Identification of line-specific strategies for improving carotenoid production in synthetic maize through data-driven mathematical modelling.

Plant J. 2016 May 7;

Authors: Comas J, Benfeitas R, Vilaprinyo E, Sorribas A, Solsona F, Farré G, Berman J, Zorrilla U, Capell T, Sandmann G, Zhu C, Christou P, Alves R

Abstract
Plant Synthetic Biology is still in its infancy. However, Synthetic Biology approaches have been used to manipulate and improve the nutritional and health value of staple food crops, such as rice, potato, or maize. With current technologies, production yields of the synthetic nutrients are a result of trial and error, and systematic rational strategies to optimize those yields are still lacking. Here, we present a workflow that combines gene expression and quantitative metabolomics with mathematical modeling to identify strategies for increasing production yields of nutritionally important carotenoids in the seed endosperm synthesized through alternative biosynthetic pathways in synthetic lines of white maize, which is normally devoid of carotenoids. Quantitative metabolomics and gene expression data are used to create and fit parameters of mathematical models that are specific for four independent maize lines. Sensitivity analysis and simulation of each model is used to predict which gene activities should be further engineered in order to increase production yields for carotenoid accumulation in each line. Some of these predictions (e.g. increasing Zmlycb/Gllycb will increase accumulated β-carotenes) are valid across the four maize lines and consistent with experimental observations in other systems. Other predictions are line-specific. The workflow is adaptable to any other biological system for which appropriate quantitative information is available. Furthermore, we validate some of the predictions using experimental data from additional synthetic maize lines for which no models were developed. This article is protected by copyright. All rights reserved.

PMID: 27155093 [PubMed - as supplied by publisher]

Modelling tumour cell proliferation from vascular structure using tissue decomposition into avascular elements.

J Theor Biol. 2016 May 4;

Authors: Besenhard MO, Jarzabek M, O'Farrell AC, Callanan JJ, Prehn JH, Byrne AT, Huber HJ

Abstract
Computer models allow the mechanistically detailed study of tumour proliferation and its dependency on nutrients. However, the computational study of large vascular tumours requires detailed information on the 3-dimensional vessel network and rather high computation times due to complex geometries. This study puts forward the idea of partitioning vascularised tissue into connected avascular elements that can exchange cells and nutrients between each other. Our method is able to rapidly calculate the evolution of proliferating as well as dead and quiescent cells, and hence a proliferative index, from a given amount and distribution of vascularisation of arbitrary complexity. Applying our model, we found that a heterogeneous vessel distribution provoked a higher proliferative index, suggesting increased malignancy, and increased the amount of dead cells compared to a more static tumour environment when a homogenous vessel distribution was assumed. We subsequently demonstrated that under certain amounts of vascularisation, cell proliferation may even increase when vessel density decreases, followed by a subsequent decrease of proliferation. This effect was due to a trade-off between an increase in compensatory proliferation for replacing dead cells and a decrease of cell population due to lack of oxygen supply in lowly vascularised tumours. Findings were illustrated by an ectopic colorectal cancer mouse xenograft model. Our presented approach can be in the future applied to study the effect of cytostatic, cytotoxic and anti-angiogenic chemotherapy and is ideally suited for translational systems biology, where rapid interaction between theory and experiment is essential.

PMID: 27155046 [PubMed - as supplied by publisher]

Polypharmacology in Drug Development: A Minireview of Current Technologies.

ChemMedChem. 2016 May 6;

Authors: Tan Z, Chaudhai R, Zhang S

Abstract
Polypharmacology, the process in which a single drug is able to bind to multiple targets specifically and simultaneously, is an emerging paradigm in drug development. The potency of a given drug can be increased through the engagement of multiple targets involved in a certain disease. Polypharmacology may also help identify novel applications of existing drugs through drug repositioning. However, many problems and challenges remain in this field. Rather than covering all aspects of polypharmacology, this Minireview is focused primarily on recently reported techniques, from bioinformatics technologies to cheminformatics approaches as well as text-mining-based methods, all of which have made significant contributions to the research of polypharmacology.

