TRK inhibitors: toward an era of agnostic targeted therapies in oncology.

Pharmacogenomics. 2019 Aug;20(13):927-929

Authors: Saleh K, Khalifeh-Saleh N, Kourie HR

PMID: 31486737 [PubMed - in process]

CYP2C9*2 is associated with indomethacin treatment failure for patent ductus arteriosus.

Pharmacogenomics. 2019 Aug;20(13):939-946

Authors: Rooney SR, Shelton EL, Aka I, Shaffer CM, Clyman RI, Dagle JM, Ryckman K, Lewis TR, Reese J, Van Driest SL, Kannankeril PJ

Abstract
Aims: To identify clinical andgenetic factors associated with indomethacin treatment failure in preterm neonates with patent ductus arteriosus (PDA). Patients & Methods: This is a multicenter cohort study of 144 preterm infants (22-32 weeks gestational age) at three centers who received at least one treatment course of indomethacin for PDA. Indomethacin failure was defined as requiring subsequent surgical intervention. Results: In multivariate analysis, gestational age (AOR 0.76, 95% CI 0.60-0.96), surfactant use (AOR 9.77, 95% CI 1.15-83.26), and CYP2C9*2 (AOR 3.74; 95% CI 1.34-10.44) were each associated with indomethacin failure. Conclusion: Age, surfactant use, and CYP2C9*2 influence indomethacin treatment outcome in preterm infants with PDA. This combination of clinical and genetic factors may facilitate targeted indomethacin use for PDA.

PMID: 31486736 [PubMed - in process]

Gene polymorphisms in VEGFA and COL2A1 are associated with response to inhaled corticosteroids in children with asthma.

Pharmacogenomics. 2019 Aug;20(13):947-955

Authors: Wan Z, Tang Y, Song Q, Zhang J, Xie W, He Y, Huang R, Zheng X, Liu C, Liu J

Abstract
Aim: The purpose of this study was to investigate the involvement of single-nucleotide polymorphisms in VEGFA, TBX21 and COL2A1 in the response to inhaled corticosteroids in asthmatic children. Subjects & methods: Children with mild-to-moderate asthma were enrolled in the study. The SEQUENOM MassARRAY method was used to sequence 27 SNP genotypes. By ranking the data from smallest to largest, we could infer whether the change in distribution of forced expiratory volume in one second/forced vital capcacity (FEV1/FVC) and fractional exhaled nitric oxide differed between genotype groups. Results: VEGFA rs3025039 T allele carriers had a smaller change in FEV1 than CC carriers (p = 0.040), and in COL2A1 rs3809324, the frequency of T allele carriers was lower than that of GG carriers (p = 0.048). rs3025039 was also associated with changes in FEV1/FVC (p = 0.016). Conclusion: VEGFA and COL2A1 polymorphisms are significantly associated with the response to inhaled corticosteroids in asthmatic children.

PMID: 31486735 [PubMed - in process]

Role of transportome in the pharmacogenomics of hepatocellular carcinoma and hepatobiliary cancer.

Pharmacogenomics. 2019 Aug;20(13):957-970

Authors: Alonso-Peña M, Espinosa-Escudero RA, Soto-Muñiz M, Sanchon-Sanchez P, Sanchez-Martin A, Marin JJ

Abstract
An important factor determining the pharmacological response to antitumor drugs is their concentrations in cancer cells, which accounts for the net interaction with their intracellular molecular targets. Accordingly, mechanisms leading to reduced intracellular levels of active agents play a crucial role in cancer chemoresistance. These include impaired drug uptake through solute carrier (SLC) proteins and efficient drug export by ATP-dependent pumps belonging to the ATP-binding cassette (ABC) superfamily of proteins. Since the net movement of drugs in-and-out the cells depends on the overall expression of carrier proteins, defining the so-called transportome, special attention has been devoted to the study of transcriptome regarding these proteins. Nevertheless, genetic variants affecting SLC and ABC genes may markedly affect the bioavailability and, hence, the efficacy of anticancer drugs.

