Establishment and application of a predictive model for gefitinib-induced severe rash based on pharmacometabolomic profiling and polymorphisms of transporters in non-small cell lung cancer.

Transl Oncol. 2020 Nov 19;14(1):100951

Authors: Guan S, Chen X, Xin S, Liu S, Yang Y, Fang W, Huang Y, Zhao H, Zhu X, Zhuang W, Wang F, Feng W, Zhang X, Huang M, Wang X, Zhang L

Abstract
BACKGROUND: Rash is a well-known predictor of survival for patients with gefitinib therapy with non-small cell lung cancer (NSCLC). However, whether patients with more severe rash obtain the more survival benefits from gefitinib is still unknown, and predicted model for severe rash is needed.
METHODS: The relationship between gefitinib-induced rash and progression free survival (PFS) was primarily explored in the retrospective cohort. The association between rash and gefitinib/metabolites concentration and genetic polymorphisms were determined by pharmacometabolomic and pharmacogenomics methods in the exploratory cohort and validated in an external cohort.
RESULTS: The survival for patients with rash was significantly higher than that of patients without rash (p = 0.0002, p = 0.0089), but no difference was found between grade 1/2 or grade 3/4. Only the concentration of gefitinib, but not its metabolites, was found to be associated with severe rash, and the cutoff value of gefitinib was 204.6 ng/mL conducted by ROC curve analysis (AUC=0.685). A predictive model for severe rash was established: gefitinib concentration (OR = 11.523, 95% CI = 2.898-64.016, p = 0.0016), SLC22A8 rs4149179(CT vs CC, OR = 3.156, 95% CI = 0.958-11.164, p = 0.0629), SLC22A1 rs4709400(CG vs CC, OR = 10.267, 95% CI = 2.067-72.465, p = 0.0087; GG vs CC, OR = 5.103, 95% CI = 1.032-33.938, p = 0.061). This model was confirmed in the validation cohort with an excellent predictive ability (AUC = 0.749, 95% CI = 0.710-0.951).
CONCLUSIONS: Our finding demonstrated that the incidence, not the severity, of gefitinib-induced rash predicted improved survival, the gefitinib concentration and polymorphisms of SLC22A8 and SLC22A1 were recommended to manage severe rash.

PMID: 33221684 [PubMed - as supplied by publisher]

Rates of complete nonadherence among atypical antipsychotic drugs: A study using blood samples from 13,217 outpatients with psychotic disorders.

Schizophr Res. 2020 Nov 18;:

Authors: Smith RL, Tveito M, Kyllesø L, Jukic MM, Ingelman-Sundberg M, Andreassen OA, Molden E

Abstract
BACKGROUND: Nonadherence to antipsychotics may cause relapse and hospitalizations in patients with psychotic disorders. The purpose was to quantify and compare the outpatient's nonadherence rates of atypical antipsychotics by objective detection in blood samples.
METHODS: Totally, 13,217 outpatients with therapeutic drug monitoring (TDM) data of atypical antipsychotics were included. An event of complete nonadherence was defined as an occurrence of undetectable level of a prescribed antipsychotic in the blood sample submitted for TDM. Patients with such an event(s) were defined as nonadherent of the respective drug treatment (outcome). The rates of nonadherence patients were compared between the drugs by logistic regression.
RESULTS: In the study population, 70.2% of the patients were prescribed doses compliant with a schizophrenia diagnosis. The mean olanzapine equivalent dose in the population was 13.4 mg (95% confidence interval (CI): 13.3, 13.6). The frequency of nonadherence patients, regardless of drug, was 3.7% (CI: 3.4-4.0). The nonadherence patient rate was lowest in clozapine-treated patients (2.2%; CI: 1.5-2.8), followed by aripiprazole (2.3%; 1.7-2.8), risperidone (2.4%; 1.6-3.0), quetiapine (2.8%; 2.3-3.2) and olanzapine (4.9%; 4.1-5.3). Users of olanzapine had significantly higher risk of complete nonadherence (Odds ratio: 1.9; CI: 1.6-2.3, p < 0.001) compared to patients treated with other antipsychotics as a group.
CONCLUSIONS: In this study, complete nonadherence of atypical antipsychotics, measured as undetectable blood level, was disclosed for ~5% of outpatients with psychotic disorders. The rate of complete nonadherence was significantly higher during olanzapine treatment compared to other atypical antipsychotics. Further studies should investigate if this reflects drug differences in tolerability or other causal relationships.

