Refluxed Esterification of Fullerene-Conjugated P25 TiO2 Promotes Free Radical Scavenging Capacity and Facilitates Antiaging Potentials in Human Cells.

ACS Appl Mater Interfaces. 2019 Jan 09;11(1):311-319

Authors: Lee KC, Chen YL, Wang CC, Huang JH, Cho EC

Abstract
Titanium dioxide nanomaterials have good capability to prevent human cells from damage under UV irradiation. However, some studies indicated that the nanoscale of titanium dioxide could potentially cause harmful effects such as free radical generation under UV irradiation and thereby accelerate the progress of cell aging. Fullerenes can scavenge large amounts of free radicals due to the fact that fullerenes contain enormous amount of π electrons with low lying lowest unoccupied molecular orbital, but its adverse properties, such as the poor solubility in water, restricted the applicability. In this study, we employed water-soluble carboxylic acid fullerenes (C60-COOH and C70-COOH) as the free radical scavenger and modify onto the surface of titanium dioxide by refluxed esterification (P25/C60-COOH or C70-COOH) technique. The conformation and properties of these nanomaterials were characterized by techniques and equipment such as X-ray diffraction, energy dispersive spectroscopy analysis, scanning electron microscopy, thermal gravimetric analysis, high-resolution transmission electron microscopy, and Fourier transform infrared spectroscopy. We also introduced methylene blue and rhodamine B as indicators to evaluate and demonstrate the scavenging capacity of these nanomaterials. Moreover, we examined the biocompatibility and UV protection capacity of our P25/fullerene composites in human 293T cells, and applied luciferase activity assay to investigate the possible underlying cell protection mechanisms exhibited by these nanomaterials. Our data indicate that both P25/C60-COOH and P25/C70-COOH could protect human cells against UV exposure. P25/C70-COOH exhibits great anti-inflammation capacity, whereas P25/C60-COOH exhibits great anti-oxidative stress and anti-DNA damage capacity. Our results suggest that most of our P25/fullerene composite materials have the ability to reduce free radicals and exhibit high biomedical potential in anti-inflammation, anti-oxidant, and anti-aging applications.

PMID: 30540433 [PubMed - indexed for MEDLINE]

Current practices in the delivery of pharmacogenomics: Impact of the recommendations of the Pharmacy Practice Model Summit.

Am J Health Syst Pharm. 2019 Apr 08;76(8):521-529

Authors: Valgus J, Weitzel KW, Peterson JF, Crona DJ, Formea CM

Abstract
PURPOSE: This report examines and evaluates pharmacogenomics as an emerging science as it relates to the Practice Advancement Initiative and its predecessor the Pharmacy Practice Model Initiative's consensus statements for optimal pharmacy practice models.
SUMMARY: Pharmacogenomics is one of many emerging sciences to impact medication management and delivery of patient care. Increasingly, biomarkers are included in drug labeling and can assist pharmacists with personalizing medicine to optimize patient therapies and avoid adverse effects. The 2011 ASHP Pharmacy Practice Model Summit generated a list of 147 consensus statements for optimal pharmacy practice. Of these, 1 statement explicitly describes adjustment of drug regimens based on genetic factors as an essential activity of pharmacist-provided drug regimens, and 9 other statements provide additional support for incorporation of this emerging science into all aspects of patient care provided by pharmacists. We describe 4 institutions that have made significant inroads to implementing pharmacogenomics, to provide a framework and serve as resources for other institutions initiating their own pharmacogenomics implementation journeys.
CONCLUSION: Through prioritized efforts of the pharmacy profession and health care institutions, pharmacogenomics will be disseminated and implemented, and the goal of the Pharmacy Practice Model Initiative's consensus statements of improving health care using patients' genetic characteristics will be realized.

PMID: 31361863 [PubMed - in process]

Pharmacogenomic potential in advanced cancer patients.

