Genome-Wide Association Study of Metamizole-Induced Agranulocytosis in European Populations.

Genes (Basel). 2020 Oct 29;11(11):

Authors: Cismaru AL, Rudin D, Ibañez L, Liakoni E, Bonadies N, Kreutz R, Carvajal A, Lucena MI, Martin J, Sancho Ponce E, Molokhia M, Eriksson N, EuDAC Collaborators, Krähenbühl S, Largiadèr CR, Haschke M, Hallberg P, Wadelius M, Amstutz U

Abstract
Agranulocytosis is a rare yet severe idiosyncratic adverse drug reaction to metamizole, an analgesic widely used in countries such as Switzerland and Germany. Notably, an underlying mechanism has not yet been fully elucidated and no predictive factors are known to identify at-risk patients. With the aim to identify genetic susceptibility variants to metamizole-induced agranulocytosis (MIA) and neutropenia (MIN), we conducted a retrospective multi-center collaboration including cases and controls from three European populations. Association analyses were performed using genome-wide genotyping data from a Swiss cohort (45 cases, 191 controls) followed by replication in two independent European cohorts (41 cases, 273 controls) and a joint discovery meta-analysis. No genome-wide significant associations (p < 1 × 10-7) were observed in the Swiss cohort or in the joint meta-analysis, and no candidate genes suggesting an immune-mediated mechanism were identified. In the joint meta-analysis of MIA cases across all cohorts, two candidate loci on chromosome 9 were identified, rs55898176 (OR = 4.01, 95%CI: 2.41-6.68, p = 1.01 × 10-7) and rs4427239 (OR = 5.47, 95%CI: 2.81-10.65, p = 5.75 × 10-7), of which the latter is located in the SVEP1 gene previously implicated in hematopoiesis. This first genome-wide association study for MIA identified suggestive associations with biological plausibility that may be used as a stepping-stone for post-GWAS analyses to gain further insight into the mechanism underlying MIA.

PMID: 33138277 [PubMed - in process]

Determination of the activity of γ-glutamyl transpeptidase and of its inhibitors by using the inner filter effect on the fluorescence of nitrogen-doped carbon dots.

Mikrochim Acta. 2020 02 21;187(3):182

Authors: Tong X, Li T, Long R, Guo Y, Wu L, Shi S

Abstract
A fluorescence (FL) probe for determination of γ-glutamyl transpeptidase (GGT) activity and evaluation of inhibitors was developed based on the inner filter effect (IFE) of nitrogen-doped carbon dots (N-CDs). Bright green emissive N-CDs were synthesized by one-step hydrothermal technique with catechol and ethylenediamine. The excitation and emission wavelengths for N-CDs were 408 and 510 nm, respectively. γ-L-Glutamyl-4-nitroanilide (γ-G4NA) was employed as the substrate of GGT. The absorption spectrum of GGT catalytic product (4-nitroaniline, 4-NA) overlapped greatly with the excitation spectrum of N-CDs. 4-NA acted as the absorber in IFE to quench the FL of N-CDs. Thus, the FL quenching of N-CDs was closely related to GGT activity. The established FL method offered good linear relationship within 2.0-10.0 U L-1 (R2, 0.982) and 10.0-110.0 U L-1 (R2, 0.998) with a low detection limit of 0.6 U L-1. The method was successfully applied to investigate GGT activity in human serum samples with acceptable recoveries (99.1-105.0%). The approach was also employed for screening GGT inhibitors from different polar extracts of Schisandra chinensis. Results indicated that this strategy presents superior characteristics for GGT sensing. This method has great potential as a candidate for diagnosis of GGT-related diseases and high-throughput drug discovery. Graphical abstract.

PMID: 32086563 [PubMed - indexed for MEDLINE]

Blood-based PD-L1 analysis in tumor-derived extracellular vesicles: Applications for optimal use of anti-PD-1/PD-L1 axis inhibitors.