PMID: 33221147 [PubMed - as supplied by publisher]

Direct evidence that the brain reward system is involved in the control of scratching behaviors induced by acute and chronic itch.

Biochem Biophys Res Commun. 2020 Nov 18;:

Authors: Setsu T, Hamada Y, Oikawa D, Mori T, Ishiuji Y, Sato D, Narita M, Miyazaki S, Furuta E, Suda Y, Sakai H, Ochiya T, Tezuka H, Iseki M, Inada E, Yamanaka A, Kuzumaki N, Narita M

Abstract
In the present study, we demonstrated that there is a direct relationship between scratching behaviors induced by itch and functional changes in the brain reward system. Using a conditional place preference test, the rewarding effect was clearly evoked by scratching under both acute and chronic itch stimuli. The induction of ΔFosB, a member of the Fos family of transcription factors, was observed in dopamine transporter (DAT)-positive dopamine neurons in the ventral tegmental area (VTA) of mice suffering from a chronic itch sensation. Based on a cellular analysis of scratching-activated neurons, these neurons highly expressed tyrosine hydroxylase (TH) and DAT genes in the VTA. Furthermore, in an in vivo microdialysis study, the levels of extracellular dopamine in the nucleus accumbens (NAcc) were significantly increased by transient scratching behaviors. To specifically suppress the mesolimbic dopaminergic pathway using pharmacogenetics, we used the TH-cre/hM4Di mice. Pharmacogenetic suppression of mesolimbic dopaminergic neurons significantly decreased scratching behaviors. Under the itch condition with scratching behaviors restricted by an Elizabethan collar, the induction of ΔFosB was found mostly in corticotropin-releasing hormone (CRH)-containing neurons of the hypothalamic paraventricular nucleus (PVN). These findings suggest that repetitive abnormal scratching behaviors under acute and chronic itch stimuli may activate mesolimbic dopamine neurons along with pleasant emotions, while the restriction of such scratching behaviors may initially induce the activation of PVN-CRH neurons associated with stress.

PMID: 33220930 [PubMed - as supplied by publisher]

Factor VIII pharmacokinetics associates with genetic modifiers of VWF and FVIII clearance in an adult hemophilia A population.

J Thromb Haemost. 2020 Nov 20;:

Authors: Ogiwara K, Swystun LL, Paine AS, Kepa S, Choi SJ, Rejtö J, Hopman W, Pabinger I, Lillicrap D

Abstract
BACKGROUND: FVIII pharmacokinetics (PK) in adult hemophilia A populations are highly variable and have been previously determined to be influenced by VWF:Ag, ABO blood group, and age. However, additional genetic determinants of FVIII PK are largely unknown.
OBJECTIVES: The contribution of VWF clearance, VWF-FVIII-binding activity, and genetic variants in VWF clearance receptors to FVIII PK in adult patients were assessed.
METHODS: FVIII PK assessment was performed in 44 adult subjects (age 18-61) with moderate or severe hemophilia A. VWF:Ag, VWFpp, VWFpp/VWF:Ag, and VWF:FVIII binding activity were measured. The VWF modifying loci CLEC4M, SCARA5, STAB2, and ABO, and the D'D3 FVIII-binding region of the VWF gene were genotyped.
RESULTS: VWF:Ag, VWFpp and VWF:FVIIIB positively correlated with FVIII half-life and negatively correlated with FVIII clearance. VWFpp/VWF:Ag negatively correlated with FVIII half-life and positively correlated with FVIII clearance. The correlation between VWFpp/VWF:Ag and FVIII half-life was stronger for type non-O patients than for type-O patients, suggesting that slower VWF clearance increases FVIII half-life. Patients heterozygous for the CLEC4M rs868875 variant had increased FVIII clearance when compared with individuals homozygous for the reference allele. The CLEC4M variable number of tandem repeat (VNTR) alleles were also associated with the rate of FVIII clearance. When compared to the quartile of patients with the fastest FVIII clearance, the quartile of patients with the slowest FVIII clearance had a decreased frequency of the CLEC4M 5-VNTR.
CONCLUSIONS: VWF-FVIII binding activity and genetic determinants of VWF clearance are important contributors to FVIII pharmacokinetics in adult patients.