Am J Health Syst Pharm. 2019 Mar 19;76(7):415-423

Authors: Nichols D, Arnold S, Weiss HL, Wu J, Durbin EB, Miller R, Kolesar J

Abstract
PURPOSE: The prevalence of pharmacogenetically actionable medications in advanced cancer patients whose therapy may be optimized with genotype data was determined.
METHODS: Patients enrolled in our institutional molecular tumor board observational cohort were included in this study. Collected data included demographics, type(s) of cancer, and outpatient medications. Medications were classified as "pharmacogenetically actionable" if there are Clinical Pharmacogenetics Implementation Consortium (CPIC) therapeutic recommendations for that medication based on the presence of germline variations. The prevalence of pharmacogenetically actionable medications in the study population was determined, and the frequency of opportunities for pharmacogenetic prescribing and adverse event (AE) mitigation were estimated.
RESULTS: In a cohort of 193 patients with advanced cancer, 65% of patients were taking a pharmacogenetically actionable medication. Approximately 10% of the outpatient medications taken by the study population had a pharmacogenetic association. The most common pharmacogenetically actionable medications being used were ondansetron (47%), capecitabine (10%), and sertraline (7%). Using published genetic variation frequencies and AE risk, we conservatively estimated that 7.1% of cancer patients would be eligible for genetic-based medication adjustment, and 101 AEs would be prevented in 10,000 patients genotyped.
CONCLUSION: Medications with pharmacogenetic associations are used commonly in the advanced cancer patient population. This widespread exposure supports the implementation of prospective genotyping in the treatment of these high-risk patients.

PMID: 31361818 [PubMed - in process]

Genetic polymorphisms analysis of pharmacogenomic VIP variants in Bai ethnic group from China.

Mol Genet Genomic Med. 2019 Jul 30;:e884

Authors: Chen W, Ding H, Cheng Y, Li Q, Dai R, Yang X, Zhang C

Abstract
BACKGROUND: The pharmacogenomics study has been widely used for the study of very important pharmacogenetic (VIP) variants among different ethnic groups. However, there is little known about the pharmacogenomics information regarding Bai family. Our study aimed to screen the polymorphism of the VIP gene in Bai nationality.
METHODS: We genotyped 81 VIP variants (selected from the PharmGKB database) in the Bai population and then compared them to the other 11 major HapMap populations by chi-square test, structure and F-statistics (Fst) analysis.
RESULTS: Our results indicated that rs20417 (PTGS2), rs4148323 (UGT1A), and rs1131596 (SLC19A1) were most different in Bai compared with most of the 11 populations from the HapMap data set. Furthermore, population structure and F-statistics (Fst) analysis also demonstrated that the Bai population has the closest genetic relationship with Han Chinese in Beijing, China (CHB), followed by Japanese in Tokyo, Japan (JPT), and the farthest population from the Yoruba in Ibadan, Nigeria (YRI).
CONCLUSIONS: Our study not only presented the genotype frequency difference between the selected population of the Bai population and the other 11 populations, but also showed that the Bai population is most similar to the CHB populations, followed by JPT. These findings would contribute to the development of individualized medicine for the Bai population.

PMID: 31361092 [PubMed - as supplied by publisher]

Characterization of T-Cell Receptor Repertoire in Patients with Rheumatoid Arthritis Receiving Biologic Therapies.

Dis Markers. 2019;2019:2364943

Authors: Chang CM, Hsu YW, Wong HS, Wei JC, Liu X, Liao HT, Chang WC

Abstract
Rheumatoid arthritis (RA) is a systematic autoimmune disease, predominantly causing chronic polyarticular inflammation and joint injury of patients. For the treatment of RA, biologic disease-modifying antirheumatic drugs (bDMARDs) have been used to reduce inflammation and to interfere with disease progression through targeting and mediating the immune system. Although the therapeutic effects of bDMARDs in RA patients have been widely reported, whether these drugs also play important roles in T-cell repertoire status is still unclear. We therefore designed the study to identify the role of T-cell repertoire profiles in RA patients with different types of bDMARD treatments. A high-throughput sequencing approach was applied to profile the T-cell receptor beta chain (TCRB) repertoire of circulating T lymphocytes in eight patients given adalimumab (anti-TNF-α) with/without the following use of either rituximab (anti-CD20) or tocilizumab (anti-IL6R). We subsequently analyzed discrepancies in the clonal diversity and CDR3 length distribution as well as usages of the V and J genes of TCRB repertoire and interrogated the association between repertoire diversity and disease activities followed by the treatment of bDMARDs in these RA patients. All groups of patients showed well-controlled DAS28 scores (<2.6) after different treatment regimens of drugs and displayed no significant statistical differences in repertoire diversity, distribution of CDR3 lengths, and usage of V and J genes of TCRB. Nonetheless, a trend between overall TCRB repertoire diversity and disease activity scores in all bDMARD-treated RA patients was observed. Additionally, age was found to be associated with repertoire diversity in RA patients treated with bDMARDs. Through the profiling of the TCR repertoire in RA patients receiving different biologic medications, our study indicated an inverse tendency between TCR repertoire diversity and disease activity after biologic treatment in RA patients.

