P53-regulated miR-320a targets PDL1 and is downregulated in malignant mesothelioma.

Cell Death Dis. 2020 Sep 14;11(9):748

Authors: Costa C, Indovina P, Mattioli E, Forte IM, Iannuzzi CA, Luzzi L, Bellan C, De Summa S, Bucci E, Di Marzo D, De Feo M, Mutti L, Pentimalli F, Giordano A

Abstract
Malignant pleural mesothelioma (MPM) is an aggressive cancer, related to asbestos exposure, which has a dismal prognosis. MPM diagnosis is late and often challenging, suggesting the need to identify more reliable molecular biomarkers. Here, we set out to identify differentially expressed miRNAs in epithelioid, biphasic, and sarcomatoid MPMs versus normal mesothelium and explored specific miRNA contribution to mesothelial tumorigenesis. We screened an LNA™-based miRNA-microrray with 14 formalin-fixed paraffin-embedded (FFPE) MPMs and 6 normal controls. Through real-time qRT-PCR we extended the analysis of a miRNA subset and further investigated miR-320a role through state-of-the-art techniques. We identified 16 upregulated and 32 downregulated miRNAs in MPMs versus normal tissue, including the previously identified potential biomarkers miR-21, miR-126, miR-143, miR-145. We showed in an extended series that miR-145, miR-10b, and miR-320a levels can discriminate tumor versus controls with high specificity and sensitivity. We focused on miR-320a because other family members were found downregulated in MPMs. However, stable miR-320a ectopic expression induced higher proliferation and migration ability, whereas miR-320a silencing reduced these processes, not supporting a classic tumor-suppressor role in MPM cell lines. Among putative targets, we found that miR-320a binds the 3'-UTR of the immune inhibitory receptor ligand PDL1 and, consistently, miR-320a modulation affects PDL1 levels in MPM cells. Finally, we showed that p53 over-expression induces the upregulation of miR-320a, along with miR-200a and miR-34a, both known to target PDL1, and reduces PDL1 levels in MPM cells. Our data suggest that PDL1 expression might be due to a defective p53-regulated miRNA response, which could contribute to MPM immune evasion or tumorigenesis through tumor-intrinsic roles.

PMID: 32929059 [PubMed - in process]

Anorexia nervosa manifesting as massive ascites, hypercholesterolemia, and sequential binge eating in an 11-year-old girl: A case report.

Medicine (Baltimore). 2020 Aug 28;99(35):e21739

Authors: Fan HH, Lin IC, Chen JE, Lee WH, Fang SB

Abstract
RATIONALE: Anorexia nervosa (AN) is a serious eating disorder associated with a distorted body image. Hypercholesterolemia has been found in patients with AN but the mechanism of hyperlipidemia in AN remains little known. Ascites in patients with AN has been attributed to hypoalbuminemia and liver diseases, but massive ascites without the aforementioned etiologies has never been reported in AN.
PATIENT CONCERNS: An 11-year-old girl was admitted for exclusion of organic underlying diseases due to severe body weight loss (18% within 3 weeks), poor appetite, and hypercholesterolemia (274 mg/dL). She complained of heartburn sensation, nausea, vomiting, constipation, and postprandial dull abdominal pain with fullness.
DIAGNOSES: The patient's condition met with all 3 of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria for diagnosing AN. On admission, her total cholesterol level was 337 mg/dL and hypocomplementemia (C3 55.5 mg/dL) was also found. Abdominal sonography and computed tomography scans showed massive ascites. However, neither proteinuria nor hypoalbuminemia was found. Upper gastroduodenal endoscopy showed chronic superficial gastritis and colonoscopy revealed negative findings. Ascites obtained by paracentesis demonstrated a transudate without bacterial infection, tuberculosis, or pancreatitis. Exploratory laparoscopy showed nonpurulent ascites. However, biopsies from the small intestine, mesentery, and liver showed chronic inflammation and fibrosis.
INTERVENTIONS: The intensive nutritional therapy by increasing total energy intake stepwise with a combination of high-energy formula and her favorite foods.
OUTCOMES: Her hypercholesterolemia, hypocomplementemia, and massive ascites resolved after her weight was restored. She developed binge eating with continuous weight gain after discharge. Her weight significantly increased to an obese level (body mass index [BMI] 25.9 kg/m) after loss to follow-up for 4 years until she returned to our emergency room due to suicide attempt.
CONCLUSION: Diagnostic crossover between subtypes in anorexia nervosa might be a potential risk factor for illness severity and poor prognosis. AN can manifest as massive ascites with normal albumin concentrations that could possibly be due to chronic inflammation of the intestinal serosa, mesentery, and peritoneal surface of the liver.

