Influence of CYP3A5 Genetic Polymorphism on Long-Term Renal Function in Chinese Kidney Transplant Recipients Using Limited Sampling Strategy and Abbreviated Area Under the Curve for Tacrolimus Monitoring.

Prog Transplant. 2020 Jun 17;:1526924820933823

Authors: Cheung CY, Chan KM, Wong YT, Chak WL, Bekers O, van Hooff JP

Abstract
INTRODUCTION: Although the association between CYP3A5 gene polymorphism and tacrolimus dosing requirements was well established, the impact on how CYP3A5 genotype affects the acute rejection and long-term renal function in patients who received kidney transplants and were treated with tacrolimus remained controversial.
DESIGN: Sixty-seven Chinese patients with kidney transplants receiving de novo tacrolimus-based immunosuppressive therapy with known CYP3A5 genotype were divided into 2 groups. Those with at least 1 CYP3A5*1 allele were CYP3A5 expressers while homozygotes for the mutant allele CYP3A5*3 were nonexpressers. Instead of trough level, our center used abbreviated area under the curve for tacrolimus monitoring. Primary outcome was the long-term renal function between both groups while secondary outcomes included the weight-adjusted daily tacrolimus dose, graft survival, incidence of biopsy-proven acute rejection (BPAR), opportunistic infection, and cancer.
RESULTS: Thirty-five (52.2%) patients were CYP3A5 expressers while 32 were nonexpressers. Mean daily tacrolimus dose in the CYP3A5 expressers and nonexpressers was 0.08 (0.03) and 0.05 (0.02) mg/kg, respectively (P < .01). Starting from 1-month posttransplant, the renal function was comparable between both groups, which persisted up to 10-year. Ten patients experienced BPAR rejection and there was no significant difference in the rejection-free survival between both groups (P = .87). There was also no significant difference in the death-censored graft survival between both groups (P = .86). Finally, the incidence of opportunistic infection and posttransplant cancer was similar between them.
DISCUSSION: There was no significant difference in renal function, graft survival, and acute rejection between CYP3A5 expressers and nonexpressers.

PMID: 32552577 [PubMed - as supplied by publisher]

Singapore COVID-19 Pandemic Response as a Successful Model Framework for Low-Resource Health Care Settings in Africa?

OMICS. 2020 Jun 16;:

Authors: Kuguyo O, Kengne AP, Dandara C

Abstract
The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus continues to spread and evolve across the planet. The crosscutting impacts of the virus, individual country responses to the virus, and the state of preparedness of local public health systems greatly vary across the world. The ostensibly late arrival of the virus in Africa has allowed learning, innovation, and adaptation of methods that have been successful in the early-hit countries. This article analyzes how Singapore has responded to the COVID-19 pandemic and proposes that adaptations of the Singapore pandemic response model would bode well for Africa's response to the COVID-19 pandemic in ways that also take into account regional differences in health care infrastructures, socioeconomic resilience, poverty, and the vast population diversity in the African continent. As the pandemic evolves, the lessons learned in Asia, in particular, and the emerging new experiences in African countries should inform, ideally in real time, how best to steer the world populations into safety, including those in low-resource health care settings. Finally, we note that the current COVID-19 pandemic is also a test for our collective ability to scale and surge public health in response to future and likely equally challenging zoonosis infections that jump from animals to humans, not to mention climate change-related planetary health calamities in the 21st century. Hence, what we learn effectively from the current COVID-19 pandemic shall have broad, enduring, and intergenerational relevance for the future of planetary heath and society.

PMID: 32552397 [PubMed - as supplied by publisher]

The rs1991517 polymorphism is a genetic risk factor for congenital hypothyroidism.