PMID: 31360262 [PubMed - in process]

Frequencies of clinically important CYP2C19 and CYP2D6 alleles are graded across Europe.

Eur J Hum Genet. 2019 Jul 29;:

Authors: Petrović J, Pešić V, Lauschke VM

Abstract
CYP2C19 and CYP2D6 are important drug-metabolizing enzymes that are involved in the metabolism of around 30% of all medications. Importantly, the corresponding genes are highly polymorphic and these genetic differences contribute to interindividual and interethnic differences in drug pharmacokinetics, response, and toxicity. In this study we systematically analyzed the frequency distribution of clinically relevant CYP2C19 and CYP2D6 alleles across Europe based on data from 82,791 healthy individuals extracted from 79 original publications and, for the first time, provide allele confidence intervals for the general population. We found that frequencies of CYP2D6 gene duplications showed a clear South-East to North-West gradient ranging from <1% in Sweden and Denmark to 6% in Greece and Turkey. In contrast, an inverse distribution was observed for the loss-of-function alleles CYP2D6*4 and CYP2D6*5. Similarly, frequencies of the inactive CYP2C19*2 allele were graded from North-West to South-East Europe. In important contrast to previous work we found that the increased activity allele CYP2C19*17 was most prevalent in Central Europe (25-33%) with lower prevalence in Mediterranean-South Europeans (11-24%). In summary, we provide a detailed European map of common CYP2C19 and CYP2D6 variants and find that frequencies of the most clinically relevant alleles are geographically graded reflective of Europe's migratory history. These findings emphasize the importance of generating pharmacogenomic data sets with high spatial resolution to improve precision public health across Europe.

PMID: 31358955 [PubMed - as supplied by publisher]

Population variability of rhesus macaque (Macaca mulatta) NAT1 gene for arylamine N-acetyltransferase 1: Functional effects and comparison with human.

Sci Rep. 2019 Jul 29;9(1):10937

Authors: Boukouvala S, Chasapopoulou Z, Giannouri D, Kontomina E, Marinakis N, Rizou SV, Stefani I, Tsirka T, Veyssière C, Zaliou S, Sabbagh A, Crouau-Roy B, Fakis G

Abstract
Human NAT1 gene for N-acetyltransferase 1 modulates xenobiotic metabolism of arylamine drugs and mutagens. Beyond pharmacogenetics, NAT1 is also relevant to breast cancer. The population history of human NAT1 suggests evolution through purifying selection, but it is unclear whether this pattern is evident in other primate lineages where population studies are scarce. We report NAT1 polymorphism in 25 rhesus macaques (Macaca mulatta) and describe the haplotypic and functional characteristics of 12 variants. Seven non-synonymous single nucleotide variations (SNVs) were identified and experimentally demonstrated to compromise enzyme function, mainly through destabilization of NAT1 protein and consequent activity loss. One non-synonymous SNV (c.560G > A, p.Arg187Gln) has also been characterized for human NAT1 with similar effects. Population haplotypic and functional variability of rhesus NAT1 was considerably higher than previously reported for its human orthologue, suggesting different environmental pressures in the two lineages. Known functional elements downstream of human NAT1 were also differentiated in rhesus macaque and other primates. Xenobiotic metabolizing enzymes play roles beyond mere protection from exogenous chemicals. Therefore, any link to disease, particularly carcinogenesis, may be via modulation of xenobiotic mutagenicity or more subtle interference with cell physiology. Comparative analyses add the evolutionary dimension to such investigations, assessing functional conservation/diversification among primates.

PMID: 31358821 [PubMed - in process]

Overview of Current Targeted Anti-Cancer Drugs for Therapy in Onco-Hematology.

