stroke due to emboli. Endovascular options include flow diverting stent or covered stent placement, coil embolization with or without stent-assistance, or ICA occlusion. Open surgical options include trapping and high-flow bypass. When bilateral lesions are present, the management algorithm must be amended. We elected to treat the asymptomatic side first (right ICA), due to the presence of a significant kink within the aneurysm on the left. Once the right side was treated successfully, the symptomatic side was treated with a multiple stent construct. The patient's six-month angiogram demonstrated occlusion of the left ICA, likely due to non-compliance with antiplatelet medications. This further reiterates the need for dual-antiplatelet therapy and patient education and compliance with flow diverting stents. We report a rare case of bilateral giant fusiform petrocavernous aneurysms treated with bilateral Pipeline embolization devices in multiple device construct, demonstrating the feasibility and safety of this treatment option for this pathology., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2020, Mantripragada et al.)
- Published
- 2020
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39. Access-Site Complications in Mechanical Thrombectomy for Acute Ischemic Stroke: A Review of Prospective Trials.
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Shapiro SZ, Sabacinski KA, Mantripragada K, Shah SS, Stein AA, Echeverry NB, MacKinnon GA, and Snelling BM
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- Brain Ischemia complications, Endovascular Procedures methods, Femoral Artery surgery, Humans, Male, Prospective Studies, Radial Artery surgery, Stroke etiology, Thrombectomy methods, Treatment Outcome, Endovascular Procedures adverse effects, Postoperative Complications epidemiology, Postoperative Complications etiology, Stroke surgery, Thrombectomy adverse effects
- Abstract
Background: A shift has occurred in interventional cardiology from transfemoral to transradial access due to a 70%-80% decrease in complications. This shift has not yet taken place in other interventional specialties, perhaps owing to the lack of generalizability of findings in the cardiology data., Purpose: Our aim was to assess data from the recent mechanical thrombectomy prospective trials to better understand the access-site complication rate., Data Sources: Articles were systematically sourced from the National Center for Biotechnology Information PubMed archive., Study Selection: According to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines, prospective, randomized controlled trials published after 2008 with mention of major and/or minor femoral access-site complications in neuroendovascular mechanical thrombectomies were included., Data Analysis: Major and minor femoral access-site complications were extracted. A total complication rate was calculated with major access-site complications alone and combined with minor access-site complications., Data Synthesis: Seven prospective studies of 339 total screened met the inclusion criteria. Eleven major access-site complications were identified in of 660 total interventions, revealing a major access-site complication rate of 1.67% for patients undergoing mechanical thrombectomy with transfemoral access. If minor access-site complications were included, 35 total incidents were detected in 763 interventions, resulting in a total complication rate of 4.59%., Limitations: Multiple unspecified vessel and procedure-related complications were mentioned in the studies., Conclusions: The overall rate of major access-site complications was 1.67% in this review, which is not low and poses a risk to patients. We suggest further investigation into the feasibility and complication rates of alternative access sites for neurointerventional procedures., (© 2020 by American Journal of Neuroradiology.)
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- 2020
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40. Publisher Correction: Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection.
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Pardiñas AF, Holmans P, Pocklington AJ, Escott-Price V, Ripke S, Carrera N, Legge SE, Bishop S, Cameron D, Hamshere ML, Han J, Hubbard L, Lynham A, Mantripragada K, Rees E, MacCabe JH, McCarroll SA, Baune BT, Breen G, Byrne EM, Dannlowski U, Eley TC, Hayward C, Martin NG, McIntosh AM, Plomin R, Porteous DJ, Wray NR, Caballero A, Geschwind DH, Huckins LM, Ruderfer DM, Santiago E, Sklar P, Stahl EA, Won H, Agerbo E, Als TD, Andreassen OA, Bækvad-Hansen M, Mortensen PB, Pedersen CB, Børglum AD, Bybjerg-Grauholm J, Djurovic S, Durmishi N, Pedersen MG, Golimbet V, Grove J, Hougaard DM, Mattheisen M, Molden E, Mors O, Nordentoft M, Pejovic-Milovancevic M, Sigurdsson E, Silagadze T, Hansen CS, Stefansson K, Stefansson H, Steinberg S, Tosato S, Werge T, Collier DA, Rujescu D, Kirov G, Owen MJ, O'Donovan MC, and Walters JTR
- Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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- 2019
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41. An InDel in Phospholipase-C-B-1 Is Linked with Euthyroid Multinodular Goiter.
