ESMO Open. 2022 May 18;7(3):100459. doi: 10.1016/j.esmoop.2022.100459. Online ahead of print.

ABSTRACT

Constitutional BRCA1/BRCA2 pathogenic or likely pathogenic variants (PVs) are associated with an increased risk for developing breast and ovarian cancers. Current evidence indicates that BRCA1/2 PVs are also associated with pancreatic cancer, and that BRCA2 PVs are associated with prostate cancer risk. The identification of carriers of constitutional PVs in the BRCA1/2 genes allows the implementation of individual and family prevention pathways, through validated screening programs and risk-reducing strategies. According to the relevant and increasing therapeutic predictive implications, the inclusion of BRCA testing in the routine management of patients with breast, ovarian, pancreatic and prostate cancers represent a key requirement to optimize medical or surgical therapeutic and prevention decision-making, and access to specific anticancer therapies. Therefore, accurate patient selection, the use of standardized and harmonized procedures, and adherence to homogeneous testing criteria, are essential elements to implement BRCA testing in clinical practice. This consensus position paper has been developed and approved by a multidisciplinary Expert Panel of 64 professionals on behalf of the AIOM-AIRO-AISP-ANISC-AURO-Fondazione AIOM-SIAPEC/IAP-SIBioC-SICO-SIF-SIGE-SIGU-SIU-SIURO-UROP Italian Scientific Societies, and a patient association (aBRCAdaBRA Onlus). The working group included medical, surgical and radiation oncologists, medical and molecular geneticists, clinical molecular biologists, surgical and molecular pathologists, organ specialists such as gynecologists, gastroenterologists and urologists, and pharmacologists. The manuscript is based on the expert consensus and reports the best available evidence, according to the current eligibility criteria for BRCA testing and counseling, it also harmonizes with current Italian National Guidelines and Clinical Recommendations.

PMID:35597177 | DOI:10.1016/j.esmoop.2022.100459

Gastroenterol Clin North Am. 2022 Jun;51(2):299-317. doi: 10.1016/j.gtc.2021.12.007. Epub 2022 Apr 27.

ABSTRACT

Reactive therapeutic drug monitoring (TDM) is considered the standard of care for optimizing biologics in inflammatory bowel disease (IBD) including Crohn's disease (CD). Preliminary data show that proactive TDM is associated with positive outcomes in IBD and can be also used to efficiently guide therapeutic decisions in specific clinical scenarios. Higher biological drug concentrations are associated with favorable therapeutic outcomes in specific IBD populations or phenotypes including pediatric CD, perianal fistulizing CD, small bowel CD, and following an ileocolonic resection for CD. Future perspectives of TDM include the use of rapid testing, pharmacogenomics, and pharmacokinetic dashboards toward individualized therapy.

PMID:35595416 | DOI:10.1016/j.gtc.2021.12.007

Neurologia (Engl Ed). 2022 May;37(4):287-303. doi: 10.1016/j.nrleng.2018.03.022. Epub 2020 Jun 1.

ABSTRACT

INTRODUCTION: Alzheimer disease (AD) is the most common cause of dementia and is considered one of the main causes of disability and dependence affecting quality of life in elderly people and their families. Current pharmacological treatment includes acetylcholinesterase inhibitors (donepezil, galantamine, rivastigmine) and memantine; however, only one-third of patients respond to treatment. Genetic factors have been shown to play a role in this inter-individual variability in drug response.

DEVELOPMENT: We review pharmacogenetic reports of AD-modifying drugs, the pharmacogenetic biomarkers included, and the phenotypes evaluated. We also discuss relevant methodological considerations for the design of pharmacogenetic studies into AD. A total of 33 pharmacogenetic reports were found; the majority of these focused on the variability in response to and metabolism of donepezil. Most of the patients included were from Caucasian populations, although some studies also include Korean, Indian, and Brazilian patients. CYP2D6 and APOE are the most frequently studied biomarkers. The associations proposed are controversial.