3 Biotech. 2020 Jun;10(6):285

Authors: Kollati Y, Akella RRD, Naushad SM, Thalla M, Reddy GB, Dirisala VR

Abstract
The objective of the current study is to explore the association of thyroid-stimulating hormone receptor (TSHR) rs1991517 polymorphism (c.2337 C > G, p.D727E) with congenital hypothyroidism (CH) through a case-control study followed by a meta-analysis. The case-control study was based on 45 CH subjects and 700 healthy controls. Meta-analysis comprised of seven published studies and our current findings (1044 CH cases and 1649 healthy controls). The allele contrast model showed that the presence of G- allele increased CH risk by 45% (OR: 1.45, 95% CI 1.20-1.76) and 41% (OR: 1.41, 95% CI 1.03-1.93) in fixed effect and random effect models, respectively. The GG- genotype is associated with 2.3-fold (95% CI 1.32-3.99) increased risk for CH in the fixed-effect model. I 2 (0.58) and Cochran's Q test (Q: 16.72, p = 0.02) revealed evidence of heterogeneity in the association. No publication bias was observed by Egger's test (p = 0.70). Sensitivity analysis revealed that even after excluding any study this polymorphism is associated with risk for CH. The rs1991517 mutation alters the binding affinity to cAMP (ΔG of 727D vs.727E: - 7.27 vs. - 7.34 kcal/mol). In conclusion, rs1991517 is a genetic risk factor for CH and exerts its impact by altering cAMP-mediated signal transduction.

PMID: 32550104 [PubMed]

NLRP3 and CARD8 polymorphisms influence risk for asbestos-related diseases.

J Med Biochem. 2020 Jan 10;39(1):91-99

Authors: Franko A, Goricar K, Kovac V, Dodic-Fikfak M, Dolzan V

Abstract
Background: This study aimed to investigate the association between NLRP3 rs35829419 and CARD8 rs2043211 polymorphisms and the risk of developing pleural plaques, asbestosis, and malignant mesothelioma (MM), and to study the influence of the interactions between polymorphisms and asbestos exposure on the risk of developing these diseases.
Methods: The case-control study included 416 subjects with pleural plaques, 160 patients with asbestosis, 154 subjects with MM and 149 subjects with no asbestos disease. The NLRP3 rs35829419 and CARD8 rs2043211 polymorphisms were determined using real-time PCR-based methods. In the statistical analysis, standard descriptive statistics was followed by univariate and multivariate logistic regression modelling.
Results: Asbestos exposure (medium and high vs low) was associated with the risk for each studied asbestos-related disease. An increased risk of pleural plaques was found for CARD8 rs2043211 at + TT genotypes (OR = 1.48, 95% CI 1.01-2.16, p = 0.042). When the analysis was performed for MM patients as cases, and pleural plaques patients as controls, a decreased MM risk was observed for carriers of CARD8 rs2043211 TT genotype (OR = 0.52, 95% CI 0.27-1.00, p = 0.049). The interactions between NLRP3 rs35829419 and CARD8 rs2043211 genotypes did not influence the risk of any asbestos-related disease. However, when testing interactions with asbestos exposure, a decreased risk of asbestosis was found for NLRP3 CA+AA genotypes (OR = 0.09, 95% CI 0.01-0.60, p = 0.014).
Conclusions: The results of our study suggest that NLRP3 and CARD8 polymorphisms could affect the risk of asbestos-related diseases.

PMID: 32549782 [PubMed]

Identification of gene expression and DNA methylation of SERPINA5 and TIMP1 as novel prognostic markers in lower-grade gliomas.