Biochim Biophys Acta Rev Cancer. 2020 Oct 30;:188463

Authors: Del Re M, van Schaik RHN, Fogli S, Mathijssen RHJ, Cucchiara F, Capuano A, Scavone C, Jenster GW, Danesi R

Abstract
Monoclonal antibodies that inhibit the programmed cell death protein 1 axis (anti-PD-1/PD-L1) are part of a new pharmacological strategy aimed at reinforcing the immune response to cancer. Despite the success in several cancer types, a significant percentage of patients do not benefit from treatment with these drugs due to intrinsic or acquired resistance or the occurrence of immune-related adverse reactions. Assessment of PD-L1 expression in tumor tissues is currently used to predict drug response in the clinics; however, there is a growing interest in identifying blood-based biomarkers that, owing to the minimally-invasive nature, can allow a dynamic monitoring of drug response in daily clinical practice. In the current review article, we discuss whether the assessment of PD-L1 mRNA and protein levels in circulating extracellular vesicles may have the potential to predict the likelihood of tumor response to anti-PD-1/PD-L1 antibodies.

PMID: 33137405 [PubMed - as supplied by publisher]

Compounding for women's health: a compounder's perspective - need, regulations, and future.

Climacteric. 2020 Nov 02;:1-6

Authors: Boomsma D, Lahoud G

Abstract
Compounding medicine involves various health-care professionals working together to produce medications that treat patient conditions including menopause and other women's health-related illnesses. These medications are compounded under the standards and guidelines mandated by individual state pharmacy boards, the US Food and Drug Administration, and other professional organizations. Contrary to commercial medications, the personalized medicine aspect of compounding medications ensures that the patient's allergies, doses, and drug delivery preferences are addressed during formulation. In the foreseeable future, compounders will continue to formulate medications that are unavailable in the commercial sector, following strict safe-practice guidelines. More importantly, the application of pharmacogenomics and three-dimensional printing to compounding medications could revolutionize compounding formulations and generate new approaches for personalized medicine.

PMID: 33135943 [PubMed - as supplied by publisher]

Phenotype-Agnostic Molecular Subtyping of Neurodegenerative Disorders: The Cincinnati Cohort Biomarker Program (CCBP).

Front Aging Neurosci. 2020;12:553635

Authors: Sturchio A, Marsili L, Vizcarra JA, Dwivedi AK, Kauffman MA, Duker AP, Lu P, Pauciulo MW, Wissel BD, Hill EJ, Stecher B, Keeling EG, Vagal AS, Wang L, Haslam DB, Robson MJ, Tanner CM, Hagey DW, El Andaloussi S, Ezzat K, Fleming RMT, Lu LJ, Little MA, Espay AJ

Abstract
Ongoing biomarker development programs have been designed to identify serologic or imaging signatures of clinico-pathologic entities, assuming distinct biological boundaries between them. Identified putative biomarkers have exhibited large variability and inconsistency between cohorts, and remain inadequate for selecting suitable recipients for potential disease-modifying interventions. We launched the Cincinnati Cohort Biomarker Program (CCBP) as a population-based, phenotype-agnostic longitudinal study. While patients affected by a wide range of neurodegenerative disorders will be deeply phenotyped using clinical, imaging, and mobile health technologies, analyses will not be anchored on phenotypic clusters but on bioassays of to-be-repurposed medications as well as on genomics, transcriptomics, proteomics, metabolomics, epigenomics, microbiomics, and pharmacogenomics analyses blinded to phenotypic data. Unique features of this cohort study include (1) a reverse biology-to-phenotype direction of biomarker development in which clinical, imaging, and mobile health technologies are subordinate to biological signals of interest; (2) hypothesis free, causally- and data driven-based analyses; (3) inclusive recruitment of patients with neurodegenerative disorders beyond clinical criteria-meeting patients with Parkinson's and Alzheimer's diseases, and (4) a large number of longitudinally followed participants. The parallel development of serum bioassays will be aimed at linking biologically suitable subjects to already available drugs with repurposing potential in future proof-of-concept adaptive clinical trials. Although many challenges are anticipated, including the unclear pathogenic relevance of identifiable biological signals and the possibility that some signals of importance may not yet be measurable with current technologies, this cohort study abandons the anchoring role of clinico-pathologic criteria in favor of biomarker-driven disease subtyping to facilitate future biosubtype-specific disease-modifying therapeutic efforts.

PMID: 33132895 [PubMed]

Clinical pharmacology applications in clinical drug development and clinical care: A focus on Saudi Arabia.