PMID: 31486734 [PubMed - in process]

Pharmacogenomics in chronic pain therapy: from disease to treatment and challenges for clinical practice.

Pharmacogenomics. 2019 Aug;20(13):971-982

Authors: Yamamoto PA, Conchon Costa AC, Lauretti GR, de Moraes NV

Abstract
Pharmacogenomics (PGx) has emerged as an encouraging tool in chronic pain therapy. Genetic variations associated with drug effectiveness or adverse reactions (amitriptyline/nortriptyline/codeine/oxycodone/tramadol-CYP2D6, amitriptyline-CYP2C19, carbamazepine-HLA-A, carbamazepine/oxcarbazepine-HLA-B) can be used to guide chronic pain management. Despite this evidence, many obstacles still need to be overcome for the effective clinical implementation of PGx. To translate the pharmacogenetic testing into actionable clinical decisions, the Clinical Pharmacogenetics Implementation Consortium has been developing guidelines for several drug-gene pairs. This review will show the applicability of PGx in chronic pain from disease to treatment; report the drug-gene pairs with strongest evidences in the clinic; and the challenges for the clinical implementation of PGx.

PMID: 31486733 [PubMed - in process]

The Impact of Pharmacogenomics in Personalized Medicine.

Adv Biochem Eng Biotechnol. 2019 Sep 05;:

Authors: Singh DB

Abstract
Recent advances in Pharmacogenomics have made it possible to understand the reasons behind the different response of a drug. Discovery of genetic variants and its association with the varying response of drug provide the basis for recommending a drug and its dose to an individual patient. Genetic makeup-based prescription, design, and implementation of therapy not only improve the outcome of treatments but also reduce the risk of toxicity and other adverse effects. A better understanding of individual variations and their effect on drug response, metabolism excretion, and toxicity will replace the trial-and-error approach of treatment. Evidence of the clinical utility of pharmacogenetics testing is only available for a few medications, and FDA labels only require pharmacogenetics testing for a small number of drugs. Although there is a great promise, there are not many examples where Pharmacogenomics impacts clinical utility. Some genetic variants related to different diseases have been reported, and many have not been studied yet. The information related to the outcome of treatment with a particular drug and a genetic variant can be used to release a warning/label for the use of that drug. There are many limitations in the way of implementing the goal of personalized medicine. Future advances in the field of genomics, diagnosis approaches, data analysis, clinical decision-making, and sustainable business model for personalization of therapy can speed up the individualization of therapy based on genetic makeup.

PMID: 31485703 [PubMed - as supplied by publisher]

Sketching the prevalence of pharmacogenomic biomarkers among populations for clinical pharmacogenomics.

Eur J Hum Genet. 2019 Sep 04;:

Authors: Patrinos GP

PMID: 31485027 [PubMed - as supplied by publisher]

Comparison of the association between circulating vitamin D3 levels and clinical outcomes in patients with asthma and chronic obstructive pulmonary disease: a prospective observational study.

Biol Pharm Bull. 2019 Sep 03;:

Authors: Hirai K, Shirai T, Suzuki Y, Shimomura T, Itoh K

Abstract
Vitamin D has an immune-modulating effect, related to the pathophysiology of asthma and chronic obstructive pulmonary disease (COPD). However, few studies have focused on the difference between patients with asthma and COPD in the association of circulating vitamin D levels with clinical outcomes. We sought to investigate the associations of circulating vitamin D levels with health-related quality of life (HR-QOL), severity, and exacerbations. Subjects included 152 asthma patients and 50 COPD patients. We measured plasma concentrations of 25-hydroxyvitamin D3 [25(OH)D3]. HR-QOL was assessed using the EuroQoL 5-Dimension (EQ-5D) and the 12-item Short Form Health Survey (SF-12) scales. Exacerbations were recorded during a one-year follow-up. Associations between plasma 25 (OH)D3 concentrations and outcome variables were evaluated using linear regression. Plasma concentrations of 25(OH)D3 were positively associated with the EQ-5D index value and the SF-12 physical component score in patients with asthma; however, such associations were not observed in patients with COPD. A significant association between severity and plasma concentrations of 25(OH)D3 was found only in patients with COPD. The hazard ratios (95% confidence interval) of plasma 25(OH)D3 concentrations (per 1 ng/mL decrease) for time to first exacerbation was 1.38 (1.10-1.75; p = 0.006) and 0.95 (0.87-1.03; p = 0.179) in patients with COPD and asthma, respectively. Lower concentrations of plasma 25(OH)D3 contributed to lower HR-QOL in patients with asthma, and were associated with severity and risk of future exacerbations in patients with COPD.

PMID: 31484846 [PubMed - as supplied by publisher]

Functional Characterization of Pharmcogenetic Variants of Human Cytochrome P450 2C9 in Korean Populations.

Biomol Ther (Seoul). 2019 Sep 05;:

Authors: Cho MA, Yoon JG, Kim V, Kim H, Lee R, Lee MG, Kim D

Abstract
Human cytochrome P450 2C9 is a highly polymorphic enzyme that is required for drug and xenobiotic metabolism. Here, we studied eleven P450 2C9 genetic variants-including three novel variants F69S, L310V, and Q324X-that were clinically identified in Korean patients. P450 2C9 variant enzymes were expressed in Escherichia coli and their bicistronic membrane fractions were prepared The CO-binding spectra were obtained for nine enzyme variants, indicating P450 holoenzymes, but not for the M02 (L90P) variant. The M11 (Q324X) variant could not be expressed due to an early nonsense mutation. LC-MS/MS analysis was performed to measure the catalytic activities of the P450 2C9 variants, using diclofenac as a substrate. Steady-state kinetic analysis revealed that the catalytic efficiency of all nine P450 2C9 variants was lower than that of the wild type P450 2C9 enzyme. The M05 (R150L) and M06 (P279T) variants showed high kcat values; however, their Km values were also high. As the M01 (F69S), M03 (R124Q), M04 (R125H), M08 (I359L), M09 (I359T), and M10 (A477T) variants exhibited higher Km and lower kcat values than that of the wild type enzyme, their catalytic efficiency decreased by approximately 50-fold compared to the wild type enzyme. Furthermore, the novel variant M07 (L310V) showed lower kcat and Km values than the wild type enzyme, which resulted in its decreased (80%) catalytic efficiency. The X-ray crystal structure of P450 2C9 revealed the presence of mutations in the residues surrounding the substrate-binding cavity. Functional characterization of these genetic variants can help understand the pharmacogenetic outcomes.

PMID: 31484472 [PubMed - as supplied by publisher]

Effect of Polymorphisms in CYP2C9 and CYP2C19 on the Disposition, Safety and Metabolism of Progesterone Administrated Orally or Vaginally.

Adv Ther. 2019 Sep 03;:

Authors: Zubiaur P, Ochoa D, Gálvez MÁ, Saiz-Rodriguez M, Román M, Aguilar M, de Pablo I, Koller D, Abad-Santos F