CONCLUSIONS: Potential pharmacogenetic biomarkers for AD have been identified; however, it is still necessary to conduct further research into other populations and to identify new biomarkers. This information could assist in predicting patient response to these drugs and contribute to better treatment decision-making in a context as complex as ageing.

PMID:35595404 | DOI:10.1016/j.nrleng.2018.03.022

Zhonghua Liu Xing Bing Xue Za Zhi. 2022 May 10;43(5):747-754. doi: 10.3760/cma.j.cn112338-20210402-00276.

ABSTRACT

Pharmacogenetic studies are designed to investigate the associations between genetic variation and treatment response for a particular drug in terms of both efficacy and adverse events and have high sample size requirements. To improve the quality of pharmacogenetic studies and facilitate the Meta-analyses to investigate statistically significant associations, Strengthening the Reporting of Pharmacogenetic Studies (STROPS) guideline was developed in 2020 based on the Strengthening the Reporting of Genetic Association Studies (STREGA) statement. The objective of this article is to present a brief introduction to the STROPS guideline and an interpretation of the key points in some items with examples for the better understanding and application.

PMID:35589583 | DOI:10.3760/cma.j.cn112338-20210402-00276

Pharmacogenomics J. 2022 May 19. doi: 10.1038/s41397-022-00280-w. Online ahead of print.

ABSTRACT

Beyond the identification of causal genetic variants in the diagnosis of Mendelian disorders, exome sequencing can detect numerous variants with potential relevance for clinical care. Clinical interventions can thus be conducted to improve future health outcomes for patients and their at-risk relatives, such as predicting late-onset genetic disorders accessible to prevention, treatment or identifying differential drug efficacy and safety. To evaluate the interest of such pharmacogenetic information, we designed an "in house" pipeline to determine the status of 122 PharmGKB (Pharmacogenomics Knowledgebase) variant-drug combinations in 31 genes. This pipeline was applied to a cohort of 90 epileptic patients who had previously an exome sequencing (ES) analysis, to determine the frequency of pharmacogenetic variants. We performed a retrospective analysis of drug plasma concentrations and treatment efficacy in patients bearing at least one relevant PharmGKB variant. For PharmGKB level 1A variants, CYP2C9 status for phenytoin prescription was the only relevant information. Nineteen patients were treated with phenytoin, among phenytoin-treated patients, none were poor metabolizers and four were intermediate metabolizers. While being treated with a standard protocol (10-23 mg/kg/30 min loading dose followed by 5 mg/kg/8 h maintenance dose), all identified intermediate metabolizers had toxic plasma concentrations (20 mg/L). In epileptic patients, pangenomic sequencing can provide information about common pharmacogenetic variants likely to be useful to guide therapeutic drug monitoring, and in the case of phenytoin, to prevent clinical toxicity caused by high plasma levels.

PMID:35590072 | DOI:10.1038/s41397-022-00280-w

Pharmgenomics Pers Med. 2022 May 9;15:465-475. doi: 10.2147/PGPM.S354011. eCollection 2022.

ABSTRACT

PURPOSE: Pharmacogenetic (PGx) panel testing could help to determine the heritable component of a rheumatoid arthritis (RA) patient's susceptibility for therapy failure and/or adverse drug reactions (ADRs) from methotrexate (MTX). Considering the literature mentioning the potential applicability of PGx panel testing within MTX regimens, we discuss the case of a patient who was treated with MTX, suffered from ADRs, and obtained a reactive PGx panel testing.

GENOTYPING: We used a commercial PGx panel test involving the ABC-transporters P-glycoprotein (P-gp; gene: ABCB1), and breast cancer resistance protein (BCRP; gene: ABCG2), the solute carriers reduced folate carrier 1 (RFC1; gene: SLC19A1), and organic anion transporting polypeptide 1B1 (OATP1B1; gene: SLCO1B1), and the enzymes inosine triphosphatase (ITPA), and glutathione transferase P1 (GSTP1). In addition, we genotyped the patient for the enzymes 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase (AICAR)/inosine monophosphate (IMP) cyclohydrolase (gene name: ATIC), gamma-glutamyl hydrolase (gene name: GGH) and methylenetetrahydrofolate reductase (gene name: MTHFR).