Saudi Pharm J. 2020 Oct;28(10):1217-1227

Authors: Alsultan A, Alghamdi WA, Alghamdi J, Alharbi AF, Aljutayli A, Albassam A, Almazroo O, Alqahtani S

Abstract
Drug development, from preclinical to clinical studies, is a lengthy and complex process. There is an increased interest in the Kingdom of Saudi Arabia (KSA) to promote innovation, research and local content including clinical trials (Phase I-IV). Currently, there are over 650 registered clinical trials in Saudi Arabia, and this number is expected to increase. An important part of drug development and clinical trials is to assure the safe and effective use of drugs. Clinical pharmacology plays a vital role in informed decision making during the drug development stage as it focuses on the effects of drugs in humans. Disciplines such as pharmacokinetics, pharmacodynamics and pharmacogenomics are components of clinical pharmacology. It is a growing discipline with a range of applications in all phases of drug development, including selecting optimal doses for Phase I, II and III studies, evaluating bioequivalence and biosimilar studies and designing clinical studies. Incorporating clinical pharmacology in research as well as in the requirements of regulatory agencies will improve the drug development process and accelerate the pipeline. Clinical pharmacology is also applied in direct patient care with the goal of personalizing treatment. Tools such as therapeutic drug monitoring, pharmacogenomics and model informed precision dosing are used to optimize dosing for patients at an individual level. In KSA, the science of clinical pharmacology is underutilized and we believe it is important to raise awareness and educate the scientific community and healthcare professionals in terms of its applications and potential. In this review paper, we provide an overview on the use and applications of clinical pharmacology in both drug development and clinical care.

PMID: 33132716 [PubMed]

Multiomic analysis of cytokines in immuno-oncology.

Expert Rev Proteomics. 2020 Oct 31;:

Authors: Jurisic V

Abstract
Introduction: Cytokines are a diverse group of peptides produced by different cell types including cancer cells and various subpopulations of immune system cells. They exert their effects as cellular secreted mediators after binding to appropriate membrane receptors. Area covered: In this modern era of a multiomic approach to immuno-oncology this paper discusses the multiple roles of cytokines in oncology and our current understanding of the complex interactions between a tumor and host (in the so-called tumor microenvironment). Because of their pivotal role in biomedicine, we focus on critical comments about advantage between many techniques which are helping our understanding of the signal transduction process, gene activation, gene regulation and their clinical significance. Expert opinion: Integrated investigations based on a multiomic approach to the interactions between cells of the immune system and cancer, which focus at different cellular, molecular and nuclear levels, and involving proteomics, genomics, transcriptomics, metabolomics and pharmacogenomics, are expected to lead to improved cancer diagnoses and treatment in the future.

PMID: 33131355 [PubMed - as supplied by publisher]

Editorial: is pharmacogenetic testing for adverse effects to IBD treatments ready for roll-out?

Aliment Pharmacol Ther. 2020 09;52(6):1076-1077

Authors: Chee D, Goodhand JR, Ahmad T

PMID: 33119171 [PubMed - indexed for MEDLINE]

PKN1 kinase-negative knock-in mice develop splenomegaly and leukopenia at advanced age without obvious autoimmune-like phenotypes.

Sci Rep. 2019 Sep 27;9(1):13977

Authors: Siddique SM, Kubouchi K, Shinmichi Y, Sawada N, Sugiura R, Itoh Y, Uehara S, Nishimura K, Okamura S, Ohsaki H, Kamoshida S, Yamashita Y, Tamura S, Sonoki T, Matsuoka H, Itoh T, Mukai H

Abstract
Protein kinase N1 (PKN1) knockout (KO) mice spontaneously form germinal centers (GCs) and develop an autoimmune-like disease with age. Here, we investigated the function of PKN1 kinase activity in vivo using aged mice deficient in kinase activity resulting from the introduction of a point mutation (T778A) in the activation loop of the enzyme. PKN1[T778A] mice reached adulthood without external abnormalities; however, the average spleen size and weight of aged PKN1[T778A] mice increased significantly compared to aged wild type (WT) mice. Histologic examination and Southern blot analyses of spleens showed extramedullary hematopoiesis and/or lymphomagenesis in some cases, although without significantly different incidences between PKN1[T778A] and WT mice. Additionally, flow cytometry revealed increased numbers in B220+, CD3+, Gr1+ and CD193+ leukocytes in the spleen of aged PKN1[T778A] mice, whereas the number of lymphocytes, neutrophils, eosinophils, and monocytes was reduced in the peripheral blood, suggesting an advanced impairment of leukocyte trafficking with age. Moreover, aged PKN1[T778A] mice showed no obvious GC formation nor autoimmune-like phenotypes, such as glomerulonephritis or increased anti-dsDNA antibody titer, in peripheral blood. Our results showing phenotypic differences between aged Pkn1-KO and PKN1[T778A] mice may provide insight into the importance of PKN1-specific kinase-independent functions in vivo.