PMID: 33219619 [PubMed - as supplied by publisher]

Genomics of hypertension: the road to precision medicine.

Nat Rev Cardiol. 2020 Nov 20;:

Authors: Padmanabhan S, Dominiczak AF

Abstract
The known genetic architecture of blood pressure now comprises >30 genes, with rare variants resulting in monogenic forms of hypertension or hypotension and >1,477 common single-nucleotide polymorphisms (SNPs) being associated with the blood pressure phenotype. Monogenic blood pressure syndromes predominantly involve the renin-angiotensin-aldosterone system and the adrenal glucocorticoid pathway, with a smaller fraction caused by neuroendocrine tumours of the sympathetic and parasympathetic nervous systems. The SNPs identified in genome-wide association studies (GWAS) as being associated with the blood pressure phenotype explain only approximately 27% of the 30-50% estimated heritability of blood pressure, and the effect of each SNP on the blood pressure phenotype is small. A paucity of SNPs from GWAS are mapped to known genes causing monogenic blood pressure syndromes. For example, a GWAS signal mapped to the gene encoding uromodulin has been shown to affect blood pressure by influencing sodium homeostasis, and the effects of another GWAS signal were mediated by endothelin. However, the majority of blood pressure-associated SNPs show pleiotropic associations. Unravelling these associations can potentially help us to understand the underlying biological pathways. In this Review, we appraise the current knowledge of blood pressure genomics, explore the causal pathways for hypertension identified in Mendelian randomization studies and highlight the opportunities for drug repurposing and pharmacogenomics for the treatment of hypertension.

PMID: 33219353 [PubMed - as supplied by publisher]

Investigating the association of Lamotrigine and Phenytoin induced Stevens-Johnson syndrome/Toxic Epidermal Necrolysis with HLA-B*1502 in Iranian population.

Exp Dermatol. 2020 Nov 20;:

Authors: Sabouri Rad S, Mortezaee R, Mojarad M, Eslahi A, Shahrokhi Y, Kiafar B, Jarahi L, Afkhami Ardakani S, Farrokhi S

