An Integrated Data Driven Approach to Drug Repositioning Using Gene-Disease Associations.

PLoS One. 2016;11(5):e0155811

Authors: Mullen J, Cockell SJ, Woollard P, Wipat A

Abstract
Drug development is both increasing in cost whilst decreasing in productivity. There is a general acceptance that the current paradigm of R&D needs to change. One alternative approach is drug repositioning. With target-based approaches utilised heavily in the field of drug discovery, it becomes increasingly necessary to have a systematic method to rank gene-disease associations. Although methods already exist to collect, integrate and score these associations, they are often not a reliable reflection of expert knowledge. Furthermore, the amount of data available in all areas covered by bioinformatics is increasing dramatically year on year. It thus makes sense to move away from more generalised hypothesis driven approaches to research to one that allows data to generate their own hypothesis. We introduce an integrated, data driven approach to drug repositioning. We first apply a Bayesian statistics approach to rank 309,885 gene-disease associations using existing knowledge. Ranked associations are then integrated with other biological data to produce a semantically-rich drug discovery network. Using this network, we show how our approach identifies diseases of the central nervous system (CNS) to be an area of interest. CNS disorders are identified due to the low numbers of such disorders that currently have marketed treatments, in comparison to other therapeutic areas. We then systematically mine our network for semantic subgraphs that allow us to infer drug-disease relations that are not captured in the network. We identify and rank 275,934 drug-disease has_indication associations after filtering those that are more likely to be side effects, whilst commenting on the top ranked associations in more detail. The dataset has been created in Neo4j and is available for download at https://bitbucket.org/ncl-intbio/genediseaserepositioning along with a Java implementation of the searching algorithm.

PMID: 27196054 [PubMed - as supplied by publisher]

Whole Exome Sequencing in a Rare Disease: A Patient with Anomalous Left Coronary Artery from the Pulmonary Artery (Bland-White-Garland Syndrome).

OMICS. 2016 May;20(5):325-327

Authors: Hekim N, Batyraliev T, Trujillano D, Wang W, Dandara C, Karben Z, Saygılı Eİ, Çetin Z, Mıhcıoğlu D, Türkmen S, İkidağ MA, Cüce MA, Rolfs A

PMID: 27195969 [PubMed - as supplied by publisher]

A Novel ECM1 Splice Site Mutation in Lipoid Proteinosis: Case Report plus Review of the Literature.

Mol Syndromol. 2016 Apr;7(1):26-31

Authors: Rey LK, Kohlhase J, Möllenhoff K, Dekomien G, Epplen JT, Hoffjan S

Abstract
Lipoid proteinosis (LP) is an autosomal recessive genodermatosis known to be caused by mutations in ECM1. Nonsense and missense mutations are the most common variations in LP. Up to date, only 6 splice site mutations have been observed. We report on a 26-year-old female LP patient from a Turkish consanguineous family carrying a novel homozygous splice site mutation in intron 8 of the ECM1 gene and summarize the current knowledge on ECM1 mutations and possible genotype-phenotype correlations.

PMID: 27194970 [PubMed]

First reported association of chronic lymphocytic leukaemia and interstitial granulomatous dermatitis.

BMJ Case Rep. 2016;2016

Authors: Riaz IB, Kamal MU, Segal RJ, Anwer F

Abstract
Interstitial granulomatous dermatitis (IGD), a rare disease, is well known to be associated with connective tissue disorders, malignancies and several drugs. We describe this first case of IGD in association with chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL). A 66-year-old woman with a 6-year history of untreated CLL/SLL, presented with a 2-month history of progressively worsening eruption of the left thigh, along with fatigue, lymphadenopathy and night sweats. Skin biopsy showed findings consistent with IGD and infiltration of CLL. The eruption was non-responsive to treatment with antibiotics and local steroids. There was a significant improvement in the rash after an initial cycle of chemotherapy (combination therapy with bendamustine and rituximab) and complete resolution by the third cycle, for the treatment of her CLL. We suggest that the possibility of an underlying haematological malignancy should be investigated in patients with a skin rash non-responsive to conventional therapy.

PMID: 27194675 [PubMed - in process]

The partnership of patient advocacy groups and clinical investigators in the rare diseases clinical research network.