RESULTS: The PGx profile of the patient revealed genetic variants in SLC19A1, ABCB1, and MTHFR, which may explain the ADRs experienced during the treatment with MTX and a potentially lower efficacy of MTX. Based on our interpretation of the PGx profile, we recommended the patient to avoid MTX in the future.

CONCLUSION: The MTX pathway is complex, which makes the interpretation of genetic variants affecting metabolism challenging. A reactive PGx panel test was applicable to explain ADRs experienced during MTX treatment for a patient with RA. However, the clinical utility of PGx-guided MTX treatment in a primary care setting is still limited. In order to base a recommendation for MTX on PGx data, we need genome-wide association studies, large prospective multicenter studies and PGx studies, which analyze different multi-gene haplotypes and gene-drug-drug interactions for MTX.

PMID:35586477 | PMC:PMC9109898 | DOI:10.2147/PGPM.S354011

BMC Bioinformatics. 2022 May 18;23(1):188. doi: 10.1186/s12859-022-04693-z.

ABSTRACT

BACKGROUND: Identifying associations among biological variables is a major challenge in modern quantitative biological research, particularly given the systemic and statistical noise endemic to biological systems. Drug sensitivity data has proven to be a particularly challenging field for identifying associations to inform patient treatment.

RESULTS: To address this, we introduce two semi-parametric variations on the commonly used concordance index: the robust concordance index and the kernelized concordance index (rCI, kCI), which incorporate measurements about the noise distribution from the data. We demonstrate that common statistical tests applied to the concordance index and its variations fail to control for false positives, and introduce efficient implementations to compute p-values using adaptive permutation testing. We then evaluate the statistical power of these coefficients under simulation and compare with Pearson and Spearman correlation coefficients. Finally, we evaluate the various statistics in matching drugs across pharmacogenomic datasets.

CONCLUSIONS: We observe that the rCI and kCI are better powered than the concordance index in simulation and show some improvement on real data. Surprisingly, we observe that the Pearson correlation was the most robust to measurement noise among the different metrics.

PMID:35585485 | DOI:10.1186/s12859-022-04693-z

Antimicrob Agents Chemother. 2022 May 18:e0013622. doi: 10.1128/aac.00136-22. Online ahead of print.

ABSTRACT

Ritonavir-boosted darunavir (DRV/r) and dolutegravir (DTG) are affected by induction of metabolizing enzymes and efflux transporters caused by rifampicin (RIF). This complicates the treatment of people living with HIV (PLWH) diagnosed with tuberculosis. Recent data showed that doubling DRV/r dose did not compensate for this effect, and hepatic safety was unsatisfactory. We aimed to evaluate the pharmacokinetics of DRV, ritonavir (RTV), and DTG in the presence and absence of RIF in peripheral blood mononuclear cells (PBMCs). PLWH were enrolled in a dose-escalation crossover study with 6 treatment periods of 7 days. Participants started with DRV/r 800/100 mg once daily (QD), RIF and DTG were added before the RTV dose was doubled, and then they received DRV/r 800/100 twice daily (BD) and then 1,600/200 QD or vice versa. Finally, RIF was withdrawn. Plasma and intra-PBMC drug concentrations were measured through validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods. Seventeen participants were enrolled but only 4 completed all study phases due to high incidence of liver toxicity. Intra-PBMC DRV trough serum concentration (Ctrough) after the addition of RIF dropped from a median (interquartile range [IQR]) starting value of 261 ng/mL (158 to 577) to 112 ng/mL (18 to 820) and 31 ng/mL (12 to 331) for 800/100 BD and 1,600/200 QD DRV/r doses, respectively. The DRV intra-PBMC/plasma ratio increased significantly (P = 0.003). DTG and RIF intra-PBMC concentrations were in accordance with previous reports in the absence of RIF or DRV/r. This study showed a differential impact of enzyme and/or transporter induction on DRV/r concentrations in plasma and PBMCs, highlighting the usefulness of studying intra-PBMC pharmacokinetics with drug-drug interactions. (This study has been registered at ClinicalTrials.gov under registration no. NCT03892161.).

