Methods to assess anticancer immune responses in orthotopic bladder carcinomas.

Methods Enzymol. 2020;635:127-137

Authors: Sweis RF

Abstract
Urothelial bladder cancer is the most common malignancy of the urinary tract resulting in over 165,000 deaths worldwide. Immunotherapies targeting the programmed cell death protein-1 (PD-1) checkpoint pathway were recently approved for the treatment of bladder cancer, but favorable responses to this treatment are still limited to a minority of patients. This resistance to therapy has driven a need to optimize syngeneic models of bladder cancer that enable evaluation of the tumor immune microenvironment under varying conditions. Several models have been in place for many years, and we discuss in this chapter the optimization of an orthotopic model of bladder cancer that can be employed to study the anti-tumor immune response.

PMID: 32122541 [PubMed - in process]

Associations of autozygosity with a broad range of human phenotypes.

Nat Commun. 2019 10 31;10(1):4957

Authors: Clark DW, Okada Y, Moore KHS, Mason D, Pirastu N, Gandin I, Mattsson H, Barnes CLK, Lin K, Zhao JH, Deelen P, Rohde R, Schurmann C, Guo X, Giulianini F, Zhang W, Medina-Gomez C, Karlsson R, Bao Y, Bartz TM, Baumbach C, Biino G, Bixley MJ, Brumat M, Chai JF, Corre T, Cousminer DL, Dekker AM, Eccles DA, van Eijk KR, Fuchsberger C, Gao H, Germain M, Gordon SD, de Haan HG, Harris SE, Hofer E, Huerta-Chagoya A, Igartua C, Jansen IE, Jia Y, Kacprowski T, Karlsson T, Kleber ME, Li SA, Li-Gao R, Mahajan A, Matsuda K, Meidtner K, Meng W, Montasser ME, van der Most PJ, Munz M, Nutile T, Palviainen T, Prasad G, Prasad RB, Priyanka TDS, Rizzi F, Salvi E, Sapkota BR, Shriner D, Skotte L, Smart MC, Smith AV, van der Spek A, Spracklen CN, Strawbridge RJ, Tajuddin SM, Trompet S, Turman C, Verweij N, Viberti C, Wang L, Warren HR, Wootton RE, Yanek LR, Yao J, Yousri NA, Zhao W, Adeyemo AA, Afaq S, Aguilar-Salinas CA, Akiyama M, Albert ML, Allison MA, Alver M, Aung T, Azizi F, Bentley AR, Boeing H, Boerwinkle E, Borja JB, de Borst GJ, Bottinger EP, Broer L, Campbell H, Chanock S, Chee ML, Chen G, Chen YI, Chen Z, Chiu YF, Cocca M, Collins FS, Concas MP, Corley J, Cugliari G, van Dam RM, Damulina A, Daneshpour MS, Day FR, Delgado GE, Dhana K, Doney ASF, Dörr M, Doumatey AP, Dzimiri N, Ebenesersdóttir SS, Elliott J, Elliott P, Ewert R, Felix JF, Fischer K, Freedman BI, Girotto G, Goel A, Gögele M, Goodarzi MO, Graff M, Granot-Hershkovitz E, Grodstein F, Guarrera S, Gudbjartsson DF, Guity K, Gunnarsson B, Guo Y, Hagenaars SP, Haiman CA, Halevy A, Harris TB, Hedayati M, van Heel DA, Hirata M, Höfer I, Hsiung CA, Huang J, Hung YJ, Ikram MA, Jagadeesan A, Jousilahti P, Kamatani Y, Kanai M, Kerrison ND, Kessler T, Khaw KT, Khor CC, de Kleijn DPV, Koh WP, Kolcic I, Kraft P, Krämer BK, Kutalik Z, Kuusisto J, Langenberg C, Launer LJ, Lawlor DA, Lee IT, Lee WJ, Lerch MM, Li L, Liu J, Loh M, London SJ, Loomis S, Lu Y, Luan J, Mägi R, Manichaikul AW, Manunta P, Másson G, Matoba N, Mei XW, Meisinger C, Meitinger T, Mezzavilla M, Milani L, Millwood IY, Momozawa Y, Moore A, Morange PE, Moreno-Macías H, Mori TA, Morrison AC, Muka T, Murakami Y, Murray AD, de Mutsert R, Mychaleckyj JC, Nalls MA, Nauck M, Neville MJ, Nolte IM, Ong KK, Orozco L, Padmanabhan S, Pálsson G, Pankow JS, Pattaro C, Pattie A, Polasek O, Poulter N, Pramstaller PP, Quintana-Murci L, Räikkönen K, Ralhan S, Rao DC, van Rheenen W, Rich SS, Ridker PM, Rietveld CA, Robino A, van Rooij FJA, Ruggiero D, Saba Y, Sabanayagam C, Sabater-Lleal M, Sala CF, Salomaa V, Sandow K, Schmidt H, Scott LJ, Scott WR, Sedaghati-Khayat B, Sennblad B, van Setten J, Sever PJ, Sheu WH, Shi Y, Shrestha S, Shukla SR, Sigurdsson JK, Sikka TT, Singh JR, Smith BH, Stančáková A, Stanton A, Starr JM, Stefansdottir L, Straker L, Sulem P, Sveinbjornsson G, Swertz MA, Taylor AM, Taylor KD, Terzikhan N, Tham YC, Thorleifsson G, Thorsteinsdottir U, Tillander A, Tracy RP, Tusié-Luna T, Tzoulaki I, Vaccargiu S, Vangipurapu J, Veldink JH, Vitart V, Völker U, Vuoksimaa E, Wakil SM, Waldenberger M, Wander GS, Wang YX, Wareham NJ, Wild S, Yajnik CS, Yuan JM, Zeng L, Zhang L, Zhou J, Amin N, Asselbergs FW, Bakker SJL, Becker DM, Lehne B, Bennett DA, van den Berg LH, Berndt SI, Bharadwaj D, Bielak LF, Bochud M, Boehnke M, Bouchard C, Bradfield JP, Brody JA, Campbell A, Carmi S, Caulfield MJ, Cesarini D, Chambers JC, Chandak GR, Cheng CY, Ciullo M, Cornelis M, Cusi D, Smith GD, Deary IJ, Dorajoo R, van Duijn CM, Ellinghaus D, Erdmann J, Eriksson JG, Evangelou E, Evans MK, Faul JD, Feenstra B, Feitosa M, Foisy S, Franke A, Friedlander Y, Gasparini P, Gieger C, Gonzalez C, Goyette P, Grant SFA, Griffiths LR, Groop L, Gudnason V, Gyllensten U, Hakonarson H, Hamsten A, van der Harst P, Heng CK, Hicks AA, Hochner H, Huikuri H, Hunt SC, Jaddoe VWV, De Jager PL, Johannesson M, Johansson Å, Jonas JB, Jukema JW, Junttila J, Kaprio J, Kardia SLR, Karpe F, Kumari M, Laakso M, van der Laan SW, Lahti J, Laudes M, Lea RA, Lieb W, Lumley T, Martin NG, März W, Matullo G, McCarthy MI, Medland SE, Merriman TR, Metspalu A, Meyer BF, Mohlke KL, Montgomery GW, Mook-Kanamori D, Munroe PB, North KE, Nyholt DR, O'connell JR, Ober C, Oldehinkel AJ, Palmas W, Palmer C, Pasterkamp GG, Patin E, Pennell CE, Perusse L, Peyser PA, Pirastu M, Polderman TJC, Porteous DJ, Posthuma D, Psaty BM, Rioux JD, Rivadeneira F, Rotimi C, Rotter JI, Rudan I, Den Ruijter HM, Sanghera DK, Sattar N, Schmidt R, Schulze MB, Schunkert H, Scott RA, Shuldiner AR, Sim X, Small N, Smith JA, Sotoodehnia N, Tai ES, Teumer A, Timpson NJ, Toniolo D, Tregouet DA, Tuomi T, Vollenweider P, Wang CA, Weir DR, Whitfield JB, Wijmenga C, Wong TY, Wright J, Yang J, Yu L, Zemel BS, Zonderman AB, Perola M, Magnusson PKE, Uitterlinden AG, Kooner JS, Chasman DI, Loos RJF, Franceschini N, Franke L, Haley CS, Hayward C, Walters RG, Perry JRB, Esko T, Helgason A, Stefansson K, Joshi PK, Kubo M, Wilson JF