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Bakhsh AD, Ladas I, Hamshere ML, Bullock M, Kirov G, Zhang L, Taylor PN, Gregory JW, Scott-Coombes D, Völzke H, Teumer A, Mantripragada K, Williams ED, Clifton-Bligh RJ, Williams NM, and Ludgate ME
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- Adult, DNA Copy Number Variations, Female, Genetic Linkage, Goiter, Nodular pathology, Haplotypes, Humans, Male, Middle Aged, Pedigree, Thyroidectomy, Genetic Predisposition to Disease, Goiter, Nodular genetics, Introns genetics, Phospholipase C beta genetics, Thyroid Gland pathology
- Abstract
Background: Euthyroid multinodular goiter (MNG) is common, but little is known about the genetic variations conferring predisposition. Previously, a family with MNG of adolescent onset was reported in which some family members developed papillary thyroid carcinomas (PTC)., Methods: Genome-wide linkage analysis and next-generation sequencing were conducted to identify genetic variants that may confer disease predisposition. A multipoint nonparametric LOD score of 3.01 was obtained, covering 19 cM on chromosome 20p. Haplotype analysis reduced the region of interest to 10 cM., Results: Analysis of copy number variation identified an intronic InDel (∼1000 bp) in the PLCB1 gene in all eight affected family members and carriers (an unaffected person who has inherited the genetic trait). This InDel is present in approximately 1% of "healthy" Caucasians. Next-generation sequencing of the region identified no additional disease-associated variant, suggesting a possible role of the InDel. Since PLCB1 contributes to thyrocyte growth regulation, the InDel was investigated in relevant Caucasian cohorts. It was detected in 0/70 PTC but 4/81 unrelated subjects with MNG (three females; age at thyroidectomy 27-59 years; no family history of MNG/PTC). The InDel frequency is significantly higher in MNG subjects compared to controls (χ
2 = 5.076; p = 0.024. PLCB1 transcript levels were significantly higher in thyroids with the InDel than without (p < 0.02)., Conclusions: The intronic PLCB1 InDel is the first variant found in familial multiple papilloid adenomata-type MNG and in a subset of patients with sporadic MNG. It may function through overexpression, and increased PLC activity has been reported in thyroid neoplasms. The potential role of the deletion as a biomarker to identify MNG patients more likely to progress to PTC merits exploration.- Published
- 2018
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42. Effects of MiR-137 genetic risk score on brain volume and cortical measures in patients with schizophrenia and controls.
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Cosgrove D, Mothersill DO, Whitton L, Harold D, Kelly S, Holleran L, Holland J, Anney R, Richards A, Mantripragada K, Owen M, O'Donovan MC, Gill M, Corvin A, Morris DW, and Donohoe G
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- Adult, Brain metabolism, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Multifactorial Inheritance, Neuropsychological Tests, Polymorphism, Single Nucleotide, Psychotic Disorders genetics, Psychotic Disorders metabolism, Psychotic Disorders pathology, Risk Factors, Schizophrenia metabolism, Schizophrenia pathology, Brain pathology, MicroRNAs genetics, Schizophrenia genetics
- Abstract
Multiple genome-wide association studies of schizophrenia have implicated genetic variants within the gene encoding microRNA-137. As risk variants within or regulated by MIR137 have been implicated in memory performance, we investigated the additive effects of schizophrenia-associated risk variants in genes empirically regulated by MIR137 on brain regions associated with memory function. A polygenic risk score (PRS) was calculated (at a p = 0.05 threshold), using this empirically regulated MIR137 gene set, to investigate associations between this PRS and structural brain measures. These measures included total brain volume, cortical thickness, cortical surface area, and hippocampal volume, in a sample of 216 individuals consisting of healthy participants (n = 171) and patients with psychosis (n = 45). We did not observe a significant association between MIR137 PRS and these cortical thickness, surface area or hippocampal volume measures linked to memory function; a significant association between increasing PRS and decreasing total brain volume, independent of diagnosis status (R
2 = 0.008, Beta = -0.09, p = 0.029), was observed. This did not survive correction for multiple testing. In conclusion, our study yielded only suggestive evidence that risk variants interacting with MIR137 impacts on cortical structure., (© 2018 Wiley Periodicals, Inc.)- Published
- 2018
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43. Tolerability of ADXS11-001 Lm-LLO Listeria-Based Immunotherapy With Mitomycin, Fluorouracil, and Radiation for Anal Cancer.