Orphanet J Rare Dis. 2016;11(1):66

Authors: Merkel PA, Manion M, Gopal-Srivastava R, Groft S, Jinnah HA, Robertson D, Krischer JP, Rare Diseases Clinical Research Network

Abstract
BACKGROUND: Among the unique features of the Rare Diseases Clinical Research Network (RDCRN) Program is the requirement for each Consortium to include patient advocacy groups (PAGs) as research partners. This development has transformed the work of the RDCRN and is a model for collaborative research. This article outlines the roles patients and PAGs play in the RDCRN and reports on the PAGs' impact on the Network's success.
METHODS: Principal Investigators from the 17 RDCRN Consortia and 28 representatives from 76 PAGs affiliated with these Consortia were contacted by email to provide feedback via an online RDCRN survey. Impact was measured in the key areas of 1) Research logistics; 2) Outreach and communication; and 3) Funding and in-kind support. Rating choices were: 1-very negative, 2-somewhat negative, 3-no impact, 4-somewhat positive, and 5-very positive.
RESULTS: Twenty-seven of the PAGs (96 %) disseminate information about the RDCRN within the patient community. The Consortium Principal Investigators also reported high levels of PAG involvement. Sixteen (94 %) Consortium Principal Investigators and 25 PAGs (89 %) reported PAGs participation in protocol review, study design, Consortium conference calls, attending Consortium meetings, or helping with patient recruitment.
CONCLUSIONS: PAGs are actively involved in shaping Consortia's research agendas, help ensure the feasibility and success of research protocols by assisting with study design and patient recruitment, and support training programs. This extensive PAG-Investigator partnership in the RDCRN has had a strongly positive impact on the success of the Network.

PMID: 27194034 [PubMed - as supplied by publisher]

Portosystemic Shunt Surgery in Patients with Idiopathic Noncirrhotic Portal Hypertension.

Ann Transplant. 2016;21:317-20

Authors: Karagul S, Yagci MA, Tardu A, Ertugrul I, Kirmizi S, Sumer F, Isik B, Kayaalp C, Yilmaz S

Abstract
BACKGROUND Idiopathic noncirrhotic portal hypertension (INCPH) is a rare disease characterized by increased portal venous pressure in the absence of cirrhosis and other causes of liver diseases. The aim of the present study was to present our results in using portosystemic shunt surgery in patients with INCPH. MATERIAL AND METHODS Patients who had been referred to our Liver Transplantation Institute for liver transplantation and who had undergone surgery from January 2010 to December 2015 were retrospectively analyzed. Patients with INCPH who had undergone portosystemic shunt procedure were included in the study. Age, sex, symptoms and findings, type of portosystemic shunt, and postoperative complications were assessed. RESULTS A total of 1307 patients underwent liver transplantation from January 2010 to December 2015. Eleven patients with INCPH who did not require liver transplantation were successfully operated on with a portosystemic shunt procedure. The mean follow-up was 30.1±19 months (range 7-69 months). There was no mortality in the perioperative period or during the follow-up. Two patients underwent surgery again due to intra-abdominal hemorrhage; one had bleeding from the surgical site except the portacaval anastomosis and the other had bleeding from the h-graft anastomosis. No patient developed encephalopathy and no patient presented with esophageal variceal bleeding after portosystemic shunt surgery. Shunt thrombosis occurred in 1 patient (9.9%). Only 1 patient developed ascites, which was controlled medically. CONCLUSIONS Portosystemic shunt surgery is a safe and effective procedure for the treatment of patients with INCPH.

PMID: 27194018 [PubMed - in process]

Altered localization and functionality of TAR DNA Binding Protein 43 (TDP-43) in niemann- pick disease type C.

