Role of Preemptive Genotyping in Preventing Serious Adverse Drug Events in South Korean Patients.

Drug Saf. 2017 01;40(1):65-80

Authors: Kim GJ, Lee SY, Park JH, Ryu BY, Kim JH

Abstract
INTRODUCTION: Preemptive and multi-variant genotyping is suggested to improve the safety of patient drug therapy. The number of South Koreans who would benefit from this approach is unknown.
OBJECTIVE: We aimed to quantify the number of patients who may experience serious adverse drug events (ADEs) due to high-risk pharmacogenetic variants and who may benefit from preemptive genotyping.
METHODS: The health claims dataset of the Korean Health Insurance Review and Assessment service for 3 % of the South Korean population for year 2011 was used to calculate the number of patients exposed to 84 drugs covered by National Health Insurance with pharmacogenomic biomarkers. The product of ADE risk-conferring genotype prevalence, ADE prevalence rates, and genotype effect sizes in South Koreans or East Asians derived from published literature and the 1000 Genomes Project, and the drug exposure data were solved to estimate the number of South Koreans in whom preemptive genotyping may prevent serious ADEs.
RESULTS: Among 1,341,077 patients in the dataset with prescriptions, 47.4 % were prescribed a drug whose response was affected by genetic variants and 31.9 % were prescribed at least one drug with serious ADEs modulated by these variants. Without genetic testing, the number of South Korean patients predicted to experience serious ADEs due to their higher ADE risk genotypes was estimated at 729. Extrapolating this to the total South Korean population indicated that approximately 24,300 patients in 2011 might have benefitted from preemptive genotyping.
CONCLUSIONS: This study quantified the number of South Korean patients predicted to have serious ADEs and demonstrated the need for preemptive genotyping to assist safer drug therapy in South Korea.

PMID: 27638658 [PubMed - indexed for MEDLINE]

Drug Safety Monitoring in Children: Performance of Signal Detection Algorithms and Impact of Age Stratification.

Drug Saf. 2016 09;39(9):873-81

Authors: Osokogu OU, Dodd C, Pacurariu A, Kaguelidou F, Weibel D, Sturkenboom MC

Abstract
INTRODUCTION: Spontaneous reports of suspected adverse drug reactions (ADRs) can be analyzed to yield additional drug safety evidence for the pediatric population. Signal detection algorithms (SDAs) are required for these analyses; however, the performance of SDAs in the pediatric population specifically is unknown. We tested the performance of two SDAs on pediatric data from the US FDA Adverse Event Reporting System (FAERS) and investigated the impact of age stratification and age adjustment on the performance of SDAs.
METHODS: We tested the performance of two established SDAs: the proportional reporting ratio (PRR) and the empirical Bayes geometric mean (EBGM) on a pediatric dataset from FAERS (2004-2012). We compared the performance of the SDAs with a published pediatric-specific reference set by calculating diagnostic test-related statistics, including the area under the curve (AUC) of receiver operating characteristics. Impact of age stratification and age-adjustment on the performance of the SDAs was assessed. Age adjustment was performed by pooling (Mantel-Hanszel) stratum-specific estimates.
RESULTS: A total of 115,674 pediatric reports (patients aged 0-18 years) comprising 893,587 drug-event combinations (DECs) were analysed. Crude values of the AUC were similar for both SDAs: 0.731 (PRR) and 0.745 (EBGM). Stratification unmasked four DECs, e.g., 'ibuprofen and thrombocytopenia'. Age adjustment did not improve performance.
CONCLUSION: The performance of the two tested SDAs was similar in the pediatric population. Age adjustment does not improve performance and is therefore not recommended to be performed routinely. Stratification can reveal new associations, and therefore is recommended when either drug use is age-specific or when an age-specific risk is suspected.

PMID: 27255487 [PubMed - indexed for MEDLINE]

Genetic effects on treatment response of umeclidinium/vilanterol in chronic obstructive pulmonary disease.

