Front Mol Biosci. 2023 Aug 4;10:1215204. doi: 10.3389/fmolb.2023.1215204. eCollection 2023.

ABSTRACT

Breast cancer is the second leading cause of cancer death in women among all cancer types. It is highly heterogeneous in nature, which means that the tumors have different morphologies and there is heterogeneity even among people who have the same type of tumor. Several staging and classifying systems have been developed due to the variability of different types of breast cancer. Due to high heterogeneity, personalized treatment has become a new strategy. Out of all breast cancer subtypes, triple-negative breast cancer (TNBC) comprises ∼10%-15%. TNBC refers to the subtype of breast cancer where cells do not express estrogen receptors, progesterone receptors, or human epidermal growth factor receptors (ERs, PRs, and HERs). Tumors in TNBC have a diverse set of genetic markers and prognostic indicators. We scanned the Cancer Cell Line Encyclopedia (CCLE) and Genomics of Drug Sensitivity in Cancer (GDSC) databases for potential drugs using human breast cancer cell lines and drug sensitivity data. Three different machine-learning approaches were used to evaluate the prediction of six effective drugs against the TNBC cell lines. The top biomarkers were then shortlisted on the basis of their involvement in breast cancer and further subjected to testing for radion resistance using data from the Cleveland database. It was observed that Panobinostat, PLX4720, Lapatinib, Nilotinib, Selumetinib, and Tanespimycin were six effective drugs against the TNBC cell lines. We could identify potential derivates that may be used against approved drugs. Only one biomarker (SETD7) was sensitive to all six drugs on the shortlist, while two others (SRARP and YIPF5) were sensitive to both radiation and drugs. Furthermore, we did not find any radioresistance markers for the TNBC. The proposed biomarkers and drug sensitivity analysis will provide potential candidates for future clinical investigation.

PMID:37602329 | PMC:PMC10436744 | DOI:10.3389/fmolb.2023.1215204

Cureus. 2023 Jul 19;15(7):e42169. doi: 10.7759/cureus.42169. eCollection 2023 Jul.

ABSTRACT

Background Clopidogrel hyporesponsiveness with decreased antiplatelet activity is prevalent in percutaneous coronary intervention (PCI) patients due to reduced function polymorphism in the CYP2C19 enzyme gene which results in poor conversion of this prodrug to an active metabolite. However, pharmacogenetic testing is not part of routine clinical practice in India. Methodology In this retrospective observational study, we observed the prevalence of loss of function (LOF) gene variants of CYP2C19 (*2, *3) in 60 patients undergoing PCI with complex anatomies in a tertiary healthcare hospital in North India. We do not have follow-up data for a few patients. However, the treatment regimen was recorded, and the occurrence of any clinical event was monitored for the remaining 52 patients for six months. Results The mean age of the patients was 61.76 ± 10.14 years. We found that 52% of patients carried these LOF mutations, of which 37% were intermediate metabolizers, while 15% were poor metabolizers of clopidogrel. However, out of 52 patients for whom follow-up data were available, 22 (42.3%) were intermediate metabolizers, while six (11.54%) showed genotypes associated with poor metabolism of clopidogrel. Clopidogrel (75 mg BD) was the primary replacement drug in place of ticagrelor (90 mg BD) during follow-up after four weeks (based on the clinician's discretion). Conclusions No major ischemic event was reported during the follow-up of these 52 patients. The intermediate metabolizers' LOF in one copy of the CYP2C19 gene seems to overcome genetic deficiency with the clopidogrel 75 mg BD regime, which is comparable to maintenance with ticagrelor 90 mg BD. This study can be extrapolated to a larger cohort to observe statistically significant differences among various groups.

PMID:37602077 | PMC:PMC10439363 | DOI:10.7759/cureus.42169

Front Genet. 2023 Aug 2;14:1261876. doi: 10.3389/fgene.2023.1261876. eCollection 2023.

NO ABSTRACT

PMID:37600661 | PMC:PMC10436194 | DOI:10.3389/fgene.2023.1261876

JPGN Rep. 2023 Jul 17;4(3):e338. doi: 10.1097/PG9.0000000000000338. eCollection 2023 Aug.

NO ABSTRACT

PMID:37600608 | PMC:PMC10435021 | DOI:10.1097/PG9.0000000000000338

J Chemother. 2023 Aug 20:1-11. doi: 10.1080/1120009X.2023.2247208. Online ahead of print.