PMID:35583344 | DOI:10.1128/aac.00136-22

Ment Health Clin. 2022 Apr 14;12(2):77-85. doi: 10.9740/mhc.2022.04.077. eCollection 2022 Apr.

ABSTRACT

Psychiatric pharmacy continues to grow and look to the future with a focus on helping individuals recover from mental health and substance use disorders. The American Association of Psychiatric Pharmacists (AAPP) considers Board Certified Psychiatric Pharmacist (BCPP) the gold standard credential that all psychiatric pharmacists should attain to demonstrate specialized knowledge and expertise in psychiatry. BCPPs are part of collaborative interprofessional teams and practice in hospitals, clinics, and diverse health systems. Two out of 3 BCPPs practicing in clinics have prescriptive authority. BCPPs improve access, safety, medication adherence, and therapeutic outcomes. Every person with a mental health and substance use disorder should have access to a BCPP providing comprehensive medication management (CMM) and psychotropic stewardship aimed at improving population health. BCPPs are in demand owing to their expertise. AAPP envisions growth and expansion of the BCPP role in many areas including coordinating psychiatric transitions of care and telehealth services, managing long-acting injectable medication clinics, providing pharmacogenomic consultation, conducting clozapine and lithium monitoring, managing medications for substance use disorders, leading medication groups, CNS drug development, research, and provider education. To prepare the workforce, colleges and schools of pharmacy should hire BCPPs for optimal curriculum development, and each student pharmacist should have an opportunity to develop a therapeutic alliance with a person recovering from psychiatric illness. Postgraduate year (PGY) 1 residencies should offer learning experiences in psychiatric pharmacy to prepare residents to enter an expanded number of PGY2 psychiatric pharmacy residencies, ultimately earning their BCPP and being well positioned to improve mental health care.

PMID:35582321 | PMC:PMC9009818 | DOI:10.9740/mhc.2022.04.077

BMC Psychiatry. 2022 May 17;22(1):342. doi: 10.1186/s12888-022-03983-3.

ABSTRACT

STUDY OBJECTIVES: Insomnia disorders as well as cardiometabolic disorders are highly prevalent in the psychiatric population compared to the general population. We aimed to investigate their association and evolution over time in a Swiss psychiatric cohort.

METHODS: Data for 2861 patients (8954 observations) were obtained from two prospective cohorts (PsyMetab and PsyClin) with metabolic parameters monitored routinely during psychotropic treatment. Insomnia disorders were based on the presence of ICD-10 "F51.0" diagnosis (non-organic insomnia), the prescription of sedatives before bedtime or the discharge letter. Metabolic syndrome was defined using the International Diabetes Federation definition, while the 10-year risk of cardiovascular event or death was assessed using the Framingham Risk Score and the Systematic Coronary Risk Estimation, respectively.

RESULTS: Insomnia disorders were observed in 30% of the cohort, who were older, predominantly female, used more psychotropic drugs carrying risk of high weight gain (olanzapine, clozapine, valproate) and were more prone to suffer from schizoaffective or bipolar disorders. Multivariate analyses showed that patients with high body mass index (OR = 2.02, 95%CI [1.51-2.72] for each ten-kg/m2 increase), central obesity (OR = 2.20, [1.63-2.96]), hypertension (OR = 1.86, [1.23-2.81]), hyperglycemia (OR = 3.70, [2.16-6.33]), high density lipoprotein hypocholesterolemia in women (OR = 1.51, [1.17-1.95]), metabolic syndrome (OR = 1.84, [1.16-2.92]) and higher 10-year risk of death from cardiovascular diseases (OR = 1.34, [1.17-1.53]) were more likely to have insomnia disorders. Time and insomnia disorders were associated with a deterioration of cardiometabolic parameters.

CONCLUSIONS: Insomnia disorders are significantly associated with metabolic worsening and risk of death from cardiovascular diseases in psychiatric patients.