Respir Med. 2016 May;114:123-6

Authors: Condreay L, Huang L, Harris E, Brooks J, Riley JH, Church A, Ghosh S

Abstract
BACKGROUND: Treatment with long-acting β2-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) for chronic obstructive pulmonary disease (COPD) is standard, but response varies. We investigated genetic association with treatment response to umeclidinium (UMEC, a LAMA), vilanterol (VI, a LABA), and combination therapy.
METHODS: Data from 17 clinical trials (N = 6075) in patients with COPD receiving once-daily UMEC/VI (125/25mcg or 62.5/25mcg), UMEC (125 or 62.5mcg), VI (25mcg) or placebo were used. Genetic association with change from baseline in trough forced expiratory volume in 1 s (FEV1) ∼24 h post-dosing was assessed for: (i) 3 β2-adrenoceptor (ADRB2) gene variants; (ii) 298 single-nucleotide polymorphisms (SNPs) with prior evidence of associations; (iii) human leukocyte antigen (HLA) alleles and (iv) genome-wide association study (GWAS) SNPs. Other endpoints were (i) reversibility at screening; and at baseline: (ii) FEV1; (iii) forced vital capacity (FVC), and (iv) FEV1/FVC ratio. Using linear regression, the inverse normal transformed residuals were pooled together, first across treatment group, then across studies for each monotherapy, then combination therapy and finally for every treated patient.
RESULTS: Of 6075 patients, 1849 received UMEC/VI, 1390 received UMEC, 1795 received VI, and 1041 received placebo. None of the ADRB2 variants, HLA alleles or GWAS variants tested were associated with treatment response or baseline endpoints. Four SNPs in FAM13A (rs7671167, rs2869967, rs1964516, rs1903003) were significantly associated with baseline FEV1/FVC ratio (p < 3 × 10(-5)) after adjusting for multiple testing.
CONCLUSIONS: No genetic association was found with treatment response to UMEC or VI when administered as monotherapies or in combination.

PMID: 27109822 [PubMed - indexed for MEDLINE]

Pharmacogenomics: Time to re-think its role in Precision Medicine.

Ann Oncol. 2017 Dec 11;:

Authors: Willis JA, Vilar E

PMID: 29236957 [PubMed - as supplied by publisher]

Adverse Events under Tacrolimus and Cyclosporine in the First 3 Years Post-Renal Transplantation in Children.

Clin Drug Investig. 2017 Dec 13;:

Authors: Lancia P, Aurich B, Ha P, Maisin A, Baudouin V, Jacqz-Aigrain E

Abstract
BACKGROUND: Progress in immunosuppression has reduced acute rejection, graft loss and mortality after renal transplantation. Adverse drug reactions are well described in adults but few data are available in children. Our objectives were to analyse the adverse events reported in the first 3 years post-transplantation in children receiving tacrolimus or cyclosporine-based immunosuppression and compare them with the information of the Summary of Product Characteristics.
METHODS: This retrospective study included all children who underwent a renal transplant at Hospital Robert Debré between 2002 and 2015. Initial immunosuppression was based on induction, calcineurin inhibitor, mycophenolate mofetil and corticosteroids. Adverse events were collected from medical records and coded using the Medical Dictionary for Regulatory Activities and the implications of tacrolimus and cyclosporine analysed. Statistical analyses were performed using SAS 9.4.
RESULTS: One hundred and twenty-five children were included. During the observation period [2.7 years (0.6-4.3)], 105 patients received tacrolimus and 39 received cyclosporine. The incidence rate for gastrointestinal disorders was 0.128 and 0.056 by patient-years of exposure (p < 0.05), under tacrolimus and cyclosporine schedules. For neutropenia, it was 0.064 and 0.014 (p < 0.05). The frequencies of toxic nephropathy and gastrointestinal pain were higher than those in the Summary of Product Characteristics of tacrolimus (> 20%) and cyclosporine (> 10%). Cosmetic events for cyclosporine and neutropenia for tacrolimus were frequently observed (18 and 14.3%, respectively), although uncommon in the Summary of Product Characteristics.
CONCLUSIONS: The exposure-adjusted incidence rate of gastrointestinal disorders and neutropenia was higher in children under the tacrolimus schedule. Our findings contribute to the evaluation of the benefit-risk balance of immunosuppressive therapy following paediatric renal transplantation.

PMID: 29236209 [PubMed - as supplied by publisher]

Pharmacogenomics Guided-Personalization of Warfarin and Tamoxifen.