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Safran H, Leonard KL, Perez K, Vrees M, Klipfel A, Schechter S, Oldenburg N, Roth L, Shah N, Rosati K, Rajdev L, Mantripragada K, Sheng IY, Barth P, and DiPetrillo TA
- Subjects
- Adult, Aged, Anus Neoplasms pathology, Bacterial Vaccines adverse effects, Bacterial Vaccines immunology, Chemoradiotherapy adverse effects, Female, Fluorouracil administration & dosage, Humans, Immunotherapy adverse effects, Male, Middle Aged, Mitomycin administration & dosage, Treatment Outcome, Tumor Burden, Anus Neoplasms therapy, Bacterial Vaccines therapeutic use, Chemoradiotherapy methods, Immunotherapy methods, Listeria monocytogenes immunology, Radiotherapy, Intensity-Modulated
- Abstract
Purpose: To obtain safety and preliminary efficacy data of the combination of ADXS11-001, live attenuated Listeria monocytogenes bacterium, with mitomycin, 5-fluorouracil (5-FU), and intensity modulated radiation therapy in locally advanced anal cancer., Patients and Methods: Eligibility included patients with previously untreated, nonmetastatic anal cancer with a primary tumor >4 cm or node-positive disease. Patients received 2 cycles of mitomycin and 5-FU concurrent with 54.0 Gy intensity modulated radiation therapy. One intravenous dose of ADXS11-001 (1 × 10
9 colony-forming units) was administered before chemoradiation; 3 additional monthly doses were given after chemoradiation., Results: Ten patients were treated, including 1 with N2 and 4 with N3 disease. Two patients had grade 3 acute toxicities after the initial dose of ADXS11-001, including chills/rigors (n = 2), back pain (n = 1), and hyponatremia (n = 1). All ADXS11-001 toxicities occurred within 24 hours of administration. There was no apparent increase in chemoradiation toxicities or myelosuppression. One patient had a grade 5 cardiopulmonary event shortly after beginning 5-FU treatment. All 9 assessable patients had complete clinical responses by sigmoidoscopy. Eight of 9 patients (89%) are progression-free at a median follow-up of 42 months., Conclusions: Preliminary data show that ADXS11-001 can be safely administered with standard chemoradiation for anal cancer. Further studies of listeria-based immunotherapy with radiation are warranted., (Copyright © 2018 Elsevier Inc. All rights reserved.)- Published
- 2018
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44. Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection.
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Pardiñas AF, Holmans P, Pocklington AJ, Escott-Price V, Ripke S, Carrera N, Legge SE, Bishop S, Cameron D, Hamshere ML, Han J, Hubbard L, Lynham A, Mantripragada K, Rees E, MacCabe JH, McCarroll SA, Baune BT, Breen G, Byrne EM, Dannlowski U, Eley TC, Hayward C, Martin NG, McIntosh AM, Plomin R, Porteous DJ, Wray NR, Caballero A, Geschwind DH, Huckins LM, Ruderfer DM, Santiago E, Sklar P, Stahl EA, Won H, Agerbo E, Als TD, Andreassen OA, Bækvad-Hansen M, Mortensen PB, Pedersen CB, Børglum AD, Bybjerg-Grauholm J, Djurovic S, Durmishi N, Pedersen MG, Golimbet V, Grove J, Hougaard DM, Mattheisen M, Molden E, Mors O, Nordentoft M, Pejovic-Milovancevic M, Sigurdsson E, Silagadze T, Hansen CS, Stefansson K, Stefansson H, Steinberg S, Tosato S, Werge T, Collier DA, Rujescu D, Kirov G, Owen MJ, O'Donovan MC, and Walters JTR
- Subjects
- Alleles, Case-Control Studies, Gene Frequency, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Inheritance Patterns, Genes, Lethal genetics, Polymorphism, Single Nucleotide, Schizophrenia genetics, Selection, Genetic
- Abstract
Schizophrenia is a debilitating psychiatric condition often associated with poor quality of life and decreased life expectancy. Lack of progress in improving treatment outcomes has been attributed to limited knowledge of the underlying biology, although large-scale genomic studies have begun to provide insights. We report a new genome-wide association study of schizophrenia (11,260 cases and 24,542 controls), and through meta-analysis with existing data we identify 50 novel associated loci and 145 loci in total. Through integrating genomic fine-mapping with brain expression and chromosome conformation data, we identify candidate causal genes within 33 loci. We also show for the first time that the common variant association signal is highly enriched among genes that are under strong selective pressures. These findings provide new insights into the biology and genetic architecture of schizophrenia, highlight the importance of mutation-intolerant genes and suggest a mechanism by which common risk variants persist in the population.