Abstract
In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding.

PMID: 31673082 [PubMed - indexed for MEDLINE]

A Survey of Precision Diagnosis and Management Capacity of Pulmonary Embolism in 90 Hospitals of China.

Clin Respir J. 2020 Mar 02;:

Authors: Wang D, Shao X, Lei J, Zhai Z

Abstract
OBJECTIVE: To conduct a survey of diagnostic facility and therapeutic capability of PE in 90 hospitals throughout China.
METHOD: It was a cross-sectional study among the participating hospitals of the National Key Research & Development Program of China -- the Precision Research of Standardized Management and Application of Pulmonary Thromboembolism to obtain the equipment and application of radiological facility to diagnose PE, laboratory tests for thrombophilia, coagulation function and the availability of anticoagulants and thrombolysis agents.
RESULTS: CTPA is capable in all 90 hospitals, 71.11% of the hospitals could perform V/Q scintigraphy, 24.44% of the hospitals do not routinely perform right heart evaluation by echocardiography. Protein C and protein S activity can be detected in half of the hospitals and warfarin pharmacogenomics test can be conducted in 40 hospitals. Immune turbidimetry was used as the detection method of D-dimer in 72.37% hospitals. 81.11% participating hospitals were equipped with new NOACs, all of which were equipped with Rivaroxaban.
CONCLUSION: The hospitals are capable for standardized diagnosis and management PE, while the capability of precise stratification, coagulation function tests, thrombophilia screening and pharmacogenomics requires further improvement.

