S100A9+ MDSC and TAM-mediated EGFR-TKI resistance in lung adenocarcinoma: the role of RELB.

Oncotarget. 2018 Jan 26;9(7):7631-7643

Authors: Feng PH, Yu CT, Chen KY, Luo CS, Wu SM, Liu CY, Kuo LW, Chan YF, Chen TT, Chang CC, Lee CN, Chuang HC, Lin CF, Han CL, Lee WH, Lee KY

Abstract
Background: Monocytic myeloid-derived suppressor cells (MDSCs), particularly the S100A9+ subset, has been shown initial clinical relevance. However, its role in EGFR-mutated lung adenocarcinoma, especially to EGFR-tyrosine kinase inhibitor (EGFR-TKI) is not clear. In a clinical setting of EGFR mutated lung adenocarcinoma, a role of the MDSC apart from T cell suppression was also investigated.
Results: Blood monocytic S100A9+ MDSC counts were higher in lung cancer patients than healthy donors, and were associated with poor treatment response and shorter progression-free survival (PFS). S100A9+ MDSCs in PBMC were well correlated to tumor infiltrating CD68+ and S100A9+ cells, suggesting an origin of TAMs. Patient's MDMs, mostly from S100A9+ MDSC, similar to primary alveolar macrophages from patients, both expressed S100A9 and CD206, attenuated EGFR-TKI cytotoxicity. Microarray analysis identified up-regulation of the RELB signaling genes, confirmed by Western blotting and functionally by RELB knockdown.
Conclusions: In conclusion, blood S100A9+ MDSC is a predictor of poor treatment response to EGFR-TKI, possibly via its derived TAMs through activation of the non-canonical NF-κB RELB pathway.
Methods: Patients with activating EGFR mutation lung adenocarcinoma receiving first line EGFR TKIs were prospectively enrolled. Peripheral blood mononuclear cells (PBMCs) were collected for MDSCs analysis and for monocyte-derived macrophages (MDMs) and stored tissue for TAM analysis by IHC. A transwell co-culture system of MDMs/macrophages and H827 cells was used to detect the effect of macrophages on H827 and microarray analysis to explore the underlying molecular mechanisms, functionally confirmed by RNA interference.

PMID: 29484139 [PubMed]

Pharmacogenetics as Personalized Medicine: Association Investigation of SOD2 rs4880, CYP2C19 rs4244285, and FCGR2A rs1801274 Polymorphisms in a Breast Cancer Population in Iraqi Women.

Clin Breast Cancer. 2018 Jan 31;:

Authors: Jabir FA, Hoidy WH

Abstract
BACKGROUND: Breast cancer is the most common cancer in women characterized by a high variable clinical outcome among individuals treated with targeted therapies.
PATIENTS AND METHODS: In this study, we performed a population-based approach intersecting high-throughput genotype data from Iraqi populations with publicly available pharmacogenomics information to estimate the frequency of genotypes correlated with responsiveness to breast cancer treatment thus improving the clinical management of this disease in an efficient and cost effective way. A total of 50 patients and 25 healthy controls were enrolled in our study. Genotyping of rs4880, rs4244285, and rs1801274 were examined in association with breast cancer in Iraqi women.
RESULTS: We found that individuals carrying the CT genotype of rs4880 manifested an increased risk of breast cancer compared with those carrying the TT genotype (odds ratio [OR], 0.171; 95% confidence interval [CI], 0.053-0.551; P = .002). In the dominant model, we observed that the CT and CC genotype of rs4880 showed an increased risk of breast cancer compared with the TT genotype (OR, 0.248; 95% CI, 0.089-0.690; P = .006). Moreover, subjects with the GA genotype of rs4244285 presented a higher risk of breast cancer than the GG genotype (OR, 0.256; 95% CI, 0.066-0.987; P = .038) and dominant models (OR, 0.025; 95% CI, 0.054-0.775; P = .013).
CONCLUSION: The analysis revealed that rs1801274 showed linkage disequilibrium and decreased risk of breast cancer. In conclusion, our study suggests that rs4880 and rs4244285 polymorphisms play an important role in development of breast cancer in an Iraqi population, and no significant association was found between rs1801274 and the risk of breast cancer.