Abstract
OBJECTIVE: Previous studies have found an association between HLA-B*1502 allele and lamotrigine-induced Stevens-Johnson syndrome (SJS)/ toxic epidermal necrosis (TEN) spectrum in Han Chinese populations. This study aims to investigate the association between HLA-B*1502 and lamotrigine- or phenytoin- induced SJS/TEN in an Iranian population.
METHODS: The medical records of twenty-eight lamotrigine-induced SJS/TEN patients and twenty-five lamotrigine-tolerant controls as well as eight phenytoin-induced SJS/TEN and twelve phenytoin-tolerant controls were extracted between March 2013 to March 2019 from the university hospitals in Mashhad, Iran. The presence of HLA-B*1502 allele was determined using real-time polymerase chain reaction (PCR).
RESULTS: Among lamotrigine-induced patients with SJS/TEN, 11 (39.3%) patients tested positive for the HLA-B*1502 while only 3 (12.0%) of the lamotrigine-tolerant controls tested positive for this allele. The risk of lamotrigine-induced SJS/TEN was significantly higher in patients with HLA-B*1502, with an odds ratio (OR) of 4.74 [95% confidence interval (CI) 1.14-19.73, p = 0.032]. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of HLA-B*1502 for lamotrigine-induced SJS/TEN was 39.29%, 88.00%, 78.57% and 56.41%, respectively. The HLA-B*1502 allele was present in 2 (25.0%) of phenytoin-induced SJS/TEN cases and 5 (41.7%) of the phenytoin-tolerant controls tested positive for HLA-B*1502 allele. The risk of phenytoin-induced SJS/TEN was not higher in the patients with HLA-B*1502 (OR = 0.467 [95% confidence interval (CI) 0.065-3.34, p = 0.642]).
SIGNIFICANCE: Lamotrigine-induced SJS/TEN is associated with HLA-B*1502 allele in an Iranian population but this is not the case for phenytoin-induced SJS/TEN.

PMID: 33217035 [PubMed - as supplied by publisher]

Optimization of voriconazole therapy for treatment of invasive aspergillosis: pharmacogenomics, but also inflammatory status need to be evaluated.

Br J Clin Pharmacol. 2020 Nov 20;:

Authors: Gautier-Veyret E, Thiebaut-Bertrand A, Roustit M, Bolcato L, Depeisses J, Schacherer M, Schummer G, Fonrose X, Stanke-Labesque F

Abstract
AIMS: Cytochrome 2C19 genotype-directed dosing of voriconazole (VRC) reduces the incidence of insufficient VRC trough concentrations (Cmin) but does not account for CYP3A polymorphisms, also involved in VRC metabolism. This prospective observational study aimed to evaluate the utility of a genetic score combining CYP2C19 and CYP3A genotypes to predict insufficient initial VRC Cmin (< 1mg/L).
METHODS: The genetic score was determined in hematological patients treated with VRC. The higher the genetic score, the faster the metabolism of the patient. Impact of genetic score was evaluated considering initial VRC Cmin and all VRC Cmin (n=159) determined during longitudinal therapeutic drug monitoring.
RESULTS: Forty-three patients were included, among whom 41 received VRC for curative indication. Thirty-six patients had a genetic score ≥ 2, among whom 11 had an initial insufficient VRC Cmin. A genetic score ≥ 2 had a positive predictive value of 0.31 for having an initial insufficient VRC Cmin and initial VRC Cmin was not associated with the genetic score. The lack of association between the genetic score and VRC Cmin may be related to the inflammatory status of the patients (C reactive protein (CRP) levels: median [Q1-Q3]: 43.0 [11.0-110.0] mg/L), as multivariate analysis performed on all VRC Cmin identified CRP as an independent determinant of the VRC Cmin adjusted for dose (p < 0.0001).
CONCLUSION: The combined genetic score did not predict low VRC exposure in patients with inflammation, which is frequent in patients with invasive fungal infections. Strategies for the individualization of VRC dose should integrate the inflammatory status of patients, in addition to pharmacogenetic variants.

PMID: 33217017 [PubMed - as supplied by publisher]

Construction and validation of an immunity-related prognostic signature for breast cancer.

Aging (Albany NY). 2020 Nov 07;12(21):21597-21612

Authors: Zhu T, Zheng J, Hu S, Zhang W, Zhou H, Li X, Liu ZQ

Abstract
Breast cancer is one of the most lethal malignancies among women, and understanding the effects of host immunity on disease progression offers the potential to improve immunotherapies against it. Here, we constructed an immunity-related gene (IRG)-based prognostic signature to stratify breast cancer patients and predict their survival. We identified differentially-expressed genes by analyzing the breast cancer transcriptome data from The Cancer Genome Atlas. Univariate Cox regression revealed 179 survival-correlated IRGs, 12 of which we used to construct an immunity-based prognostic signature that stratified breast cancer patients into high- and low-risk groups. The signature was an independent predictor for survival and was validated in an independent dataset. We also investigated the correlations between our prognostic signature and immune infiltrates and found that signature-derived risk scores correlated negatively with infiltration of B cells, CD4+ T cells, CD8+ T cells, neutrophils and dendritic cells. Our results show that the proposed prognostic signature reflects the tumor immune microenvironment, which makes it a potential indicator for survival that warrants further research to assess its clinical utility.