Abstract
INTRODUCTION: Exogenous progesterone is prescribed for a variety of conditions with endogenous progesterone deficiency, e.g. menstrual alterations, primary or secondary infertility or premenopause. To the best of our knowledge, no pharmacogenetic studies have been published in relation to exogenous progesterone pharmacokinetic safety or progesterone metabolites so far.
METHODS: Candidate-gene study where we evaluated whether five single-nucleotide polymorphisms (CYP2C9*2, *3, CYP2C19*2, *3 and *17) were related to the pharmacokinetics, safety and metabolism of progesterone in 24 healthy volunteers who received a 200-mg progesterone formulation either orally or vaginally.
RESULTS: The vaginal formulation had an average AUCt value approximately 18 times greater than the oral formulation. CYP2C19 intermediate metabolizers (IM) consistently showed higher adjusted AUCt and adjusted Cmax than extensive metabolizers (EM) (P < 0.05); CYP2C9 EM incongruently exhibited higher adjusted Cmax and longer half-life than IM (p < 0.05).
CONCLUSION: This is the first study that reports variability in progesterone disposition according to the CYP2C19 and CYP2C9 phenotype. We suggest that CYP2C19 may condition progesterone disposition and that it may be more relevant than CYP2C9. This study lays the foundations for further in-depth research to evaluate the pharmacogenetics of progesterone.
TRIAL REGISTRATION: EudraCT numbers are 2012-005105-43 and 2012-005011-10.

PMID: 31482508 [PubMed - as supplied by publisher]

In silico drug repositioning: from large-scale transcriptome data to therapeutics.

Arch Pharm Res. 2019 Sep 03;:

Authors: Kwon OS, Kim W, Cha HJ, Lee H

Abstract
Drug repositioning is an attractive alternative to conventional drug development when new beneficial effects of old drugs are clinically validated because pharmacokinetic and safety profiles are generally already available. Since ~ 30% of drugs newly approved by the US food and drug administration (FDA) are developed through drug repositioning, identifying novel usage for existing drugs is an emerging strategy for developing disease treatments. With advances in next-generation sequencing technologies, available transcriptome data related to diseases have expanded rapidly. Harnessing these resources enables a better understanding of disease mechanisms and drug mode of action (MOA), and moves toward personalized pharmacotherapy. In this review, we briefly outline publicly available large-scale transcriptome databases and tools for drug repositioning. We also highlight recent approaches leading to the discovery of novel drug targets, drug response biomarkers, drug indications, and drug MOA.

PMID: 31482491 [PubMed - as supplied by publisher]

Pharmacogenetics: Role of Single Nucleotide Polymorphisms.

Methods Mol Biol. 2019;2054:137-145

Authors: Yucesan E, Ozten N

Abstract
Genome sequencing methods have basically similar algorithms, although they show a few differences between the platforms. The human genome contains approximately three billion base pairs, and this amount is huge and therefore impossible to sequence at one step. However, this amount is not a problem for developed technology. Researchers break DNA into small random pieces and then sequence and reassemble. Library preparation, sequencing, bioinformatic approaches and reporting. High-quality library preparation is critical and the most important part of the next-generation sequencing workflow. Successful sequencing directly requires high-quality libraries. Sequencing is second step and all high-throughput sequencing approaches are generally based on conventional Sanger sequencing. After preparation of library and sequencing, later steps are completely computer-based (in silico) approaches called as bioinformatics.

PMID: 31482453 [PubMed - in process]

Creating reproducible pharmacogenomic analysis pipelines.

Sci Data. 2019 Sep 03;6(1):166

Authors: Mammoliti A, Smirnov P, Safikhani Z, Ba-Alawi W, Haibe-Kains B

Abstract
The field of pharmacogenomics presents great challenges for researchers that are willing to make their studies reproducible and shareable. This is attributed to the generation of large volumes of high-throughput multimodal data, and the lack of standardized workflows that are robust, scalable, and flexible to perform large-scale analyses. To address this issue, we developed pharmacogenomic workflows in the Common Workflow Language to process two breast cancer datasets in a reproducible and transparent manner. Our pipelines combine both pharmacological and molecular profiles into a portable data object that can be used for future analyses in cancer research. Our data objects and workflows are shared on Harvard Dataverse and Code Ocean where they have been assigned a unique Digital Object Identifier, providing a level of data provenance and a persistent location to access and share our data with the community.

PMID: 31481707 [PubMed - in process]

Canine albumin polymorphisms and their impact on drug plasma protein binding.