PMID: 29482947 [PubMed - as supplied by publisher]

COL3A1 and SNAP91: novel glioblastoma markers with diagnostic and prognostic value.

Oncotarget. 2016 Oct 25;7(43):70494-70503

Authors: Gao YF, Mao XY, Zhu T, Mao CX, Liu ZX, Wang ZB, Li L, Li X, Yin JY, Zhang W, Zhou HH, Liu ZQ

Abstract
Although patients with glioblastoma (GBM) have grave prognosis, significant variability in patient outcome is observed. This study aims to identify novel targets for GBM diagnosis and therapy. Microarray data (GSE4290, GSE7696, and GSE4412) obtained from the Gene Expression Omnibus was used to identify the differentially expressed genes (DEGs) by significant analysis of microarray (SAM). Intersection of the identified DEGs for each profile revealed 46 DEGs in GBM. A subset of common DEGs were validated by real-time reverse transcription quantitative PCR (qPCR). The prognostic value of some of the markers was also studied. We determined that RRM2 and COL3A1 were increased and directly correlated with glioma grade, while SH3GL2 and SNAP91 were decreased in GBM and inversely correlated with glioma grade. Kaplan-Meir analysis of GSE7696 revealed that COL3A1 and SNAP91 correlated with survival, suggesting that COL3A1 and SNAP91 may be suitable biomarkers for diagnostic or therapeutic strategies for GBM.

PMID: 27655637 [PubMed - indexed for MEDLINE]

Next-generation sequencing reveals substantial genetic contribution to dementia with Lewy bodies.

Neurobiol Dis. 2016 Oct;94:55-62

Authors: Geiger JT, Ding J, Crain B, Pletnikova O, Letson C, Dawson TM, Rosenthal LS, Pantelyat A, Gibbs JR, Albert MS, Hernandez DG, Hillis AE, Stone DJ, Singleton AB, North American Brain Expression Consortium, Hardy JA, Troncoso JC, Scholz SW

Abstract
Dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia after Alzheimer's disease. Although an increasing number of genetic factors have been connected to this debilitating condition, the proportion of cases that can be attributed to distinct genetic defects is unknown. To provide a comprehensive analysis of the frequency and spectrum of pathogenic missense mutations and coding risk variants in nine genes previously implicated in DLB, we performed exome sequencing in 111 pathologically confirmed DLB patients. All patients were Caucasian individuals from North America. Allele frequencies of identified missense mutations were compared to 222 control exomes. Remarkably, ~25% of cases were found to carry a pathogenic mutation or risk variant in APP, GBA or PSEN1, highlighting that genetic defects play a central role in the pathogenesis of this common neurodegenerative disorder. In total, 13% of our cohort carried a pathogenic mutation in GBA, 10% of cases carried a risk variant or mutation in PSEN1, and 2% were found to carry an APP mutation. The APOE ε4 risk allele was significantly overrepresented in DLB patients (p-value <0.001). Our results conclusively show that mutations in GBA, PSEN1, and APP are common in DLB and consideration should be given to offer genetic testing to patients diagnosed with Lewy body dementia.

PMID: 27312774 [PubMed - indexed for MEDLINE]

14 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2018/02/27

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Vitamin D receptor (VDR) non-synonymous single nucleotide polymorphisms (nsSNPs) affect the calcitriol drug response - A theoretical insight.