J Pers Med. 2017 Dec 13;7(4):

Authors: Wigle TJ, Jansen LE, Teft WA, Kim RB

Abstract
The use of pharmacogenomics to personalize drug therapy has been a long-sought goal for warfarin and tamoxifen. However, conflicting evidence has created reason for hesitation in recommending pharmacogenomics-guided care for both drugs. This review will provide a summary of the evidence to date on the association between cytochrome P450 enzymes and the clinical end points of warfarin and tamoxifen therapy. Further, highlighting the clinical experiences that we have gained over the past ten years of running a personalized medicine program, we will offer our perspectives on the utility and the limitations of pharmacogenomics-guided care for warfarin and tamoxifen therapy.

PMID: 29236081 [PubMed]

A genome-wide screen for FTY720-sensitive mutants reveals genes required for ROS homeostasis.

Microb Cell. 2017 Nov 27;4(12):390-401

Authors: Hagihara K, Kinoshita K, Ishida K, Hojo S, Kameoka Y, Satoh R, Takasaki T, Sugiura R

Abstract
Fingolimod hydrochloride (FTY720), a sphingosine-1-phosphate (S1P) analogue, is an approved immune modulator for the treatment of multiple sclerosis (MS). Notably, in addition to its well-known mode of action as an S1P modulator, accumulating evidence suggests that FTY720 induces apoptosis in various cancer cells via reactive oxygen species (ROS) generation. Although the involvement of multiple signaling molecules, such as JNK (Jun N-terminal kinase), Akt (alpha serine/threonine-protein kinase) and Sphk has been reported, the exact mechanisms how FTY720 induces cell growth inhibition and the functional relationship between FTY720 and these signaling pathways remain elusive. Our previous reports using the fission yeast Schizosaccharomyces pombe as a model system to elucidate FTY720-mediated signaling pathways revealed that FTY720 induces an increase in intracellular Ca2+ concentrations and ROS generation, which resulted in the activation of the transcriptional responses downstream of Ca2+/calcineurin signaling and stress-activated MAPK signaling, respectively. Here, we performed a genome-wide screening for genes whose deletion induces FTY720-sensitive growth in S. pombe and identified 49 genes. These gene products are related to the biological processes involved in metabolic processes, transport, transcription, translation, chromatin organization, cytoskeleton organization and intracellular signal transduction. Notably, most of the FTY720-sensitive deletion cells exhibited NAC-remedial FTY720 sensitivities and dysregulated ROS homeostasis. Our results revealed a novel gene network involving ROS homeostasis and the possible mechanisms of the FTY720 toxicity.

PMID: 29234668 [PubMed]

Interleukin-6 Induces DEC1, Promotes DEC1 Interaction with RXRα and Suppresses the Expression of PXR, CAR and Their Target Genes.

Front Pharmacol. 2017;8:866

Authors: Ning R, Zhan Y, He S, Hu J, Zhu Z, Hu G, Yan B, Yang J, Liu W

Abstract
Inflammatory burden is a primary cellular event in many liver diseases, and the overall capacity of drug elimination is decreased. PXR (pregnane X receptor) and CAR (constitutive androstane receptor) are two master regulators of genes encoding drug-metabolizing enzymes and transporters. DEC1 (differentiated embryonic chondrocyte-expressed gene 1) is a ligand-independent transcription factor and reportedly is induced by many inflammatory cytokines including IL-6. In this study, we used primary hepatocytes (human and mouse) as well as HepG2 cell line and demonstrated that IL-6 increased DEC1 expression and decreased the expressions of PXR, CAR, and their target genes. Overexpression of DEC1 had similar effect as IL-6 on the expression of these genes, and knockdown of DEC1 reversed their downregulation by IL-6. Interestingly, neither IL-6 nor DEC1 altered the expression of RXRα, a common dimerization partner for many nuclear receptors including PXR and CAR. Instead, DEC1 was found to interact with RXRα and IL-6 enhanced the interaction. These results conclude that DEC1 uses diverse mechanisms of action and supports IL-6 downregulation of drug-elimination genes and their regulators.

PMID: 29234281 [PubMed]

Cohort profile: the Scottish Research register SHARE. A register of people interested in research participation linked to NHS data sets.