PMID: 33216733 [PubMed - as supplied by publisher]

Adverse drug event presentation and tracking (ADEPT): semiautomated, high throughput pharmacovigilance using real-world data.

JAMIA Open. 2020 Oct;3(3):413-421

Authors: Geva A, Stedman JP, Manzi SF, Lin C, Savova GK, Avillach P, Mandl KD

Abstract
Objective: To advance use of real-world data (RWD) for pharmacovigilance, we sought to integrate a high-sensitivity natural language processing (NLP) pipeline for detecting potential adverse drug events (ADEs) with easily interpretable output for high-efficiency human review and adjudication of true ADEs.
Materials and methods: The adverse drug event presentation and tracking (ADEPT) system employs an open source NLP pipeline to identify in clinical notes mentions of medications and signs and symptoms potentially indicative of ADEs. ADEPT presents the output to human reviewers by highlighting these drug-event pairs within the context of the clinical note. To measure incidence of seizures associated with sildenafil, we applied ADEPT to 149 029 notes for 982 patients with pediatric pulmonary hypertension.
Results: Of 416 patients identified as taking sildenafil, NLP found 72 [17%, 95% confidence interval (CI) 14-21] with seizures as a potential ADE. Upon human review and adjudication, only 4 (0.96%, 95% CI 0.37-2.4) patients with seizures were determined to have true ADEs. Reviewers using ADEPT required a median of 89 s (interquartile range 57-142 s) per patient to review potential ADEs.
Discussion: ADEPT combines high throughput NLP to increase sensitivity of ADE detection and human review, to increase specificity by differentiating true ADEs from signs and symptoms related to comorbidities, effects of other medications, or other confounders.
Conclusion: ADEPT is a promising tool for creating gold standard, patient-level labels for advancing NLP-based pharmacovigilance. ADEPT is a potentially time savings platform for computer-assisted pharmacovigilance based on RWD.

PMID: 33215076 [PubMed]

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Diabetes Affects the A1 Adenosine Receptor-Dependent Action of Diadenosine Tetraphosphate (Ap4A) on Cortical and Medullary Renal Blood Flow.

J Vasc Res. 2020 Nov 18;:1-11

Authors: Kreft E, Sałaga-Zaleska K, Sakowicz-Burkiewicz M, Dąbkowski K, Szczepánska-Konkel M, Jankowski M

Abstract
Diabetes through adenosine A1 receptor (A1R) and P2 receptors (P2Rs) may lead to disturbances in renal microvasculature. We investigated the renal microvascular response to Ap4A, an agonist of P2Rs, in streptozotocin-induced diabetic rats. Using laser Doppler flowmetry, renal blood perfusion (RBP) was measured during infusion of Ap4A alone or in the presence of A1R antagonist, either DPCPX (8-cyclopentyl-1,3-dipropylxanthine) or 8-cyclopentyltheophylline (CPT). Ap4A induced a biphasic response in RBP: a phase of rapid decrease was followed by a rapid increase, which was transient in diabetic rats but extended for 30 min in nondiabetic rats. Phase of decreased RBP was not affected by DPCPX or CPT in either group. Early and extended increases in RBP were prevented by DPCPX and CPT in nondiabetic rats, while in diabetic rats, the early increase in RBP was not affected by these antagonists. A1R mRNA and protein levels were increased in isolated glomeruli of diabetic rats, but no changes were detected in P2Y1R and P2Y2R mRNA. Presence of unblocked A1R is a prerequisite for the P2R-mediated relaxing effect of Ap4A in nondiabetic conditions, but influence of A1R on P2R-mediated renal vasorelaxation is abolished under diabetic conditions.