J Mol Graph Model. 2018 Feb 12;81:14-24

Authors: Muthusamy K, Nagamani S

Abstract
Pharmacogenetics and pharmacogenomics have become presumptive with advancements in next-generation sequencing technology. In complex diseases, distinguishing the feasibility of pathogenic and neutral disease-causing variants is a time consuming and expensive process. Recent drug research and development processes mainly rely on the relationship between the genotype and phenotype through Single nucleotide polymorphisms (SNPs). The SNPs play an indispensable role in elucidating the individual's vulnerability to disease and drug response. The understanding of the interplay between these leads to the establishment of personalized medicine. In order to address this issue, we developed a computational pipeline of vitamin D receptor (VDR) for SNP centered study by application of elegant molecular docking and molecular dynamics simulation approaches. In a few SNPs the volume of the binding cavities has increased in mutant structures when compared to the wild type, indicating a weakening in interaction (699.1 Å3 in wild type Vs. 738.8 in Leu230Val, 820.7 Å3 in Arg247Leu). This also differently reflected in the H-bond interactions and binding free energies -169.93 kcal/mol (wild type) Vs -156.43 kcal/mol (R154W), -105.49 kcal/mol (R274L) in Leu230Val and Arg247Leu respectively. Although we could not find noteworthy changes in the binding free energies and binding pocket in the remaining mutations, the H-bond interactions made these SNPs deleterious. Thus, we further analyzed the H-bond interactions and distances using molecular dynamics (MD) simulation studies.

PMID: 29476931 [PubMed - as supplied by publisher]

Phosphorylation of AKT and ERK1/2 and mutations of PIK3CA and PTEN are predictive of breast cancer cell sensitivity to everolimus in vitro.

Cancer Chemother Pharmacol. 2018 Feb 23;:

Authors: Citi V, Del Re M, Martelli A, Calderone V, Breschi MC, Danesi R

Abstract
BACKGROUND: Everolimus is the hydroxyethyl derivative of sirolimus and a strong inhibitor of mammalian target of rapamycin (mTOR). This drug has immunosuppressive and anticancer activities and the present in vitro study was aimed at identifying the cellular and molecular profiles of breast cancer cells predictive of sensitivity to everolimus.
MATERIALS AND METHODS: MCF-7, T-47D, ZR-75-1, CAMA-1, HCC-1500 and MCF-10A cells were used and viability was assessed using WST-1 dye. Sensitivity to everolimus was correlated with phosphorylation of AKT (Ser473/Thr308), mTOR (Ser2448), and ERK1/2 (Thr202/Tyr204) and mutational profile of KRAS, NRAS, BRAF, PIK3CA, PTEN, TSC1, TSC2 and FRAP genes. Protein phosphorylation was evaluated by AlphaScreen SureFire, while the mutational status was examined by digital droplet PCR and Sanger sequencing.
RESULTS: Everolimus showed a transient growth inhibition in non-tumorigenic cells, while in tumorigenic lines the drug suppressed the proliferation in a concentration-dependent manner but with different potency (IC50) and efficacy (Emax), being ZR-75-1 the most sensitive and T47D the least sensitive. MCF-7, T47D and HCC1500 had activating mutations in PIK3CA gene, while loss-of-activity PTEN mutations were detected in sensitive cell lines, including ZR-75-1, which showed no changes or minimal increase in the amount of p-AKT(Ser473/Thr308) and p-ERK1/2(Thr202/Tyr204) induced by everolimus compared to the resistant cell line T47D in which phosphorylation of AKT and ERK was increased.
CONCLUSIONS: Cellular levels of p-AKT(Ser473/Thr308) and p-ERK1/2(Thr202/Tyr204), activating mutations of PIK3CA and inactivating mutations of PTEN may predict response to everolimus in breast cancer cells; these findings have potential applications for treatment personalization of everolimus in breast cancer patients.

PMID: 29476223 [PubMed - as supplied by publisher]

14 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2018/02/24

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

15 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2018/02/23

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

[MODERN VIEWS ON THE PHARMACOGENETICS OF PAIN.]

Anesteziol Reanimatol. 2017 Sep;61:219-223

Authors: Makharin OA, Zhenilo VM, Patyuchenko OY

Abstract
Quality anesthesia during surgery and in the postoperative period remains a topical problem of modern anesthesiology. The study of genetic characteristics of a patient is a goal that may be allow us to develop a personalized approach to solve this problem. The purpose of the review is a synthesis of literature data about the influence of genetic factors on pain perception and its treatment. The review included information obtained from SCOPUS, MedLine, EMBASE. The search keywords were: pain, pharmacogenetics, polymorphism, analgesics.Describe the effect ofgene polymorphisms of OPRM, 5HTRIA, 5HTR2A, COMT GCHI, SCN9A, KCNSI, CACNA2D3, CACNG2, PTGSI, PTGS2, MDRJ/ABCB] on the perception of pain, and CYP2D6, CYP2C9, CYP3A4 on the pharmacokinetics and pharmacodynamics of medi- cations used in the treatment of pain.