- Published
- 2018
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45. PPX and Concurrent Radiation for Newly Diagnosed Glioblastoma Without MGMT Methylation: A Randomized Phase II Study: BrUOG 244.
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Elinzano H, Glantz M, Mrugala M, Kesari S, Piccioni DE, Kim L, Pan E, Yunus S, Coyle T, Timothy K, Evans D, Mantripragada K, Boxerman J, DiPetrillo T, Donahue JE, Hebda N, Mitchell KM, Rosati KL, and Safran H
- Subjects
- Academic Medical Centers, Adult, Aged, Aged, 80 and over, Brain Neoplasms pathology, DNA Methylation, Disease-Free Survival, Dose-Response Relationship, Drug, Dose-Response Relationship, Radiation, Female, Follow-Up Studies, Glioblastoma pathology, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Neoplasm Invasiveness pathology, Neoplasm Staging, Paclitaxel administration & dosage, Polyglutamic Acid administration & dosage, Radiotherapy, Adjuvant, Single-Blind Method, Survival Analysis, Treatment Outcome, United States, Brain Neoplasms mortality, Brain Neoplasms therapy, DNA Modification Methylases metabolism, DNA Repair Enzymes metabolism, Glioblastoma mortality, Glioblastoma therapy, Paclitaxel analogs & derivatives, Polyglutamic Acid analogs & derivatives, Tumor Suppressor Proteins metabolism
- Abstract
Purpose: Efficacy signals but substantial myelosuppression were demonstrated in a single arm phase II study of paclitaxel poliglumex (PPX) in combination with temozolomide (TMZ) and radiation therapy (RT) for first-line treatment of glioblastoma. The objective of this randomized phase II trial was to assess the efficacy and safety of single-agent PPX with RT (PPX/RT) versus TMZ with RT (TMZ/RT) for glioblastoma without O-methylguanine-DNA methyltransferase (MGMT) methylation., Materials and Methods: Patients with glioblastoma with unmethylated MGMT without prior chemotherapy or RT were eligible. Patients were randomly assigned 2:1 to PPX, 50 mg/m/wk for 6 weeks, or standard TMZ, with concurrent 60.0 Gy RT. One month after completion of chemoradiation all patients received standard maintenance TMZ. The primary endpoint was progression-free survival (PFS)., Results: Of the 164 patients enrolled, 86 were MGMT unmethylated. Of these, 63 patients were randomized (42 to PPX/RT and 21 to TMZ/RT). Fifty-nine patients could be analyzed. The median PFS was 9 months in the PPX/RT group and 9.5 months in the TMZ/RT group (hazard ratio in the PPX/RT group, 1.10; 95% confidence interval, 0.79-2.08; P=0.75). Median overall survival was 16 versus 14.8 months for PPX/RT and TMZ/RT groups, respectively (hazard ratio, 1.44; 95% confidence interval, 0.75-2.77; P=0.27). In the PPX and TMZ groups 44% versus 22% of patients, respectively, experienced one or more grade 3 or higher toxicities during chemoradiation., Conclusions: PPX/RT did not improve PFS or overall survival. This study provides an effective trial design for screening RT sensitizers in glioblastoma.
- Published
- 2018
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46. Cognitive Characterization of Schizophrenia Risk Variants Involved in Synaptic Transmission: Evidence of CACNA1C's Role in Working Memory.