PMID: 32871893 [PubMed - indexed for MEDLINE]

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

pharmacogenomics

These pubmed results were generated on 2020/09/15

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

Communicating unexpected pharmacogenomic results to biobank contributors: A focus group study.

Patient Educ Couns. 2020 Sep 02;:

Authors: Meagher KM, Curtis SH, Borucki S, Beck A, Srinivasan T, Cheema A, Sharp RR

Abstract
OBJECTIVES: The goals of this study were to explore 1) the impact of returning unexpected pharmacogenomic (PGx) results to biobank contributors, and 2) participant views about improving communication.
METHODS: We conducted a qualitative focus group study with biobank participants (N = 54) who were notified by mail of an individual research result indicating increased risk for adverse events associated with the common cancer drug 5-fluorouracil (5-FU). We employed a framework approach for analysis.
RESULTS: Our results revealed three themes illustrating participants' questions and uncertainty, especially regarding how to share results with health providers and family members, and remember them over time. Participants valued results for themselves and others, and for the future of medicine. Risk perception was framed by health identity. "Toxicity narratives," or familiarity with another's adverse reaction to chemotherapy, increased the sense of importance participants reported.
CONCLUSION: These focus group results highlight research participant remaining questions and high valuation of PGx results, even when unexpected.
PRACTICE IMPLICATIONS: We identify PGx research participants' needs for clear clinical translation messaging that attends to health identity, pragmatics of sharing information with family members, and patient perceptions of barriers to transferring research results to a clinical context.

PMID: 32919825 [PubMed - as supplied by publisher]

Precision Medicine: Steps along the Road to Combat Human Cancer.

Cells. 2020 Sep 09;9(9):

Authors: Nassar SF, Raddassi K, Ubhi B, Doktorski J, Abulaban A

Abstract
The diagnosis and treatment of diseases such as cancer is becoming more accurate and specialized with the advent of precision medicine techniques, research and treatments. Reaching down to the cellular and even sub-cellular level, diagnostic tests can pinpoint specific, individual information from each patient, and guide providers to a more accurate plan of treatment. With this advanced knowledge, researchers and providers can better gauge the effectiveness of drugs, radiation, and other therapies, which is bound to lead to a more accurate, if not more positive, prognosis. As precision medicine becomes more established, new techniques, equipment, materials and testing methods will be required. Herein, we will examine the recent innovations in assays, devices and software, along with next generation sequencing in genomics diagnostics which are in use or are being developed for personalized medicine. So as to avoid duplication and produce the fullest possible benefit, all involved must be strongly encouraged to collaborate, across national borders, public and private sectors, science, medicine and academia alike. In this paper we will offer recommendations for tools, research and development, along with ideas for implementation. We plan to begin with discussion of the lessons learned to date, and the current research on pharmacogenomics. Given the steady stream of advances in imaging mass spectrometry and nanoLC-MS/MS, and use of genomic, proteomic and metabolomics biomarkers to distinguish healthy tissue from diseased cells, there is great potential to utilize pharmacogenomics to tailor a drug or drugs to a particular cohort of patients. Such efforts very well may bring increased hope for small groups of non-responders and those who have demonstrated adverse reactions to current treatments.