PMID: 29465208 [PubMed - in process]

Pharmacogenetic Testing May Improve Drug Treatments and Shorten Disability Leaves.

Benefits Q. 2017;33(1):43-49

Authors: Lefaivre A, Litinski V, Vandenhurk M

Abstract
This article describes how methods of personalized medicine-specifically, pharmacogenetic (PGx) testing-can benefit private health plans, benefits managers, care providers and consumers alike. The authors cover pharmacogenomics as a science and also introduce an innovative way to optimize drug treatments. The article touches on some important clinical outcomes drawn from a recent study in community pharmacy and reviews the application and return on investment of PGx testing in disability and medication management.

PMID: 29465186 [PubMed - in process]

Genetic variations in genes of the stress response pathway are associated with prolonged abstinence from heroin.

Pharmacogenomics. 2018 Feb 21;:

Authors: Levran O, Peles E, Randesi M, Correa da Rosa J, Shen PH, Rotrosen J, Adelson M, Kreek MJ

Abstract
AIM: This study assesses whether genetic variants in stress-related genes are associated with prolonged abstinence from heroin in subjects that are not in long-term methadone treatment.
METHODS: Frequencies of 117 polymorphisms in 30 genes were compared between subjects with history of heroin addiction, either without agonist treatment (n = 129) or in methadone maintenance treatment (n = 923).
RESULTS: SNP rs1500 downstream of CRHBP and an interaction of SNPs rs10482672 (NR3C1) and rs4234955 (NPY1R/NPY5R) were significantly associated with prolonged abstinence without agonist treatment.
CONCLUSION: This study suggests that variability in stress-related genes may contribute to the ability of certain subjects to remain in prolonged abstinence from heroin, possibly due to higher resilience to stress.

PMID: 29465008 [PubMed - as supplied by publisher]

Implications of KRAS mutations in acquired resistance to treatment in NSCLC.

Oncotarget. 2018 Jan 19;9(5):6630-6643

Authors: Re MD, Rofi E, Restante G, Crucitta S, Arrigoni E, Fogli S, Maio MD, Petrini I, Danesi R

Abstract
Rationale: KRAS is the most common and, simultaneously, the most ambiguous oncogene implicated in human cancer. Despite KRAS mutations were identified in Non Small Cell Lung Cancers (NSCLCs) more than 20 years ago, selective and specific inhibitors aimed at directly abrogating KRAS activity are not yet available. Nevertheless, many therapeutic approaches have been developed potentially useful to treat NSCLC patients mutated for KRAS and refractory to both standard chemotherapy and targeted therapies.The focus of this review will be to provide an overview of the network related to the intricate molecular KRAS pathways, stressing on preclinical and clinical studies that investigate the predictive value of KRAS mutations in NSCLC patients.
Materials and Methods: A bibliographic search of the Medline database was conducted for articles published in English, with the keywords KRAS, KRAS mutations in non-small cell lung cancer, KRAS and tumorigenesis, KRAS and TKIs, KRAS and chemotherapy, KRAS and monoclonal antibody, KRAS and immunotherapy, KRAS and drugs, KRAS and drug resistance.

PMID: 29464099 [PubMed]

Capecitabine efficacy is correlated with TYMP and RB expression in PDX established from triple-negative breast cancers.

Clin Cancer Res. 2018 Feb 20;:

Authors: Marangoni E, Laurent C, Coussy F, El Botty R, Chateau-Joubert S, Servely JL, de Plater L, Assayag F, Dahmani A, Montaudon E, Némati F, Fleury J, Vacher S, Gentien D, Rapinat A, Foidart P, Sounni NE, Noël A, Salomon A, Lae M, Decaudin D, Roman-Roman S, Bièche I, Piccard M, Reyal F