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Cosgrove D, Mothersill O, Kendall K, Konte B, Harold D, Giegling I, Hartmann A, Richards A, Mantripragada K, Owen MJ, O'Donovan MC, Gill M, Rujescu D, Walters J, Corvin A, Morris DW, and Donohoe G
- Subjects
- Adult, Brain diagnostic imaging, Brain physiology, Brain Mapping, Female, Genetic Loci, Genome-Wide Association Study, Humans, Magnetic Resonance Imaging, Male, Neural Pathways diagnostic imaging, Neural Pathways physiology, Neuropsychological Tests, Polymorphism, Single Nucleotide, Psychotic Disorders genetics, Calcium Channels, L-Type genetics, Cognition, Genetic Predisposition to Disease, Memory, Short-Term physiology, Schizophrenia genetics, Synaptic Transmission genetics
- Abstract
With >100 common variants associated with schizophrenia risk, establishing their biological significance is a priority. We sought to establish cognitive effects of risk variants at loci implicated in synaptic transmission by (1) identifying GWAS schizophrenia variants whose associated gene function is related to synaptic transmission, and (2) testing for association between these and measures of neurocognitive function. We selected variants, reported in the largest GWAS to date, associated with genes involved in synaptic transmission. Associations between genotype and cognitive test score were analyzed in a discovery sample (988 Irish participants, including 798 with psychosis), and replication samples (528 UK patients with schizophrenia/schizoaffective disorder; 921 German participants including 362 patients with schizophrenia). Three loci showed significant associations with neuropsychological performance in the discovery samples. This included an association between the rs2007044 (risk allele G) within CACNA1C and poorer working memory performance (increased errors B (95% CI)=0.635-4.535, p=0.012), an effect driven mainly by the psychosis groups. In an fMRI analysis of working memory performance (n=84 healthy participants, a subset of the discovery sample), we further found evidence that the same CACNA1C allele was associated with decreased functional connectivity between the right dorsolateral prefrontal cortex and right superior occipital gyrus/cuneus and anterior cingulate cortex. In conclusion, these data provide evidence to suggest that the CACNA1C risk variant rs2007044 is associated with poorer memory function that may result from risk carriers' difficulty with top-down initiated responses caused by dysconnectivity between the right DLPFC and several cortical regions.
- Published
- 2017
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47. The emerging role of the FKBP5 gene polymorphisms in vulnerability-stress model of schizophrenia: further evidence from a Serbian population.
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Mihaljevic M, Zeljic K, Soldatovic I, Andric S, Mirjanic T, Richards A, Mantripragada K, Pekmezovic T, Novakovic I, and Maric NP
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- Adult, Case-Control Studies, Disease Susceptibility, Female, Humans, Male, Models, Theoretical, Polymorphism, Single Nucleotide, Risk Factors, Serbia, Young Adult, Adult Survivors of Child Adverse Events, Gene-Environment Interaction, Neuroticism, Psychotic Disorders etiology, Psychotic Disorders genetics, Schizophrenia etiology, Schizophrenia genetics, Siblings, Stress, Psychological complications, Tacrolimus Binding Proteins genetics
- Abstract
Increased reactivity to stress is observed in patients with schizophrenia spectrum disorders and their healthy siblings in comparison with the general population. Additionally, higher levels of neuroticism, as a proposed psychological measure of stress sensitivity, increase the risk of schizophrenia. HPA axis dysregulation is one of the possible mechanisms related to the vulnerability-stress model of schizophrenia, and recent studies revealed a possible role of the functional genetic variants of FK506-binding protein 51 (FKBP5) gene which modulate activity of HPA axis. The purpose of the present study was to investigate impact of FKBP5 on schizophrenia in Serbian patients and to explore relationship between genetic variants and neuroticism by using the case-sibling-control design. In 158 subjects, we measured psychotic experiences, childhood trauma and neuroticism. Nine single-nucleotide polymorphisms (rs9295158, rs3800373, rs9740080, rs737054, rs6926133, rs9380529, rs9394314, rs2766533 and rs12200498) were genotyped. The genetic influence was modeled using logistic regression, and the relationship between genetic variants and neuroticism was assessed by linear mixed model. Our results revealed genetic main effect of FKBP5 risk alleles (A allele of rs9296158 and T allele of rs3800373) and AGTC "risk" haplotype combination (rs9296158, rs3800373, rs9470080 and rs737054, respectively) on schizophrenia, particularly when childhood trauma was set as a confounding factor. We confirmed strong relationship between neuroticism and psychotic experiences in patients and siblings and further showed relationship between higher levels of neuroticism and FKBP5 risk variants suggesting potential link between biological and psychosocial risk factors. Our data support previous findings that trauma exposure shapes FKBP5 impact on schizophrenia.
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- 2017
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48. Cognitive analysis of schizophrenia risk genes that function as epigenetic regulators of gene expression.