Acta Neuropathol Commun. 2016;4(1):52

Authors: Dardis A, Zampieri S, Canterini S, Newell KL, Stuani C, Murrell JR, Ghetti B, Fiorenza MT, Bembi B, Buratti E

Abstract
Niemann-Pick type C (NPC) disease is a lysosomal storage disorder characterized by the occurrence of visceral and neurological symptoms. At present, the molecular mechanisms causing neurodegeneration in this disease are unknown. Here we report the altered expression and/or mislocalization of the TAR-DNA binding protein 43 (TDP-43) in both NPC mouse and in a human neuronal model of the disease. We also report the neuropathologic study of a NPC patient's brain, showing that while TDP-43 is below immunohistochemical detection in nuclei of cerebellar Purkinje cells, it has a predominant localization in the cytoplasm of these cells. From a functional point of view, the TDP-43 mislocalization, that occurs in a human experimental neuronal model system, is associated with specific alterations in TDP-43 controlled genes. Most interestingly, treatment with N-Acetyl-cysteine (NAC) or beta-cyclodextrin (CD) can partially restore TDP-43 nuclear localization. Taken together, the results of these studies extend the role of TDP-43 beyond the Amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD)/Alzheimer disease (AD) spectrum. These findings may open novel research/therapeutic avenues for a better understanding of both NPC disease and the TDP-43 proteinopathy disease mechanism.

PMID: 27193329 [PubMed - in process]

Novel European SLC1A4 variant: infantile spasms and population ancestry analysis.

J Hum Genet. 2016 May 19;

Authors: Conroy J, M Allen N, Gorman K, O'Halloran E, Shahwan A, Lynch B, Lynch SA, Ennis S, King MD

Abstract
SLC1A4 deficiency is a recently described neurodevelopmental disorder associated with microcephaly, global developmental delay, abnormal myelination, thin corpus callosum and seizures. It has been mainly reported in the Ashkenazi-Jewish population with affected individuals homozygous for the p.Glu256Lys variant. Exome sequencing performed in an Irish proband identified a novel homozygous nonsense SLC1A4 variant [p.Trp453*], confirming a second case of SLC1A4-associated infantile spasms. As this is the first European identified, population ancestry analysis of the Exome Aggregation Consortium database was performed to determine the wider ethnic background of SLC1A4 deficiency carriers. p.Glu256Lys was found in Hispanic and South Asian populations. Other potential disease-causing variants were also identified. Investigation for SLC1A4 deficiency should be performed regardless of ethnicity and extend to include unexplained early-onset epileptic encephalopathy.Journal of Human Genetics advance online publication, 19 May 2016; doi:10.1038/jhg.2016.44.

PMID: 27193218 [PubMed - as supplied by publisher]

A partial trace amine-associated receptor 1 agonist exhibits properties consistent with a methamphetamine substitution treatment.

Addict Biol. 2016 May 19;

Authors: Pei Y, Asif-Malik A, Hoener M, Canales JJ

Abstract
Recent evidence suggests that the trace amine-associated receptor 1 (TAAR1) plays a pivotal role in the regulation of dopamine (DA) transmission and psychostimulant action. Several selective TAAR1 agonists have previously shown efficacy in models of cocaine addiction. However, the effects of TAAR1 activation on methamphetamine (METH)-induced behaviours are less well understood, as indeed are the underlying neurochemical mechanisms mediating potential interactions between TAAR1 and METH. Here, in a progressive ratio schedule of reinforcement the partial TAAR1 agonist, RO5263397, reduced the break-point for METH self-administration, while significantly increasing responding maintained by food reward. Following self-administration and extinction training, RO5263397 completely blocked METH-primed reinstatement of METH seeking. Moreover, when used as a substitute, unlike a low dose of METH, which sustained vigorous responding when substituting for the training dose of METH, RO5263397 was not self-administered at any dose, thus exhibiting no apparent abuse liability. Fast-scan cyclic voltammetry experiments showed that RO5263397 prevented METH-induced DA overflow in slices of the nucleus accumbens, while having no effect on DA transmission in its own right. Collectively, the present observations demonstrate that partial TAAR1 activation decreases the motivation to self-administer METH, blocks METH-primed reinstatement of METH seeking and prevents METH-induced DA elevations in the nucleus accumbens, and strongly support the candidacy of TAAR1-based medications as potential substitute treatment in METH addiction.

PMID: 27193165 [PubMed - as supplied by publisher]

Clinical and pathologic features of patients with non-epithelial ovarian cancer: retrospective analysis of a single institution 15-year experience.