Abstract
PURPOSE: triple-negative breast cancer (TNBC) patients with residual disease after neoadjuvant chemotherapy have a poor outcome. We developed patient-derived xenografts (PDX) from residual tumors to identify efficient chemotherapies and predictive biomarkers in a context of resistance to anthracyclines and taxanes-based treatments.
EXPERIMENTAL DESIGN: PDX were established from residual tumors of primary breast cancer patients treated in neoadjuvant setting. TNBC PDX were treated by anthracyclines, taxanes, platins and capecitabine. Predictive biomarkers were identified by transcriptomic and immunohistological analysis. Downregulation of RB1 was performed by siRNA in a cell line established from a PDX.
RESULTS: residual TNBC PDX were characterized by a high tumor take, a short latency and a poor prognosis of the corresponding patients. With the exception of BRCA1/2 mutated models, residual PDX were resistant to anthracyclines, taxanes, and platins. Capecitabine, the oral prodrug of 5-FU, was highly efficient in 60% of PDX with two models showing complete responses. Prior treatment of a responder PDX with 5-FU increased expression of thymidylate synthase and decreased efficacy of capecitabine. Transcriptomic and IHC analyses of 32 TNBC PDX, including both residual tumors and treatment-naïve derived tumors, identified RB and TYMP proteins as predictive biomarkers for capecitabine response. Finally, RB1 knockdown in a cell line established from a capecitabine-responder PDX decreased sensitivity to 5-FU treatment.
CONCLUSIONS: we identified capecitabine as efficient chemotherapy in TNBC PDX models established from residual disease and resistant to anthracyclines, taxanes and platins. RB positivity and high expression of TYMP were significantly associated with capecitabine response.

PMID: 29463559 [PubMed - as supplied by publisher]

Defining drug response for stratified medicine.

Drug Discov Today. 2017 Jan;22(1):173-179

Authors: Lonergan M, Senn SJ, McNamee C, Daly AK, Sutton R, Hattersley A, Pearson E, Pirmohamed M

Abstract
The premise for stratified medicine is that drug efficacy, drug safety, or both, vary between groups of patients, and biomarkers can be used to facilitate more targeted prescribing, with the aim of improving the benefit:risk ratio of treatment. However, many factors can contribute to the variability in response to drug treatment. Inadequate characterisation of the nature and degree of variability can lead to the identification of biomarkers that have limited utility in clinical settings. Here, we discuss the complexities associated with the investigation of variability in drug efficacy and drug safety, and how consideration of these issues a priori, together with standardisation of phenotypes, can increase both the efficiency of stratification procedures and identification of biomarkers with the potential for clinical impact.

PMID: 27818254 [PubMed - indexed for MEDLINE]

Managing the Risk of CYP3A Induction in Drug Development: A Strategic Approach.

Drug Metab Dispos. 2017 Jan;45(1):35-41

Authors: Jones BC, Rollison H, Johansson S, Kanebratt KP, Lambert C, Vishwanathan K, Andersson TB

Abstract
Induction of cytochrome P450 (P450) can impact the efficacy and safety of drug molecules upon multiple dosing with coadministered drugs. This strategy is focused on CYP3A since the majority of clinically relevant cases of P450 induction are related to these enzymes. However, the in vitro evaluation of induction is applicable to other P450 enzymes; however, the in vivo relevance cannot be assessed because the scarcity of relevant clinical data. In the preclinical phase, compounds are screened using pregnane X receptor reporter gene assay, and if necessary structure-activity relationships (SAR) are developed. When projects progress toward the clinical phase, induction studies in a hepatocyte-derived model using HepaRG cells will generate enough robust data to assess the compound's induction liability in vivo. The sensitive CYP3A biomarker 4β-hydroxycholesterol is built into the early clinical phase I studies for all candidates since rare cases of in vivo induction have been found without any induction alerts from the currently used in vitro methods. Using this model, the AstraZeneca induction strategy integrates in vitro assays and in vivo studies to make a comprehensive assessment of the induction potential of new chemical entities. Convincing data that support the validity of both the in vitro models and the use of the biomarker can be found in the scientific literature. However, regulatory authorities recommend the use of primary human hepatocytes and do not advise the use of sensitive biomarkers. Therefore, primary human hepatocytes and midazolam studies will be conducted during the clinical program as required for regulatory submission.