Medicina (Kaunas). 2019 Jul 28;55(8):

Authors: Crisci S, Amitrano F, Saggese M, Muto T, Sarno S, Mele S, Vitale P, Ronga G, Berretta M, Di Francia R

Abstract
The upgraded knowledge of tumor biology and microenviroment provides information on differences in neoplastic and normal cells. Thus, the need to target these differences led to the development of novel molecules (targeted therapy) active against the neoplastic cells' inner workings. There are several types of targeted agents, including Small Molecules Inhibitors (SMIs), monoclonal antibodies (mAbs), interfering RNA (iRNA) molecules and microRNA. In the clinical practice, these new medicines generate a multilayered step in pharmacokinetics (PK), which encompasses a broad individual PK variability, and unpredictable outcomes according to the pharmacogenetics (PG) profile of the patient (e.g., cytochrome P450 enzyme), and to patient characteristics such as adherence to treatment and environmental factors. This review focuses on the use of targeted agents in-human phase I/II/III clinical trials in cancer-hematology. Thus, it outlines the up-to-date anticancer drugs suitable for targeted therapies and the most recent finding in pharmacogenomics related to drug response. Besides, a summary assessment of the genotyping costs has been discussed. Targeted therapy seems to be an effective and less toxic therapeutic approach in onco-hematology. The identification of individual PG profile should be a new resource for oncologists to make treatment decisions for the patients to minimize the toxicity and or inefficacy of therapy. This could allow the clinicians to evaluate benefits and restrictions, regarding costs and applicability, of the most suitable pharmacological approach for performing a tailor-made therapy.

PMID: 31357735 [PubMed - in process]

Translational epidemiology: The powerful tool for precision cancer medicine.

J Cancer Res Ther. 2019;15(2):269-271

Authors: Fu Z, Zhang R, Li P, Jia M

Abstract
Although this is an exciting time for translational medicine, systematic approaches and strategies to conduct translational research are sparse. We highlight in this editorial the opportunities to collaborate across disciplines and to forge new interdisciplinary collaborative ventures from the perspective of epidemiology. We specifically outline some feasible research areas, wherein Translational Epidemiology may readily speed up the translation of research for Precision Medicine.

PMID: 30964096 [PubMed - indexed for MEDLINE]

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The Evolving Role of Thiopurines in Inflammatory Bowel Disease.

Curr Treat Options Gastroenterol. 2019 Jul 27;:

Authors: Kapur S, Hanauer SB

Abstract
PURPOSE OF REVIEW: With the advent of biologic therapies for the treatment of inflammatory bowel disease, the roles of thiopurines have continued to evolve. This review will focus on recent advances in pharmacology and the safety and efficacy of thiopurines as maintenance therapies for steroid-induced remissions and post-surgical maintenance of remission and as combination therapies to reduce immunogenicities of biologic agents.
RECENT FINDINGS: Due to pharmacogenetics of thiopurine S-methyltransferase, thiopurine dosing is more effectively based on monitoring of thiopurine metabolites rather than weight-based dosing. Thiopurines continue to have a role as maintenance therapy after steroid-induced remissions and in combination with biologics to induce and maintain remission. Safety monitoring includes measurements of blood counts, liver chemistries, and dermatologic evaluations and protection from sun exposure. Thiopurines appear to be safe during pregnancies and while very uncommon, lymphomas (including hepatosplenic T cell lymphomas) remain a recognized risk, particularly in younger and older males.

PMID: 31352659 [PubMed - as supplied by publisher]

Preanalytical heterogeneity in Fecal Calprotectin measurement needs to be considered for tight control: author's reply.

Clin Gastroenterol Hepatol. 2019 Jul 24;:

Authors: Kennedy NA, Lees CW

PMID: 31351132 [PubMed - as supplied by publisher]

Pharmacogenomics in clinical care.