PMID: 32916938 [PubMed - as supplied by publisher]

Influence of SH2B3, MTHFD1L, GGCX, and ITGB3 Gene Polymorphisms on theVariability on Warfarin Dosage Requirements and Susceptibility to CVD in the Jordanian Population.

J Pers Med. 2020 Sep 09;10(3):

Authors: Al-Eitan LN, Almasri AY, Khasawneh RH, Alghamdi MA

Abstract
The purpose of this study was to investigate the effects of the SH2B3, MTHFD1L, GGCX, and ITGB3 gene variants on the efficacy of warfarin treatment and its effects on the risk of cardiovascular disorders in Jordanian patients. The selected genes and their polymorphisms are involved in many Genome-Wide Association Study (GWAS) associated with cardiovascular disease and the variability of warfarin therapy. The current study conducted a genetic association and pharmacogenetics study in (212) Jordanian cardiovascular patients treated with warfarin and (213) healthy controls. DNA extraction and the Mass ARRAY™ system were used to genotype ten selected polymorphisms within four genes (SH2B3, MTHFD1L, GGCX, and ITGB3). This study confirmed a genetic association of MTHFD1L rs6922269 Single Nucleotide Polymorphism (SNP) with warfarin sensitivity during the initial and stabilization phases of treatment. Moreover, this SNP showed significant differences in the initial and maintenance doses of warfarin. This study also found an association between the genetic haplotypes (AGC and GAT) within the SH2B3 gene and responsiveness to warfarin. However, possession of an MTHFD1L rs491552 variant allele was found to affect the outcome measure of the international normalized ratio (INR) during the stabilization phase of warfarin treatment. In contrast, there was no association between all selected SNPs and susceptibility to cardiovascular disorders. This study extends the current understanding of the high variability of the warfarin response, including variability in dose requirements and susceptibility to cardiovascular disease in the Jordanian-Arab population. Other studies on a larger sample and in different ethnic groups could help to better understand the pharmacogenetics of warfarin and its application in personalized medicine.

PMID: 32916786 [PubMed - as supplied by publisher]

Costing Methods as a Means to Measure the Costs of Pharmacogenomics Testing.

J Appl Lab Med. 2020 Sep 01;5(5):1005-1016

Authors: Siamoglou S, Karamperis K, Mitropoulou C, Patrinos GP

Abstract
Clinical implementation of pharmacogenomics and personalized medicine interventions relies on addressing important financial aspects of the delivery of genetic testing to the patients, be it from public or private providers. Details on how to determine the cost items of the genetic testing are often limited. The goal of this study is to present a costing methodology in order to estimate and measure the costs as far as the technical process of pharmacogenomics testing is concerned. Moreover, an overall cost mindset strategy based on the selective genotyping workflow to guide specialized laboratories of interest effectively is provided. We particularly accounted for the resources consumed within the laboratory premises such as cost of reagents for DNA isolation, cost of consumables, cost of personnel, while costs associated with patient recruitment, blood sample collection and maintenance, administration costs in the hospital, and costs of blood sample shipment were not taken into consideration. Our article presents the first-time detailed information on a costing framework for pharmacogenomic testing that could be employed to laboratories involved in routine clinical implementation of pharmacogenomics.

PMID: 32916714 [PubMed - as supplied by publisher]

First report of pharmacogenomic profiling in an outpatient spine setting: preliminary results from a pilot study.

World Neurosurg. 2020 Sep 08;:

Authors: Cottrill E, Pennington Z, Ahmed AK, Jiang B, Ehresman J, Zhu A, Perdomo-Pantoja A, Lubelski D, Sciubba DM, Witham T, MacDonald K, Lee CH, Jeffrey Lai CW, Theodore N