BMJ Open. 2017 Feb 01;7(2):e013351

Authors: McKinstry B, Sullivan FM, Vasishta S, Armstrong R, Hanley J, Haughney J, Philip S, Smith BH, Wood A, Palmer CN

Abstract
PURPOSE: Recruitment to trials is often difficult. Many trials fail to meet recruitment targets resulting in underpowered studies which waste resources and the time of those who participated. While there is evidence that many people are willing to take part in research, particularly if it involves a condition from which they suffer, researchers are unable to easily contact such people often relying on busy clinicians to identify them. Many clinicians perceive themselves as too busy to take part in research activities. The Scottish Health Research Register SHARE adopts an approach which asks the public to consent to their data held in National Health Service databases to be used to determine their suitability for research projects. Additionally, participants can consent for spare blood, left after routine venepuncture to be automatically identified in the laboratory and stored for future research studies.
PARTICIPANTS: Anyone over the age of 16 years in Scotland can participate. Participants are approached through a range of methods including directly at outpatient clinics and general practitioners practices, leaflets with hospital letters and personal email from employers.
FINDINGS TO DATE: SHARE has recruited around 130 000 people. SHARE has demonstrated that it can quickly and efficiently recruit to studies, over 20 until now. In addition, it can be used to administer questionnaire studies by email and recruit to patient and public involvement groups.
FUTURE PLANS: SHARE continues to steadily recruit with the ambition of eventually achieving 1 000 000 people in Scotland. We are steadily increasing the number of data sets we use for identifying participants. We are adding a mobile app which will facilitate dissemination about research and allow the collection of physiological and activity data if desired. We anticipate that SHARE will soon become the main source of health research recruitment in Scotland.

PMID: 28148535 [PubMed - indexed for MEDLINE]

BIRC5 (survivin): a pejorative prognostic marker in stage II/III breast cancer with no response to neoadjuvant chemotherapy.

Breast Cancer Res Treat. 2016 Oct;159(3):499-511

Authors: Hamy AS, Bieche I, Lehmann-Che J, Scott V, Bertheau P, Guinebretière JM, Matthieu MC, Sigal-Zafrani B, Tembo O, Marty M, Asselain B, Spyratos F, de Cremoux P

Abstract
PURPOSE: Neoadjuvant systemic therapy (NAC) is currently used in the treatment of stage II/III breast cancer. Pathological complete response as a surrogate endpoint for clinical outcomes is not completely validated for all subgroups of breast cancers. Therefore, there is a need for reliable predictive tests of the most effective treatment.
METHODS: We used a combination of predictive clinical, pathological, and gene expression-based markers of response to NAC in a prospective phase II multicentre randomized clinical trial in breast cancer patients, with a long follow-up (8 years). This study concerned the subpopulation of 188 patients with similar levels of pathological response rates to sequential epirubicin/cyclophosphamide and docetaxel to determine predictive marker of pCR and DFS. We used a set of 45 genes selected from high throughput analysis and a standardized RT-qPCR. We analyzed the predictive markers of pathological complete response (pCR) and DFS in the overall population and DFS the subpopulation of 159 patients with no pCR.
RESULTS: In the overall population, combining both clinical and genomic variables, large tumor size, low TFF1, and MYBL2 overexpression were significantly associated with pCR. T4 Stage, lymphovascular invasion, negative PR status, histological type, and high values of CCNB1 were associated with DFS. In the no pCR population, only lymphovascular invasion and high values of BIRC5 were associated with DFS.
CONCLUSIONS: We confirm the importance of ER-related and proliferation genes in the prediction of pCR in NAC-treated breast cancer patients. Furthermore, we identified BIRC5 (survivin) as a main pejorative prognostic factor in patients with breast cancers with no pCR. These results also open perspective for predictive markers of new targeted therapies.

PMID: 27592112 [PubMed - indexed for MEDLINE]

Pharmacogenetics predictors of methylphenidate efficacy in childhood ADHD.