PMID: 27154144 [PubMed - as supplied by publisher]

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Drug repositioning based on comprehensive similarity measures and Bi-Random Walk algorithm.

Bioinformatics. 2016 May 5;

Authors: Luo H, Wang J, Li M, Luo J, Peng X, Wu FX, Pan Y

Abstract
MOTIVATION: Drug repositioning, which aims to identify new indications for existing drugs, offers a promising alternative to reduce the total time and cost of traditional drug development. Many computational strategies for drug repositioning have been proposed, which are based on similarities among drugs and diseases. Current studies typically use either only drug-related properties (e.g. chemical structures) or only disease-related properties (e.g. phenotypes) to calculate drug or disease similarity respectively, while not taking into account the influence of known drug-disease association information on the similarity measures.
RESULTS: In this article, based on the assumption that similar drugs are normally associated with similar diseases and vice versa, we propose a novel computational method named MBiRW, which utilizes some comprehensive similarity measures and Bi-Random walk algorithm to identify potential novel indications for a given drug. By integrating drug or disease features information with known drug-disease associations, the comprehensive similarity measures are firstly developed to calculate similarity for drugs and diseases. Then drug similarity network and disease similarity network are constructed, and they are incorporated into a heterogeneous network with known drug-disease interactions. Based on the drug-disease heterogeneous network, Bi-Random walk algorithm is adopted to predict novel potential drug-disease associations. Computational experiment results from various datasets demonstrate that the proposed approach has reliable prediction performance and outperforms several recent computational drug repositioning approaches. Moreover, case studies of five selected drugs further confirm the superior performance of our method to discover potential indications for drugs practically.
AVAILABILITY: http://github.com//bioinfomaticsCSU/MBiRW CONTACT: jxwang@mail.csu.edu.cn SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

PMID: 27153662 [PubMed - as supplied by publisher]

Drug Repurposing for Terminal-Stage Cancer Patients.

Am J Public Health. 2016 Jun;106(6):e3

Authors: Cvek B

PMID: 27153031 [PubMed - as supplied by publisher]

Repurposing drugs for treatment of tuberculosis: a role for non-steroidal anti-inflammatory drugs.

Br Med Bull. 2016 May 5;

Authors: Maitra A, Bates S, Shaik M, Evangelopoulos D, Abubakar I, McHugh TD, Lipman M, Bhakta S

Abstract
INTRODUCTION: The number of cases of drug-resistant Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), has risen rapidly in recent years. This has led to the resurgence in repurposing existing drugs, such as non-steroidal anti-inflammatory drugs (NSAIDs), for anti-TB treatment.
SOURCES OF DATA: Evidence from novel drug screening in vitro, in vivo, pharmacokinetic/pharmacodynamics analyses and clinical trials has been used for the preparation of this systematic review of the potential of NSAIDs for use as an adjunct in new TB chemotherapies.
AREAS OF AGREEMENT: Certain NSAIDs have demonstrated inhibitory properties towards actively replicating, dormant and drug-resistant clinical isolates of M. tuberculosis cells.
AREAS OF CONTROVERSY: NSAIDs are a diverse class of drugs, which have reported off-target activities, and their endogenous antimicrobial mechanism(s) of action is still unclear.
GROWING POINTS: It is essential that clinical trials of NSAIDs continue, in order to assess their suitability for addition to the current TB treatment regimen. Repurposing molecules such as NSAIDs is a vital, low-risk strategy to combat the trend of rapidly increasing antibiotic resistance.

PMID: 27151954 [PubMed - as supplied by publisher]

Management and Treatment of Dengue and Chikungunya - Natural Products to the Rescue.

