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]

Genome-wide association study identifies common variants associated with pharmacokinetics of psychotropic drugs.

J Psychopharmacol. 2015 Aug;29(8):884-91

Authors: Athanasiu L, Smorr LL, Tesli M, Røssberg JI, Sønderby IE, Spigset O, Djurovic S, Andreassen OA

Abstract
Individual variation in pharmacokinetics of psychotropic drugs, particularly metabolism, is an important factor to consider in pharmacological treatment in psychiatry. A large proportion of this variance is still not accounted for, but evidence so far suggests the involvement of genetic factors. We performed a genome-wide association study (GWAS) with concentration dose ratio (CDR) as sub-phenotype to assess metabolism rate of psychotropic drugs in a homogenous Norwegian sample of 1334 individuals diagnosed with a severe mental disorder. The GWAS revealed one genome-wide significant marker (rs16935279, p-value=3.95×10(-10), pperm=7.5×10(-4)) located in an intronic region of the lncRNA LOC100505718. Carriers of the minor allele have a lower metabolism rate of antiepileptic drugs compared to major allele carriers. In addition, several nominally significant associations between single nucleotide polymorphisms (SNPs) and CDR for antipsychotic, antidepressant and antiepileptic drugs were disclosed. We consider standardised CDR to be a useful measure of the metabolism rate of a drug. The present findings indicate that common gene variants could affect the metabolism of psychotropic drugs. This warrants further investigations into the functional mechanisms involved as it may lead to identification of predictive markers as well as novel drug targets.

PMID: 25944848 [PubMed - indexed for MEDLINE]

Building a glaucoma interaction network using a text mining approach.

BioData Min. 2016;9:17

Authors: Soliman M, Nasraoui O, Cooper NG

Abstract
BACKGROUND: The volume of biomedical literature and its underlying knowledge base is rapidly expanding, making it beyond the ability of a single human being to read through all the literature. Several automated methods have been developed to help make sense of this dilemma. The present study reports on the results of a text mining approach to extract gene interactions from the data warehouse of published experimental results which are then used to benchmark an interaction network associated with glaucoma. To the best of our knowledge, there is, as yet, no glaucoma interaction network derived solely from text mining approaches. The presence of such a network could provide a useful summative knowledge base to complement other forms of clinical information related to this disease.
RESULTS: A glaucoma corpus was constructed from PubMed Central and a text mining approach was applied to extract genes and their relations from this corpus. The extracted relations between genes were checked using reference interaction databases and classified generally as known or new relations. The extracted genes and relations were then used to construct a glaucoma interaction network. Analysis of the resulting network indicated that it bears the characteristics of a small world interaction network. Our analysis showed the presence of seven glaucoma linked genes that defined the network modularity. A web-based system for browsing and visualizing the extracted glaucoma related interaction networks is made available at http://neurogene.spd.louisville.edu/GlaucomaINViewer/Form1.aspx.
CONCLUSIONS: This study has reported the first version of a glaucoma interaction network using a text mining approach. The power of such an approach is in its ability to cover a wide range of glaucoma related studies published over many years. Hence, a bigger picture of the disease can be established. To the best of our knowledge, this is the first glaucoma interaction network to summarize the known literature. The major findings were a set of relations that could not be found in existing interaction databases and that were found to be new, in addition to a smaller subnetwork consisting of interconnected clusters of seven glaucoma genes. Future improvements can be applied towards obtaining a better version of this network.

PMID: 27152122 [PubMed]

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Inhibition of Cholesterol Esterification in the Adrenal Gland by ATR101/PD132301-2, A Promising Case of Drug Repurposing.

Endocrinology. 2016 May;157(5):1719-1721

Authors: Kroiss M, Fassnacht M

PMID: 27149038 [PubMed - as supplied by publisher]

How Reliable Are Ligand-Centric Methods for Target Fishing?

Front Chem. 2016;4:15

Authors: Peón A, Dang CC, Ballester PJ

Abstract
Computational methods for Target Fishing (TF), also known as Target Prediction or Polypharmacology Prediction, can be used to discover new targets for small-molecule drugs. This may result in repositioning the drug in a new indication or improving our current understanding of its efficacy and side effects. While there is a substantial body of research on TF methods, there is still a need to improve their validation, which is often limited to a small part of the available targets and not easily interpretable by the user. Here we discuss how target-centric TF methods are inherently limited by the number of targets that can possibly predict (this number is by construction much larger in ligand-centric techniques). We also propose a new benchmark to validate TF methods, which is particularly suited to analyse how predictive performance varies with the query molecule. On average over approved drugs, we estimate that only five predicted targets will have to be tested to find two true targets with submicromolar potency (a strong variability in performance is however observed). In addition, we find that an approved drug has currently an average of eight known targets, which reinforces the notion that polypharmacology is a common and strong event. Furthermore, with the assistance of a control group of randomly-selected molecules, we show that the targets of approved drugs are generally harder to predict. The benchmark and a simple target prediction method to use as a performance baseline are available at http://ballester.marseille.inserm.fr/TF-benchmark.tar.gz.