Drug Metab Dispos. 2019 Sep 03;:

Authors: Costa AP, Court MH, Burke NS, Zhu Z, Mealey KL, Villarino NF

Abstract
Drug binding to plasma proteins is routinely determined during drug development. Albumin polymorphisms c.1075G>T (p.Ala359Ser) and c.1422A>T (p.Glu474Asp) were previously shown to alter plasma protein binding of a drug candidate (4-[1-[3-chloro-4-[n'-(2-methylphenyI)ureido]phenylacetyI]-(45)-fluoro-(2S)-pyrroIidine-2-yl]methoxybenzoic acid, D01-4582) in a colony of Beagles. Our study investigated the hypothesis that drug-protein binding in plasma from dogs with albumin H1 (reference) allele would be greater than in plasma from albumin H2 allele dogs (c.1075G>T and c.1422A>T) (n = 6 per group). Plasma protein binding extent of four drugs (D01-4582, celecoxib, mycophenolic acid, and meloxicam) was evaluated using ultracentrifugation or equilibrium dialysis. Free and total drug concentrations were analyzed by liquid chromatography-mass spectrometry. The albumin gene coding region was sequenced in 100 dogs to detect novel gene variants, and H1/H2 allele frequency determined in a large and varied population (n = 1446 from 61 breeds and mixed-breed dogs). For meloxicam, H1 allele plasma had statistically significant higher free drug fractions (P = 0.041) than H2 allele plasma. No significant difference was identified for plasma protein binding of D01-4582, celecoxib or mycophenolic acid. c.1075G>T and c.1422A>T were the most common SNPs in canine albumin, present concurrently in most study dogs and occasionally identified independently. In conclusion, albumin polymorphism c.1075G>T and c.1422A>T seems to affect the extent of plasma protein binding of meloxicam but not D01-4582, celecoxib, mycophenolic acid. SIGNIFICANCE STATEMENT: These results suggest that c.1075G>T and c.1422A>T are frequent in the dog population and can influence the extent of plasma protein binding of some drugs. The impact of albumin polymorphisms on plasma drug disposition will depend on intrinsic total and/or free drug clearances. Albumin polymorphisms could result in inter-individual variability in drug disposition. Thus, albumin genotyping could improve interpretation of canine pharmacokinetic data generated during the drug development process for humans and dogs.  .

PMID: 31481400 [PubMed - as supplied by publisher]

Effectiveness of a Pharmacogenetic Tool at Improving Treatment Efficacy in Major Depressive Disorder: A Meta-Analysis of Three Clinical Studies.

Pharmaceutics. 2019 Sep 02;11(9):

Authors: Vilches S, Tuson M, Vieta E, Álvarez E, Espadaler J

Abstract
Several pharmacogenetic tests to support drug selection in psychiatric patients have recently become available. The current meta-analysis aimed to assess the clinical utility of a commercial pharmacogenetic-based tool for psychiatry (Neuropharmagen®) in the treatment management of depressive patients. Random-effects meta-analysis of clinical studies that had examined the effect of this tool on the improvement of depressive patients was performed. Effects were summarized as standardized differences between treatment groups. A total of 450 eligible subjects from three clinical studies were examined. The random effects model estimated a statistically significant effect size for the pharmacogenetic-guided prescription (d = 0.34, 95% CI = 0.11-0.56, p-value = 0.004), which corresponded to approximately a 1.8-fold increase in the odds of clinical response for pharmacogenetic-guided vs. unguided drug selection. After exclusion of patients with mild depression, the pooled estimated effect size increased to 0.42 (95% CI = 0.19-0.65, p-value = 0.004, n = 287), corresponding to an OR = 2.14 (95% CI = 1.40-3.27). These results support the clinical utility of this pharmacogenetic-based tool in the improvement of health outcomes in patients with depression, especially those with moderate-severe depression. Additional pragmatic RCTs are warranted to consolidate these findings in other patient populations.

PMID: 31480800 [PubMed]

Evidence to Support Inclusion of Pharmacogenetic Biomarkers in Randomised Controlled Trials.