PMID: 32119187 [PubMed - as supplied by publisher]

Quantitative Transcriptional Biomarkers of Xenobiotic Receptor Activation in Rat Liver for The Early Assessment of Drug Safety Liabilities.

Toxicol Sci. 2020 Mar 02;:

Authors: Podtelezhnikov AA, Monroe JJ, Aslamkhan AG, Pearson K, Qin C, Tamburino AM, Loboda AP, Glaab WE, Sistare FD, Tanis KQ

Abstract
The robust transcriptional plasticity of liver mediated through xenobiotic receptors underlies its ability to respond rapidly and effectively to diverse chemical stressors. Thus, drug-induced gene expression changes in liver serve not only as biomarkers of liver injury, but also as mechanistic sentinels of adaptation in metabolism, detoxification and tissue protection from chemicals. Modern RNA sequencing methods offer an unmatched opportunity to quantitatively monitor these processes in parallel and to contextualize the spectrum of dose-dependent stress, adaptation, protection and injury responses induced in liver by drug treatments. Using this approach, we profiled the transcriptional changes in rat liver following daily oral administration of 120 different compounds, many of which are known to be associated with clinical risk for drug induced liver injury (DILI) by diverse mechanisms. Clustering, correlation and linear modeling analyses were used to identify and optimize co-expressed gene signatures modulated by drug treatment. Here, we specifically focused on prioritizing 9 key signatures for their pragmatic utility for routine monitoring in initial rat tolerability studies just prior to entering drug development. These signatures are associated with 5 canonical xenobiotic nuclear receptors (AHR, CAR, PXR, PPARα, ER), 3 mediators of reactive metabolite mediated stress responses (NRF2, NRF1, P53), and 1 liver response following activation of the innate immune response (IIR). Comparing paradigm chemical inducers of each receptor to the other compounds surveyed enabled us to identify sets of optimized gene expression panels and associated scoring algorithms proposed as quantitative mechanistic biomarkers with high sensitivity, specificity and quantitative accuracy. These findings were further qualified using public datasets, Open TG-GATEs and DrugMatrix, and internal development compounds. With broader collaboration and additional qualification, the quantitative toxicogenomic framework described here could inform candidate selection prior to committing to drug development, as well as complement and provide a deeper understanding of the conventional toxicology study endpoints used later in drug development.

PMID: 32119089 [PubMed - as supplied by publisher]

Impact of Population and Pharmacogenetics Variations on Efavirenz Pharmacokinetics and Immunologic Outcomes During Anti-Tuberculosis Co-Therapy: A Parallel Prospective Cohort Study in Two Sub-Sahara African Populations.

Front Pharmacol. 2020;11:26

Authors: Mugusi S, Habtewold A, Ngaimisi E, Amogne W, Yimer G, Minzi O, Makonnen E, Sudfeld C, Burhenne J, Aklillu E