Comb Chem High Throughput Screen. 2016 May 6;

Authors: Suroowan S, Mahomoodally F, Ragoo L

Abstract
Neglected tropical diseases (NTDs) flourish mostly in impoverished developing nations of the world. It is estimated that NTDs plague up to 1 billion people every year thereby inducing a massive economic and health burden worldwide. Following explosive outbreaks mostly in Asia, Latin America, Europe and the Indian Ocean, two common NTDs namely, Chikungunya and Dengue both transmitted by an infected mosquito vector principally Aedes aegypti have emerged as a major public health threat. Given the limitations of conventional medicine in specifically targeting the Chikungunya and Dengue virus (CHIKV and DENV), natural products present an interesting avenue to explore in the quest of developing novel anti; mosquito, CHIKV and DENV agents. In this endeavor, a number of plant extracts, isolated compounds, essential oils and seaweeds have shown promising larvicidal and insecticidal activity against some mosquito vectors as well as anti CHIKV and DENV activity in-vitro. Other natural products that have depicted good potential against these diseases include; the symbiotic bacterial genus Wolbachia which can largely reduce the life span and infectivity of mosquito vectors and the marine Cyanobacterium Trichodesmium erythraeum which has shown anti-CHIKV activity at minimal cytotoxic level. The impetus of modern drug discovery approaches such as high throughput screening, drug repositioning, synthesis and computer-aided drug design will undeniably enhance the process of developing more stable lead molecules from natural products which have shown promising antiviral activity in-vitro.

PMID: 27151484 [PubMed - as supplied by publisher]

DrugGenEx-Net: a novel computational platform for systems pharmacology and gene expression-based drug repurposing.

BMC Bioinformatics. 2016;17(1):202

Authors: Issa NT, Kruger J, Wathieu H, Raja R, Byers SW, Dakshanamurthy S

Abstract
BACKGROUND: The targeting of disease-related proteins is important for drug discovery, and yet target-based discovery has not been fruitful. Contextualizing overall biological processes is critical to formulating successful drug-disease hypotheses. Network pharmacology helps to overcome target-based bottlenecks through systems biology analytics, such as protein-protein interaction (PPI) networks and pathway regulation.
RESULTS: We present a systems polypharmacology platform entitled DrugGenEx-Net (DGE-NET). DGE-NET predicts empirical drug-target (DT) interactions, integrates interaction pairs into a multi-tiered network analysis, and ultimately predicts disease-specific drug polypharmacology through systems-based gene expression analysis. Incorporation of established biological network annotations for protein target-disease, -signaling pathway, -molecular function, and protein-protein interactions enhances predicted DT effects on disease pathophysiology. Over 50 drug-disease and 100 drug-pathway predictions are validated. For example, the predicted systems pharmacology of the cholesterol-lowering agent ezetimibe corroborates its potential carcinogenicity. When disease-specific gene expression analysis is integrated, DGE-NET prioritizes known therapeutics/experimental drugs as well as their contra-indications. Proof-of-concept is established for immune-related rheumatoid arthritis and inflammatory bowel disease, as well as neuro-degenerative Alzheimer's and Parkinson's diseases.
CONCLUSIONS: DGE-NET is a novel computational method that predicting drug therapeutic and counter-therapeutic indications by uniquely integrating systems pharmacology with gene expression analysis. DGE-NET correctly predicts various drug-disease indications by linking the biological activity of drugs and diseases at multiple tiers of biological action, and is therefore a useful approach to identifying drug candidates for re-purposing.

PMID: 27151405 [PubMed - in process]

Sharpening nature's tools for efficient tuberculosis control: A review of the potential role and development of host-directed therapies and strategies for targeted respiratory delivery.

Adv Drug Deliv Rev. 2016 May 2;

Authors: O'Connor G, Gleeson LE, Fagan-Murphy A, Cryan SA, O'Sullivan MP, Keane J

Abstract
Centuries since it was first described, tuberculosis (TB) remains a significant global public health issue. Despite ongoing holistic measures implemented by health authorities and a number of new oral treatments reaching the market, there is still a need for an advanced, efficient TB treatment. An adjunctive, host-directed therapy designed to enhance endogenous pathways and hence compliment current regimens could be the answer. The integration of drug repurposing, including synthetic and naturally occurring compounds, with a targeted drug delivery platform is an attractive development option. In order for a new anti-tubercular treatment to be produced in a timely manner, a multidisciplinary approach should be taken from the outset, including stakeholders from academia, the pharmaceutical industry, and regulatory bodies keeping the patient as the key focus. Pre-clinical considerations for the development of a targeted host-directed therapy are discussed here.