Mol Psychiatry. 2017 Dec 12;:

Authors: Myer NM, Boland JR, Faraone SV

Abstract
Stimulant medication has long been effective in treating attention-deficit/hyperactivity disorder (ADHD) and is currently the first-line pharmacological treatment for children. Both methylphenidate and amphetamine modulate extracellular catecholamine levels through interaction with dopaminergic, adrenergic and serotonergic system components; it is therefore likely that catecholaminergic molecular components influence the effects of ADHD treatment. Using meta-analysis, we sought to identify predictors of pharmacotherapy to further the clinical implementation of personalized medicine. We identified 36 studies (3647 children) linking the effectiveness of methylphenidate treatment with DNA variants. Pooled-data revealed a statistically significant association between single nucleotide polymorphisms (SNPs) rs1800544 ADRA2A (odds ratio: 1.69; confidence interval: 1.12-2.55), rs4680 COMT (odds ratio (OR): 1.40; confidence interval: 1.04-1.87), rs5569 SLC6A2 (odds ratio: 1.73; confidence interval: 1.26-2.37) and rs28386840 SLC6A2 (odds ratio: 2.93; confidence interval: 1.76-4.90), and, repeat variants variable number tandem repeat (VNTR) 4 DRD4 (odds ratio: 1.66; confidence interval: 1.16-2.37) and VNTR 10 SLC6A3 (odds ratio: 0.74; confidence interval: 0.60-0.90), whereas the following variants were not statistically significant: rs1947274 LPHN3 (odds ratio: 0.95; confidence interval: 0.71-1.26), rs5661665 LPHN3 (odds ratio: 1.07; confidence interval: 0.84-1.37) and VNTR 7 DRD4 (odds ratio: 0.68; confidence interval: 0.47-1.00). Funnel plot asymmetry among SLC6A3 studies was identified and attributed largely to small study effects. Egger's regression test and Duval and Tweedie's 'trim and fill' were used to examine and correct for publication bias. These findings have major implications for advancing our therapeutic approach to childhood ADHD treatment.Molecular Psychiatry advance online publication, 12 December 2017; doi:10.1038/mp.2017.234.

PMID: 29230023 [PubMed - as supplied by publisher]

Comparative clinical trial of the variability factors of the exposure indices used for the drug monitoring of two tacrolimus formulations in kidney transplant recipients.

Pharmacol Res. 2017 Dec 08;:

Authors: Marquet P, Albano L, Woillard JB, Rostaing L, Kamar N, Sakarovitch C, Gatault P, Buchler M, Charpentier B, Thervet E, Cassuto E

Abstract
BACKGROUND: Several studies found differences in tacrolimus whole blood trough levels (C0) or area-under-the curve (AUC) between the twice-daily (Tac-BID) and once-daily (Tac-OD) formulations given to kidney transplant recipients at equal doses. As C0 is widely used as a surrogate of the AUC for individual dose adjustment, this study investigated the correlation and proportionality between C0 and the 24h-AUC, depending on the formulation, time post-transplantation, pharmacogenetics traits and other individual characteristics.
METHODS: 45 adult kidney transplant recipients were randomized to receive either Tac OD or Tac BID. On days 8±1 (D8) and 90±3 (month 3, M3), blood samples were collected over 24h in both groups. Tacrolimus concentrations were determined using HPLC-MS/MS and common CYP3A5, CYP3A4 and ABCB1 genotypes characterized using allelic discrimination assays. Tacrolimus population pharmacokinetics was studied in the two patient groups using the Iterative Two Stage (ITS) technique, considering a one-compartment model with two gamma laws to describe the absorption phase. Bayesian estimation based on the C0, C1h and C3h concentrations was employed to estimate individual Tac AUC0-12h and AUC12-24h (for Tac BID), or AUC0-24h (for Tac OD). Multiple linear regression was used to evaluate the influence of Tac formulation, post-transplantation period, recipient gender, existing glucose metabolism disorders, and CYP3A5, CYP3A4 and ABCB1 genotypes on C0, AUC0-24h and the AUC-to-trough concentration ratios.
RESULTS: The Full Analysis Set comprised 22 patients on Tac OD and 20 on Tac BID. Tac exposure indices as well as their time evolution were similar in the two groups. Multi-linear modeling analysis showed that the Tac dose was higher with Tac-OD than Tac-BID, on D8 than at M3 and in CYP3A5 expressors (p<0.0001 for all). No such influence was found on C0 or C24h, while the AUC0-24h was significantly higher on D8 than at M3. The AUC0-24h/C0 ratio was not affected by the drug formulation and the polymorphisms studied, but it was significantly lower on D8 than at M3 (p=7.8×10-5). In contrast, both the post-transplantation period (p=1.53×10-4), and CYP3A5 expression (p=0.003) had a significant influence on the AUC0-24h/C24h ratio, explaining 19% and 12% of its variability, respectively. Consistently, for both Tac formulations, the AUC0-24h was better correlated with C24h than C0, and for Tac-BID the AUC0-12h was better correlated with C12h than C0.
CONCLUSIONS: This study confirms that the precisely timed 12h- or 24h-post-dose blood concentration (as opposed to the vaguely defined 'trough level') is a convenient surrogate of the 24h-AUC of tacrolimus for the two TAC formulations over the first 3 months post-transplantation. Still, for a given C24h value, AUC0-24h was higher on D8 and in CYP3A5 expressors. Bayesian estimation of AUC0-12h for TAC BID and AUC0-24h for TAC OD is feasible using only 3 time points within the first 3hours, thus giving access to the actual overall exposure.