PeerJ. 2020;8:e9262

Authors: Zeng WJ, Yang YL, Wen ZP, Chen P, Chen XP, Gong ZC

Abstract
Background: Lower-grade gliomas (LGGs) is characteristic with great difference in prognosis. Due to limited prognostic biomarkers, it is urgent to identify more molecular markers to provide a more objective and accurate tumor classification system for LGGs.
Methods: In the current study, we performed an integrated analysis of gene expression data and genome-wide methylation data to determine novel prognostic genes and methylation sites in LGGs.
Results: To determine genes that differentially expressed between 44 short-term survivors (<2 years) and 48 long-term survivors (≥2 years), we searched LGGs TCGA RNA-seq dataset and identified 106 differentially expressed genes. SERPINA5 and TIMP1 were selected for further study. Kaplan-Meier plots showed that SERPINA5 and TIMP1 expression were significantly correlated with overall survival (OS) and relapse-free survival (RFS) in TCGA LGGs patients. We next validated the correlation between the candidate genes expression and clinical outcome in CGGA LGGs patients. Multivariate analysis showed that TIMP1 mRNA expression had a significant prognostic value independent of other variables (HR = 4.825, 95% CI = 1.370-17.000, P = 0.014). Then, differential methylation sites were identified from differentially candidate gene expression groups, and all four methylation sites were significantly negatively correlated with gene expression (spearman r <  - 0.5, P < 0.0001). Moreover, hyper-methylation of four methylation sites indicated better OS (P < 0.05), and three of them also shown statistical significantly association with better RFS, except for SERPINA5 cg15509705 (P = 0.0762).
Conclusion: Taken together, these findings indicated that the gene expression and methylation of SERPINA5 and TIMP1 may serve as prognostic predictors in LGGs and may help to precise the current histology-based tumors classification system and to provide better stratification for future clinical trials.

PMID: 32547876 [PubMed]

Identification of Altered Genes in Gallbladder Cancer as Potential Driver Mutations for Diagnostic and Prognostic Purposes: A Computational Approach.

Cancer Inform. 2020;19:1176935120922154

Authors: D'Afonseca V, Arencibia AD, Echeverría-Vega A, Cerpa L, Cayún JP, Varela NM, Salazar M, Quiñones LA

Abstract
Prognostic markers for cancer can assist in the evaluation of survival probability of patients and help clinicians to assess the available treatment modalities. Gallbladder cancer (GBC) is a rare tumor that causes 165 087 deaths in the world annually. It is the most common cancer of the biliary tract and has a particularly high incidence in Chile, Japan, and northern India. Currently, there is no accurate diagnosis test or effective molecular markers for GBC identification. Several studies have focused on the discovery of genetic alterations in important genes associated with GBC to propose novel diagnosis pathways and to create prognostic profiles. To achieve this, we performed data-mining of GBC in public repositories, harboring 133 samples of GBC, allowing us to describe relevant somatic mutations in important genes and to propose a genetic alteration atlas for GBC. In our results, we reported the 14 most altered genes in GBC: arid1a, arid2, atm, ctnnb1, erbb2, erbb3, kmt2c, kmt2d, kras, pik3ca, smad4, tert, tp53, and znf521 in samples from Japan, the United States, Chile, and China. Missense mutations are common among these genes. The annotations of many mutations revealed their importance in cancer development. The observed annotations mentioned that several mutations found in this repository are probably oncogenic, with a putative loss-of-function. In addition, they are hotspot mutations and are probably linked to poor prognosis in other cancers. We identified another 11 genes, which presented a copy number alteration in gallbladder database samples, which are ccnd1, ccnd3, ccne1, cdk12, cdkn2a, cdkn2b, erbb2, erbb3, kras, mdm2, and myc. The findings reported here can help to detect GBC cancer through the development of systems based on genetic alterations, for example, the development of a mutation panel specifically for GBC diagnosis, as well as the creation of prognostic profiles to accomplish the development of GBC and its prevalence.

PMID: 32546937 [PubMed]

ERCC2 gene single-nucleotide polymorphism as a prognostic factor for locally advanced head and neck carcinomas after definitive cisplatin-based radiochemotherapy.