J Am Assoc Nurse Pract. 2019 Jul 23;:

Authors: Wysocki K, Seibert D

Abstract
Health care designed specifically for a person based on their genetic makeup ("personalized" or "precision" medicine) is expanding rapidly, especially in the area of drug selection. Pharmacogenomic (PGx) testing, when drugs and doses are selected based on an individual's genetic profile, is increasingly being used to guide the selection of drugs or therapies to optimize outcomes and minimize side effects. Based on an individual's genetic blueprint, health care providers now have important information about how a drug is likely to behave in that individual's body. Pharmacogenomic information on drug labels is now available for nearly 250 drugs. Health care organizations are also increasingly making this information available to customers to reduce emergency department visits, improve outcomes (selecting the right chemotherapy doses), and reduce cost. This study reviews some of the challenges and benefits on using PGx testing to improve clinical outcomes.

PMID: 31348145 [PubMed - as supplied by publisher]

Overexpression of TK1 and CDK9 in plasma-derived exosomes is associated with clinical resistance to CDK4/6 inhibitors in metastatic breast cancer patients.

Breast Cancer Res Treat. 2019 Jul 26;:

Authors: Del Re M, Bertolini I, Crucitta S, Fontanelli L, Rofi E, De Angelis C, Diodati L, Cavallero D, Gianfilippo G, Salvadori B, Fogli S, Falcone A, Scatena C, Naccarato AG, Roncella M, Ghilli M, Morganti R, Fontana A, Danesi R

Abstract
PURPOSE: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) improve progression-free survival (PFS) in patients with hormone receptor-positive (HR+) advanced breast cancer. However, a better knowledge of predictive biomarkers of response and resistance to CDK4/6i is needed. Therefore, the present article addresses the role of the mRNA expression of thymidine kinase 1 (TK1), CDK4, 6 and 9 in plasma-derived exosomes and their relevance in the pharmacologic activity of CDK4/6i.
METHODS: Blood samples of 40 HR+/HER2- advanced breast cancer patients were collected before (T0) the administration of palbociclib plus hormonal therapy and after 3 months (T1). RNA was isolated from exosomes and analysed for the expression of TK1, CDK 4, 6 and 9 by digital droplet PCR (ddPCR).
RESULTS: A higher value of TK1 copies/ml at baseline (T0) was significantly associated with the number of previous lines of chemotherapy (p = 0.009). In patients with PD, a significant increase was observed in the number of copies/ml of TK1 (p = 0.01) and CDK9 (p = 0.03) comparing T1 vs. T0 values. No significant correlations between response to treatment and clinical parameters were found at univariate analysis. High baseline CDK4 expression was significantly correlated with longer PFS in patients treated with fulvestrant + palbociclib (low versus high: 6.45 months vs. not reached, p = 0.01).
CONCLUSIONS: The present study demonstrates that, in plasma-derived exosomes, high baseline CDK4 mRNA levels are associated with response to palbociclib plus hormonal therapy, while the increase in TK1 and CDK9 mRNA copies/ml is associated with clinical resistance.

PMID: 31346846 [PubMed - as supplied by publisher]

LC-MS/MS determination of ginsenoside compound K and its metabolite 20 (S)-protopanaxadiol in human plasma and urine: applications in a clinical study.

Bioanalysis. 2019 Mar;11(5):365-380

Authors: Yang L, Wang CY, Xie XN, Wang YC, Peng JB, Huang WH, Chen Y, Ouyang DS, Tan ZR

Abstract
AIM: Ginsenoside compound K (CK) is considered to be a potential therapeutic drug for rheumatoid arthritis because of its good anti-inflammatory activity. The purpose of this work was to establish a rapid, sensitive and specific method for determination of CK and its active metabolite 20(S)-protopanaxadiol (20(S)-PPD). Materials & methods: The analytes and internal standards were extracted by liquid-liquid extraction. Then, were separated by high performance liquid phase and determined by triple quadrupole mass spectrometry.
RESULTS: A LC-MS/MS using liquid-liquid extraction was developed for determining CK over the concentration range 1.00-1002.00 ng/ml and 0.15-54.30 ng/ml for 20(S)-PPD. The lower limits of quantification for CK and 20(S)-PPD were 1.00 and 0.15 ng/ml, respectively.
CONCLUSION: This method was successfully validated for detecting both CK and 20(S)-PPD in the human plasma and urine, and was proved to be suitable for the pharmacokinetic study of CK in healthy Chinese volunteers.
CLINICAL TRIAL REGISTRATION NUMBER: ChiCTR-TRC-14004824.