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Whitton L, Cosgrove D, Clarkson C, Harold D, Kendall K, Richards A, Mantripragada K, Owen MJ, O'Donovan MC, Walters J, Hartmann A, Konte B, Rujescu D, Gill M, Corvin A, Rea S, Donohoe G, and Morris DW
- Subjects
- Adult, Alleles, Brain metabolism, Cognition physiology, Cognition Disorders psychology, Epigenomics, Female, Gene Expression Regulation genetics, Gene Frequency, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Ireland, Male, Memory, Short-Term physiology, Middle Aged, Polymorphism, Single Nucleotide genetics, Psychotic Disorders genetics, Risk Factors, Schizophrenic Psychology, Cognition Disorders genetics, Epigenesis, Genetic genetics, Schizophrenia genetics
- Abstract
Epigenetic mechanisms are an important heritable and dynamic means of regulating various genomic functions, including gene expression, to orchestrate brain development, adult neurogenesis, and synaptic plasticity. These processes when perturbed are thought to contribute to schizophrenia pathophysiology. A core feature of schizophrenia is cognitive dysfunction. For genetic disorders where cognitive impairment is more severe such as intellectual disability, there are a disproportionally high number of genes involved in the epigenetic regulation of gene transcription. Evidence now supports some shared genetic aetiology between schizophrenia and intellectual disability. GWAS have identified 108 chromosomal regions associated with schizophrenia risk that span 350 genes. This study identified genes mapping to those loci that have epigenetic functions, and tested the risk alleles defining those loci for association with cognitive deficits. We developed a list of 350 genes with epigenetic functions and cross-referenced this with the GWAS loci. This identified eight candidate genes: BCL11B, CHD7, EP300, EPC2, GATAD2A, KDM3B, RERE, SATB2. Using a dataset of Irish psychosis cases and controls (n = 1235), the schizophrenia risk SNPs at these loci were tested for effects on IQ, working memory, episodic memory, and attention. Strongest associations were for rs6984242 with both measures of IQ (P = 0.001) and episodic memory (P = 0.007). We link rs6984242 to CHD7 via a long range eQTL. These associations were not replicated in independent samples. Our study highlights that a number of genes mapping to risk loci for schizophrenia may function as epigenetic regulators of gene expression but further studies are required to establish a role for these genes in cognition. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)
- Published
- 2016
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49. FOLFOX+Nab-Paclitaxel (FOLFOX-A) for Advanced Pancreatic Cancer: A Brown University Oncology Research Group Phase I Study.
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Safran H, Charpentier KP, Perez K, Mantripragada K, Miner T, DiPetrillo T, Kuritzky B, Apor E, Bishop K, Luppe D, Mitchell K, and Rosati K
- Subjects
- Adenocarcinoma mortality, Adult, Aged, Albumins administration & dosage, Albumins adverse effects, Antineoplastic Combined Chemotherapy Protocols adverse effects, Disease-Free Survival, Dose-Response Relationship, Drug, Drug Administration Schedule, Fluorouracil administration & dosage, Fluorouracil adverse effects, Fluorouracil therapeutic use, Humans, Infusions, Intravenous, Kaplan-Meier Estimate, Leucovorin administration & dosage, Leucovorin adverse effects, Leucovorin therapeutic use, Maximum Tolerated Dose, Middle Aged, Neoplasm Invasiveness pathology, Neoplasm Staging, Organoplatinum Compounds administration & dosage, Organoplatinum Compounds adverse effects, Organoplatinum Compounds therapeutic use, Oxaliplatin, Paclitaxel administration & dosage, Paclitaxel adverse effects, Pancreatic Neoplasms mortality, Prognosis, Prospective Studies, Risk Assessment, Survival Analysis, Treatment Outcome, Adenocarcinoma drug therapy, Adenocarcinoma pathology, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms pathology
- Abstract
Background: The Brown University Oncology Research Group performed a phase I study to remove irinotecan from FOLFIRINOX (5-fluorouracil, oxaliplatin, irinotecan, and leucovorin) and substitute nab-paclitaxel., Methods: Patients with newly diagnosed advanced pancreatic adenocarcinoma were eligible. Patients received oxaliplatin 85 mg/m, leucovorin 400 mg/m, and 5-fluorouracil 2400 mg/m with 3 dose levels of nab-paclitaxel (125, 150, and 175 mg/m) every 2 weeks. Dose-limiting toxicities were assessed in the first 2 cycles of treatment. The final dose level was expanded to assess cumulative neurotoxicity., Results: Thirty-five patients were entered; 24 with metastatic and 11 with locally advanced pancreatic cancer. The maximum tolerated dose of nab-paclitaxel was 150 mg/m every 2 weeks with FOLFOX. Cumulative neuropathy was the most important toxicity. Grade 3 neuropathy developed in 2 of the first 6 patients at 10 and 11 cycles of FOLFOX-A. Following an amendment to reduce oxaliplatin to 65 mg/m if grade 2 neuropathy developed, no additional patients developed grade 3 neurotoxicity. Twenty-one of 35 patients (60%) had a partial response. The median survival for patients with metastatic disease was 15 months., Conclusions: The maximum tolerated dose of nab-paclitaxel is 150 mg/m every 2 weeks with FOLFOX. The regimen of FOLFOX-A represents a promising treatment for pancreatic cancer.