Abstract
OBJECTIVE: Pharmacogenomics may help personalize medicine and improve therapeutic selection. This is the first study investigating how pharmacogenomic testing may inform analgesic selection in patients with spine pathology. We sought to profile pharmacogenetic differences in pain-medication-metabolizing enzymes across patients presenting to an outpatient spine clinic, and offer provide preliminary evidence that genetic polymorphisms may help explain inter-patient differences in preoperative pain refractory to conservative management.
METHODS: Adults presenting to our outpatient spine clinic with chief complaints of neck and/or back pain were prospectively enrolled over 9 months. Patients completed the Wong-Baker FACES and Numerical Pain Rating Scales for their chief pain complaint, and provided detailed medication histories, and cheek swab samples for genomic analysis.
RESULTS: Thirty adults were included (mean age: 60.6±15.3 years). Chief concern was neck pain in 23%, back pain in 67%, and combined neck/back pain in 10%. At enrollment, patient analgesic regimens comprised 3±1 unique medications, including 1±1 opioids. After genomic analysis, 14/30 patients (47%) were identified as suboptimal metabolizers of ≥1 medications in their analgesic regimen. Of these, 93% were suboptimal metabolizers of their prescribed opioid analgesic. Nonetheless, pain scores were similar between optimal and suboptimal metabolizer groups.
CONCLUSIONS: This pilot study demonstrates that a large proportion of the spine outpatient population may be using pain medications for which they are suboptimal metabolizers. Further studies should assess whether these pharmacogenomic differences translate to differences in odds of receiving therapeutic benefit from surgery, or if they can be used to generate more effective postoperative analgesic regimens.

PMID: 32916348 [PubMed - as supplied by publisher]

iGMDR: Integrated Pharmacogenetic Resource Guide to Cancer Therapy and Research.

Genomics Proteomics Bioinformatics. 2020 Sep 08;:

Authors: Chen X, Guo Y, Chen X

Abstract
Current pharmacogenetic studies have obtained many genetic models that can predict the therapeutic efficacy of anticancer drugs. Although some of these models are of crucial importance and have been used in clinical practice, these very valuable models have not been well adopted into cancer research to promote the development of cancer therapies due to the lack of integration and standards for the existing data of the pharmacogenetic studies. For this purpose, we built a resource investigating genetic model of drug response (iGMDR), which integrates the models from in vitro and in vivo pharmacogenetic studies with different omics data from a variety of technical systems. In this study, we introduced a standardized process for all integrations, and described how users can utilize these models to gain insights into cancer. iGMDR is freely accessible at https://igmdr.modellab.cn.

PMID: 32916316 [PubMed - as supplied by publisher]

PanGPCR: Predictions for Multiple Targets, Repurposing and Side Effects.

Bioinformatics. 2020 Sep 11;:

Authors: Liu LC, Ho MY, Su BH, Wang SY, Hsu MT, Tseng YJ

Abstract
SUMMARY: Drug discovery targeting G protein-coupled receptors (GPCRs), the largest known class of therapeutic targets, is challenging. To facilitate the rapid discovery and development of GPCR drugs, we built a system, PanGPCR, to predict multiple potential GPCR targets and their expression locations in the tissues, side effects and possible repurposing of GPCR drugs. With PanGPCR, the compound of interest is docked to a library of 36 experimentally determined crystal structures comprising of 46 docking sites for human GPCRs, and a ranked list is generated from the docking studies to assess all GPCRs and their binding affinities. Users can determine a given compound's GPCR targets and its repurposing potential accordingly. Moreover, potential side effects collected from the SIDER database and mapped to 45 tissues and organs are provided by linking predicted off-targets and their expressed sequence tag profiles. With PanGPCR, multiple targets, repurposing potential and side effects can be determined by simply uploading a small ligand.
AVAILABILITY AND IMPLEMENTATION: PanGPCR is freely accessible at https://gpcrpanel.cmdm.tw/index.html.
SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

PMID: 32915954 [PubMed - as supplied by publisher]

[Efforts toward the Development of Pharmacist Involvement in Genomic Medicine].