PMID: 29229354 [PubMed - as supplied by publisher]

No genetic association detected with mepolizumab efficacy in severe asthma.

Respir Med. 2017 Nov;132:178-180

Authors: Condreay L, Chiano M, Ortega H, Buchan N, Harris E, Bleecker ER, Thompson PJ, Humbert M, Gibson P, Yancey S, Ghosh S

Abstract
BACKGROUND AND OBJECTIVES: Treatment with mepolizumab, a humanized monoclonal antibody to interleukin-5, reduces the rate of asthma exacerbations and the requirement for systemic glucocorticoids while maintaining asthma control. Treatment decisions are guided by predictors of response, including blood eosinophil thresholds in patients with frequent exacerbations despite intensive anti-inflammatory and controller treatment. Identification of additional predictors of response could aid treatment decisions. We investigated genetic associations that may predict response to mepolizumab-treatment.
METHODS: In this post hoc analysis of DREAM and MENSA, association of genetic markers was tested in patients with severe asthma treated with mepolizumab who provided consent for pharmacogenetic research. Association was tested in a tiered approach with alpha spend differing for candidate genetic markers selected for prior history of association with relevant traits or pathways and in a genome-wide analyses (p < 4.7 × 10-4 and p < 5 × 10-8, respectively). Efficacy endpoints included: clinically significant exacerbation rate (tested using a negative binomial model), time to first exacerbation (tested with a Cox proportional hazards model), change in exacerbation rate, change in eosinophil count, and change in IgE level (tested by linear regression).
RESULTS: No genetic marker was significantly associated with the primary endpoint, clinically significant exacerbation rate. One genetic marker was associated with time to first clinically significant exacerbation, but this association was driven by the DREAM data and was not supported in additional sensitivity analyses by treatment regimen/dose.
CONCLUSION: No genetic effect on mepolizumab-treatment response was identified in this population on intensive asthma treatment, with history of frequent exacerbations and pre-selected for airway eosinophilia.

PMID: 29229094 [PubMed - in process]

Long noncoding RNA SFTA1P promoted apoptosis and increased cisplatin chemosensitivity via regulating the hnRNP-U-GADD45A axis in lung squamous cell carcinoma.

Oncotarget. 2017 Nov 14;8(57):97476-97489

Authors: Li L, Yin JY, He FZ, Huang MS, Zhu T, Gao YF, Chen YX, Zhou DB, Chen X, Sun LQ, Zhang W, Zhou HH, Liu ZQ

Abstract
Chemotherapeutic insensitivity remains one of the major obstacles in clinical treatment of lung squamous cell carcinoma (LSCC). Recently, increasing evidence has suggested that long non-coding RNAs (lncRNAs) promote tumorigenesis in many cancer types. However, the potential biological roles and regulatory mechanisms of lncRNAs in response to cisplatin treatment are poorly understood. Here, we found that lncRNA SFTA1P (surfactant associated 1, pseudogene), highly expressed in lung, was down-regulated in LSCC tissues and could be induced upon cisplatin treatment in LSCC cells. Elevated SFTA1P induced apoptosis and enhanced the sensitivity to cisplatin of LSCC cells. We further identified that hnRNP-U (heterogeneous nuclear ribonucleoprotein U) was down-regulated in LSCCs and positively correlated with patients' poor prognosis as well as SFTA1P. Mechanistic studies revealed that SFTA1P could up-regulate hnRNP-U expression. In addition, we identified that hnRNP-U enhanced cisplatin-induced apoptosis through up-regulation of GADD45A, high expression of which was correlated with good prognosis in LSCC patients. Our findings demonstrated that SFTA1P might serve as a useful biomarker for LSCC diagnosis and a predictor for cisplatin chemotherapy response in patients with LSCC.