Clin Transl Oncol. 2016 May 18;

Authors: Kempf E, Desamericq G, Vieites B, Diaz-Padilla I, Calvo E, Estevez P, Garcia-Arreza A, Martinez-Maestre MA, Duran I

Abstract
PURPOSE: Non-epithelial ovarian cancers (NEOCs) are rare diseases. Despite their overall good prognosis, the best management and current prognostic factors remain unclear. The objective of our study was to assess the clinical and pathological features of NEOC patients treated in our institution in the last 15 years and to explore risk factors for relapse and survival.
METHODS/PATIENTS: All patients with a pathological diagnosis of NEOC referred to the medical oncology department at Hospital Universitario Virgen del Rocio between 1999 and 2014 were included. Demographics, tumor characteristics, treatment procedures, and clinical follow-up were retrospectively collected. Risk factors for disease-free survival (DFS) and overall survival (OS) were assessed.
RESULTS: Fifty-seven patients were included, 33 (58 %) had a sex cord-stromal tumor (SCST) and 24 (42 %) had a germ-cell tumor (GCT). Median age, non-conservative surgery rates and DFS were lower in the GCT cohort; however, salvage chemotherapy led to a high proportion of complete responses in this group translating into a 90 % 3-year OS rate in both NEOC subtypes. The only identified risk factors statistically significant were stage and tumour relapse that associated, respectively, with DFS (HR = 8.84; 95 % CI 1.85-42) and OS (HR = 11.02; 95 % CI 1.76-68.7).
CONCLUSIONS: Despite their rarity, NEOCs remain a highly curable group of neoplasm. In our series, a more conservative treatment approach in ovarian GCTs revealed comparable OS outcomes to SCST. No new risk factors that would help in patient stratification were identified.

PMID: 27193130 [PubMed - as supplied by publisher]

A de novo 0.63 Mb 6q25.1 deletion associated with growth failure, congenital heart defect, underdeveloped cerebellar vermis, abnormal cutaneous elasticity and joint laxity.

Am J Med Genet A. 2015 Sep;167A(9):2042-51

Authors: Salpietro V, Ruggieri M, Mankad K, Di Rosa G, Granata F, Loddo I, Moschella E, Calabro MP, Capalbo A, Bernardini L, Novelli A, Polizzi A, Seidler DG, Arrigo T, Briuglia S

Abstract
Deletions of the long arm of chromosome 6 are rare and are characterized by great clinical variability according to the deletion breakpoint. We report a on 6-year-old girl with a de novo 0.63 Mb deletion on chromosome 6q25.1 who demonstrated multiple congenital anomalies including a ventricular septal defect and an underdeveloped cerebellar vermis. She presented with severe pre- and post-natal growth failure, hyperextensible small joints (Beighton scores = 8/9; with normal parental scores), and an abnormally elastic, redundant skin. Abnormally high upper/lower segment ratio (i.e., 1.34 = > 3SD), mild dysmorphic facial features and developmental delay were also present. The girl's phenotype was compared with: (i) two girls, each previously reported by Bisgaard et al. and Caselli et al. with similar albeit larger (2.6-7.21 Mb) deletions; (ii) seven additional individuals (6 M; 1 F) harboring deletions within the 6q25.1 region reported in the literature; and (iii) ten further patients (5 M; 4 F; 1 unrecorded sex) recorded in the DECIPHER 6.0 database. We reported on the present girl as her findings could contribute to advance the phenotype of 6q deletions. In addition, the present deletion is the smallest so far recorded in the 6q25 region encompassing eight known genes [vs. 41 of Bisgaard et al., and 23 of Caselli et al.,], including the TAB2 (likely responsible for the girl's congenital heart defect), LATS1 gene, and the UST gene (a regulator of the homeostasis of proteoglycans, which could have played a role in the abnormal dermal and cartilage elasticity).

PMID: 25940952 [PubMed - indexed for MEDLINE]

Adenosine Hypothesis of Antipsychotic Drugs Revisited: Pharmacogenomics Variation in Nonacute Schizophrenia.