PMID: 33207336 [PubMed - as supplied by publisher]

The Impact of Mass Spectrometry on Patients' Medical and Nonmedical Lives.

Lab Med. 2020 Nov 18;:

Authors: Wu AHB

Abstract
OBJECTIVE: The various forms of mass spectrometry (MS) instrumentation have had a major impact on testing for analytes performed with clinical and forensic laboratories over the past decade. Improvements in MS instrumentation have led to the use of MS in many areas.
METHODS: To highlight the value of MS testing, short reports are presented that are relevant to the following fields: pain management, transplant medicine, clinical toxicology, designer drug testing, genetic metabolic disorders, nutrition, dietary exposure to heavy metals, herbals and supplements, forensic pathology, pharmacogenomics, homeland security, performance enhancing drugs and peptides, clinical microbiology, physician licensing, and environmental exposures. These reports are based on real patients. The "stories" have been altered to comply with privacy regulations.
RESULTS: Analysis of MS provides objective results that have an impact on many areas of medicine and society as a whole. Accurate analysis has an impact on guidance for medical practices.
CONCLUSION: The value of MS testing will continue to grow in the years to come.

PMID: 33206177 [PubMed - as supplied by publisher]

COVID-19: unanswered questions and work for a better knowledge.

Minerva Med. 2020 Nov 18;:

Authors: Cusato J

PMID: 33205643 [PubMed - as supplied by publisher]

Pharmacogenomics of genetic polymorphism within the genes responsible for SARS-CoV-2 susceptibility and the drug-metabolising genes used in treatment.

Rev Med Virol. 2020 Nov 17;:e2194

Authors: Al-Eitan LN, Alahmad SZ

Abstract
The ongoing outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) represents a significant challenge to international health. Pharmacogenomics aims to identify the different genetic variations that exist between individuals and populations in order to determine appropriate treatment protocols to enhance the efficacy of drugs and reduce their side-effects. This literature review provides an overview of recent studies of genetic polymorphisms in genes that mediate the SARS-CoV-2 infection mechanism (ACE1, ACE2, TMPRSS2 and CD26). In addition, genetic variations in the drug-metabolising enzyme genes of several selected drugs used in the treatment of COVID-19 are summarised. This may help construct an effective health protocol based on genetic biomarkers to optimise response to treatment. Potentially, pharmacogenomics could contribute to the development of effective high-throughput assays to improve patient evaluation, but their use will also create ethical, medical, regulatory, and legal issues, which should now be considered in the era of personalised medicine.

PMID: 33205496 [PubMed - as supplied by publisher]

CYP450 polymorphisms and clinical pharmacogenetics of ibuprofen after lower third molar extraction.

Eur J Clin Pharmacol. 2020 Nov 17;:

Authors: Weckwerth GM, Dionísio TJ, Costa YM, Colombini-Ishiquiriama BL, Oliveira GM, Torres EA, Bonjardim LR, Calvo AM, Moore T, Absher DM, Santos CF