- Published
- 2016
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50. Deletions at 22q11.2 in idiopathic Parkinson's disease: a combined analysis of genome-wide association data.
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Mok KY, Sheerin U, Simón-Sánchez J, Salaka A, Chester L, Escott-Price V, Mantripragada K, Doherty KM, Noyce AJ, Mencacci NE, Lubbe SJ, Williams-Gray CH, Barker RA, van Dijk KD, Berendse HW, Heutink P, Corvol JC, Cormier F, Lesage S, Brice A, Brockmann K, Schulte C, Gasser T, Foltynie T, Limousin P, Morrison KE, Clarke CE, Sawcer S, Warner TT, Lees AJ, Morris HR, Nalls MA, Singleton AB, Hardy J, Abramov AY, Plagnol V, Williams NM, and Wood NW
- Subjects
- Adult, Age of Onset, Aged, Aged, 80 and over, Comorbidity, DNA Copy Number Variations, DiGeorge Syndrome epidemiology, Female, Humans, Male, Middle Aged, Parkinson Disease epidemiology, DiGeorge Syndrome genetics, Genome-Wide Association Study, Parkinson Disease genetics
- Abstract
Background: Parkinson's disease has been reported in a small number of patients with chromosome 22q11.2 deletion syndrome. In this study, we screened a series of large, independent Parkinson's disease case-control studies for deletions at 22q11.2., Methods: We used data on deletions spanning the 22q11.2 locus from four independent case-control Parkinson's disease studies (UK Wellcome Trust Case Control Consortium 2, Dutch Parkinson's Disease Genetics Consortium, US National Institute on Aging, and International Parkinson's Disease Genomics Consortium studies), which were independent of the original reports of chromosome 22q11.2 deletion syndrome. We did case-control association analysis to compare the proportion of 22q11.2 deletions found, using the Fisher's exact test for the independent case-control studies and the Mantel-Haenszel test for the meta-analyses. We retrieved clinical details of patients with Parkinson's disease who had 22q11.2 deletions from the medical records of these patients., Findings: We included array-based copy number variation data from 9387 patients with Parkinson's disease and 13 863 controls. Eight patients with Parkinson's disease and none of the controls had 22q11.2 deletions (p=0·00082). In the 8451 patients for whom age at onset data were available, deletions at 22q11.2 were associated with Parkinson's disease age at onset (Mann-Whitney U test p=0·001). Age at onset of Parkinson's disease was lower in patients carrying a 22q11.2 deletion (median 37 years, 95% CI 32·0-55·5; mean 42·1 years [SD 11·9]) than in those who did not carry a deletion (median 61 years, 95% CI 60·5-61·0; mean 60·3 years [SD 12·8]). A 22q11.2 deletion was present in more patients with early-onset (p<0·0001) and late-onset Parkinson's disease (p=0·016) than in controls, and in more patients with early-onset than late-onset Parkinson's disease (p=0·005)., Interpretation: Clinicians should be alert to the possibility of 22q11.2 deletions in patients with Parkinson's disease who have early presentation or features associated with the chromosome 22q11.2 deletion syndrome, or both., Funding: UK Medical Research Council, UK Wellcome Trust, Parkinson's UK, Patrick Berthoud Trust, National Institutes of Health, "Investissements d'Avenir" ANR-10-IAIHU-06, Dutch Parkinson Foundation (Parkinson Vereniging), Neuroscience Campus Amsterdam, National Institute for Health Research, National Institute on Aging, National Institutes of Health., (Copyright © 2016 Mok et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2016
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