OMICS. 2016 May;20(5):283-289

Authors: Turčin A, Dolžan V, Porcelli S, Serretti A, Plesničar BK

Abstract
The existing antipsychotic therapy is based on dopamine hyperfunction and glutamate hypofunction hypotheses of schizophrenia. Adenosine receptors (ADORA) have a neuromodulatory role and can control dopaminergic and glutamatergic systems. To elucidate the effect of ADORA polymorphisms on psychopathological symptoms and adverse effects in patients with schizophrenia on long-term antipsychotic treatment, we examined 127 nonacute schizophrenia outpatients in a cross-sectional study using the Positive and Negative Symptoms Scale, Simpson-Angus Scale, Barnes Akathisia Rating Scale, and Abnormal Involuntary Movement Scale. All patients were genotyped for 18 polymorphisms in ADORA1, ADORA2A, and ADORA3. We found an association between ADORA1 rs3766566 and psychopathological symptoms (p = 0.006), in particular, with positive psychopathological symptoms (p = 0.010) and general psychopathological symptoms (p = 0.023), between ADORA2A rs2298383 and general psychopathological symptoms (p = 0.046), and between ADORA2A rs5751876 and akathisia (p = 0.015). Haplotype analysis showed an association between ADORA1 CTCAACG haplotype and overall psychopathological symptoms (p = 0.019), positive psychopathological symptoms (p = 0.021), and akathisia (p = 0.028). ADORA2A TCCTC haplotype was associated with parkinsonism (p = 0.014). ADORA3 CACTAC was associated with akathisia (p = 0.042), whereas CACTAT was associated with akathisia (p = 0.045) and tardive dyskinesia (p = 0.023). The results of this first comprehensive study on ADORA polymorphisms in patients with nonacute schizophrenia receiving long-term antipsychotic therapy suggest an important neuromodulatory role of ADORA receptors in both psychopathological symptoms and adverse effects of antipsychotics.

PMID: 27195966 [PubMed - as supplied by publisher]

Genome-Wide Association Study of Absolute QRS Voltage Identifies Common Variants of TBX3 as Genetic Determinants of Left Ventricular Mass in a Healthy Japanese Population.

PLoS One. 2016;11(5):e0155550

Authors: Sano M, Kamitsuji S, Kamatani N, Tabara Y, Kawaguchi T, Matsuda F, Yamagishi H, Fukuda K, Japan Pharmacogenomics Data Science Consortium (JPDSC)

Abstract
Left ventricular hypertrophy (LVH) represents a common final pathway leading to heart failure. We have searched for genetic determinants of left ventricular (LV) mass using values for absolute electrocardiographic QRS voltage in a healthy Japanese population. After adjusting for covariates, the corrected S and R wave voltages in leads V1 and V5 from 2,994 healthy volunteers in the Japan Pharmacogenomics Data Science Consortium (JPDSC) database were subjected to a genome-wide association study. Potential associations were validated by an in silico replication study using an independent Japanese population obtained from the Nagahama Prospective Genome Cohort for Comprehensive Human Bioscience. We identified a novel association between the lead V5, R wave voltage in Japanese individuals and SNP rs7301743[G], which maps near the gene encoding T-box transcription factor Tbx3. Meta-analysis of two independent Japanese datasets demonstrated a marginally significant association of SNP rs7301743 in TBX3|MED13L with a 0.071 mV (95% CI, 0.038-0.11 mV) shorter R wave amplitude in the V5 lead per minor allele copy (P = 7.635 x 10-8). The transcriptional repressor, TBX3, is proposed to suppress the development of working ventricular myocardium. Our findings suggest that genetic variation of Tbx3 is associated with LV mass in a healthy Japanese population.

PMID: 27195777 [PubMed - as supplied by publisher]

Genotyping NUDT15 can predict the dose reduction of 6-MP for children with acute lymphoblastic leukemia especially at a preschool age.

J Hum Genet. 2016 May 19;

Authors: Suzuki H, Fukushima H, Suzuki R, Hosaka S, Yamaki Y, Kobayashi C, Sakai A, Imagawa K, Iwabuchi A, Yoshimi A, Nakao T, Kato K, Tsuchida M, Kiyokawa N, Koike K, Noguchi E, Fukushima T, Sumazaki R