Yakugaku Zasshi. 2020;140(5):673-675

Authors: Sakurai H

Abstract
Since September of 2017, the Department of Pharmacy at Keio University Hospital has participated in activities of the A-3 Group in the "Program for Promoting a Platform of Genomics-based Drug Discovery" conducted by the Japan Agency for Medical Research and Development (AMED). The A-3 Group works to develop programs for fostering human resources in genomic medicine in order to solve various problems, and the Keio Department of Pharmacy plans and holds twice-yearly seminars for pharmacists interested in genomic medicine. In this review, we give an overview of efforts toward the development of pharmacists involved in genomic medicine, and we present the results of questionnaires about previous seminars.

PMID: 32378671 [PubMed - indexed for MEDLINE]

Using genetics to guide treatment and drug development in cardiovascular medicine: time to reveal the proof in the pudding.

Cardiovasc Res. 2020 02 01;116(2):e30-e32

Authors: Nicholls SJ

PMID: 31845983 [PubMed - indexed for MEDLINE]

Advances in the Genetics and Genomics of Heart Failure.

Curr Cardiol Rep. 2020 Sep 10;22(11):132

Authors: Reza N, Owens AT

Abstract
PURPOSE OF REVIEW: The purpose of this review is to provide an update on the recent advances in the genetics and genomics of dilated cardiomyopathy and heart failure.
RECENT FINDINGS: Over the last decade, the approach to the discovery of the genetic contribution to heart failure has evolved from investigation of rare variants implicated in Mendelian cardiomyopathies through linkage studies and candidate gene studies to the exploration of the contribution of common variants through large-scale genome-wide association and genome-first studies. The combination and integration of multiple of case-control heart failure cohorts, refinement of the heart failure phenotype, and utilization of large biobanks linked to electronic health records have advanced the understanding of the heritability of heart failure.

PMID: 32910329 [PubMed - in process]

Human Leukocyte Antigen Gene Testing and Carbamazepine-Induced Toxic Epidermal Necrolysis: A Study of Pediatric Practice.

J Cutan Med Surg. 2020 Sep 10;:1203475420952422

Authors: Asgarpour JMS, Lam LM, Vogel TK, Goez HR, Fiorillo L

Abstract
BACKGROUND: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening drug-induced dermatologic conditions. SJS/TEN occurs in 1-10 per 10 000 patients taking carbamazepine (CBZ) (Pratt VM, McLeod HL, Rubinstein WS et al. Medical Genetics Summaries. National Center for Biotechnology Information US; 2018: 1-527). The development of SJS/TEN is associated with variable drug metabolism and presence of an at-risk HLA haplotype. HLA-B*15:02 and HLA-A*31:01 haplotypes can produce a hyperimmune response in the setting of CBZ use in patients of Asian and European descent, respectively (Schneider JA, Cohen PR. Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: A concise review with a comprehensive summary of therapeutic interventions emphasizing supportive measures. Adv Ther. 2017; 34:1235-1244).
OBJECTIVE: The US Food and Drug Administration (FDA) and the Canadian pharmacogenomics Network for Drug Safety (CPNDS) recommend that patients with high-risk ethnic backgrounds should be genetic tested before initiating CBZ (Sukasem C, Chaichan C, Nakkrut T et al. Association between HLA-B Alleles and Carbamazepine-induced maculopapular exanthema and severe cutaneous reactions in Thai patients. Journal of Immunology Research. 2018; 1-11).We sought out to assess the awareness of this in prescribing practitioners and their standard of practice.
MATERIALS AND METHODS: We created a 15-question survey and distributed to pediatric neurologists and pediatricians at the University of Alberta. We hypothesized that there was a discordance between the standard of practice and the recommendation by the FDA and CPNDS.
RESULTS: The survey results indicated a lack of awareness of the at-risk ethnicities for CBZ-induced SJS/TEN. HLA gene testing was rarely done prior to initiation of CBZ in high-risk patients. In addition, there was a lack of awareness for standard of care for genetic testing in Canada and worldwide.
CONCLUSIONS: Our results demonstrate an evident gap between current prescriber practices and existing FDA and CPNDS recommendations to screen for HLA genotypes. We hope that this study captures the realistic potential to improve patient outcomes.