PMID: 27151307 [PubMed - as supplied by publisher]

Gene-specific mitochondria dysfunctions in human TARDBP and C9ORF72 fibroblasts.

Acta Neuropathol Commun. 2016;4(1):47

Authors: Onesto E, Colombrita C, Gumina V, Borghi MO, Dusi S, Doretti A, Fagiolari G, Invernizzi F, Moggio M, Tiranti V, Silani V, Ratti A

Abstract
Dysregulation of RNA metabolism represents an important pathogenetic mechanism in both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) due to the involvement of the DNA/RNA-binding proteins TDP-43 and FUS and, more recently, of C9ORF72. A potential link between dysregulation of RNA metabolism and mitochondrial dysfunction is recently emerged in TDP-43 disease models. To further investigate the possible relationship between these two pathogenetic mechanisms in ALS/FTD, we studied mitochondria functionality in human mutant TARDBP(p.A382T) and C9ORF72 fibroblasts grown in galactose medium to induce a switch from a glycolytic to an oxidative metabolism. In this condition we observed significant changes in mitochondria morphology and ultrastructure in both mutant cells with a fragmented mitochondria network particularly evident in TARDBP(p.A382T) fibroblasts. From analysis of the mitochondrial functionality, a decrease of mitochondria membrane potential with no alterations in oxygen consumption rate emerged in TARDBP fibroblasts. Conversely, an increased oxygen consumption and mitochondria hyperpolarization were observed in C9ORF72 fibroblasts in association to increased ROS and ATP content. We found evidence of autophagy/mitophagy in dynamic equilibrium with the biogenesis of novel mitochondria, particularly in mutant C9ORF72 fibroblasts where an increase of mitochondrial DNA content and mass, and of PGC1-α protein was observed. Our imaging and biochemical data show that wild-type and mutant TDP-43 proteins do not localize at mitochondria so that the molecular mechanisms responsible for such mitochondria impairment remain to be further elucidated. For the first time our findings assess a link between C9ORF72 and mitochondria dysfunction and indicate that mitochondria functionality is affected in TARDBP and C9ORF72 fibroblasts with gene-specific features in oxidative conditions. As in neuronal metabolism mitochondria are actively used for ATP production, we speculate that TARDBP and C9ORF72 mutations might trigger cell death by impairing not only RNA metabolism, but also mitochondria activity in ALS/FTD neurons.

PMID: 27151080 [PubMed - in process]

Gene-manipulated Adipocytes for the Treatment of Various Intractable Diseases.

Yakugaku Zasshi. 2016;136(5):705-9

Authors: Kuroda M, Bujo H, Aso M, Saito Y, Yokote K

Abstract
Although protein replacement is an effective treatment for serum protein deficiencies such as diabetes and hemophilia, recombinant protein products are not available for all rare inherited diseases due to the instability of the recombinant proteins and/or to cost. Gene therapy is the most attractive option for treating patients with such rare diseases. To develop an effective ex vivo gene therapy-based protein replacement treatment requires recipient cells that differ from those used in standard gene therapy, which is performed to correct the function of the recipient cells. Adipose tissue is an expected source of proliferative cells for cell-based therapies, including regenerative medicine and gene transfer applications. Based on recent advances in cell biology and extensive clinical experience in transplantation therapy for adipose tissue, we focused on the mature adipocyte fraction, which is the floating fraction after collagenase digestion and centrifugation of adipose tissue. Proliferative adipocytes were propagated from the floating fraction by the ceiling culture technique. These cells are designated as ceiling culture-derived proliferative adipocytes (ccdPAs). We first focused on lecithin:cholesterol acyltransferase (LCAT) deficiency, an inherited metabolic disorder caused by lcat gene mutation, and ccdPAs as a therapeutic gene vehicle for LCAT replacement therapy. In our recent in vitro and animal model studies, we developed an adipose cell manipulation procedure using advanced gene transduction methods and transplantation scaffolds. We herein introduce the progress made in novel adipose tissue-based therapeutic strategies for the treatment of protein deficiencies and describe their future applications for other intractable diseases.