J Pers Med. 2019 Sep 01;9(3):

Authors: Johnson D, Hughes D, Pirmohamed SM, Jorgensen A

Abstract
Pharmacogenetics and biomarkers are becoming normalised as important technologies to improve drug efficacy rates, reduce the incidence of adverse drug reactions, and make informed choices for targeted therapies. However, their wider clinical implementation has been limited by a lack of robust evidence. Suitable evidence is required before a biomarker's clinical use, and also before its use in a clinical trial. We have undertaken a review of five pharmacogenetic biomarker-guided randomised controlled trials (RCTs) and evaluated the evidence used by these trials to justify biomarker inclusion. We assessed and quantified the evidence cited in published rationale papers, or where these were not available, obtained protocols from trial authors. Very different levels of evidence were provided by the trials. We used these observations to write recommendations for future justifications of biomarker use in RCTs and encourage regulatory authorities to write clear guidelines.

PMID: 31480618 [PubMed]

Molecular Functionality of Cytochrome P450 4 (CYP4) Genetic Polymorphisms and Their Clinical Implications.

Int J Mol Sci. 2019 Aug 31;20(17):

Authors: Jarrar YB, Lee SJ

Abstract
Enzymes in the cytochrome P450 4 (CYP4) family are involved in the metabolism of fatty acids, xenobiotics, therapeutic drugs, and signaling molecules, including eicosanoids, leukotrienes, and prostanoids. As CYP4 enzymes play a role in the maintenance of fatty acids and fatty-acid-derived bioactive molecules within a normal range, they have been implicated in various biological functions, including inflammation, skin barrier, eye function, cardiovascular health, and cancer. Numerous studies have indicated that genetic variants of CYP4 genes cause inter-individual variations in metabolism and disease susceptibility. Genetic variants of CYP4A11, 4F2 genes are associated with cardiovascular diseases. Mutations of CYP4B1, CYP4Z1, and other CYP4 genes that generate 20-HETE are a potential risk for cancer. CYP4V2 gene variants are associated with ocular disease, while those of CYP4F22 are linked to skin disease and CYP4F3B is associated with the inflammatory response. The present study comprehensively collected research to provide an updated view of the molecular functionality of CYP4 genes and their associations with human diseases. Functional analysis of CYP4 genes with clinical implications is necessary to understand inter-individual variations in disease susceptibility and for the development of alternative treatment strategies.

PMID: 31480463 [PubMed - in process]

Limited Sampling Strategies Supporting Individualized Dose Adjustment of Intravenous Busulfan in Children and Young Adults.

Ther Drug Monit. 2019 Aug 29;:

Authors: Teitelbaum Z, Nassar L, Scherb I, Fink D, Ring G, Lurie Y, Krivoy N, Bentur Y, Efrati E, Kurnik D

Abstract
BACKGROUND AND AIMS: Therapeutic drug monitoring (TDM) for busulfan supports dose adjustment during conditioning for stem cell transplantation. The authors aimed to develop and validate limited sampling strategies (LSS) of 4 to 5 samples for a precise estimation of the area under plasma concentration-time curve (AUC) for busulfan, as an alternative to an intensive sampling strategy (ISS) requiring 9 to 10 samples.
METHODS: ISS TDM data from 297 patients (≤ 18 years of age) were used. AUCLSS was calculated by using the trapezoidal rule and multiple linear regression (MLR). Unlike more complex modeling methods, MLR does not require sophisticated software or advanced training for personnel. MLR coefficients were estimated in the development subset containing a randomly selected 50% of the records and were then used to calculate the AUCLSS of the remaining records (the validation subset). The agreement between dose adjustment recommendations (DAR) based on ISS and LSS, in the validation subset, was evaluated by a Bland-Altman analysis. A DAR deviating from an ISS-based reference by < 15% was deemed acceptable.
RESULTS: Twelve LSSs were acceptable. Sampling at 0, 120, 180, and 240 minutes after the start of the second infusion (LSS15) yielded the best performance, with DAR deviating from the reference by < 10% for 95% of cases, and the AUCLSS was determined as follows:AUCLSS = 74.7954 × C(0) + 81.8948 × C(120) + 38.1771 × C(180) + 138.1404 × C(240) + 54.1837This LSS and LSS 13 performed similarly well in an independent external validation.
CONCLUSIONS: MLR-based estimates of AUCLSS provide DARs that deviate minimally from the reference. LSSs allow the reduction of patient discomfort, a ∼50% reduction of TDM-related workload for nursing staff and blood loss and a ∼25% reduction in laboratory workload. These benefits may encourage wider use of busulfan TDM, supporting safe and efficacious personalized dosing.