Abstract
PURPOSE: This study hypothesized that drugs accumulate in the bloodstream of poor-metabolizing patients and may have more adverse effects and different pain perceptions and aimed to investigate the influence of CYP450 polymorphisms on acute postoperative pain, swelling, and trismus controlled by ibuprofen (600 mg) in 200 volunteers after dental extraction. In addition, surgical outcomes can determine pain, edema, and trismus and indicate inflammatory reactions after oral surgeries.
METHODS: Genetic sequencing was performed to identify CYP450 polymorphisms and the surgical parameters evaluated: pre and postoperative swelling, trismus, and temperature; self-reported postoperative pain with visual analog scale (VAS); rescue medication consumed; and severity of adverse reactions.
RESULTS: A multiple linear regression model with independent variables [single nucleotide polymorphisms (SNPs), BMI (body mass index), duration, and difficulty of surgery] and dependent variables [postoperative pain by sum of pain intensity difference (SPID), trismus, and swelling] was used for analysis. The duration of surgery was a predictor for pain at 8 h and 96 h after surgery, and BMI was a predictor for both swelling and trismus on the 2nd postoperative day. When evaluating CYP2C8 and C9 genotyped SNPs, it was observed that normal metabolizers showed higher pain levels than the intermediate/poor metabolizers on the postoperative periods as compared with time 0 h. In another analysis, the poor metabolizers for CYP2C8 and C9 presented lower levels of postoperative pain after 8 h and used rescue medication earlier than normal metabolizers.
CONCLUSION: Ibuprofen 600 mg was very effective in controlling inflammatory pain after lower third molar surgeries, without relevant adverse reactions; although in a very subtle way, patients with poor metabolism had higher levels of pain in the first hours, and no longer after 8 h, and used pain relief medication earlier.
TRIAL REGISTRATION: The study was registered with ClinicalTrials.gov ID (NCT03169127), on March 16th, 2017.

PMID: 33205280 [PubMed - as supplied by publisher]

Molecular Profiling Reveals a Common Metabolic Signature of Tissue Fibrosis.

Cell Rep Med. 2020 Jul 21;1(4):100056

Authors: Zhang J, Muise ES, Han S, Kutchukian PS, Costet P, Zhu Y, Kan Y, Zhou H, Shah V, Huang Y, Saigal A, Akiyama TE, Shen XL, Cai TQ, Shah K, Carballo-Jane E, Zycband E, Yi L, Tian Y, Chen Y, Imbriglio J, Smith E, Devito K, Conway J, Ma LJ, Hoek M, Sebhat IK, Peier AM, Talukdar S, McLaren DG, Previs SF, Jensen KK, Pinto S

Abstract
Fibrosis, or the accumulation of extracellular matrix, is a common feature of many chronic diseases. To interrogate core molecular pathways underlying fibrosis, we cross-examine human primary cells from various tissues treated with TGF-β, as well as kidney and liver fibrosis models. Transcriptome analyses reveal that genes involved in fatty acid oxidation are significantly perturbed. Furthermore, mitochondrial dysfunction and acylcarnitine accumulation are found in fibrotic tissues. Substantial downregulation of the PGC1α gene is evident in both in vitro and in vivo fibrosis models, suggesting a common node of metabolic signature for tissue fibrosis. In order to identify suppressors of fibrosis, we carry out a compound library phenotypic screen and identify AMPK and PPAR as highly enriched targets. We further show that pharmacological treatment of MK-8722 (AMPK activator) and MK-4074 (ACC inhibitor) reduce fibrosis in vivo. Altogether, our work demonstrate that metabolic defect is integral to TGF-β signaling and fibrosis.

PMID: 33205063 [PubMed]

Dual deficiency of DPD and UGT1A1 in a case of colon cancer.

Pharmacogenomics. 2020 Nov 18;:

Authors: Rawlley B, Diab O, Al-Rajabi R, Carroll E, Melancon T, Kasi A

PMID: 33203301 [PubMed - as supplied by publisher]

Effect of CYP2D6 genetic polymorphism on peak propafenone concentration: no significant effect of CYP2D6*10.