Abstract
Efavirenz-based combination antiretroviral-therapy (cART) is the recommended regimen during tuberculosis (TB) therapy. In a multi-national parallel prospective-cohort study, we investigated the impact of population and pharmacogenetic variations for efavirenz pharmacokinetics, auto-induction, and immunologic outcome during antituberculosis treatment. A total of 921 treatment-naïve HIV patients with (196 Ethiopians and 231 Tanzanians) or without TB co-infection (285 Ethiopians and 209 Tanzanians) were enrolled and treated with efavirenz-based cART. TB-HIV patients started rifampicin-based anti-TB therapy 4 weeks before cART. Efavirenz plasma concentrations were measured on the 4th and 16th weeks of cART. Genotyping for CYP2B6, CYP3A5, ABCB1, UGT2B7, and SLCO1B1 was done. CD4 cells-count was measured at baseline, 12th, 24th, and 48th weeks of cART. Among HIV-only cohort, plasma efavirenz concentration and median CD4 cell count were significantly higher in Tanzanians than Ethiopians, and both CYP2B6 genotype and population-variation were significant predictors of efavirenz plasma concentration. Within-population analyses indicated a pronounced efavirenz autoinduction in Tanzanians as reflected by a significant decrease of plasma efavirenz concentration over time (p = 0.0001), but not in Ethiopians. Among TB-HIV cohort, there were no significant between-population differences in plasma efavirenz concentrations or CD4 cell-recovery, and CYP2B6 genotype but not population-variation was a significant predictor of efavirenz plasma exposure. In Tanzanian patients, short-term anti-TB co-treatment significantly reduced the mean plasma efavirenz concentration in CYP2B6*1/*1 genotype at week-4 (p = 0.005), but not at week-16 of cART. In Ethiopian patients, anti-TB cotreatment increased the mean plasma efavirenz concentration among CYP2B6*6 carriers at week-4 (p = 0.003) and week-16 (p = 0.035) of cART. In general, long-term anti-TB co-treatment increased plasma efavirenz concentration at week 16 of cART in both Ethiopians and Tanzanians being higher in CYP2B6*6/*6 > *1/*6 > *1/*1 genotypes. In TB-HIV patients, baseline body mass index (BMI), viral load, and WHO clinical-stage but not genotype, population-variation, or efavirenz concentration were significant predictors of immunologic outcome at week-48. In summary efavirenz auto-induction, pharmacokinetics, and the immunologic outcome are influenced by population-variation, anti-TB co-medication, and CYP2B6 genotype. CYP2B6 genotype is a significant predictor of efavirenz plasma exposure regardless of population-variation or antituberculosis co-treatment, but population-variation is insignificant during antituberculosis treatment. CYP2B6 genotype, population, and geographic differences need to be considered for efavirenz dosage-optimization.

PMID: 32116703 [PubMed]

Progress in Genetic Polymorphisms Related to Lipid Disturbances Induced by Atypical Antipsychotic Drugs.

Front Pharmacol. 2019;10:1669

Authors: Li N, Cao T, Wu X, Tang M, Xiang D, Cai H

Abstract
Metabolic side effects such as weight gain and disturbed lipid metabolism are often observed in the treatment of atypical antipsychotic drugs (AAPDs), which contribute to an excessive prevalence of metabolic syndrome among schizophrenic patients. Great individual differences are observed but the underlying mechanisms are still uncertain. Research on pharmacogenomics indicates that gene polymorphisms involved in the pathways controlling food intake and lipid metabolism may play a significant role. In this review, relevant genes (HTR2C, DRD2, LEP, NPY, MC4R, BDNF, MC4R, CNR1, INSIG2, ADRA2A) and genetic polymorphisms related to metabolic side effects of AAPDs especially dyslipidemia were summarized. Apart from clinical studies, in vitro and in vivo evidence is also analyzed to support related theories. The association of central and peripheral mechanisms is emphasized, enabling the possibility of using peripheral gene expression to predict the central status. Novel methodological development of pharmacogenomics is in urgent need, so as to provide references for individualized medication and further to shed some light on the mechanisms underlying AAPD-induced lipid disturbances.

PMID: 32116676 [PubMed]

Drugs in pregnancy: Pharmacologic and physiologic changes that affect clinical care.

Semin Perinatol. 2020 Jan 25;:151221

Authors: Pinheiro EA, Stika CS

Abstract
Pharmacologic interventions play a major role in obstetrical care throughout pregnancy, labor and delivery and the postpartum. Traditionally, obstetrical providers have utilized standard dosing regimens developed for non-obstetrical indications based on pharmacokinetic knowledge from studies in men or non-pregnant women. With the recognition of pregnancy as a special pharmacokinetic population in the late 1990s, investigators have begun to study drug disposition in this unique patient dyad. Many of the basic physiologic changes that occur during pregnancy have significant impact on drug absorption, distribution and clearance. Activity of Phase I and Phase II drug metabolizing enzymes are differentially altered by pregnancy, resulting in drug concentrations sufficiently different for some medications that efficacy or toxicity is affected. Placental transporters play a major dynamic role in determining fetal drug exposure. In the past two decades, we have begun to expand our understanding of obstetrical pharmacology; however, to truly optimize pharmacologic care of our pregnant patients and their developing fetus, additional research is critically needed.

PMID: 32115202 [PubMed - as supplied by publisher]

Predictors of blood pressure control in patients with resistant hypertension after intensive management in two expert centres: the Brussels-Torino experience.