PMID:35581641 | DOI:10.1186/s12888-022-03983-3

BMC Bioinformatics. 2022 May 17;23(1):184. doi: 10.1186/s12859-022-04720-z.

ABSTRACT

BACKGROUND: The mechanism of action for most cancer drugs is not clear. Large-scale pharmacogenomic cancer cell line datasets offer a rich resource to obtain this knowledge. Here, we present an analysis strategy for revealing biological pathways that contribute to drug response using publicly available pharmacogenomic cancer cell line datasets.

METHODS: We present a custom machine-learning based approach for identifying biological pathways involved in cancer drug response. We test the utility of our approach with a pan-cancer analysis of ML210, an inhibitor of GPX4, and a melanoma-focused analysis of inhibitors of BRAFV600. We apply our approach to reveal determinants of drug resistance to microtubule inhibitors.

RESULTS: Our method implicated lipid metabolism and Rac1/cytoskeleton signaling in the context of ML210 and BRAF inhibitor response, respectively. These findings are consistent with current knowledge of how these drugs work. For microtubule inhibitors, our approach implicated Notch and Akt signaling as pathways that associated with response.

CONCLUSIONS: Our results demonstrate the utility of combining informed feature selection and machine learning algorithms in understanding cancer drug response.

PMID:35581546 | DOI:10.1186/s12859-022-04720-z

Healthc Inform Res. 2022 Apr;28(2):176-180. doi: 10.4258/hir.2022.28.2.176. Epub 2022 Apr 30.

NO ABSTRACT

PMID:35576986 | DOI:10.4258/hir.2022.28.2.176

Cardiovasc Res. 2022 May 16:cvac085. doi: 10.1093/cvr/cvac085. Online ahead of print.

ABSTRACT

AIMS: The adenylate cyclase type 9 (ADCY9) gene appears to determine atherosclerotic outcomes in patients treated with dalcetrapib. In mice, we recently demonstrated that Adcy9 inactivation potentiates endothelial function and inhibits atherogenesis. The objective of this study was to characterize the contribution of ADCY9 to the regulation of endothelial signaling pathways involved in atherosclerosis.

METHODS AND RESULTS: We show that ADCY9 is expressed in the endothelium of mouse aorta and femoral arteries. We demonstrate that ADCY9 inactivation in cultured endothelial cells paradoxically increases cAMP accumulation in response to the adenylate cyclase activators forskolin and vasoactive intestinal peptide (VIP). Reciprocally, ADCY9 overexpression decreases cAMP production. Using mouse femoral artery arteriography, we show that Adcy9 inactivation potentiates VIP-induced endothelial-dependent vasodilation. Moreover, Adcy9 inactivation reduces mouse atheroma endothelial permeability in different vascular beds. ADCY9 overexpression reduces forskolin-induced phosphorylation of Ser157-vasodilator-stimulated phosphoprotein (VASP) and worsens thrombin-induced fall of RAP1 activity, both leading to increased endothelial permeability. ADCY9 inactivation in thrombin-stimulated human coronary artery endothelial cells results in cAMP accumulation, increases p-Ser157-VASP and inhibits endothelial permeability. MLC2 phosphorylation and actin stress fiber increases in response to thrombin were reduced by ADCY9 inactivation, suggesting actin cystoskeleton regulation. Finally, using the Miles assay, we demonstrate that Adcy9 regulates thrombin-induced endothelial permeability in vivo in normal and atherosclerotic animals.

CONCLUSION: Adcy9 is expressed in endothelial cells and regulates local cAMP and endothelial functions including permeability relevant to atherogenesis.

PMID:35576489 | DOI:10.1093/cvr/cvac085

Cardiovasc Res. 2022 May 16:cvac079. doi: 10.1093/cvr/cvac079. Online ahead of print.