PMID: 27777246 [PubMed - indexed for MEDLINE]

Propranolol induced G0/G1/S phase arrest and apoptosis in melanoma cells via AKT/MAPK pathway.

Oncotarget. 2016 10 18;7(42):68314-68327

Authors: Zhou C, Chen X, Zeng W, Peng C, Huang G, Li X, Ouyang Z, Luo Y, Xu X, Xu B, Wang W, He R, Zhang X, Zhang L, Liu J, Knepper TC, He Y, McLeod HL

Abstract
Both preclinical and epidemiology studies associate β-adrenoceptors-blockers (β-blockers) with activity against melanoma. However, the underlying mechanism is still unclear, especially in acral melanoma. In this study, we explored the effect of propranolol, a non-selective β-blocker, on the A375 melanoma cell line, two primary acral melanoma cell lines (P-3, P-6) and mice xenografts. Cell viability assay demonstrated that 50μM-400μM of propranolol inhibited viability in a concentration and time dependent manner with an IC50 ranging from 65.33μM to 148.60μM for 24h -72h treatment, but propranolol (less than 200μM) had no effect on HaCaT cell line. Western blots showed 100μM propranolol significantly reduced the expression of Bcl-2 while increasing the expressions of Bax, cytochrome c, cleaved capase-9 and cleaved caspase-3, and down-regulated the levels of p-AKT, p-BRAF, p-MEK1/2 and p-ERK1/2 in melanoma cells, after a 24h incubation. The in vivo data confirmed the isolation results. Mice received daily ip. administration of propranolol at the dose of 2 mg/kg for 3 weeks and the control group was treated with the same volume of saline. The mean tumor volume at day 21 in A375 xenografts was 82.33 ± 3.75mm3vs. 2044.67 ± 54.57mm3 for the propranolol-treated mice and the control group, respectively, and 31.66 ± 4.67 mm3vs. 1074.67 ± 32.17 mm3 for the P-3 xenografts. Propranolol also reduced Ki67, inhibited phosphorylation of AKT, BRAF, MEK1/2 and ERK1/2 in xenografts. These are the first data to demonstrate that propranolol might inhibit melanoma by activating the intrinsic apoptosis pathway and inactivating the MAPK and AKT pathways.

PMID: 27582542 [PubMed - indexed for MEDLINE]

N-acetylcysteine in a Double-Blind Randomized Placebo-Controlled Trial: Toward Biomarker-Guided Treatment in Early Psychosis.

Schizophr Bull. 2018 Feb 15;44(2):317-327

Authors: Conus P, Seidman LJ, Fournier M, Xin L, Cleusix M, Baumann PS, Ferrari C, Cousins A, Alameda L, Gholam-Rezaee M, Golay P, Jenni R, Woo TW, Keshavan MS, Eap CB, Wojcik J, Cuenod M, Buclin T, Gruetter R, Do KQ

Abstract
Biomarker-guided treatments are needed in psychiatry, and previous data suggest oxidative stress may be a target in schizophrenia. A previous add-on trial with the antioxidant N-acetylcysteine (NAC) led to negative symptom reductions in chronic patients. We aim to study NAC's impact on symptoms and neurocognition in early psychosis (EP) and to explore whether glutathione (GSH)/redox markers could represent valid biomarkers to guide treatment. In a double-blind, randomized, placebo-controlled trial in 63 EP patients, we assessed the effect of NAC supplementation (2700 mg/day, 6 months) on PANSS, neurocognition, and redox markers (brain GSH [GSHmPFC], blood cells GSH levels [GSHBC], GSH peroxidase activity [GPxBC]). No changes in negative or positive symptoms or functional outcome were observed with NAC, but significant improvements were found in favor of NAC on neurocognition (processing speed). NAC also led to increases of GSHmPFC by 23% (P = .005) and GSHBC by 19% (P = .05). In patients with high-baseline GPxBC compared to low-baseline GPxBC, subgroup explorations revealed a link between changes of positive symptoms and changes of redox status with NAC. In conclusion, NAC supplementation in a limited sample of EP patients did not improve negative symptoms, which were at modest baseline levels. However, NAC led to some neurocognitive improvements and an increase in brain GSH levels, indicating good target engagement. Blood GPx activity, a redox peripheral index associated with brain GSH levels, could help identify a subgroup of patients who improve their positive symptoms with NAC. Thus, future trials with antioxidants in EP should consider biomarker-guided treatment.