Pharmacogenomics J. 2020 Jun 16;:

Authors: Guberina M, Sak A, Pöttgen C, Tinhofer-Keilholz I, Budach V, Balermpas P, Von der Grün J, Rödel CM, Gikka E, Grosu AL, Abdollahi A, Debus J, Belka C, Pigorsch S, Combs S, Mönnich D, Zips D, De-Colle C, Welz S, Linge A, Lohaus F, Baretton G, Gauler T, Baumann M, Krause M, Schuler M, Bankfalvi A, Höing B, Lang S, Stuschke M

Abstract
Identifying patients with locally advanced head and neck carcinoma on high risk of recurrence after definitive concurrent radiochemotherapy is of key importance for the selection for consolidation therapy and for individualized treatment intensification. In this multicenter study we analyzed recurrence-associated single-nucleotide polymorphisms (SNPs) in DNA repair genes in tumor DNA from 132 patients with locally advanced head and neck carcinoma (LadHnSCC). Patients were treated with definitive radiotherapy and simultaneous cisplatin-based chemotherapy at six partner sites of the German Cancer Consortium (DKTK) Radiation Oncology Group from 2005 to 2011. For validation, a group of 20 patients was available. Score selection method using proportional hazard analysis and leave-one-out cross-validation were performed to identify markers associated with outcome. The SNPs rs1799793 and rs13181 were associated with survival and the same SNPs and in addition rs17655 with freedom from loco-regional relapse (ffLRR) in the trainings datasets from all patients. The homozygote major rs1799793 genotype at the ERCC2 gene was associated with better (Hazard ratio (HR): 0.418 (0.234-0.744), p = 0.003) and the homozygote minor rs13181 genotype at ERCC2 with worse survival (HR: 2.074, 95% CI (1.177-3.658), p = 0.017) in comparison to the other genotypes. At the ffLRR endpoint, rs1799793 and rs13181 had comparable prognostic value. The rs1799793 and rs13181 genotypes passed the leave-one-out cross-validation procedure and associated with survival and ffLRR in patients with LadHnSCC treated with definitive radiochemotherapy. While findings were confirmed in a small validation dataset, further validation is underway within a prospective biomarker study of the DKTK.

PMID: 32546699 [PubMed - as supplied by publisher]

Concordance between predicted HLA type using next generation sequencing data generated for non-HLA purposes and clinical HLA type.

Hum Immunol. 2020 Jun 13;:

Authors: Moyer AM, Dukek B, Duellman P, Schneider B, Wakefield L, Skierka JM, Avula R, Bhagwate AV, Kalari KR, Kreuter JD, Goetz MP, Boughey JC, Black JL, Gandhi MJ

Abstract
We explored the feasibility of obtaining accurate HLA type using pre-existing NGS data not generated for HLA purposes. 83 exomes and 500 targeted NGS pharmacogenomic panels were analyzed using Omixon HLA Explore, OptiType, and/or HLA-Genotyper software. Results were compared against clinical HLA genotyping. 765 (94.2%) Omixon and 769 (94.7%) HLA-Genotyper of 812 germline allele calls across class I/II loci and 402 (99.5%) of 404 OptiType class I calls were concordant to the second field (i.e. HLA-A*02:01). An additional 19 (2.3%) Omixon, 39 (4.8%) HLA-Genotyper, and 2 (0.5%) OptiType allele calls were first field concordant (i.e. HLA-A*02). Using Omixon, four alleles (0.4%) were discordant and 24 (3.0%) failed to call, while 4 alleles (0.4%) were discordant using HLA-Genotyper. Tumor exomes were also evaluated and were 85.4%, 91.6%, and 100% concordant (Omixon and HLA-Genotyper with 96 alleles tested, and Optitype with 48 class I alleles, respectively). The 15 exomes and 500 pharmacogenomic panels were 100% concordant for each pharmacogenomic allele tested. This work has broad implications spanning future clinical care (pharmacogenomics, tumor response to immunotherapy, autoimmunity, etc.) and research applications.

PMID: 32546429 [PubMed - as supplied by publisher]

Retraction notice to "Design, synthesis, and biological evaluation of heterotetracyclic quinolinone derivatives as anticancer agents targeting topoisomerases" [Eur. J. Med. Chem. 190 (2020) 112074].