ABSTRACT

AIMS: Gene expression biosignatures may hold promise to individualize antiplatelet therapy in conjunction with current guidelines and risk scores. The Aspirin Response Signature (ARS) score is comprised of a weighted sum of correlated, prothrombotic gene transcripts measured in whole blood. In prior work where volunteers were exposed to aspirin 325 mg daily, higher ARS score was associated with lower platelet function; separately, in a clinical cohort of patients, higher ARS scores were associated with increased risk of adverse cardiovascular events. To better understand this apparent paradox, we measured ARS gene expression and score in volunteers to determine aspirin dose-response and ticagrelor relationships with ARS score and separately in patients to assess whether ARS is associated with incident bleeding.

METHODS AND RESULTS: Blood samples were collected from volunteers (N = 188) who were exposed to 4 weeks of daily aspirin 81 mg, daily aspirin 325 mg, and/or twice-daily ticagrelor 90 mg. ARS scores were calculated from whole blood RNA qPCR, and platelet function and protein expression were assessed in platelet-rich plasma. In mixed linear regression models, aspirin 81 mg exposure was not associated with changes in ARS gene expression or score. Aspirin 325 mg exposure resulted in a 6.0% increase in ARS gene expression (p = 7.5 × 10-9 vs. baseline, p = 2.1 × 10-4 vs. aspirin 81 mg) and an increase in expression of platelet proteins corresponding to ARS genes. Ticagrelor exposure resulted in a 30.7% increase in ARS gene expression (p < 1 × 10-10 vs. baseline and each aspirin dose) and ARS score (p = 7.0 × 10-7 vs. baseline, p = 3.6 × 10-6 and 5.59 × 10-4 vs. aspirin 81 mg and 325 mg, respectively). Increases in ARS gene expression or score were associated with the magnitude of platelet inhibition across agents. To assess the association between ARS scores and incident bleeding, ARS scores were calculated in patients undergoing cardiac catheterization (N = 1421), of whom 25.4% experienced bleeding events over a median 6.2 years of follow-up. In a Cox model adjusting for demographics and baseline antithrombotic medication use, patients with ARS scores above the median had a higher risk of incident bleeding (HR 1.26 [95% CI 1.01-1.56], p = 0.038).

CONCLUSIONS: The ARS is an Antiplatelet Response Signature which increases in response to greater platelet inhibition due to antiplatelet therapy and may represent a homeostatic mechanism to prevent bleeding. ARS scores could inform future strategies to prevent bleeding while maintaining antiplatelet therapy's benefit of ischemic cardiovascular event protection.

PMID:35576481 | DOI:10.1093/cvr/cvac079

Am J Med Genet B Neuropsychiatr Genet. 2022 May 16. doi: 10.1002/ajmg.b.32893. Online ahead of print.

ABSTRACT

The presented article is relevant, as the main goals of schizophrenia treatment are to achieve a response to psychopharmacotherapy, reduction and stabilization of psychopathological symptoms, qualitative remission, which in general implies the creation of a stable quality of life for the patient. The purpose of the study was to evaluate the population features of the frequency distribution of alleles and genotypes of polymorphic genetic variants of according to genome-wide association studies analysis of pharmacokinetics-associated antipsychotic medications, in an ethnically homogeneous Kazakh population. The research material was deoxyribonucleic acid (DNA) isolated from the peripheral blood of 1,800 conditionally healthy persons of Kazakh nationality. DNA isolation was carried out by the magnetic polyvinyl alcohol magnetic particle separation method. The analysis of the frequency distribution of the studied genotypes in the Kazakh population showed their compliance with the Hardy-Weinberg equilibrium for all studied polymorphisms (p > .05). The obtained results showed that CYP2C19 (rs4244285, rs4986893) polymorphisms occurs in Kazakhs significantly more often than European and a number of Asian populations, which significantly affects the decrease in effectiveness and increases the risk of side complications during therapy with antipsychotic medications in the Kazakh population.

PMID:35574727 | DOI:10.1002/ajmg.b.32893

Expert Opin Drug Saf. 2022 May 16. doi: 10.1080/14740338.2022.2078303. Online ahead of print.

ABSTRACT

BACKGROUND: The use of hydroxychloroquine (HCQ) in the first COVID-19 epidemic wave raised concerns about its safety.