Blood Press. 2019 10;28(5):336-344

Authors: Pappaccogli M, Di Monaco S, Coralie G, Petit G, Eula E, Ritscher S, Lengelé JP, Fanelli E, Severino F, Renkin J, Avataneo V, Wallemacq P, Toennes SW, de Timary P, Rabbia F, Persu A

Abstract
Background: Management of resistant hypertension (RHTN) is challenging and often implies the use of complex polypharmacy and interventional therapies. The main objectives of this study were (i) to describe the characteristics of patients with RHTN referred to two expert centres; (ii) to identify predictors of blood pressure (BP) control after intensive management. Methods: We reviewed electronic medical files of all patients referred for RHTN to the Brussels and Torino centres, and extracted detailed clinical data, informations on drug adherence and psychological profile. All patients with confirmed diagnosis of RHTN, according to office and ambulatory BP monitoring (ABPM) measurements, were considered eligible. Results: 313 patients (51% men; age: 56 ± 12 years; office BP 177/98 mmHg; 24-hour ABPM 153/90 mmHg) were included. At the end of follow-up (median: 2 years [1-4]), only 26% of patients (n = 81) reached BP control. When compared to patients remaining resistant, patients eventually controlled had lower pulse pressure (71 vs. 82 mmHg, p < 0.001), less often myocardial infarction (6% vs. 20%, p < 0.005) and showed a higher recourse to cognitive reappraisal as far as emotion regulation is concerned (4.8 ± 1.1 vs. 3.9 ± 1.2, p = 0.009; ERQ Questionnaire). In a multivariate analysis looking for predictors of controlled BP, only the psychological characteristic of cognitive reappraisal (i.e., changing one's thoughts about a potentially emotion-eliciting event) remained significant (OR 2.06 [1.10; 3.84], p = 0.02). Conclusions: Even in expert centres, only a minority of patients with RHTN reached BP control, irrespective of the centre involved or the interventions applied. Patients who eventually responded to therapy had lower arterial stiffness and less cardiac organ damage. Furthermore, besides vascular damage, the single predictor of BP control was the ability to modify the emotional impact of stressful situations.

PMID: 31257937 [PubMed - indexed for MEDLINE]

Genetic Variations and Precision Medicine.

Perspect Health Inf Manag. 2019;16(Spring):1a

Authors: Alzu'bi AA, Zhou L, Watzlaf VJM

Abstract
The time and costs associated with the sequencing of a human genome have decreased significantly in recent years. Many people have chosen to have their genomes sequenced to receive genomics-based personalized healthcare services. To reach the goal of genomics-based precision medicine, health information management (HIM) professionals need to manage and analyze patients' genomic data. Two important pieces of information from the genome sequence are the risk of genetic diseases and the specific medication or pharmacogenomic results for the individual patient, both of which are linked to a patient's genetic variations. In this review article, we introduce genetic variations, including their data types, relevant databases, and some currently available analysis methods and systems. HIM professionals can choose to use these databases, methods, and systems in the management and analysis of patients' genomic data.

PMID: 31019429 [PubMed - indexed for MEDLINE]

Progranulin Stimulates the In Vitro Maturation of Pro-Cathepsin D at Acidic pH.

J Mol Biol. 2019 03 01;431(5):1038-1047

Authors: Butler VJ, Cortopassi WA, Argouarch AR, Ivry SL, Craik CS, Jacobson MP, Kao AW

Abstract
Single-copy loss-of-function mutations in the progranulin gene (PGRN) underlie the neurodegenerative disease frontotemporal lobar degeneration, while homozygous loss-of-function of PGRN results in the lysosomal storage disorder neuronal ceroid lipofuscinosis. Despite evidence that normal PGRN levels are critical for neuronal health, the function of this protein is not yet understood. Here, we show that PGRN stimulates the in vitro maturation of the lysosomal aspartyl protease cathepsin D (CTSD). CTSD is delivered to the endolysosomal system as an inactive precursor (proCTSD) and requires sequential cleavage steps via intermediate forms to achieve the mature state (matCTSD). In co-immunoprecipitation experiments, PGRN interacts predominantly with immature pro- and intermediate forms of CTSD. PGRN enhances in vitro conversion of proCTSD to matCTSD in a concentration-dependent manner. Differential scanning fluorimetry shows a destabilizing effect induced by PGRN on proCTSD folding (∆Tm = -1.7 °C at a 3:1 molar ratio). We propose a mechanism whereby PGRN binds to proCTSD, destabilizing the propeptide from the enzyme catalytic core and favoring conversion to mature forms of the enzyme. Further understanding of the role of PGRN in CTSD maturation will assist in the development of targeted therapies for neurodegenerative disease.

PMID: 30690031 [PubMed - indexed for MEDLINE]

The potentiation of menadione on imatinib by down-regulation of ABCB1 expression.

Clin Exp Pharmacol Physiol. 2020 Feb 28;:

Authors: Xiao FY, Zhou FJ, Yuan F, Kuang W, Zhou G, Zhou HH, Shan C

Abstract
Imatinib was the first BCR-ABL inhibitor used in clinical practice to treat chronic myeloid leukemia (CML) and significantly improve the life expectancy of CML patients in the chronic phase. However, a portion of CML patients are resistant to imatinib. This study aimed to determine whether menadione (Vitamin K3) can improve imatinib efficacy in CML and to thoroughly explore the combination regimen mechanism between imatinib and menadione. Menadione improved imatinib efficacy in K562 cells by downregulating ABCB1 expression and increased the intracellular concentration of imatinib, which confirmed that this combination regimen is more effective than imatinib monotherapy. The results demonstrate that menadione and imatinib combination therapy may be a promising approach to refractory CML.