PMID: 30873858 [PubMed - indexed for MEDLINE]

Carboxylated carbon nanomaterials in cell cycle and apoptotic cell death regulation.

J Biotechnol. 2019 Apr 20;296:14-21

Authors: Lee KC, Lo PY, Lee GY, Zheng JH, Cho EC

Abstract
Carbon nanomaterials, include carbon nanotubes and graphene nanosheets, have drawn an increasing amount of attention because of their potential applications in daily life or in providing novel therapeutic possibilities for treating diseases. However, the overall biocompatibility, the potential toxic effects of carbon nanomaterials toward human cells, and their modulations in cellular mechanism, are not fully understood. Herein, four types of carbon nanomaterials, include long and short carbon nanotubes and graphene nanosheets, at low and high concentrations, were functionalized and dispersed in the biocompatible buffer for assessment. The surface structure, the morphology, and chemical composition of carbon nanomaterials were characterized. Also, biological assays investigating cellular viability, vitality, cell cycle, and apoptotic cell death were applied on cells co-incubated with nanomaterials, to evaluate the biocompatibility of these nanomaterials in human cells. Our data suggested that even though co-incubation of nanomaterials did not seem to affect the viability of cells notably, high concentrations (50 ug/ml) of SW could lead to unhealthy cells, and we observed dramatic G2 arrest effect mediated by p21 induction in high SW incubated cells. Other nanomaterials at high concentration may also alter cell cycle profile of the cells. In summary, our data demonstrated that these nanomaterials could regulate cell cycle and lead to apoptosis at high concentrations, and the underling molecular mechanisms have been addressed. Caution should be taken on their concentration when nanomaterials are in used in future medical applications.

PMID: 30853641 [PubMed - indexed for MEDLINE]

DNA methylation alterations as therapeutic prospects in thyroid cancer.

J Endocrinol Invest. 2019 Apr;42(4):363-370

Authors: Zhang K, Li C, Liu J, Tang X, Li Z

Abstract
BACKGROUND: Thyroid cancer is one of the most common endocrine malignancies. Although the 10-year survival rate of differentiated thyroid cancer (DTC) is about 90% after conventional treatments, a small proportion of patients still suffer from tumor recurrence or drug resistance.
OBJECTIVE: This review article summarizes recent researches and clinical trials related to target drugs that reduce mortality in thyroid cancer.
METHODS: This is a review of the recent literature and clinical trials on the three main aspects including methylation genes in thyroid cancers, the relationship between BRAF mutation and gene methylation, target and dehypermethylation drugs in clinical trials.
RESULTS: We propose new approaches to treating malignant thyroid cancer, based on advances in understanding the relationship between genetic and epigenetic changes in thyroid cancer. Although the effect of traditional treatment for thyroid cancer is relatively good, a small proportion of patients still suffer from tumor recurrence or drug resistance. Molecular targeted drugs and dehypermethylation drugs have more promising outcomes in aggressive thyroid cancer compared with conventional treatments.
CONCLUSION: Based on what was discussed in this review, we suggest that integration of epigenetic and targeted therapies into conventional treatments will reduce the occurrence of refractory radioiodine differentiated thyroid cancer and improve the outcomes in aggressive thyroid cancer patients.

PMID: 29992502 [PubMed - indexed for MEDLINE]

SigMat: a classification scheme for gene signature matching.

Bioinformatics. 2018 07 01;34(13):i547-i554

Authors: Xiao J, Blatti C, Sinha S

Abstract
Motivation: Several large-scale efforts have been made to collect gene expression signatures from a variety of biological conditions, such as response of cell lines to treatment with drugs, or tumor samples with different characteristics. These gene signature collections are utilized through bioinformatics tools for 'signature matching', whereby a researcher studying an expression profile can identify previously cataloged biological conditions most related to their profile. Signature matching tools typically retrieve from the collection the signature that has highest similarity to the user-provided profile. Alternatively, classification models may be applied where each biological condition in the signature collection is a class label; however, such models are trained on the collection of available signatures and may not generalize to the novel cellular context or cell line of the researcher's expression profile.
Results: We present an advanced multi-way classification algorithm for signature matching, called SigMat, that is trained on a large signature collection from a well-studied cellular context, but can also classify signatures from other cell types by relying on an additional, small collection of signatures representing the target cell type. It uses these 'tuning data' to learn two additional parameters that help adapt its predictions for other cellular contexts. SigMat outperforms other similarity scores and classification methods in identifying the correct label of a query expression profile from as many as 244 or 500 candidate classes (drug treatments) cataloged by the LINCS L1000 project. SigMat retains its high accuracy in cross-cell line applications even when the amount of tuning data is severely limited.
Availability and implementation: SigMat is available on GitHub at https://github.com/JinfengXiao/SigMat.
Supplementary information: Supplementary data are available at Bioinformatics online.