RESEARCH DESIGN AND METHODS: All the adverse reactions (ADR) suspected to be induced by HCQ and submitted to the Spanish Pharmacovigilance Database were studied. A disproportionality analysis was performed to determine adverse effects reported with non-Covid and Covid patients. To explore potential drug-drug interactions, Omega (Ω) statistics was calculated.

RESULTS: More severe cases were reported when used in COVID-19. Main differences in frequency were observed in hepatobiliary, skin, gastrointestinal, eye, nervous system and heart ADRs. During the COVID-19 pandemic, high disproportionality in reports was found for Torsade de Pointes/QT prolongation with a ROR (-ROR) of 132.8 (76.7); severe hepatotoxicity, 18.7 (14.7); dyslipidaemias, 12.1 (6.1); shock, 9.5 (6.9) and ischaemic colitis, 8.9 (2.6). Myopathies, haemolytic disorders and suicidal behaviour increased their disproportionality during the pandemic. Disproportionality was observed for neoplasms, haematopoietic cytopaenias and interstitial lung disease in the pre-COVID-19 period. Potential interactions were showed between HCQ and azithromycin, ceftriaxone, lopinavir and tocilizumab.

CONCLUSIONS: The way in which HCQ has been used during the Covid-19 pandemic has resulted in a change in the profile of spontaneous reporting HCQ-related ADR in Spain. Of particular concern during the pandemic were arrhythmias, hepatotoxicity, severe skin reactions and suicide risk, but not ocular disorders. Some of the new ADRs identified will require more detailed analyses.

PMID:35574687 | DOI:10.1080/14740338.2022.2078303

Front Mol Biosci. 2022 Apr 29;9:844721. doi: 10.3389/fmolb.2022.844721. eCollection 2022.

ABSTRACT

Background: Cytotoxic CD8+ T-cell exhaustion is the major barrier for immunotherapy in tumors. Recent studies have reported that the basic leucine zipper activating transcription factor-like transcription factor (BATF) is responsible for countering cytotoxic CD8+ T-cell exhaustion. Nevertheless, the expression and roles of BATF in tumors have been poorly explored. Methods: In the present study, we conducted a multi-omics analysis, including gene expression, methylation status, DNA alterations, pharmacogenomics, and survival status based on data from the Cancer Genome Atlas (TCGA) database to discern expression patterns and prognostic roles of BATF in tumors. We also explored potential roles of BATF in a pan-cancer cohort by performing immune infiltration, Gene Ontology (GO) enrichment, and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. In vitro assay was also performed to explore roles of BATF in tumor cells. Results: We found that BATF was aberrantly upregulated in 27 types of tumors with respect to the corresponding normal tissues. Abnormal BATF expression in tumors predicted survival times of patients in a tissue-dependent manner. The results of GO, immune infiltration, and KEGG analysis revealed that increased BATF expression in tumors participated in modulating immune cell infiltration via immune-related pathways. BATF expression could also predict immunotherapeutic and chemotherapy responses in cancers. Moreover, knockdown of BATF suppresses tumor cell viability. Conclusion: Our present study reports the vital roles of BATF in tumors and provides a theoretical basis for targeting BATF therapy.

PMID:35573731 | PMC:PMC9098817 | DOI:10.3389/fmolb.2022.844721

Front Aging Neurosci. 2022 Apr 27;14:749991. doi: 10.3389/fnagi.2022.749991. eCollection 2022.

ABSTRACT

Alzheimer's Disease (AD) is a complex neurodegenerative disease that gravely affects patients and imposes an immense burden on caregivers. Apolipoprotein E4 (APOE4) has been identified as the most common genetic risk factor for AD, yet the molecular mechanisms connecting APOE4 to AD are not well understood. Past transcriptomic analyses in AD have revealed APOE genotype-specific transcriptomic differences; however, these differences have not been explored at a single-cell level. To elucidate more complex APOE genotype-specific disease-relevant changes masked by the bulk analysis, we leverage the first two single-nucleus RNA sequencing AD datasets from human brain samples, including nearly 55,000 cells from the prefrontal and entorhinal cortices. In each brain region, we performed a case versus control APOE genotype-stratified differential gene expression analysis and pathway network enrichment in astrocytes, microglia, neurons, oligodendrocytes, and oligodendrocyte progenitor cells. We observed more global transcriptomic changes in APOE4 positive AD cells and identified differences across APOE genotypes primarily in glial cell types. Our findings highlight the differential transcriptomic perturbations of APOE isoforms at a single-cell level in AD pathogenesis and have implications for precision medicine development in the diagnosis and treatment of AD.