PMID: 31562379 [PubMed - indexed for MEDLINE]

Rare Functional Variants Associated with Antidepressant Remission in Mexican-Americans: Short title: Antidepressant remission and pharmacogenetics in Mexican-Americans.

J Affect Disord. 2020 Oct 17;279:491-500

Authors: Wong ML, Arcos-Burgos M, Liu S, Licinio AW, Yu C, Chin EWM, Yao WD, Lu XY, Bornstein SR, Licinio J

Abstract
INTRODUCTION: Rare genetic functional variants can contribute to 30-40% of functional variability in genes relevant to drug action. Therefore, we investigated the role of rare functional variants in antidepressant response.
METHOD: Mexican-American individuals meeting the Diagnostic and Statistical Manual-IV criteria for major depressive disorder (MDD) participated in a prospective randomized, double-blind study with desipramine or fluoxetine. The rare variant analysis was performed using whole-exome genotyping data. Network and pathway analyses were carried out with the list of significant genes.
RESULTS: The Kernel-Based Adaptive Cluster method identified functional rare variants in 35 genes significantly associated with treatment remission (False discovery rate, FDR <0.01). Pathway analysis of these genes supports the involvement of the following gene ontology processes: olfactory/sensory transduction, regulation of response to cytokine stimulus, and meiotic cell cycleprocess.
LIMITATIONS: Our study did not have a placebo arm. We were not able to use antidepressant blood level as a covariate. Our study is based on a small sample size of only 65 Mexican-American individuals. Further studies using larger cohorts are warranted.
CONCLUSION: Our data identified several rare functional variants in antidepressant drug response in MDD patients. These have the potential to serve as genetic markers for predicting drug response.
TRIAL REGISTRATION: ClinicalTrials.gov NCT00265291.

PMID: 33128939 [PubMed - as supplied by publisher]

Polymorphisms PSCA rs2294008, IL-4 rs2243250 and MUC1 rs4072037 are associated with gastric cancer in a high risk population.

Mol Biol Rep. 2020 Oct 31;:

Authors: Gonzalez-Hormazabal P, Retamales-Ortega R, Musleh M, Bustamante M, Stambuk J, Pisano R, Valladares H, Lanzarini E, Chiong H, Suazo J, Quiñones LA, Varela NM, Castro VG, Jara L, Verdugo RA, Berger Z

Abstract
Genetic variants are considered risk factors for gastric cancer. To date, 61 polymorphisms have been identified as associated with this disease. The aim of the present study was to analyze the association of some of those polymorphisms with GC in Chile. We performed a case-control study including 310 gastric cancer cases and 311 controls to assess the association of 36 single-nucleotide polymorphisms genotyped by Global Screening Array (GSA). Three polymorphisms was significantly associated: PSCA rs2294008 (allele model, OR = 1.49, 95%CI 1.17-1.88, P = 1.08 × 10-3), IL-4 rs2243250 (allele model, OR = 1.28, 95%CI 1.01-1.62, P = 0.04), and MUC1 rs4072037 (allele model, OR = 0.78, 95%CI 0.61-0.99, P = 0.04).PSCA rs2294008, IL-4 rs2243250 and MUC1 rs4072037 are associated with gastric cancer in Chile. It suggests that those polymorphisms could be used as biomarkers to assess the genetic risk for this cancer outside of the previously studied populations, not only for East Asians and Caucasians populations.

PMID: 33128686 [PubMed - as supplied by publisher]

Review of the Pharmacokinetics and Pharmacodynamics of Intravenous Busulfan in Paediatric Patients.