Eur J Med Chem. 2020 Aug 01;199:112490

Authors: Lee JF, Chang TY, Liu ZF, Lee NZ, Yeh YH, Chen YS, Chen TC, Chou HS, Li TK, Lee SB, Lin MH

Abstract
This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the authors. The authors regret to inform that they would like to withdraw this accepted article, due to serious errors in authorship, affiliations, material sources and supporting grant names/numbers. The authors sincerely apologize for these oversights and miscommunications the study caused.

PMID: 32546328 [PubMed - in process]

Cohort Profile: The Right Drug, Right Dose, Right Time: Using Genomic Data to Individualize Treatment Protocol (RIGHT Protocol).

Int J Epidemiol. 2020 02 01;49(1):23-24k

Authors: Bielinski SJ, St Sauver JL, Olson JE, Larson NB, Black JL, Scherer SE, Bernard ME, Boerwinkle E, Borah BJ, Caraballo PJ, Curry TB, Doddapaneni H, Formea CM, Freimuth RR, Gibbs RA, Giri J, Hathcock MA, Hu J, Jacobson DJ, Jones LA, Kalla S, Koep TH, Korchina V, Kovar CL, Lee S, Liu H, Matey ET, McGree ME, McAllister TM, Moyer AM, Muzny DM, Nicholson WT, Oyen LJ, Qin X, Raj R, Roger VL, Rohrer Vitek CR, Ross JL, Sharp RR, Takahashi PY, Venner E, Walker K, Wang L, Wang Q, Wright JA, Wu TJ, Wang L, Weinshilboum RM

PMID: 31378813 [PubMed - indexed for MEDLINE]

MOTS-c inhibits Osteolysis in the Mouse Calvaria by affecting osteocyte-osteoclast crosstalk and inhibiting inflammation.

Pharmacol Res. 2019 09;147:104381

Authors: Yan Z, Zhu S, Wang H, Wang L, Du T, Ye Z, Zhai D, Zhu Z, Tian X, Lu Z, Cao X

Abstract
The Mitochondrial-derived peptide MOTS-c has recently been reported as a 16-amino acid peptide regulating metabolism and homeostasis in different cells. However, its effects on immune cells and bone metabolism are rarely reported. Here we demonstrate that MOTS-c treatment in ultra-high molecular weight polyethylene (UHMWPE) particle-induced osteolysis mouse model alleviated bone erosion and inflammation. MOTS-c increased osteoprotegerin (OPG)/ receptor activator of nuclear factor kappa-B ligand (RANKL) ratio in osteocytes, leading to inhibition of osteoclastogenesis. In primary bone marrow macrophages (BMMs) MOTS-c alleviated STAT1 and NF-κB phosphorylation triggered by UHMWPE particles. Promoting ROS production or suppressing peroxisome proliferator-activated receptor γ (PPARγ) coactivator-1α (PGC-1α) by adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) repression blocked these anti-inflammatory effects of MOTS-c treatment. Taken together, these findings provide evidence that the small peptide inhibits osteoclastogenesis by regulating osteocyte OPG/RANKL secretion and suppressing inflammation via restraining NF-κB and STAT1 pathway. Moreover, its effects on NF-κB activation is dependent on the AMPK-PGC-1α-ROS axis, suggesting its potential use in osteolysis and other inflammation disorders.

PMID: 31369811 [PubMed - indexed for MEDLINE]

Study of tocopherol content and its potential antioxidant activity in commercial lipid emulsions for parenteral nutrition.

Pharmazie. 2020 Jun 01;75(6):240-241

Authors: Novak A, Gutiérrez-Zamora M, Pérez-Lozano P, Suñé-Negre JM, Llop JM, Ticó JR, Miñarro M, García-Montoya E, Van Schepdael A

Abstract
The objective of this study was to determine the content and evaluate the potential antioxidant effect of tocopherols in commercially available lipid emulsions, using a simple validated method adequate for further routine use. During the study, variability between manufacturers as well as between three non-consecutive batches of the same emulsion was observed. Furthermore, addition of α-tocopherol to lipid emulsions as excipient yields more stable emulsions and potentially a beneficial clinical effect. It was concluded that the variation of the tocopherol content between batches implies the importance of control and specification of tocopherol content by the manufacturers.