PMID: 32112424 [PubMed - as supplied by publisher]

Calcaneal quantitative ultrasound and urine retinol binding protein in HIV-positive antiretroviral-treated patients in Uganda: a pilot study.

J Infect Dis. 2020 Feb 28;:

Authors: Costa C, Scabini S, Kaimal A, Kasozi W, Cusato J, Kafufu B, Borderi M, Mwaka E, Di Perri G, Lamorde M, Calcagno A, Castelnuovo B

Abstract
BACKGROUND: Data on bone health and renal impairment in people with HIV in resource-limited settings are limited. The primary aim was to investigate the potential role of calcaneal Quantitative Ultrasound in predicting bone mineral density (BMD) reduction in a population of Ugandan HIV+ individuals on long-term antiretroviral therapy (ART); the secondary endpoint was to assess the prevalence of proximal tubular dysfunction and the correlation among elevated urine retinol binding protein/creatinine ratio (uRBP/uCr) and reduced BMD.
METHODS: We conducted a cross-sectional study at the Infectious Diseases Institute, Kampala, Uganda. We included 101 HIV+ adults on continuous ART for ≥10 years that had undergone DXA scan during the previous 12 months. All patients underwent calcaneal quantitative ultrasound evaluation and urine samples collection.
RESULTS: DXA BMD measurements were significantly associated (p<0.01) with calcaneal speed of sound, broadband ultrasound attenuation, and quantitative ultrasound index. 47 individuals (47%) had abnormal uRBP/uCr values. A significant inverse correlation between uRBP/uCr and DXA T-scores [lumbar (p=0.031), femoral neck (p>0.001) and total hip (p=0.002)] was observed.
CONCLUSIONS: Calcaneal quantitative ultrasound results showed a moderate correlation with DXA scan outputs. Secondly, the identified high prevalence of subclinical tubular impairment highlights the importance of expanding access to TDF-sparing regimens in resource-limited settings.

PMID: 32112093 [PubMed - as supplied by publisher]

Treatment response classes in major depressive disorder identified by model-based clustering and validated by clinical prediction models.

Transl Psychiatry. 2019 08 05;9(1):187

Authors: Paul R, Andlauer TFM, Czamara D, Hoehn D, Lucae S, Pütz B, Lewis CM, Uher R, Müller-Myhsok B, Ising M, Sämann PG

Abstract
The identification of generalizable treatment response classes (TRC[s]) in major depressive disorder (MDD) would facilitate comparisons across studies and the development of treatment prediction algorithms. Here, we investigated whether such stable TRCs can be identified and predicted by clinical baseline items. We analyzed data from an observational MDD cohort (Munich Antidepressant Response Signature [MARS] study, N = 1017), treated individually by psychopharmacological and psychotherapeutic means, and a multicenter, partially randomized clinical/pharmacogenomic study (Genome-based Therapeutic Drugs for Depression [GENDEP], N = 809). Symptoms were evaluated up to week 16 (or discharge) in MARS and week 12 in GENDEP. Clustering was performed on 809 MARS patients (discovery sample) using a mixed model with the integrated completed likelihood criterion for the assessment of cluster stability, and validated through a distinct MARS validation sample and GENDEP. A random forest algorithm was used to identify prediction patterns based on 50 clinical baseline items. From the clustering of the MARS discovery sample, seven TRCs emerged ranging from fast and complete response (average 4.9 weeks until discharge, 94% remitted patients) to slow and incomplete response (10% remitted patients at week 16). These proved stable representations of treatment response dynamics in both the MARS and the GENDEP validation sample. TRCs were strongly associated with established response markers, particularly the rate of remitted patients at discharge. TRCs were predictable from clinical items, particularly personality items, life events, episode duration, and specific psychopathological features. Prediction accuracy improved significantly when cluster-derived slopes were modelled instead of individual slopes. In conclusion, model-based clustering identified distinct and clinically meaningful treatment response classes in MDD that proved robust with regard to capturing response profiles of differently designed studies. Response classes were predictable from clinical baseline characteristics. Conceptually, model-based clustering is translatable to any outcome measure and could advance the large-scale integration of studies on treatment efficacy or the neurobiology of treatment response.

PMID: 31383853 [PubMed - indexed for MEDLINE]

Pharmacogenetic interactions between antiretroviral drugs and vaginally administered hormonal contraceptives.