ABSTRACT

Voriconazole (VRC) displays highly variable pharmacokinetics impacting treatment efficacy and safety. To provide evidence for optimizing VRC therapy regimens, the authors set out to determine the factors impacting VRC steady-state trough concentration (Cmin) in patients with various albumin (Alb) level. A total of 275 blood samples of 120 patients and their clinical characteristics and genotypes of CYP2C19, CYP3A4, CYP3A5, CYP2C9, FMO3, ABCB1, POR, NR1I2 and NR1I3 were included in this study. Results of multivariate linear regression analysis demonstrated that C-reactive protein (CRP) and total bilirubin (T-Bil) were predictors of the VRC Cmin adjusted for dose in patients with hypoalbuminemia (Alb < 35 g/L) (R2 = 0.16, P < 0.001). Additionally, in patients with normal albumin level (Alb ≥ 35 g/L), it resulted in a significant model containing factors of the poor metabolizer (PM) CYP2C19 genotype and CRP level (R2 = 0.26, P < 0.001). Therefore, CRP and T-Bil levels ought to receive greater consideration than genetic factors in patients with hypoalbuminemia.

PMID:37599449 | DOI:10.1080/1120009X.2023.2247208

Expert Opin Drug Metab Toxicol. 2023 Aug 20. doi: 10.1080/17425255.2023.2249404. Online ahead of print.

ABSTRACT

INTRODUCTION: Parkinson's disease is a chronic neurodegenerative multisystemic disorder that affects approximately 2% of the population over 65 years old. This disorder is characterized by motor symptoms which are frequently accompanied by non-motor symptoms such as cognitive disorders. Current drug therapies aim to reduce the symptoms and increase the patient's life expectancy. Nevertheless, there is heterogeneity in therapy response in terms of efficacy and adverse effects. This wide range in response may be linked to genetic variability in the human genome. Thus, pharmacogenomics may help to tailor and personalize drug therapy for Parkinson's disease.

AREAS COVERED: This review describes and updates the clinical impact of genetic factors associated with the efficacy and adverse drug reactions related to common medications used to treat Parkinson's disease. Additionally, we highlight current informative recommendations for the drug treatment of Parkinson's disease.

EXPERT OPINION: The pharmacokinetic, pharmacodynamic, and safety profiles of Parkinson's disease drugs do not favor the development of pharmacogenetic tests with a high probability of success. The chances of obtaining ground-breaking pharmacogenetics biomarkers for Parkinson's disease therapy are limited. Nevertheless, additional information on the metabolism of certain drugs, and an analysis of the potential of pharmacogenetics in novel drugs could be of interest.

PMID:37599424 | DOI:10.1080/17425255.2023.2249404

Drug Alcohol Depend. 2023 Aug 12;251:110925. doi: 10.1016/j.drugalcdep.2023.110925. Online ahead of print.

ABSTRACT

BACKGROUND: Cannabis produces various acute psychotropic effects, with marked individual differences. Cannabis use is a risk factor for developing psychotic disorders. The main component responsible for these effects is Δ9-tetrahydrocannabinol (THC). Here we investigated the neural basis of acute THC effects and its modulation by catechol-methyl-transferase (COMT) Val158Met genotype.

METHODS: Resting state functional MRI data of healthy occasional cannabis users were combined and re-analyzed from three double-blind, placebo-controlled, within-subject pharmacological functional magnetic resonance imaging studies (total N=87). Functional connectivity after placebo and THC was compared in three functional networks (salience, executive and default mode network) and a network implicated in psychosis (the hippocampus-midbrain-striatum network). COMT genotype modulation of subjective effects and connectivity was examined.

RESULTS: THC reduced connectivity in the salience network, specifically from the right insula to both the left insula and anterior cingulate cortex. We found a trend towards decreased connectivity in the hippocampus-midbrain-striatum network after THC. COMT genotype modulated subjective effects of THC, with strongest dysphoric reactions in Met/Met individuals. In addition, reduced connectivity after THC was demonstrated in the hippocampus-midbrain-striatum network of Met/Met individuals only.

CONCLUSIONS: In this large multisite study we found that THC robustly decreases connectivity in the salience network, involved in processing awareness and salient information. Connectivity changes in the hippocampus-midbrain-striatum network may reflect the acute psychotic-like effects of THC. COMT genotype modulation of THC's impact on subjective effects and functional connectivity provides further evidence for involvement of prefrontal dopamine levels in the acute effects of cannabis.

PMID:37598453 | DOI:10.1016/j.drugalcdep.2023.110925

Farm Hosp. 2023 Aug 17:S1130-6343(23)00095-8. doi: 10.1016/j.farma.2023.07.004. Online ahead of print.