PMID: 32539917 [PubMed - in process]

Interethnic differences in the prevalence of main cardiovascular pharmacogenetic biomarkers.

Pharmacogenomics. 2020 Jun 16;:

Authors: Mirzaev K, Abdullaev S, Sozaeva J, Grishina E, Sozaeva M, Zhuchkova S, Gimaldinova N, Sidukova E, Poptsova M, Suleymanov S, Burashnikova I, Shikaleva A, Kachanova A, Fedorinov D, Sychev D

Abstract
Background: The aim of this study was to determine the prevalence of CYP2C9, VKORC1, CYP2C19, ABCB1, CYP2D6 and SLCO1B1 genes polymorphisms among residents of the Volga region (Chuvash and Mari) and northern Caucasus (Kabardins and Ossetians). Materials & methods: The study involved 845 apparently healthy volunteers of both sexes of the four different ethnic groups living in the Russian Federation: 238 from the Chuvash ethnic group, 206 Mari, 157 Kabardins and 244 Ossetians. Results: Significant differences were identified in allele frequency of CYP2C9, VKORC1, CYP2C19, ABCB1, CYP2D6 and SLCO1B1 genes polymorphisms between the Chuvash and Kabardins, Chuvash and Ossetians, Mari and Kabardians, Mari and Ossetians.

PMID: 32539557 [PubMed - as supplied by publisher]

Functional genomics based on germline genome-wide association studies of endocrine therapy for breast cancer.

Pharmacogenomics. 2020 Jun 16;:

Authors: Zayas J, Qin S, Yu J, Ingle JN, Wang L

Abstract
Breast cancer is the most common invasive cancer in women worldwide. Functional follow-up of breast cancer genome-wide association studies has led to the discovery of genes that regulate endocrine therapy response in a SNP- and drug-dependent manner. Here, we will present four examples in which functional genomic studies from breast cancer clinical trials led to novel pharmacogenomic insights and molecular mechanisms of selective estrogen receptor modulators and aromatase inhibitors. The approach utilized for studying genetic variability described in this review offers substantial potential for meaningful discoveries that move the field toward precision medicine for patients.

PMID: 32539536 [PubMed - as supplied by publisher]

Involvement of CYP2D6 and CYP2B6 on tramadol pharmacokinetics.

Pharmacogenomics. 2020 Jun 15;:

Authors: Saiz-Rodríguez M, Ochoa D, Román M, Zubiaur P, Koller D, Mejía G, Abad-Santos F

Abstract
This study included 24 healthy volunteers who received a single 37.5 mg oral dose of tramadol. We analyzed 18 polymorphisms within CYP2D6, CYP2B6, CYP3A, COMT, ABCB1, SLC22A1 and OPRM1 genes by quantitative PCR, to study whether these polymorphisms affect its pharmacokinetics, pharmacodynamics and safety. CYP2D6 intermediate metabolizers (n = 6) showed higher tramadol plasma concentrations and lower clearance compared with normal and ultrarapid metabolizers. CYP2B6 G516T T/T (n = 2) genotype was also associated to higher tramadol plasma levels. No other polymorphism affected tramadol pharmacokinetics. Three volunteers experienced a prolonged QTc not associated with the genetic variants studied or altered phamacokinetic parameters. The correlation of CYP2B6 genotype with higher tramadol concentrations is remarkable since its influence on its elimination is also relevant and has been less studied to date. However, given our small sample size, it is important to interpret our results with caution.

PMID: 32538291 [PubMed - as supplied by publisher]

Tumor-Derived Exosomes in Immunosuppression and Immunotherapy.