Clin Pharmacokinet. 2020 Oct 30;:

Authors: Lawson R, Staatz CE, Fraser CJ, Hennig S

Abstract
We aimed to review the pharmacokinetics (PK) of intravenous busulfan in paediatric patients, identify covariate factors influencing exposure, investigate evidence of changes in PK behaviour over time, and correlate exposure with efficacy and toxicity outcomes. A literature review was undertaken of original research published between 2007 and 2019, investigating the PK and pharmacodynamics (PD) of intravenous busulfan in patients ≤ 18 years of age. The review identified 41 publications characterising the PK, and 45 publications describing the PD, of busulfan. Median typical clearance (CL) was 0.22 L/h/kg and median typical volume of distribution was 0.69 L/kg. Patient weight, age, glutathione-S-transferase A1 (GSTA1) genotype and busulfan dosing day/time were the most commonly identified factors affecting CL. Of nine studies investigating changes in CL, seven reported reduced CL over the 4-day course of treatment. Exposure monitoring methods and therapeutic targets were heterogeneous across studies. Relationships between busulfan exposure and patient outcomes were observed in five studies. One study observed a cumulative area under the concentration-time curve over all days of treatment of between 78 and 101 mg/L·h, and two studies observed an average concentration at first dose of < 600 ng/mL improved overall survival, transplant-related mortality, or relapse. One study observed increased sinusoidal obstructive syndrome with maximum busulfan concentration > 1.88 ng/mL. Patient weight, age and GSTA1 genotype are important covariates to consider when individualising busulfan therapy. Reduced busulfan CL over time may need to be accounted for, particularly in patients not receiving phenytoin co-therapy. Standardised monitoring of busulfan exposure over the entire course of treatment and further investigation of the role of busulfan metabolites and pharmacogenomics is warranted.

PMID: 33128207 [PubMed - as supplied by publisher]

Clinically relevant updates of the HbVar database of human hemoglobin variants and thalassemia mutations.

Nucleic Acids Res. 2020 Oct 30;:

Authors: Giardine BM, Joly P, Pissard S, Wajcman H, K Chui DH, Hardison RC, Patrinos GP

Abstract
HbVar (http://globin.bx.psu.edu/hbvar) is a widely-used locus-specific database (LSDB) launched 20 years ago by a multi-center academic effort to provide timely information on the numerous genomic variants leading to hemoglobin variants and all types of thalassemia and hemoglobinopathies. Here, we report several advances for the database. We made clinically relevant updates of HbVar, implemented as additional querying options in the HbVar query page, allowing the user to explore the clinical phenotype of compound heterozygous patients. We also made significant improvements to the HbVar front page, making comparative data querying, analysis and output more user-friendly. We continued to expand and enrich the regular data content, involving 1820 variants, 230 of which are new entries. We also increased the querying potential and expanded the usefulness of HbVar database in the clinical setting. These several additions, expansions and updates should improve the utility of HbVar both for the globin research community and in a clinical setting.

PMID: 33125055 [PubMed - as supplied by publisher]

Impact of CYP2C19, CYP3A4, ABCB1, and FMO3 genotypes on plasma voriconazole in Thai patients with invasive fungal infections.

Pharmacol Res Perspect. 2020 Dec;8(6):e00665

Authors: Chuwongwattana S, Jantararoungtong T, Prommas S, Medhasi S, Puangpetch A, Sukasem C

Abstract
Voriconazole is the first-line antifungal choice in the treatment of invasive fungal infections (IFIs). Single nucleotide polymorphisms (SNPs) in drug-metabolizing and transporter genes may affect voriconazole pharmacokinetics. This study aimed to determine the frequency of the CYP2C19 rs4244285, rs4986893, rs72552267, and rs12248560, CYP3A4 rs4646437, ABCB1 rs1045642, and FMO3 rs2266782 alleles and determine the association between these genetic variants and voriconazole concentrations in Thai patients with invasive fungal infections. The study comprised 177 Thai patients with IFIs in whom seven SNPs in CYP2C19, CYP3A4, ABCB1, and FMO3 were genotyped using TaqMan real-time polymerase chain reaction (RT-PCR) 5´ nuclease assays, and voriconazole plasma concentrations were measured by high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). Of the 177 patients included, 31 were <12 years and 146 were ≥12 years. The CYP2C19 allele frequencies were 0.29 for *2, 0.060 for *3, 0.003 for *6, and 0.008 for *17. The allele frequency of CYP3A4 (rs4646437) was 0.26, ABCB1 (rs1045642) was 0.36, and FMO3 (rs2266782) was 0.16. The median voriconazole dose/weight was significantly lower in patients aged ≥12 years when compared to the patients aged <12 years (P < .001). Patients aged <12 years with CYP2C19*1/*2 exhibited significantly higher median voriconazole plasma concentrations than those with the CYP2C19*1/*1 (P = .038). However, there were no significant differences in median voriconazole plasma concentrations among the CYP2C19 genotypes in the patients aged ≥12 years. There was a lack of association observed among the CYP3A4, ABCB1, and FMO3 genotypes on the plasma voriconazole concentrations in both groups of patients. Our findings indicate that voriconazole plasma concentrations are affected by the CYP2C19*2 allele in patients aged <12 years but not in patients aged ≥12 years.