PMID: 29228625 [PubMed]

Tannic acid attenuates TGF-β1-induced epithelial-to-mesenchymal transition by effectively intervening TGF-β signaling in lung epithelial cells.

J Cell Physiol. 2018 Mar;233(3):2513-2525

Authors: Pattarayan D, Sivanantham A, Krishnaswami V, Loganathan L, Palanichamy R, Natesan S, Muthusamy K, Rajasekaran S

Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and an irreversible lung disorder characterized by the accumulation of fibroblasts and myofibroblasts in the extracellular matrix. The transforming growth factor-β1 (TGF-β1)-induced epithelial-to-mesenchymal transition (EMT) is thought to be one of the possible sources for a substantial increase in the number of fibroblasts/myofibroblasts in IPF lungs. Tannic acid (TA), a natural dietary polyphenolic compound has been shown to possess diverse pharmacological effects. However, whether TA can inhibit TGF-β1-mediated EMT in lung epithelial cells remains enigmatic. Both the human adenocarcinomic alveolar epithelial (A549) and normal bronchial epithelial (BEAS-2B) cells were treated with TGF-β1 with or without TA. Results showed that TA addition, markedly inhibited TGF-β1-induced EMT as assessed by reduced expression of N-cadherin, type-1-collagen, fibronectin, and vimentin. Furthermore, TA inhibited TGF-β1-induced cell proliferation through inducing cell cycle arrest at G0/G1 phase. TGF-β1-induced increase in the phosphorylation of Smad (Smad2 and 3), Akt as well as that of mitogen activated protein kinase (ERK1/2, JNK1/2, and p38) mediators was effectively inhibited by TA. On the other hand, TA reduced the TGF-β1-induced increase in TGF-β receptors expression. Using molecular docking approach, FTIR, HPLC and Western blot analyses, we further identified the direct binding of TA to TGF-β1. Finally, we conclude that TA might directly interact with TGF-β1, thereby repressing TGF-β signaling and subsequent EMT process in lung epithelial cells. Further animal studies are needed to clarify its potential therapeutic benefit in pulmonary fibrosis.

PMID: 28771711 [PubMed - indexed for MEDLINE]

Phosphorylation of Farnesoid X Receptor at Serine 154 Links Ligand Activation With Degradation.

Mol Endocrinol. 2016 Oct;30(10):1070-1080

Authors: Hashiguchi T, Arakawa S, Takahashi S, Gonzalez FJ, Sueyoshi T, Negishi M

Abstract
Comparison of 11 human nuclear receptor amino acid sequences revealed a conserved phosphorylation motif within their DNA-binding domains as an intramolecular signal that regulates proteolytic degradation. Nuclear receptors use this signal to either degrade or proscribe degradation through either the proteasome or nonproteasome pathways. A phosphomimetic farnesoid X receptor (FXR) S154D mutant neither bound to nor trans-activated an FXR-response element-driven reporter gene and was rapidly degraded in COS-1 cells. Ectopically expressed FXR had increased Ser154 phosphorylation in COS-1 cells after ligand treatment, and knock-down of the nuclear vaccinia-related kinase 1 (VRK1) greatly reduced this phosphorylation. FXR was phosphorylated at Ser154 in the nucleus of centrilobular hepatocytes only in ligand-treated mice. Thus, FXR Ser154 phosphorylation is a rheostat for activation and subsequent degradation that controls receptor levels and activity.

PMID: 27571290 [PubMed - indexed for MEDLINE]

Discrimination of FCGR2B polymorphism without coamplification of FCGR2A and FCGR2C genes.

Int J Immunogenet. 2017 Dec 11;:

Authors: Bonatti F, Adorni A, Percesepe A, Martorana D

Abstract
The FCGR locus is characterized by high polymorphism and sequence homology. In particular, the Ile232Thr polymorphism in the FCGR2B gene results in inaccurate genotyping in most published papers. The purpose of the study was to develop an accurate genotyping assay able to discriminate this polymorphism.