PMID: 27150923 [PubMed - in process]

Controversies with Kalydeco: Newspaper coverage in Canada and the United States of the cystic fibrosis "wonder drug".

J Cyst Fibros. 2016 Apr 14;

Authors: Rachul C, Toews M, Caulfield T

Abstract
BACKGROUND: The cystic fibrosis drug, Kalydeco, has attracted attention both for its effectiveness in particular CF patients and its substantial price tag. An analysis of newspaper portrayals of Kalydeco provides an opportunity to examine how policy issues associated with rare diseases and orphan drugs are being represented in the popular press.
METHODS: We conducted a content analysis of 203 newspaper articles in Canada and the U.S. that mention Kalydeco. Articles were analyzed for their main frame, discussion of Kalydeco, including issues of drug development, patient access, and reimbursement, and overall tone.
RESULTS: In Canadian newspaper coverage, 77.4% of articles were framed as human interest stories featuring individual patients seeking public funding for Kalydeco, yet only 7.5% mentioned any budgetary limitations in doing so. In contrast, U.S. newspaper coverage was framed as a financial/economic story in 43.1% of articles and a medical/scientific story in 27.8%.
CONCLUSIONS: Newspaper coverage varied significantly between Canada, where Kalydeco is predominantly a story about increasing patient access through full government funding, and the U.S., where Kalydeco is largely a financial story about the economic impact of Kalydeco. The difference in coverage may be due to differences in public funding between the healthcare systems of these two countries.

PMID: 27150823 [PubMed - as supplied by publisher]

ECL-cell carcinoids and carcinoma in patients homozygous for an inactivating mutation in the gastric H(+) K(+) ATPase alpha subunit.

APMIS. 2016 May 6;

Authors: Fossmark R, Calvete O, Mjønes P, Benitez J, Waldum HL

Abstract
A family with a missense variant of the ATP4A gene encoding the alpha subunit of the gastric proton pump (H(+) K(+) ATPase) has recently been described. Homozygous siblings were hypergastrinemic (median gastrin 486 pM) and had gastric tumours diagnosed at a median age of 33 years. In the current histopathological study, we further characterized the tumours found in the gastric corpus. The tumours had the histological appearance of carcinoids (NET G1 or G2) and were immunoreactive for the general neuroendocrine markers chromogranin A (CgA) and synaptophysin as well as the ECL-cell markers vesicular monoamine transporter 2 (VMAT2) and histidine decarbozylase (HDC). One of the tumours consisted of a NET G2 component, but also had a component with glandular growth, which morphologically was classified as an intestinal type adenocarcinoma. Many glands of the adenocarcinoma contained a large proportion of cells positive for neuroendocrine markers, especially the small vesicle marker synaptophysin and the cytoplasmic enzyme HDC. In conclusion, patients homozygous for an inactivating ATP4A mutation develop gastric ECL-cell carcinoids in their 3rd or 4th decade. The adenocarcinoma may be classified as neuroendocrine with ECL-cell differentiation.

PMID: 27150581 [PubMed - as supplied by publisher]

Treacher Collins Syndrome: A Systematic Review of Evidence-Based Treatment and Recommendations.