PMID: 29950002 [PubMed - indexed for MEDLINE]

L1000FWD: fireworks visualization of drug-induced transcriptomic signatures.

Bioinformatics. 2018 06 15;34(12):2150-2152

Authors: Wang Z, Lachmann A, Keenan AB, Ma'ayan A

Abstract
Motivation: As part of the NIH Library of Integrated Network-based Cellular Signatures program, hundreds of thousands of transcriptomic signatures were generated with the L1000 technology, profiling the response of human cell lines to over 20 000 small molecule compounds. This effort is a promising approach toward revealing the mechanisms-of-action (MOA) for marketed drugs and other less studied potential therapeutic compounds.
Results: L1000 fireworks display (L1000FWD) is a web application that provides interactive visualization of over 16 000 drug and small-molecule induced gene expression signatures. L1000FWD enables coloring of signatures by different attributes such as cell type, time point, concentration, as well as drug attributes such as MOA and clinical phase. Signature similarity search is implemented to enable the search for mimicking or opposing signatures given as input of up and down gene sets. Each point on the L1000FWD interactive map is linked to a signature landing page, which provides multifaceted knowledge from various sources about the signature and the drug. Notably such information includes most frequent diagnoses, co-prescribed drugs and age distribution of prescriptions as extracted from the Mount Sinai Health System electronic medical records. Overall, L1000FWD serves as a platform for identifying functions for novel small molecules using unsupervised clustering, as well as for exploring drug MOA.
Availability and implementation: L1000FWD is freely accessible at: http://amp.pharm.mssm.edu/L1000FWD.
Supplementary information: Supplementary data are available at Bioinformatics online.

PMID: 29420694 [PubMed - indexed for MEDLINE]

Interaction of Dietary Linoleic Acid and α-Linolenic Acids with rs174547 in FADS1 Gene on Metabolic Syndrome Components among Vegetarians.

Nutrients. 2019 Jul 23;11(7):

Authors: Ching YK, Chin YS, Appukutty M, Ramanchadran V, Yu CY, Ang GY, Gan WY, Chan YM, Teh LK, Salleh MZ

Abstract
Fatty acid desaturase 1 (FADS1) gene controls the fatty acid metabolism pathway in the human body. The lower intake of α-linolenic acid (ALA) than linoleic acid (LA) among vegetarians may disrupt the fatty acid metabolism and limit the conversion of ALA to anti-inflammatory products such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). This cross-sectional study aimed to determine the interaction of rs174547 in FADS1 gene with LA and ALA on metabolic syndrome (MetS) components. A total of 200 Chinese and Indian vegetarians in Kuala Lumpur and Selangor, Malaysia participated in the present study. The data on socio-demographic characteristics, vegetarianism practices, dietary practices, anthropometric measurements, blood pressure (BP), and overnight venous fasting blood samples were collected from the vegetarians. The rs174547 in FADS1 gene was significantly associated with MetS and its components such as waist circumference (WC) and fasting blood glucose (FBG). Multiple logistic regression analyses revealed that vegetarians with TT genotype of rs174547 in FADS1 gene had higher odds for MetS, larger WC, higher BP, and a lower level of HDL-c. Two-way ANOVA analysis showed that LA interacts with rs174547 in FADS1 gene to affect HDL-c (p < 0.05) among vegetarians. The present findings suggest the need to develop dietary guidelines for vegetarians in Malaysia. Prospective studies are also needed to affirm the interaction between LA and rs174547 in FADS1 gene on HDL-c among Malaysian vegetarians.

PMID: 31340443 [PubMed - in process]