Pharmacogenet Genomics. 2020 Feb 26;:

Authors: Haas DW, Cramer YS, Godfrey C, Rosenkranz SL, Aweeka F, Berzins B, Coombs R, Coughlin K, Moran LE, Gingrich D, Zorrilla CD, Baker P, Cohn SE, Scarsi KK, AIDS Clinical Trials Group A5316 Study Team

Abstract
OBJECTIVE: In AIDS Clinical Trials Group study A5316, efavirenz lowered plasma concentrations of etonogestrel and ethinyl estradiol, given as a vaginal ring, while atazanavir/ritonavir increased etonogestrel and lowered ethinyl estradiol concentrations. We characterized the pharmacogenetics of these interactions.
METHODS: In A5316, women with HIV enrolled into control (no antiretrovirals), efavirenz [600 mg daily with nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)], and atazanavir/ritonavir (300/100 mg daily with NRTIs) groups. On day 0, a vaginal ring was inserted, releasing etonogestrel/ethinyl estradiol 120/15 μg/day. Intensive plasma sampling for antiretrovirals was obtained on days 0 and 21, and single samples for etonogestrel and ethinyl estradiol on days 7, 14, and 21. Seventeen genetic polymorphisms were analyzed.
RESULTS: The 72 participants in this analysis included 25, 24 and 23 in the control, efavirenz, and atazanavir/ritonavir groups, respectively. At day 21 in the efavirenz group, CYP2B6 genotype was associated with increased plasma efavirenz exposure (P = 3.2 × 10), decreased plasma concentrations of etonogestrel (P = 1.7 × 10), and decreased ethinyl estradiol (P = 6.7 × 10). Compared to controls, efavirenz reduced median etonogestrel concentrations by at least 93% in CYP2B6 slow metabolizers versus approximately 75% in normal and intermediate metabolizers. Efavirenz reduced median ethinyl estradiol concentrations by 75% in CYP2B6 slow metabolizers versus approximately 41% in normal and intermediate metabolizers.
CONCLUSION: CYP2B6 slow metabolizer genotype worsens the pharmacokinetic interaction of efavirenz with hormonal contraceptives administered by vaginal ring. Efavirenz dose reduction in CYP2B6 slow metabolizers may reduce, but will likely not eliminate, this interaction.

PMID: 32106141 [PubMed - as supplied by publisher]

Down-regulating NQO1 promotes cellular proliferation in K562 cells via elevating DNA synthesis.

Life Sci. 2020 Feb 24;:117467

Authors: Xiao FY, Jiang ZP, Yuan F, Zhou FJ, Kuang W, Zhou G, Chen XP, Liu R, Zhou HH, Zhao XL, Cao S

Abstract
BACKGROUND: NQO1 protein acts as a cellular protective system, on account of its role as a quinone reductase and redox regulator. Nonetheless, new NQO1 roles are emerging-including its regulation of the cellular proliferation of many tumor cells-and this enzyme has been found to relate to the incidence of various diseases, including chronic myeloid leukemia. However, the mechanisms through which NQO1 influences leukemia progression remain unclear.
MARTIAL AND METHODS: The current study looks to name NQO1 as a novel molecular target that modulates DNA synthesis and chronic myeloid leukemia growth.
RESULTS AND CONCLUSION: Our results indicate that the frequency of the T allele of NQO1 polymorphism in chronic myeloid leukemia patients is higher than that among healthy East Asian individuals (0.492 vs. 0.419) and much higher than the average level of the general population (0.492 vs. 0.289) (1000 Genomes). Functionally, NQO1 knockdown increases the protein expression of the TOP2A and MCM complex, and consequently promotes DNA synthesis and K562 cell growth. NQO1 knockdown also promotes tumorigenesis in a xenograft model. NQO1 overexpression, on the other hand, was found to have the opposite effects.
SIGNIFICANCE: Our results show that NQO1 downregulation promotes K562 cellular proliferation via the elevation of DNA synthesis.

PMID: 32105706 [PubMed - as supplied by publisher]

Association of PARP1 polymorphisms with response to chemotherapy in patients with high-risk neuroblastoma.