Plast Reconstr Surg. 2016 Jan;137(1):191-204

Authors: Plomp RG, van Lieshout MJ, Joosten KF, Wolvius EB, van der Schroeff MP, Versnel SL, Poublon RM, Mathijssen IM

Abstract
BACKGROUND: No reviews or guidelines are available on evidence-based treatment for the multidisciplinary approach in Treacher Collins syndrome. The authors' aim is to provide an evidence-based review of multidisciplinary treatment of Treacher Collins syndrome based on levels of evidence and supported with graded recommendations.
METHODS: A systematic search was performed by means of the PubMed, Web-of-Science, Embase, and Cochrane Central databases (1985 to January of 2014). Included were clinical studies (with five or more Treacher Collins syndrome patients) related to therapy, diagnosis, or risk of concomitant diseases. Level of evidence of the selected articles was rated according to the American Society of Plastic Surgeons evidence-based clinical practice guidelines. After two panelists had reviewed each abstract separately, a consensus method was used to solve any disagreements concerning article inclusion.
RESULTS: Of the 2433 identified articles, 63 studies (Level of Evidence II through V) were included. Conclusions and recommendations were extracted consecutively for the following items: upper airway; ear, hearing, and speech; the eye, eyelashes, and lacrimal system; growth, feeding, and swallowing; the nose; psychosocial factors; and craniofacial reconstruction.
CONCLUSIONS: In this systematic review, current evidence for the multidisciplinary treatment of Treacher Collins syndrome is provided, recommendations for treatment are made, and a proposed algorithm for treatment is presented. Although some topics are well supported, others, especially ocular, nasal, speech, feeding, and swallowing problems, lack sufficient evidence. In addition, craniofacial surgical reconstruction lacks a sufficient level of evidence to provide a sound basis for a full treatment protocol. Despite the rarity of the syndrome, more research is needed to compare outcomes of several surgical treatments, especially in orbitozygomatic/maxillary regions.

PMID: 26710023 [PubMed - indexed for MEDLINE]

Kullback-Leibler divergence for detection of rare haplotype common disease association.

Eur J Hum Genet. 2015 Nov;23(11):1558-65

Authors: Lin S

Abstract
Rare haplotypes may tag rare causal variants of common diseases; hence, detection of such rare haplotypes may also contribute to our understanding of complex disease etiology. Because rare haplotypes frequently result from common single-nucleotide polymorphisms (SNPs), focusing on rare haplotypes is much more economical compared with using rare single-nucleotide variants (SNVs) from sequencing, as SNPs are available and 'free' from already amassed genome-wide studies. Further, associated haplotypes may shed light on the underlying disease causal mechanism, a feat unmatched by SNV-based collapsing methods. In recent years, data mining approaches have been adapted to detect rare haplotype association. However, as they rely on an assumed underlying disease model and require the specification of a null haplotype, results can be erroneous if such assumptions are violated. In this paper, we present a haplotype association method based on Kullback-Leibler divergence (hapKL) for case-control samples. The idea is to compare haplotype frequencies for the cases versus the controls by computing symmetrical divergence measures. An important property of such measures is that both the frequencies and logarithms of the frequencies contribute in parallel, thus balancing the contributions from rare and common, and accommodating both deleterious and protective, haplotypes. A simulation study under various scenarios shows that hapKL has well-controlled type I error rates and good power compared with existing data mining methods. Application of hapKL to age-related macular degeneration (AMD) shows a strong association of the complement factor H (CFH) gene with AMD, identifying several individual rare haplotypes with strong signals.

PMID: 25735482 [PubMed - indexed for MEDLINE]

DisGeNET-RDF: Harnessing the Innovative Power of the Semantic Web to Explore the Genetic Basis of Diseases.

Bioinformatics. 2016 Apr 22;

Authors: Queralt-Rosinach N, Piñero J, Bravo À, Sanz F, Furlong LI

Abstract
MOTIVATION: DisGeNET-RDF makes available knowledge on the genetic basis of human diseases in the Semantic Web (SW). Gene-disease associations (GDAs) and their provenance metadata are published as human-readable and machine-processable web resources. The information on GDAs included in DisGeNET-RDF is interlinked to other biomedical databases to support the development of bioinformatics approaches for translational research through evidence-based exploitation of a rich and fully interconnected Linked Open Data (LOD).
AVAILABILITY: http://rdf.disgenet.org/ CONTACT: support@disgenet.org.