J Immunol Res. 2020;2020:6272498

Authors: Olejarz W, Dominiak A, Żołnierzak A, Kubiak-Tomaszewska G, Lorenc T

Abstract
Tumor-derived exosomes (TEX) are involved in cancer development, metastasis, and disease progression. They can modulate angiogenesis to elevate the malignant degree of tumor cells. TEX carry immunosuppressive factors affecting the antitumor activities of immune cells. Tumor cells as well as immune cells secrete immunologically active exosomes which affect intercellular communication, antigen presentation, activation of immune cells, and immune surveillance. Cell proliferation and immune response suppression create a favorable microenvironment for tumor. TEX can inhibit immune cell proliferation, induce apoptosis of activated CD8+ Teffs, suppress NK cell activity, interfere with monocyte differentiation, and promote Treg as well as MDSC expansion. Exosomes of microenvironment cells may also contribute to the development of drug resistance in cancer therapy. An important role of TEX in modulating the sensitivity of tumor cells to immunotherapy is a promising area of research to make the cancer therapy more successful.

PMID: 32537468 [PubMed - in process]

Individualized Medication Management in Ontario Long-Term Care Clinical Impact on Management of Depression, Pain, and Dementia.

J Am Med Dir Assoc. 2020 Jun;21(6):823-829.e5

Authors: Dorfman R, London Z, Metias M, Kabakchiev B, Mukerjee G, Moser A

Abstract
OBJECTIVES: Assess the potential benefits of identifying drug-gene interactions in nursing home (NH) residents on multiple medications. Reduce the use of high-risk medications for residents with reduced drug metabolism.
DESIGN: Open-label, nonrandomized, mixed methods study.
SETTING: Four NHs in Ontario.
MEASUREMENTS: Potential drug therapy problems (DTPs) for study cohort were identified during a medication review by a pharmacist using pharmacogenetic (PGx) clinical decision support to identify medication change opportunities. The number of DTPs identified during a standard medication review was compared with the number of DTPs identified with a PGx clinical decision support. Analysis of medication dispensing data at enrollment compared with dispensing in a 60-day window following medication review were compared for the PGx-tested study cohort with controls.
RESULTS: Prescription patterns of 90 study participants were compared with 895 controls for the same time period. Study participants were on 7 to 47 drugs, of which drugs with PGx indications ranged from 1 to 17 medications. The average medication load was 4.6 medications with PGx indications per person, whereas the controls were on 3.5 PGx drugs. Furthermore, 94% of cases and 84% of controls were on 2 or more drugs with PGx indication during the study period. Pharmacogenetic analysis identified 114 distinct DTPs in the 90 study participants, of which 29 were classified as serious. In this study, over 35% of residents were treated with antidepressants; of these, 64% have altered CYP2C19 or CYP2D6 metabolism and could benefit from drug dose adjustment or from a switch to alternative antidepressants. Twenty percent of residents were treated with hydromorphone, of which 30% have reduced response to opioids because of variations in the OPRM1 gene.
CONCLUSIONS AND IMPLICATIONS: This study demonstrated the clinical potential of PGx-based medication optimization for NH residents, impacting the management of depression, chronic pain, heart disease, and gastrointestinal symptoms.

PMID: 32536434 [PubMed - in process]

Restoring mitofusin balance prevents axonal degeneration in a Charcot-Marie-Tooth type 2A model.

J Clin Invest. 2019 03 18;129(4):1756-1771

Authors: Zhou Y, Carmona S, Muhammad AKMG, Bell S, Landeros J, Vazquez M, Ho R, Franco A, Lu B, Dorn GW, Wang S, Lutz CM, Baloh RH

Abstract
Mitofusin-2 (MFN2) is a mitochondrial outer-membrane protein that plays a pivotal role in mitochondrial dynamics in most tissues, yet mutations in MFN2, which cause Charcot-Marie-Tooth disease type 2A (CMT2A), primarily affect the nervous system. We generated a transgenic mouse model of CMT2A that developed severe early onset vision loss and neurological deficits, axonal degeneration without cell body loss, and cytoplasmic and axonal accumulations of fragmented mitochondria. While mitochondrial aggregates were labeled for mitophagy, mutant MFN2 did not inhibit Parkin-mediated degradation, but instead had a dominant negative effect on mitochondrial fusion only when MFN1 was at low levels, as occurs in neurons. Finally, using a transgenic approach, we found that augmenting the level of MFN1 in the nervous system in vivo rescued all phenotypes in mutant MFN2R94Q-expressing mice. These data demonstrate that the MFN1/MFN2 ratio is a key determinant of tissue specificity in CMT2A and indicate that augmentation of MFN1 in the nervous system is a viable therapeutic strategy for the disease.