PMID: 32909461 [PubMed - as supplied by publisher]

Pharmacokinetics and drug-drug interactions of isoniazid and efavirenz in pregnant women living with HIV in high TB incidence settings: importance of genotyping.

Clin Pharmacol Ther. 2020 Sep 09;:

Authors: Gausi K, Wiesner L, Norman J, Wallis CL, Onyango-Makumbi C, Chipato T, Haas DW, Browning R, Chakhtoura N, Montepiedra G, Aaron L, McCarthy K, Bradford S, Vhembo T, Stranix-Chibanda L, Masheto GR, Violari A, Mmbaga BT, Aurpibul L, Bhosale R, Nevrekhar N, Rouzier V, Kabugho E, Mutambanengwe M, Chanaiwa V, Nyati M, Mhembere T, Tongprasert F, Hesseling A, Shin K, Zimmer B, Costello D, Jean-Philippe P, Sterling TR, Theron G, Weinberg A, Gupta A, Denti P, IMPAACT P1078 (TB APPRISE) Study Group Team

Abstract
World Health Organization guidelines recommend that individuals living with HIV receive ≥6 months of isoniazid preventive therapy, including pregnant women. Yet, plasma isoniazid exposure during pregnancy, in the antiretroviral therapy era, has not been well described. We investigated pregnancy-induced and pharmacogenetic-associated pharmacokinetic changes and drug-drug-interactions between isoniazid and efavirenz in pregnant women. 847 women received isoniazid for 28 weeks, either during pregnancy or at 12 weeks postpartum, and 786 women received efavirenz. After adjusting for NAT2 and CYP2B6 genotype and weight, pregnancy increased isoniazid and efavirenz clearance by 26% and 15%, respectively. Isoniazid decreased efavirenz clearance by 7% in CYP2B6 normal metabolizers and 13% in slow and intermediate metabolizers. Overall, both isoniazid and efavirenz exposures were reduced during pregnancy, but the main determinants of drug concentration were NAT2 and CYP2B6 genotypes, which resulted in a 5-fold difference for both drugs between rapid and slow metabolizers.

PMID: 32909316 [PubMed - as supplied by publisher]

Correction: Influence of CYP3A polymorphisms on tacrolimus pharmacokinetics in kidney transplant recipients.

Pharmacogenomics J. 2020 Sep 09;:

Authors: Hannachi I, Chadli Z, Kerkeni E, Kolsi A, Hammouda M, Chaabane A, Fredj NB, Touitou Y, Boughattas NA, Aouam K

Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper.

PMID: 32908236 [PubMed - as supplied by publisher]

Phenoconversion of Cytochrome P450 Metabolism: A Systematic Review.

J Clin Med. 2020 Sep 07;9(9):

Authors: Klomp SD, Manson ML, Guchelaar HJ, Swen JJ

Abstract
Phenoconversion is the mismatch between the individual's genotype-based prediction of drug metabolism and the true capacity to metabolize drugs due to nongenetic factors. While the concept of phenoconversion has been described in narrative reviews, no systematic review is available. A systematic review was conducted to investigate factors contributing to phenoconversion and the impact on cytochrome P450 metabolism. Twenty-seven studies met the inclusion criteria and were incorporated in this review, of which 14 demonstrate phenoconversion for a specific genotype group. Phenoconversion into a lower metabolizer phenotype was reported for concomitant use of CYP450-inhibiting drugs, increasing age, cancer, and inflammation. Phenoconversion into a higher metabolizer phenotype was reported for concomitant use of CYP450 inducers and smoking. Moreover, alcohol, pregnancy, and vitamin D exposure are factors where study data suggested phenoconversion. The studies reported genotype-phenotype discrepancies, but the impact of phenoconversion on the effectiveness and toxicity in the clinical setting remains unclear. In conclusion, phenoconversion is caused by both extrinsic factors and patient- and disease-related factors. The mechanism(s) behind and the extent to which CYP450 metabolism is affected remain unexplored. If studied more comprehensively, accounting for phenoconversion may help to improve our ability to predict the individual CYP450 metabolism and personalize drug treatment.