PMID: 27148522 [PubMed]

Chloroquine-containing compounds: a patent review (2010 - 2014).

Expert Opin Ther Pat. 2015;25(9):1003-24

Authors: Njaria PM, Okombo J, Njuguna NM, Chibale K

Abstract
INTRODUCTION: Chloroquine (CQ) has been well known for its antimalarial effects since World War II. However, it is gradually being phased out from clinical use against malaria due to emergence of CQ-resistant Plasmodium falciparum strains. Besides low cost and tolerability, ongoing research has revealed interesting biochemical properties of CQ that have inspired its repurposing/repositioning in the management of various infectious/noninfectious diseases. Consequently, several novel compounds and compositions based on its scaffold have been studied and patented.
AREAS COVERED: In this review, patents describing CQ and its derivatives/compositions over the last 5 years are analyzed. The review highlights the rationale, chemical structures, biological evaluation and potential therapeutic application of CQ, its derivatives and compositions.
EXPERT OPINION: Repurposing efforts have dominantly focused on racemic CQ with no studies exploring the effect of the (R) and (S) enantiomers, which might potentially have additional benefits in other diseases. Additionally, evaluating other similarly acting antimalarials in clinical use and structural analogs could help maximize the intrinsic value of the 4-aminoquinolines. With regard to cancer therapy, successful repurposing of CQ-containing compounds will require linking the mode of action of these antimalarials with the signaling pathways that drive cancer cell proliferation to facilitate the development of a 4-amino-7-chloroquinoline that can be used as a synergistic partner in anticancer combination chemotherapy.

PMID: 26013494 [PubMed - indexed for MEDLINE]

Complex media and enzymatic kinetics.

Anal Chem. 2016 May 5;

Authors: Bakalis EO, Soldà A, Kosmas MK, Rapino S, Zerbetto F

Abstract
Enzymatic reactions in complex environments often take place with concentrations of enzyme comparable to that of substrate molecules. Two such cases occur when an enzyme is used to detect low concentrations of substrate/analyte or inside a living cell. Such concentrations do not agree with standard in-vitro conditions, aimed at satisfying one of the founding hypothesis of the Michaelis-Menten reaction scheme, MM. It would be desirable to generalize the classical approach, and show its applicability to complex systems. A permeable micrometrically-structured hydrogel matrix was fabricated by protein cross-linking. Glucose oxidase enzyme (GOx) was embedded in the matrix and used as a prototypical system. The concentration of H2O2 was monitored in time and fitted by an accurate solution of the enzymatic kinetic scheme, which is expressed in terms of simple functions. The approach can also find applications in digital micro-fluidics and in systems biology where the kinetics response in the linear regimes often employed must be replaced.

PMID: 27149003 [PubMed - as supplied by publisher]

Understanding the Causes and Implications of Endothelial Metabolic Variation in Cardiovascular Disease through Genome-Scale Metabolic Modeling.

Front Cardiovasc Med. 2016;3:10

Authors: McGarrity S, Halldórsson H, Palsson S, Johansson PI, Rolfsson Ó

Abstract
High-throughput biochemical profiling has led to a requirement for advanced data interpretation techniques capable of integrating the analysis of gene, protein, and metabolic profiles to shed light on genotype-phenotype relationships. Herein, we consider the current state of knowledge of endothelial cell (EC) metabolism and its connections to cardiovascular disease (CVD) and explore the use of genome-scale metabolic models (GEMs) for integrating metabolic and genomic data. GEMs combine gene expression and metabolic data acting as frameworks for their analysis and, ultimately, afford mechanistic understanding of how genetic variation impacts metabolism. We demonstrate how GEMs can be used to investigate CVD-related genetic variation, drug resistance mechanisms, and novel metabolic pathways in ECs. The application of GEMs in personalized medicine is also highlighted. Particularly, we focus on the potential of GEMs to identify metabolic biomarkers of endothelial dysfunction and to discover methods of stratifying treatments for CVDs based on individual genetic markers. Recent advances in systems biology methodology, and how these methodologies can be applied to understand EC metabolism in both health and disease, are thus highlighted.