Pharmacogenomics. 2020 Nov 18;:

Authors: Doki K, Shirayama Y, Sekiguchi Y, Aonuma K, Kohda Y, Ieda M, Homma M

Abstract
Aim: The study aims to investigate the clinical implication of nonfunctional poor metabolizer (PM) alleles and intermediate metabolizer (IM) alleles of CYP2D6, including the CYP2D6*10 allele which shows substrate-dependent decrease in enzymatic activity, in antiarrhythmic therapy using propafenone. Materials & methods: We examined serum propafenone concentrations and metabolic ratio, which was expressed as serum concentrations of propafenone to 5-hydroxypropafenone, in 66 Japanese patients with tachyarrhythmias. Results: The peak propafenone concentration and metabolic ratio in CYP2D6 PM allele carriers were higher than those in extensive metabolizer (EM)/EM, EM/IM and IM/IM genotype groups. Conclusion: Results suggest that CYP2D6 PM alleles affect peak propafenone concentration, but the CYP2D6 IM allele CYP2D6*10 has no clinical implication in propafenone dosing.

PMID: 33203295 [PubMed - as supplied by publisher]

Cancer-Associated Angiogenesis: The Endothelial Cell as a Checkpoint for Immunological Patrolling.

Cancers (Basel). 2020 Nov 15;12(11):

Authors: Solimando AG, Summa S, Vacca A, Ribatti D

Abstract
Cancer-associated neo vessels' formation acts as a gatekeeper that orchestrates the entrance and egress of patrolling immune cells within the tumor milieu. This is achieved, in part, via the directed chemokines' expression and cell adhesion molecules on the endothelial cell surface that attract and retain circulating leukocytes. The crosstalk between adaptive immune cells and the cancer endothelium is thus essential for tumor immune surveillance and the success of immune-based therapies that harness immune cells to kill tumor cells. This review will focus on the biology of the endothelium and will explore the vascular-specific molecular mediators that control the recruitment, retention, and trafficking of immune cells that are essential for effective antitumor immunity. The literature revision will also explore how abnormalities in the tumor endothelium impair crosstalk with adaptive immune cells and how targeting these abnormalities can improve the success of immune-based therapies for different malignancies, with a particular focus on the paradigmatic example represented by multiple myeloma. We also generated and provide two original bio-informatic analyses, in order to sketch the physiopathology underlying the endothelial-neoplastic interactions in an easier manner, feeding into a vicious cycle propagating disease progression and highlighting novel pathways that might be exploited therapeutically.

PMID: 33203154 [PubMed]

Histological Evaluation and Gene Expression Profiling of Autophagy-Related Genes for Cartilage of Young and Senescent Rats.

Int J Mol Sci. 2020 Nov 15;21(22):

Authors: Arias C, Saavedra N, Leal K, Vásquez B, Abdalla DSP, Salazar LA

Abstract
Autophagy is a cellular mechanism that protects cells from stress by digesting non-functional cellular components. In the cartilage, chondrocytes depend on autophagy as a principal mechanism to maintain cellular homeostasis. This protective role diminishes prior to the structural damage that normally occurs during aging. Considering that aging is the main risk factor for osteoarthritis, evaluating the expression of genes associated with autophagy in senescent cartilage might allow for the identification of potential therapeutic targets for treatment. Thus, we studied two groups of young and senescent rats. A histological analysis of cartilage and gene expression quantification for autophagy-related genes were performed. In aged cartilage, morphological changes were observed, such as an increase in cartilage degeneration as measured by the modified Mankin score, a decrease in the number of chondrocytes and collagen II (Col2a1), and an increase in matrix metalloproteinase 13 (Mmp13). Moreover, 84 genes associated with autophagy were evaluated by a PCR array analysis, and 15 of them were found to be significantly decreased with aging. Furthermore, an in silico analysis based on by two different bioinformatics software tools revealed that several processes including cellular homeostasis, autophagosome assembly, and aging-as well as several biological pathways such as autophagy, insulin-like growth factor 1 (IGF-1) signaling, PI3K (phosphoinositide 3-kinase)/AKT (serine/threonine kinase) signaling, and mammalian target of rapamycin (mTOR) signaling-were enriched. In conclusion, the analysis identified some potential targets for osteoarthritis treatment that would allow for the development of new therapeutic strategies for this chronic disease.

PMID: 33203108 [PubMed - in process]