PMID: 33124772 [PubMed - in process]

High prevalence of CYP2D6 ultrarapid metabolizers in a mestizo Colombian population in relation to Hispanic mestizo populations.

Pharmacogenomics. 2020 Oct 30;:

Authors: Sarmiento AP, Dorado P, Borbón A, Andrés F, LLerena A, Moya GE, Ferreiro V, Tarazona-Santos E, Rodrigues-Soares F, Sarmiento AP, Borbón A, Barrantes R, Jiménez-Arce G, Céspedes-Garro C, Rodeiro I, Delgado R, Remirez D, Calzadilla LR, Terán E, Hernández F, Terán S, Ortiz-Lopez R, Rojas-Martinez A, Perez-Paramo YX, López-López M, Ortega-Vázquez A, Monroy-Jaramillo N, Jung-Cook H, Fricke-Galindo I, Sosa-Macías M, Galaviz-Hernández C, Lares-Aseff I, Lazalde-Ramos BP, Ramírez-Roa R, Tinoco CA, Grazina M, LLerena A, Peñas-Lledó EM, Cobaleda J, Andrés F, Dorado P, Fariñas H, Estévez-Carrizo FE

Abstract
Background: Interethnic differences in CYP2D6 allele frequency have been demonstrated across Latin-American countries. Only one previous study describing CYP2D6 genotypes in Colombian population has been performed. Thus, this study aimed to evaluate the CYP2D6 genetic variability in a mestizo Colombian population, as well as the similarities and differences concerning other Hispanic mestizo (HM) populations. Methodology: Two hundred and twelve unrelated healthy Colombian subjects were studied, in which different CYP2D6 polymorphisms were analyzed by extra long-PCR and real-time PCR. Results/discussion: A high percentage of ultrarapid metabolizers (18.4%) was found, representing the highest frequency calculated within the HM populations studied. However, the percentage of poor metabolizers (4.7%) was similar to those previously reported in HM populations.

PMID: 33124522 [PubMed - as supplied by publisher]

Magnetoencephalographic signatures of hierarchical rule learning in newborns.

Dev Cogn Neurosci. 2020 Oct 10;46:100871

Authors: Moser J, Schleger F, Weiss M, Sippel K, Dehaene-Lambertz G, Preissl H

Abstract
Estimating the extent to which newborn humans process input from their environment, especially regarding the depth of processing, is a challenging question. To approach this problem, we measured brain responses in 20 newborns with magnetoencephalography (MEG) in a "local-global" auditory oddball paradigm in which two-levels of hierarchical regularities are presented. Results suggest that infants in the first weeks of life are able to learn hierarchical rules, yet a certain level of vigilance seems to be necessary. Newborns detected violations of the first-order regularity and displayed a mismatch response between 200-400 ms. Violations of the second-order regularity only evoked a late response in newborns in an active state, which was expressed by a high heart rate variability. These findings are in line with those obtained in human adults and older infants suggesting a continuity in the functional architecture from term-birth on, despite the immaturity of the human brain at this age.

PMID: 33122158 [PubMed - as supplied by publisher]

The Protective Effect of Metformin against Oxandrolone-Induced Infertility in Male Rats.