PMID: 31479045 [PubMed - as supplied by publisher]

Vitamin D supplementation ameliorates severity of generalized anxiety disorder (GAD).

Metab Brain Dis. 2019 Sep 02;:

Authors: Eid A, Khoja S, AlGhamdi S, Alsufiani H, Alzeben F, Alhejaili N, Tayeb HO, Tarazi FI

Abstract
This study investigated the effects of vitamin D supplementation on Generalized Anxiety Disorder (GAD) clinical symptoms and neurochemical biomarkers including serotonin, neopterin and kynurenine. Thirty male and female patients diagnosed with GAD and had vitamin D deficiency were recruited from the psychiatric clinic at King Abdulaziz University Hospital and divided into two groups; one group of patients (n = 15) received standard of care (SOC) plus 50,000 IU vitamin D (once/week) for 3 months, while the other group (n = 15) received SOC alone. Biochemical parameters including serum vitamin D, serotonin, neopterin and kynurenine were measured for all patients enrolled in the trial. In addition, the Generalized Anxiety Disorder 7-item (GAD-7) scale was used to measure the severity of GAD symptoms in both vitamin D treated- and untreated-patients. Significant improvements in GAD scores were observed in the vitamin D-treated group compared to the group that did not receive vitamin D. In addition, serum serotonin concentrations were significantly increased while serum neopterin were significantly decreased in vitamin D-treated vs. untreated patients. In contrast, no significant differences were found in serum kynurenine concentrations at the end of the study period between the two groups. No changes either in GAD-7 scores or in any of the biochemical measurements were observed in the group that received only SOC after 3 months. Vitamin D supplementation was effective in ameliorating the severity of GAD symptoms by increasing serotonin concentrations and decreasing the levels of the inflammatory biomarker neopterin in GAD patients.

PMID: 31478182 [PubMed - as supplied by publisher]

An intron retained bioluminescence reporter for real-time imaging of pre-mRNA splicing in living subjects.

Anal Chem. 2019 Sep 02;:

Authors: Zheng H, Chen S, Wang X, Xie J, Tian J, Wang F

Abstract
Pre-mRNA splicing in the information exchange from DNA to protein is a critical step in all eukaryotes. However, there is currently a lack of noninvasive approaches for monitoring mRNA splicing events in cells. In this study, we presented a genetically encoded bioluminescence reporter, Rluc-intron, for noninvasive real-time monitoring the pre-mRNA splicing process in living cells and animals. It was designed by inserting a renilla luciferase (Rluc) gene into an intron sequence manipulated by RNA splicing modulator. We demonstrated that the splicing reporter Rluc-intron could provide real-time and quantitative information of the splicing activity responded to extracellular stimuli in living cells. In addition, Rluc-intron reporter is able to successfully quantify and image the pre-mRNA splicing in living mice in a noninvasive and longitudinal manner. This bioluminescence reporter provides the advantageous properties of systematic discovery of splicing modulators, which give the advances in pharmacogenomics and would produce new approach in the therapy of human diseases caused by splicing disorder.

PMID: 31476865 [PubMed - as supplied by publisher]