PMID: 29227030 [PubMed - as supplied by publisher]

Pharmacokinetics and pharmacogenetics of anti-tubercular drugs: a tool for treatment optimization?

Expert Opin Drug Metab Toxicol. 2017 Dec 10;:

Authors: Motta I, Calcagno A, Bonora S

Abstract
Introduction WHO global strategy is to end tuberculosis epidemic by 2035. Pharmacokinetic and pharmacogenetic studies are increasingly performed and might confirm their potential role in optimizing treatment outcome in specific settings and populations. Insufficient drug exposure seems to be a relevant factor in tuberculosis outcome and for the risk of phenotypic resistance. Areas Covered This review discusses available pharmacokinetic and pharmacogenetic data of first and second-line antitubercular agents in relation to efficacy and toxicity. Pharmacodynamic implications of optimized drugs and new options regimens are reviewed. Moreover a specific session describes innovative investigations on drug penetration. Expert Opinion The optimal use of available antitubercular drugs is paramount for tuberculosis control and eradication. Whilst trials are still on-going, higher rifampicin doses should be reserved to treatment for tubercular meningitis. Therapeutic Drug Monitoring with limiting sampling strategies is advised in patients at risk of failure or with slow treatment response. Further studies are needed in order to provide definitive recommendations of pharmacogenetic-based individualization: however lower isoniazid doses in NAT2 slow acetylators and higher rifampicin doses in individuals with SLCO1B1 loss of function genes are promising strategies. Finally in order to inform tailored strategies we need more data on tissue drug penetration and pharmacological modelling.

PMID: 29226732 [PubMed - as supplied by publisher]

Pharmacogenetics of platinum-based chemotherapy in non-small cell lung cancer: predictive validity of polymorphisms of ERCC1.

Expert Opin Drug Metab Toxicol. 2017 Dec 11;:

Authors: Hamilton G, Rath B

Abstract
INTRODUCTION: The efficacy of platinum based chemotherapy for patients with non-small cell lung cancer (NSCLC) is limited by chemoresistance. Platinum drugs damage DNA by introducing intrastrand and interstrand crosslinks which result in cell death. Excision repair cross-complementing 1 (ERCC1) is a member of the nucleotide excision repair (NER) pathway which erases such defects. Single nucleotide polymorphisms (SNPs) in ERCC1 impair this activity and have been suggested to predict the response to chemotherapy. Area covered. Among the polymorphisms of proteins involved in uptake, metabolism, cytotoxicity and efflux of platinum drugs, codon 118 C/T and C8092A in ERCC1 are the best characterized SNPs studied for their predictive power. Here, the divergent results for studies of these markers in NSCLC are summarized and the reasons for this contradictory data discussed. Expert Opinion. Cytotoxicity of platinum compounds comprise complex cellular processes for which DNA repair may not constitute the rate limiting step. These drugs are administered as doublets to histologically diverse patients and, furthermore, the NER pathway in ERCC1 wildtype cohorts may be still impaired by the chemotherapeutics applied. At present, assessment of a limited number of polymorphism in DNA repair proteins is not reliably associated with response to treatment in NSCLC patients.

PMID: 29226731 [PubMed - as supplied by publisher]

Recent advances in acute pain management: understanding the mechanisms of acute pain, the prescription of opioids, and the role of multimodal pain therapy.

F1000Res. 2017;6:2065

Authors: Wardhan R, Chelly J

Abstract
In this review, we discuss advances in acute pain management, including the recent report of the joint American Pain Society and American Academy of Pain Medicine task force on the classification of acute pain, the role of psychosocial factors, multimodal pain management, new non-opioid therapy, and the effect of the "opioid epidemic". In this regard, we propose that a fundamental principle in acute pain management is identifying patients who are most at risk and providing an "opioid free anesthesia and postoperative analgesia". This can be achieved by using a multimodal approach that includes regional anesthesia and minimizing the dose and the duration of opioid prescription. This allows prescribing medications that work through different mechanisms. We shall also look at the recent pharmacologic and treatment advances made in acute pain and regional anesthesia.

PMID: 29225793 [PubMed]