J Cell Mol Med. 2020 Feb 27;:

Authors: Avitabile M, Lasorsa VA, Cantalupo S, Cardinale A, Cimmino F, Montella A, Capasso D, Haupt R, Amoroso L, Garaventa A, Quattrone A, Corrias MV, Iolascon A, Capasso M

Abstract
The genetic aetiology and the molecular mechanisms that characterize high-risk neuroblastoma are still little understood. The majority of high-risk neuroblastoma patients do not take advantage of current induction therapy. So far, one of the main reasons liable for cancer therapeutic failure is the acquisition of resistance to cytotoxic anticancer drugs, because of the DNA repair system of tumour cells. PARP1 is one of the main DNA damage sensors involved in the DNA repair system and genomic stability. We observed that high PARP1 mRNA level is associated with unfavourable prognosis in 3 public gene expression NB patients' datasets and in 20 neuroblastomas analysed by qRT-PCR. Among 4983 SNPs in PARP1, we selected two potential functional SNPs. We investigated the association of rs907187, in PARP1 promoter, and rs2048426 in non-coding region with response chemotherapy in 121 Italian patients with high-risk NB. Results showed that minor G allele of rs907187 associated with induction response of patients (P = .02) and with decrease PARP1 mRNA levels in NB cell line (P = .003). Furthermore, rs907187 was predicted to alter the binding site of E2F1 transcription factor. Specifically, allele G had low binding affinity with E2F1 whose expression positively correlates with PARP1 expression and associated with poor prognosis of patients with NB. By contrast, we did not find genetic association for the SNP rs2048426. These data reveal rs907187 as a novel potential risk variant associated with the failure of induction therapy for high-risk NB.

PMID: 32103589 [PubMed - as supplied by publisher]

Liver macrophages inhibit the endogenous antioxidant response in obesity-associated insulin resistance.

Sci Transl Med. 2020 Feb 26;12(532):

Authors: Azzimato V, Jager J, Chen P, Morgantini C, Levi L, Barreby E, Sulen A, Oses C, Willerbrords J, Xu C, Li X, Shen JX, Akbar N, Haag L, Ellis E, Wålhen K, Näslund E, Thorell A, Choudhury RP, Lauschke VM, Rydén M, Craige SM, Aouadi M

Abstract
Obesity and insulin resistance are risk factors for nonalcoholic fatty liver disease (NAFLD), the most common chronic liver disease worldwide. Because no approved medication nor an accurate and noninvasive diagnosis is currently available for NAFLD, there is a clear need to better understand the link between obesity and NAFLD. Lipid accumulation during obesity is known to be associated with oxidative stress and inflammatory activation of liver macrophages (LMs). However, we show that although LMs do not become proinflammatory during obesity, they display signs of oxidative stress. In livers of both humans and mice, antioxidant nuclear factor erythroid 2-related factor 2 (NRF2) was down-regulated with obesity and insulin resistance, yielding an impaired response to lipid accumulation. At the molecular level, a microRNA-targeting NRF2 protein, miR-144, was elevated in the livers of obese insulin-resistant humans and mice, and specific silencing of miR-144 in murine and human LMs was sufficient to restore NRF2 protein expression and the antioxidant response. These results highlight the pathological role of LMs and their therapeutic potential to restore the impaired endogenous antioxidant response in obesity-associated NAFLD.

PMID: 32102936 [PubMed - in process]

The clinical relevance of multiple DPYD polymorphisms on patients candidate for fluoropyrimidine based-chemotherapy. An Italian case-control study.

Br J Cancer. 2019 04;120(8):834-839

Authors: Iachetta F, Bonelli C, Romagnani A, Zamponi R, Tofani L, Farnetti E, Nicoli D, Damato A, Banzi M, Casali B, Pinto C

Abstract
BACKGROUND: Deleterious polymorphisms in the gene encoding DPD (DPYD) may result in severe reduction of DPD enzymatic activity that causes life-threatening toxicities when the standard dose of fluorouracil is used. The best panel of single-nucleotide polymorphism (SNPs) of DPYD is not well defined.
METHODS: In 2011, we began screening DPYD*2A in patients candidate for fluoropyrimidine-based chemotherapy. We planned a case-control study with all cases of DPYD*2A wild type who developed toxicity ≥G3 and with a cohort of patients who did not present severe toxicities. Then, we tested the additional SNPs: c.2846A>T, c.1679T>G, c.2194G>A.
RESULTS: From 2011 to 2016, we screened 1827 patients for DPD deficiency; of those, 31 subjects (1.7%) showed DPYD*2A SNP. We selected 146 subjects who developed severe toxicities (Cases) and 220 patients who experienced no or mild toxicities (Controls); 53 patients carried one of the additional SNPs: 35 subjects (66%) fell into the Cases and 18 (34%) into the Controls (p < 0.0001). c.2194G>A was the most frequent SNP (12.5%) and showed a correlation with neutropenia. We confirmed that c.2846A>T and c.1679T>G were related to various toxicities.
CONCLUSIONS: The additional DPYD polymorphisms could enhance the prevention of fluoropyrimidine toxicity. c.2194G>A is the most frequent polymorphism and it was found to be associated with neutropenia.

PMID: 30858516 [PubMed - indexed for MEDLINE]

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pharmacogenomics

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21 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 2020/02/27

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.