Abstract
The pharmacokinetics among children has been altered dynamically. The difference between children and adults is caused by immaturity in things such as metabolic enzymes and transport proteins. The periods when these alterations happen vary from a few days to some years after birth. We hypothesized that the effect of gene polymorphisms associated with the dose of medicine could be influenced by age. In this study, we analyzed 51 patients with childhood acute lymphoblastic leukemia (ALL) retrospectively. We examined the associations between the polymorphism in NUDT15 and clinical data, especially the dose of 6-mercaptopurine (6-MP). Ten of the patients were heterozygous for the variant allele in NUDT15. In patients under 7 years old with NUDT15 variant allele, the average administered dose of 6-MP was lower than that for the patients homozygous for the wild-type allele (P=0.04). Genotyping of NUDT15 could be a beneficial to estimate the tolerated dose of 6-MP for patients with childhood ALL, especially at a preschool age in Japan. Furthermore, the analysis with stratification by age might be useful in pharmacogenomics among children.Journal of Human Genetics advance online publication, 19 May 2016; doi:10.1038/jhg.2016.55.

PMID: 27193222 [PubMed - as supplied by publisher]

Exploiting microRNA Specificity and Selectivity: Paving a Sustainable Path Towards Precision Medicine.

Adv Exp Med Biol. 2015;888:1-3

Authors: Santulli G

Abstract
In his State of the Union address before both chambers of the US Congress, President Barack Obama called for increased investment in US infrastructure and research and announced the launch of a new Precision Medicine Initiative, aiming to accelerate biomedical discovery. Due to their well-established selectivity and specificity, microRNAs can represent a useful tool, both in diagnosis and therapy, in forging the path towards the achievement of precision medicine. This introductory chapter represents a guide for the Reader in examining the functional roles of microRNAs in the most diverse aspects of clinical practice, which will be explored in this third volume of the microRNA trilogy.

PMID: 26663175 [PubMed - indexed for MEDLINE]

[Functional annotation of rice WRKY transcription factors based on their transcriptional features].

Yi Chuan. 2016 Feb;38(2):126-36

Authors: Liyun L, Jianan S, Shuo Y, Caiqiang S, Guozhen L

Abstract
Transcription factors regulate alteration of transcription levels. Recently, huge amount of transcriptomic data are accumulated via the application of high throughput sequencing technology, and it is reasonable to postulate that in-depth analysis of transcription data could be used to enhance gene annotation. In this study, we chose the gene family of rice WRKY transcription factors. Based on literature search, the transcriptional data under different biological processes, including biotic and abiotic stress, development, and nutrient absorption and hormone treatments were analyzed systematically. To the end, we summarize the list of differentially expressed WRKY genes. We also expect that such information will enrich their functional annotation and also provide direct clues for subsequent functional studies.

PMID: 26907776 [PubMed - indexed for MEDLINE]

Genetic Approaches to Study Plant Responses to Environmental Stresses: An Overview.

Biology (Basel). 2016;5(2)

Authors: Moustafa K, Cross JM

Abstract
The assessment of gene expression levels is an important step toward elucidating gene functions temporally and spatially. Decades ago, typical studies were focusing on a few genes individually, whereas now researchers are able to examine whole genomes at once. The upgrade of throughput levels aided the introduction of systems biology approaches whereby cell functional networks can be scrutinized in their entireties to unravel potential functional interacting components. The birth of systems biology goes hand-in-hand with huge technological advancements and enables a fairly rapid detection of all transcripts in studied biological samples. Even so, earlier technologies that were restricted to probing single genes or a subset of genes still have their place in research laboratories. The objective here is to highlight key approaches used in gene expression analysis in plant responses to environmental stresses, or, more generally, any other condition of interest. Northern blots, RNase protection assays, and qPCR are described for their targeted detection of one or a few transcripts at a once. Differential display and serial analysis of gene expression represent non-targeted methods to evaluate expression changes of a significant number of gene transcripts. Finally, microarrays and RNA-seq (next-generation sequencing) contribute to the ultimate goal of identifying and quantifying all transcripts in a cell under conditions or stages of study. Recent examples of applications as well as principles, advantages, and drawbacks of each method are contrasted. We also suggest replacing the term "Next-Generation Sequencing (NGS)" with another less confusing synonym such as "RNA-seq", "high throughput sequencing", or "massively parallel sequencing" to avoid confusion with any future sequencing technologies.

PMID: 27196939 [PubMed - as supplied by publisher]

Revealing oxidative damage to enzymes of carbohydrate metabolism in yeast: An integration of 2D DIGE, quantitative proteomics and bioinformatics.