PMID: 29462456 [PubMed - in process]

The Impact of NOD2 Variants on Fecal Microbiota in Crohn's Disease and Controls Without Gastrointestinal Disease.

Inflamm Bowel Dis. 2018 Feb 15;24(3):583-592

Authors: Kennedy NA, Lamb CA, Berry SH, Walker AW, Mansfield J, Parkes M, Simpkins R, Tremelling M, Nutland S, UK IBD Genetics Consortium, Parkhill J, Probert C, Hold GL, Lees CW

Abstract
Background/Aims: Current models of Crohn's disease (CD) describe an inappropriate immune response to gut microbiota in genetically susceptible individuals. NOD2 variants are strongly associated with development of CD, and NOD2 is part of the innate immune response to bacteria. This study aimed to identify differences in fecal microbiota in CD patients and non-IBD controls stratified by NOD2 genotype.
Methods: Patients with CD and non-IBD controls of known NOD2 genotype were identified from patients in previous UK IBD genetics studies and the Cambridge bioresource (genotyped/phenotyped volunteers). Individuals with known CD-associated NOD2 mutations were matched to those with wild-type genotype. We obtained fecal samples from patients in clinical remission with low fecal calprotectin (<250 µg/g) and controls without gastrointestinal disease. After extracting DNA, the V1-2 region of 16S rRNA genes were polymerase chain reaction (PCR)-amplified and sequenced. Analysis was undertaken using the mothur package. Volatile organic compounds (VOC) were also measured.
Results: Ninety-one individuals were in the primary analysis (37 CD, 30 bioresource controls, and 24 household controls). Comparing CD with nonIBD controls, there were reductions in bacterial diversity, Ruminococcaceae, Rikenellaceae, and Christensenellaceae and an increase in Enterobacteriaceae. No significant differences could be identified in microbiota by NOD2 genotype, but fecal butanoic acid was higher in Crohn's patients carrying NOD2 mutations.
Conclusions: In this well-controlled study of NOD2 genotype and fecal microbiota, we identified no significant genotype-microbiota associations. This suggests that the changes associated with NOD2 genotype might only be seen at the mucosal level, or that environmental factors and prior inflammation are the predominant determinant of the observed dysbiosis in gut microbiota.

PMID: 29462388 [PubMed - in process]

Improving stability of prediction models based on correlated omics data by using network approaches.

PLoS One. 2018;13(2):e0192853

Authors: Tissier R, Houwing-Duistermaat J, Rodríguez-Girondo M

Abstract
Building prediction models based on complex omics datasets such as transcriptomics, proteomics, metabolomics remains a challenge in bioinformatics and biostatistics. Regularized regression techniques are typically used to deal with the high dimensionality of these datasets. However, due to the presence of correlation in the datasets, it is difficult to select the best model and application of these methods yields unstable results. We propose a novel strategy for model selection where the obtained models also perform well in terms of overall predictability. Several three step approaches are considered, where the steps are 1) network construction, 2) clustering to empirically derive modules or pathways, and 3) building a prediction model incorporating the information on the modules. For the first step, we use weighted correlation networks and Gaussian graphical modelling. Identification of groups of features is performed by hierarchical clustering. The grouping information is included in the prediction model by using group-based variable selection or group-specific penalization. We compare the performance of our new approaches with standard regularized regression via simulations. Based on these results we provide recommendations for selecting a strategy for building a prediction model given the specific goal of the analysis and the sizes of the datasets. Finally we illustrate the advantages of our approach by application of the methodology to two problems, namely prediction of body mass index in the DIetary, Lifestyle, and Genetic determinants of Obesity and Metabolic syndrome study (DILGOM) and prediction of response of each breast cancer cell line to treatment with specific drugs using a breast cancer cell lines pharmacogenomics dataset.

PMID: 29462177 [PubMed - in process]