Curr Pharm Des. 2020 Oct 28;:

Authors: Abed AF, Jarrar YB, Al-Ameer HJ, Al-Awaida W, Lee SJ

Abstract
BACKGROUND: Oxandrolone is a synthetic testosterone analogue that is widely used among bodybuilders and athletes. However, oxandrolone causes male infertility. Recently, it was found that metformin reduces the risk of infertility associated with diabetes mellitus.
AIM: This study aimed to investigate the protective effects of metformin against oxandrolone-induced infertility in male rats.
METHODS: Rats continuously received one of four treatments (n=7) over 14 days: control DMSO administration, oxandrolone administration, metformin administration, or co-administration of oxandrolone and metformin. Doses were equivalent to those used for human treatment. Subsequently, testicular and blood samples were collected for morphological, biochemical, and histological examination. In addition, gene expression of the testosterone synthesizing enzyme CYP11A1 was analyzed in the testes using RT-PCR.
RESULTS: Oxandrolone administration induced male infertility by significantly reducing relative weights of testes by 48%, sperm count by 82%, and serum testosterone levels by 96% (ANOVA, P value < 0.05). In addition, histological examination determined that oxandrolone caused spermatogenic arrest which was associated with 2-fold downregulation of testicular CYP11A1 gene expression. However, co-administration of metformin with oxandrolone significantly ameliorated toxicological alterations induced by oxandrolone exposure (ANOVA, P value < 0.05).
CONCLUSION: Metformin administration protected against oxandrolone-induced infertility in male rats. Further clinical studies are needed to confirm the protective effect of metformin against oxandrolone-induced infertility among athletes.

PMID: 33121403 [PubMed - as supplied by publisher]

Translating Science to Medicine: When Will the Rubber Meet the Road?

Eur Urol. 2019 11;76(5):560-561

Authors: Tosoian JJ, Chinnaiyan AM

PMID: 31506226 [PubMed - indexed for MEDLINE]

The evolution of long noncoding RNA acceptance in prostate cancer initiation, progression, and its clinical utility in disease management.

Eur Urol. 2019 11;76(5):546-559

Authors: Ramnarine VR, Kobelev M, Gibb EA, Nouri M, Lin D, Wang Y, Buttyan R, Davicioni E, Zoubeidi A, Collins CC

Abstract
CONTEXT: It is increasingly evident that non-protein-coding regions of the genome can give rise to transcripts that form functional layers of the cancer genome. One of most abundant classes in these regions is long noncoding RNAs (lncRNAs). They have gained increasing attention in prostate cancer (PCa) and paved the way for a greater understanding of these cryptic regulators in cancer.
OBJECTIVE: To review current research exploring the functional biology of lncRNAs in PCa over the past three decades.
EVIDENCE ACQUISITION: A systematic review was performed using PubMed to search for reports with terms "long noncoding RNA", "prostate", and "cancer" over the past 30 yr (1988-2018).
EVIDENCE SYNTHESIS: We comprehensively surveyed the literature collected and summarise experiments leading to the characterisation of lncRNAs in PCa. A historical timeline of lncRNA identification is described, where each lncRNA is categorised mechanistically and within the primary areas of carcinogenesis: tumour risk and initiation, tumour promotion, tumour suppression, and tumour treatment resistance. We describe select lncRNAs that exemplify these areas. We also review whether these lncRNAs have a clinical utility in PCa diagnosis, prognosis, and prediction, and as therapeutic targets.
CONCLUSIONS: The biology of lncRNA is multifaceted, demonstrating a complex array of molecular and cellular functions. These studies reveal that lncRNAs are involved in every stage of PCa. Their clinical utility for diagnosis, prognosis, and prediction of PCa is well supported, but further evaluation for their therapeutic candidacy is needed. We provide a detailed resource and view inside the lncRNA landscape for other cancer biologists, oncologists, and clinicians.
PATIENT SUMMARY: In this study, we review current knowledge of the non-protein-coding genome in prostate cancer (PCa). We conclude that many of these regions are functional and a source of accurate biomarkers in PCa. With a strong research foundation, they hold promise as future therapeutic targets, yet clinical trials are necessary to determine their intrinsic value to PCa disease management.

PMID: 31445843 [PubMed - indexed for MEDLINE]

MicroRNAs: Turning the Tide in Testicular Cancer.

Eur Urol. 2019 Nov;76(5):541-542

Authors: Singla N, Lafin JT, Bagrodia A

Abstract
MicroRNAs are poised to radically change the way we care for patients with germ cell tumors (GCTs) across all disease states, from diagnosis to managing chemorefractory disease. miR-371a-3p is a promising candidate biomarker that may precisely individualize GCT treatment paradigms.

PMID: 31230742 [PubMed - indexed for MEDLINE]