PMID:35572130 | PMC:PMC9093608 | DOI:10.3389/fnagi.2022.749991

Clin Transl Sci. 2022 May 15. doi: 10.1111/cts.13295. Online ahead of print.

ABSTRACT

Relapsed or resistant lupus nephritis (LN) is considered a difficult-to-treat type of LN, and enteric-coated mycophenolate sodium (EC-MPS) has been used in this condition. Therapeutic drug monitoring using the area under the plasma mycophenolic acid concentration from 0 to 12 h postdose (MPA-AUC0-12h ) ≥45 μg.h/ml is a useful approach to achieve the highest efficiency. This study assessed EC-MPS's pharmacokinetic (PK) and pharmacodynamic (PD) profiles and investigated an optimal level of the single time point of plasma MPA concentration. Nineteen biopsy-proven patients with class III/IV LN received 1440 mg/day of EC-MPS for 24 weeks. PK (maximum plasma MPA concentration [Cmax ], time to Cmax , and MPA-AUC0-12h ) and PD (activity of inosine-5'-monophosphate dehydrogenase [IMPDH]) parameters were measured at weeks 2, 8, 16, and 24. We found that IMPDH activity decreased from baseline by 31-42% within 2-4 h after dosing, coinciding with the increased plasma MPA concentration. MPA-AUC0-12h ≥45 μg.h/ml was best predicted by a single time point MPA concentration at C0.5, C2, C3, C4, and C8 (r2 = 0.516, 0.514, 0.540, 0.611, and 0.719, respectively), independent of dose, albumin, urine protein/creatinine ratio, and urinalysis. The MPA-C0.5 cutoff of 2.03 g/ml yielded the highest overall sensitivity of 85% and specificity of 88.2% in predicting MPA-AUC0-12h ≥45 μg.h/ml. A single timepoint of plasma MPA-C0.5 ≥2.03 μg/ml may help guide EC-MPS adjustment to achieve adequate drug exposure. Further study of EC-MPS used to validate this cutoff is warranted.

PMID:35570339 | DOI:10.1111/cts.13295

Clin Transl Sci. 2022 May 15. doi: 10.1111/cts.13305. Online ahead of print.

ABSTRACT

Pharmacokinetics is the cornerstone of understanding drug absorption, distribution, metabolism, and elimination. It is also the key to describing variability in drug response caused by drug-drug interactions, pharmacogenetics, impaired kidney- and liver function, etc. This tutorial aims to provide a guideline and step-by-step tutorial on essential considerations when designing clinical pharmacokinetic studies and reporting results. This includes a comprehensive guide on how to conduct the statistical analysis and a complete code for the statistical software R. As an example, we created a mock dataset simulating a clinical pharmacokinetic drug-drug interaction study with 12 subjects who were administered 2 mg oral midazolam with and without an inducer of cytochrome P450 3A (CYP3A). We provide a step-by-step guide to the statistical analysis of this clinical pharmacokinetic study, including sample size/power calculation, descriptive statistics, non-compartmental analyses, and hypothesis testing. The different analyses and parameters are described in detail, and we provide a complete R code ready to use in supplementary files. Finally, we discuss important considerations when designing and reporting clinical pharmacokinetic studies. The scope of this tutorial is not limited to drug-drug interaction studies, and with minor adjustments, it applies to all types of clinical pharmacokinetic studies. This work was done by early-career researchers, for early-career researchers. We hope this tutorial may help early-career researchers when getting started on their own pharmacokinetic studies. We encourage you to use this as an inspiration and starting point and continuously evolve your statistical skills.

PMID:35570335 | DOI:10.1111/cts.13305