Proteomics. 2016 May 19;

Authors: Boone C, Grove R, Adamcova D, Braga C, Adamec J

Abstract
Clinical usage of lidocaine, a pro-oxidant has been linked with severe, mostly neurological complications. The mechanism(s) causing these complications is independent of the blockade of voltage gated sodium channels. The budding yeast S. cerevisiae lacks voltage gated sodium channels, thus provides an ideal system to investigate lidocaine induced protein and pathway alterations. Whole proteome alterations leading to these complications have not been identified. To address this S. cerevisiae was grown to stationary phase and exposed to an LC50 dose of lidocaine. The differential proteomes of lidocaine treatment and control were resolved six hours post exposure using 2D DIGE. Amine reactive dyes and carbonyl reactive dyes were used to assess protein abundance and protein oxidation, respectively. Quantitative analysis of these dyes ( ≥ 1.5-fold alteration, p ≤ 0.05 ) revealed a total of 33 proteoforms identified by mass spectrometry differing in abundance and/or oxidation upon lidocaine exposure. Network analysis showed enrichment of apoptotic proteins and cell wall maintenance proteins; while the abundance of proteins central to carbohydrate metabolism, such as triosephosphate isomerase and glyceraldehyde-3-phosphate dehydrogenase, and redox proteins superoxide dismutase and peroxiredoxin were significantly decreased. Enzymes of carbohydrate metabolism, such as phosphoglycerate kinase and enolase, the TCA cycle enzyme aconitase, and multiple ATP synthase subunits were found to be oxidatively modified. Also, the activity of aconitase was found to be decreased. Overall these data suggest that toxic doses of lidocaine induce significant disruption of glycolytic pathways, energy production, and redox balance potentially leading to cell malfunction and death. This article is protected by copyright. All rights reserved.

PMID: 27193513 [PubMed - as supplied by publisher]

Peptide-based systems analysis of inflammation induced myeloid-derived suppressor cells reveals diverse signaling pathways.

Proteomics. 2016 May 19;

Authors: Choksawangkarn W, Graham LM, Burke M, Lee SB, Ostrand-Rosenberg S, Fenselau C, Edwards NJ

Abstract
A better understanding of molecular signaling between myeloid-derived suppressor cells (MDSC), tumor cells, T-cells, and inflammatory mediators is expected to contribute to more effective cancer immunotherapies. We focus on plasma membrane associated proteins, which are critical in signaling and intercellular communication, and investigate changes in their abundance in MDSC of tumor-bearing mice subject to heightened versus basal inflammatory conditions. Using spectral counting, we observed statistically significant differential abundances for thirty-five proteins associated with the plasma membrane, most notably the pro-inflammatory proteins S100A8 and S100A9 which induce MDSC and promote their migration. We also tested whether the peptides associated with canonical pathways showed a statistically significant increase or decrease subject to heightened versus basal inflammatory conditions. Collectively, these studies used bottom-up proteomic analysis to identify plasma membrane associated pro-inflammatory molecules and pathways that drive MDSC accumulation, migration, and suppressive potency. This article is protected by copyright. All rights reserved.

PMID: 27193397 [PubMed - as supplied by publisher]

Minimum network constraint on reverse engineering to develop biological regulatory networks.

J Theor Biol. 2015 Sep 7;380:9-15

Authors: Shao B, Wu J, Tian B, Ouyang Q

Abstract
Reconstructing the topological structure of biological regulatory networks from microarray expression data or data of protein expression profiles is one of major tasks in systems biology. In recent years, various mathematical methods have been developed to meet this task. Here, based on our previously reported reverse engineering method, we propose a new constraint, i.e., the minimum network constraint, to facilitate the reconstruction of biological networks. Three well studied regulatory networks (the budding yeast cell cycle network, the fission yeast cell cycle network, and the SOS network of Escherichia coli) were used as the test sets to verify the performance of this method. Numerical results show that the biological networks prefer to use the minimal networks to fulfill their functional tasks, making it possible to apply minimal network criteria in the network reconstruction process. Two scenarios were considered in the reconstruction process: generating data using different initial conditions; and generating data from knock out and over-expression experiments. In both cases, network structures are revealed faithfully in a few steps using our approach.

PMID: 25981630 [PubMed - indexed for MEDLINE]