PMID: 27148541 [PubMed]

Corrigendum: Synechocystis: not just a plug-bug for CO2, but a green E. coli.

Front Bioeng Biotechnol. 2016;4:32

Authors: Branco Dos Santos F, Du W, Hellingwerf KJ

Abstract
[This corrects the article on p. 36 in vol. 2, PMID: 25279375.].

PMID: 27148526 [PubMed - as supplied by publisher]

Data-based Reconstruction of Gene Regulatory Networks of Fungal Pathogens.

Front Microbiol. 2016;7:570

Authors: Guthke R, Gerber S, Conrad T, Vlaic S, Durmuş S, Çakır T, Sevilgen FE, Shelest E, Linde J

Abstract
In the emerging field of systems biology of fungal infection, one of the central roles belongs to the modeling of gene regulatory networks (GRNs). Utilizing omics-data, GRNs can be predicted by mathematical modeling. Here, we review current advances of data-based reconstruction of both small-scale and large-scale GRNs for human pathogenic fungi. The advantage of large-scale genome-wide modeling is the possibility to predict central (hub) genes and thereby indicate potential biomarkers and drug targets. In contrast, small-scale GRN models provide hypotheses on the mode of gene regulatory interactions, which have to be validated experimentally. Due to the lack of sufficient quantity and quality of both experimental data and prior knowledge about regulator-target gene relations, the genome-wide modeling still remains problematic for fungal pathogens. While a first genome-wide GRN model has already been published for Candida albicans, the feasibility of such modeling for Aspergillus fumigatus is evaluated in the present article. Based on this evaluation, opinions are drawn on future directions of GRN modeling of fungal pathogens. The crucial point of genome-wide GRN modeling is the experimental evidence, both used for inferring the networks (omics 'first-hand' data as well as literature data used as prior knowledge) and for validation and evaluation of the inferred network models.

PMID: 27148247 [PubMed]

Research Infrastructure for Collaborative Team Science: Challenges in Technology-Supported Workflows in and Across Laboratories, Institutions, and Geographies.

Semin Nephrol. 2015 May;35(3):291-302

Authors: Mirel B, Luo A, Harris M

Abstract
Collaborative research has many challenges. One under-researched challenge is how to align collaborators' research practices and evolving analytical reasoning with technologies and configurations of technologies that best support them. The goal of such alignment is to enhance collaborative problem solving capabilities in research. Toward this end, we draw on our own research and a synthesis of the literature to characterize the workflow of collaborating scientists in systems-level renal disease research. We describe the various phases of a hypothetical workflow among diverse collaborators within and across laboratories, extending from their primary analysis through secondary analysis. For each phase, we highlight required technology supports, and. At time, complementary organizational supports. This survey of supports matching collaborators' analysis practices and needs in research projects to technological support is preliminary, aimed ultimately at developing a research capability framework that can help scientists and technologists mutually understand workflows and technologies that can help enable and enhance them.

PMID: 26215866 [PubMed - indexed for MEDLINE]

APOL1 Kidney Disease Risk Variants: An Evolving Landscape.

Semin Nephrol. 2015 May;35(3):222-36

Authors: Dummer PD, Limou S, Rosenberg AZ, Heymann J, Nelson G, Winkler CA, Kopp JB

Abstract
Apolipoprotein L1 (APOL1) genetic variants account for much of the excess risk of chronic and end-stage kidney disease, which results in a significant global health disparity for persons of African ancestry. We estimate the lifetime risk of kidney disease in APOL1 dual-risk allele individuals to be at least 15%. Experimental evidence suggests a direct role of APOL1 in pore formation, cellular injury, and programmed cell death in renal injury. The APOL1 BH3 motif, often associated with cell death, is unlikely to play a role in APOL1-induced cytotoxicity because it is not conserved within the APOL family and is dispensable for cell death in vitro. We discuss two models for APOL1 trypanolytic activity: one involving lysosome permeabilization and another involving colloid-osmotic swelling of the cell body, as well as their relevance to human pathophysiology. Experimental evidence from human cell culture models suggests that both mechanisms may be operative. A systems biology approach whereby APOL1-associated perturbations in gene and protein expression in affected individuals are correlated with molecular pathways may be productive to elucidate APOL1 function in vivo.

PMID: 26215860 [PubMed - indexed for MEDLINE]