PMID: 27153650 [PubMed - as supplied by publisher]

Predicting the Unpredictable: Drug-Induced QT Prolongation and Torsades de Pointes.

J Am Coll Cardiol. 2016 Apr 5;67(13):1639-50

Authors: Schwartz PJ, Woosley RL

Abstract
Drug-induced long QT syndrome (diLQTS) and congenital LQTS (cLQTS) share many features, and both syndromes can result in life-threatening torsades de pointes (TdP). Our understanding of their mechanistic and genetic similarities has led to their improved clinical management. However, our inability to prevent diLQTS has resulted in removal of many medicines from the market and from development. Genetic and clinical risk factors for diLQTS and TdP are well known and raise the possibility of TdP prevention. Clinical decision support systems (CDSS) can scan the patient's electronic health records for clinical risk factors predictive of diLQTS and warn when a drug that can cause TdP is prescribed. CDSS have reduced prescriptions of QT-prolonging drugs, but these relatively small changes lack the power to reduce TdP. The growing genetic evidence linking diLQTS to cLQTS suggests that prevention of TdP in the future may require inclusion of both genetic and clinical predictors into CDSS.

PMID: 27150690 [PubMed - in process]

Clinical Evaluation of Cisplatin Sensitivity of Germline Polymorphisms in Neoadjuvant Chemotherapy for Urothelial Cancer.

Clin Genitourin Cancer. 2016 Mar 10;

Authors: O'Donnell PH, Alanee S, Stratton KL, Garcia-Grossman IR, Cao H, Ostrovnaya I, Plimack ER, Manschreck C, Ganshert C, Smith ND, Steinberg GD, Vijai J, Offit K, Stadler WM, Bajorin DF

Abstract
BACKGROUND: Level 1 evidence has demonstrated increased overall survival with cisplatin-based neoadjuvant chemotherapy for patients with muscle-invasive urothelial cancer. Usage remains low, however, in part because neoadjuvant chemotherapy will not be effective for every patient. To identify the patients most likely to benefit, we evaluated germline pharmacogenomic markers for association with neoadjuvant chemotherapy sensitivity in 2 large cohorts of patients with urothelial cancer.
PATIENTS AND METHODS: Patients receiving neoadjuvant cisplatin-based chemotherapy for muscle-invasive urothelial cancer were eligible. Nine germline single nucleotide polymorphisms (SNPs) potentially conferring platinum sensitivity were tested for an association with a complete pathologic response to neoadjuvant chemotherapy (pT0) or elimination of muscle-invasive cancer (<pT2).
RESULTS: The data from 205 patients were analyzed-59 patients were included in the discovery set and 146 in an independent replication cohort-from 3 institutions. The stage pT0 (26%) and < pT2 (50%) rates were consistent across the discovery and replication populations. Using a multivariate recessive genetic model, rs244898 in RARS (odds ratio, 6.8; 95% confidence interval, 1.8-28.9; P = .006) and rs7937567 in GALNTL4 (odds ratio, 4.8; 95% confidence interval, 1.1-22.6; P = .04) were associated with pT0 in the discovery set. Despite these large effects, neither were associated with achievement of pT0 in the replication set. A third SNP, rs10964552, was associated with stage < pT2 in the discovery set but also failed to replicate.
CONCLUSION: Germline SNPs previously associated with platinum sensitivity were not associated with the neoadjuvant chemotherapy response in a large replication cohort of patients with urothelial cancer. These results emphasize the need for replication when evaluating pharmacogenomic markers and demonstrate that multi-institutional efforts are feasible and will be necessary to achieve advances in urothelial cancer pharmacogenomics.

PMID: 27150640 [PubMed - as supplied by publisher]

The Pharmacogenomics of Bipolar Disorder study (PGBD): identification of genes for lithium response in a prospective sample.