PMID: 32906709 [PubMed]

Pretreatment of Diabetic Adipose-derived Stem Cells with mitoTEMPO Reverses their Defective Proangiogenic Function in Diabetic Mice with Critical Limb Ischemia.

Cell Transplant. 2019 12;28(12):1652-1663

Authors: Lian K, Wang Q, Zhao S, Yang M, Chen G, Chen Y, Li C, Gao H, Li C

Abstract
Adipose-derived stem cells (ADSCs) have the ability to migrate to injury sites and facilitate tissue repair by promoting angiogenesis. However, the therapeutic effect of ADSCs from patients with diabetes is impaired due to oxidative stress. Given that diabetes is a group of metabolic disorders and mitochondria are a major source of reactive oxygen species (ROS), it is possible that mitochondrial ROS plays an important role in the induction of diabetic ADSC (dADSC) dysfunction. ADSCs isolated from diabetic mice were treated with mitoTEMPO, a mitochondrial ROS scavenger, or TEMPO, a universal ROS scavenger, for three passages. The results showed that pretreatment with mitoTEMPO increased the proliferation, multidifferentiation potential, and the migration and proangiogenic capacities of dADSCs to levels similar to those of ADSCs from control mice, whereas pretreatment with TEMPO showed only minor effects. Mechanistically, mitoTEMPO pretreatment enhanced the mitochondrial antioxidant capacity of dADSCs, and knockdown of superoxide dismutase reduced the restored mitochondrial antioxidant capacity and attenuated the proangiogenic effects induced by mitoTEMPO pretreatment. In addition, mitoTEMPO pretreatment improved the survival of dADSCs in diabetic mice with critical limb ischemia, showing protective effects similar to those of control ADSCs. Pretreatment of dADSCs with mitoTEMPO decreased limb injury and improved angiogenesis in diabetic mice with critical limb ischemia. These findings suggested that short-term pretreatment of dADSCs with a mitochondrial ROS scavenger restored their normal functions, which may be an effective strategy for improving the therapeutic effects of ADSC-based therapies in patients with diabetes.

PMID: 31684763 [PubMed - indexed for MEDLINE]

Population pharmacokinetic meta-analysis of individual data to design the first randomized efficacy trial of vancomycin in neonates and young infants.

J Antimicrob Chemother. 2019 08 01;74(8):2128-2138

Authors: Jacqz-Aigrain E, Leroux S, Thomson AH, Allegaert K, Capparelli EV, Biran V, Simon N, Meibohm B, Lo YL, Marques R, Peris JE, Lutsar I, Saito J, Nakamura H, van den Anker JN, Sharland M, Zhao W

Abstract
OBJECTIVES: In the absence of consensus, the present meta-analysis was performed to determine an optimal dosing regimen of vancomycin for neonates.
METHODS: A 'meta-model' with 4894 concentrations from 1631 neonates was built using NONMEM, and Monte Carlo simulations were performed to design an optimal intermittent infusion, aiming to reach a target AUC0-24 of 400 mg·h/L at steady-state in at least 80% of neonates.
RESULTS: A two-compartment model best fitted the data. Current weight, postmenstrual age (PMA) and serum creatinine were the significant covariates for CL. After model validation, simulations showed that a loading dose (25 mg/kg) and a maintenance dose (15 mg/kg q12h if <35 weeks PMA and 15 mg/kg q8h if ≥35 weeks PMA) achieved the AUC0-24 target earlier than a standard 'Blue Book' dosage regimen in >89% of the treated patients.
CONCLUSIONS: The results of a population meta-analysis of vancomycin data have been used to develop a new dosing regimen for neonatal use and to assist in the design of the model-based, multinational European trial, NeoVanc.

PMID: 31049551 [PubMed - indexed for MEDLINE]

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

pharmacogenomics

These pubmed results were generated on 2020/09/10

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