PMID: 30882371 [PubMed - indexed for MEDLINE]

Sirt6 alleviated liver fibrosis by deacetylating conserved lysine 54 on Smad2 in hepatic stellate cells.

Hepatology. 2020 Jun 14;:

Authors: Zhang J, Li Y, Liu Q, Huang Y, Li R, Wu T, Zhang Z, Zhou J, Huang H, Tang Q, Huang C, Zhao Y, Zhang G, Jiang W, Mo L, Zhang J, Xie W, He J

Abstract
Activation of hepatic stellate cells (HSCs) is a central driver of fibrosis. This study aimed to elucidate the role of the deacetylase Sirt6 in HSC activation and liver fibrosis. Gain- and loss-of-function models were used to study the function of Sirt6 in HSC activation. Mass spectrometry was used to determine the specific acetylation site. The lecithin retinol acyltransferase (Lrat)-driven CreERT2 mouse line was created to generate HSC-specific conditional Sirt6-knockout mice (Sirt6△HSC ). We found that Sirt6 is most abundantly expressed in HSCs as compared with other liver cell types. The expression of Sirt6 was decreased in activated HSCs and in fibrotic livers of mice and humans. Sirt6 knockdown and Sirt6 overexpression increased and decreased fibrogenic gene expression, respectively, in HSCs. Mechanistically, Sirt6 inhibited the phosphorylation and nuclear localization of Smad2. Further study demonstrated that Sirt6 could directly interact with Smad2, deacetylate Smad2, and decrease the transcription of TGF-β/Smad2 signaling. Mass spectrometry revealed that Sirt6 deacetylated conserved lysine 54 on Smad2. Mutation of lysine 54 to alanine in Smad2 abolished the regulatory effect of Sirt6. In vivo, specific ablation of Sirt6 in HSCs exacerbated hepatocyte injury and cholestasis-induced liver fibrosis in mice. With targeted delivery of the Sirt6 agonist MDL-800, its concentration was 9.28-fold higher in HSCs as compared with other liver cells and alleviated hepatic fibrosis. CONCLUSIONS: Sirt6 plays a key role in HSC activation and liver fibrosis by deacetylating the pro-fibrogenic transcription factor Smad2. Sirt6 may be a potential therapeutic target for liver fibrosis.

PMID: 32535965 [PubMed - as supplied by publisher]

Developing drugs for tissue agnostic indications: a paradigm shift in leveraging cancer biology for precision medicine.

Clin Pharmacol Ther. 2020 Jun 14;:

Authors: Seligson ND, Knepper TC, Ragg S, Walko CM

Abstract
Targeted therapies have reshaped the landscape of the development of cancer therapeutics. Recent biomarker driven, tissue agnostic clinical trials represent a significant paradigm shift in precision cancer medicine. Despite their growth in pre-clinical and clinical studies, to date only a few biomarker driven, tissue agnostic indications have seen approval by the FDA. These approvals include pembrolizumab in microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors, as well as both larotrectinib and entrectinib in NTRK fusion positive tumors. Complex cancer biology, clinical trial design, and identification of resistance mechanisms represent some of the challenges that future tissue agnostic therapies have to overcome. In this review, we present a brief history of the development of tissue agnostic therapies, comparing the similarities in the approval of pembrolizumab, larotrectinib, and entrectinib for tissue agnostic indications. We also explore the future of tissue agnostic cancer therapeutics while identifying important challenges for the future of drug targeting tissue agnostic indications will face.

PMID: 32535906 [PubMed - as supplied by publisher]