BMC Psychiatry. 2016;16(1):129

Authors: Oedegaard KJ, Alda M, Anand A, Andreassen OA, Balaraman Y, Berrettini WH, Bhattacharjee A, Brennand KJ, Burdick KE, Calabrese JR, Calkin CV, Claasen A, Coryell WH, Craig D, DeModena A, Frye M, Gage FH, Gao K, Garnham J, Gershon E, Jakobsen P, Leckband SG, McCarthy MJ, McInnis MG, Maihofer AX, Mertens J, Morken G, Nievergelt CM, Nurnberger J, Pham S, Schoeyen H, Shekhtman T, Shilling PD, Szelinger S, Tarwater B, Yao J, Zandi PP, Kelsoe JR

Abstract
BACKGROUND: Bipolar disorder is a serious and common psychiatric disorder characterized by manic and depressive mood switches and a relapsing and remitting course. The cornerstone of clinical management is stabilization and prophylaxis using mood-stabilizing medications to reduce both manic and depressive symptoms. Lithium remains the gold standard of treatment with the strongest data for both efficacy and suicide prevention. However, many patients do not respond to this medication, and clinically there is a great need for tools to aid the clinician in selecting the correct treatment. Large genome wide association studies (GWAS) investigating retrospectively the effect of lithium response are in the pipeline; however, few large prospective studies on genetic predictors to of lithium response have yet been conducted. The purpose of this project is to identify genes that are associated with lithium response in a large prospective cohort of bipolar patients and to better understand the mechanism of action of lithium and the variation in the genome that influences clinical response.
METHODS/DESIGN: This study is an 11-site prospective non-randomized open trial of lithium designed to ascertain a cohort of 700 subjects with bipolar I disorder who experience protocol-defined relapse prevention as a result of treatment with lithium monotherapy. All patients will be diagnosed using the Diagnostic Interview for Genetic Studies (DIGS) and will then enter a 2-year follow-up period on lithium monotherapy if and when they exhibit a score of 1 (normal, not ill), 2 (minimally ill) or 3 (mildly ill) on the Clinical Global Impressions of Severity Scale for Bipolar Disorder (CGI-S-BP Overall Bipolar Illness) for 4 of the 5 preceding weeks. Lithium will be titrated as clinically appropriate, not to exceed serum levels of 1.2 mEq/L. The sample will be evaluated longitudinally using a wide range of clinical scales, cognitive assessments and laboratory tests. On relapse, patients will be discontinued or crossed-over to treatment with valproic acid (VPA) or treatment as usual (TAU). Relapse is defined as a DSM-IV manic, major depressive or mixed episode or if the treating physician decides a change in medication is clinically necessary. The sample will be genotyped for GWAS. The outcome for lithium response will be analyzed as a time to event, where the event is defined as clinical relapse, using a Cox Proportional Hazards model. Positive single nucleotide polymorphisms (SNPs) from past genetic retrospective studies of lithium response, the Consortium on Lithium Genetics (ConLiGen), will be tested in this prospective study sample; a meta-analysis of these samples will then be performed. Finally, neurons will be derived from pluripotent stem cells from lithium responders and non-responders and tested in vivo for response to lithium by gene expression studies. SNPs in genes identified in these cellular studies will also be tested for association to response.
DISCUSSION: Lithium is an extraordinarily important therapeutic drug in the clinical management of patients suffering from bipolar disorder. However, a significant proportion of patients, 30-40 %, fail to respond, and there is currently no method to identify the good lithium responders before initiation of treatment. Converging evidence suggests that genetic factors play a strong role in the variation of response to lithium, but only a few genes have been tested and the samples have largely been retrospective or quite small. The current study will collect an entirely unique sample of 700 patients with bipolar disorder to be stabilized on lithium monotherapy and followed for up to 2 years. This study will produce useful information to improve the understanding of the mechanism of action of lithium and will add to the development of a method to predict individual response to lithium, thereby accelerating recovery and reducing suffering and cost.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01272531 Registered: January 6, 2011.

PMID: 27150464 [PubMed - in process]