ABSTRACT

Pharmacy service is to provide individualized pharmaceutical care for patients, which should follow the current evidence-based pharmacy, and constantly verify the evidence and then produce new evidence. In pharmaceutical care, differences are often found in the efficacy and adverse reactions of drugs among individuals, even within individuals, which are closely related to patients' genetics, liver and kidney functions, disease states, and drug interactions. Back in the 1980s, therapeutic drug monitoring (TDM) has been applied to routinely monitor the blood drug concentration of patients taking antiepileptic drugs or immunosuppressants after transplantation to provide individualized dosage recommendations and accumulate a large amount of pharmacokinetic (PK)/pharmacodynamic (PD) data. As individualized pharmaceutical care proceeds, the concept of precision medicine was introduced into pharmacy services in combination with evidence-based pharmacy, PK/PD theories, and big data to further promote the TDM technology and drugs, and carry out pharmacogenomics analysis. The TDM and pharmacogenomics have been applied gradually to the fields of antimicrobial, antitumor, and antipsychotic drugs and immunosuppressants. Based on the concept of precision pharmacy, we adopted approaches including PK/PD, quantitative pharmacology, population pharmacokinetics, and big data machine learning to provide more personalized pharmacy services, which is mainly for special patients, such as critical patients, patients with interaction risk of multiple drugs, patients with liver and renal insufficiency, pregnant women, children, and elderly patients. As the service pattern of precision pharmacy has been constructed and constantly improved, better evidence in clinical practice will be produced to provide patients with better precision pharmacy service.

PMID:37598018 | DOI:10.1016/j.farma.2023.07.004

Expert Rev Clin Immunol. 2023 Aug 18. doi: 10.1080/1744666X.2023.2249237. Online ahead of print.

ABSTRACT

INTRODUCTION: Janus kinase inhibitors (JAKi) have dramatically improved the treatment of various autoimmune, and myeloproliferative disorders. Recently concern has arisen regarding their safety in patients with rheumatoid arthritis.

AREAS COVERED: Here we provide a comprehensive summary of the major current and emerging JAKi and their indications, address recent studies on comparative safety, and provide insight into their future and use. We emphasize that the application of the research findings on a case-by-case basis should consider a patient's age, comorbidities, disease for which JAKi is being considered, disease activity, the JAKi target(s), alternate treatment options available for the patient, and the planned duration of JAKi.

EXPERT OPINION: Rheumatologists are used to prescribing therapies in which a risk to benefit assessment is required as well as with screening and monitoring for safety of medications. Thus, rheumatologists are already practiced in applying specific criteria to effectively screen and monitor patients who are candidates for JAKi therapy. Ongoing research will help to clarify any mechanisms underlying differential safety signals between JAK and other therapies, what the balance between risk and efficacy is, who the susceptible subpopulations are, and whether safety signals are shared between different JAKis and across indications.

PMID:37596779 | DOI:10.1080/1744666X.2023.2249237

Pharmacoeconomics. 2023 Aug 19. doi: 10.1007/s40273-023-01309-z. Online ahead of print.

ABSTRACT

OBJECTIVE: To assess the cost-effectiveness of pharmacogenomics (PGx)-based warfarin (i.e., warfarin dosing following genetic testing), apixaban, and rivaroxaban oral anticoagulation versus standard warfarin for the treatment of newly diagnosed patients with nonvalvular atrial fibrillation (AF) aged ≥ 65 years.

METHODS: We developed a Markov decision-analytic model to compare costs [2017 Canadian dollars (C$)] and quality-adjusted life years (QALYs) from the Ontario health care payer perspective over a life-time horizon. The parameters used in the model were derived from the published literature, the Ontario health care administrative database, and expert opinion. To account for the uncertainty of model parameters, we conducted extensive deterministic and probabilistic sensitivity analyses. The results were summarized using incremental cost-effectiveness ratios (ICERs) and cost-effectiveness acceptability curves.

RESULTS: We found that PGx-based warfarin had an ICER of C$17,584/QALY compared with standard warfarin, and apixaban had an ICER of C$64,590/QALY compared with PGx-based warfarin in our base-case analysis. Rivaroxaban was extendedly dominated by PGx-based warfarin and apixaban. The probabilistic sensitivity analysis showed that apixaban, rivaroxaban, PGx-based warfarin, and standard warfarin were cost-effective at some willingness-to-pay (WTP) thresholds. PGx-based warfarin had a higher probability of being cost-effective than apixaban (51.3% versus 14.3%) at a WTP threshold of C$50,000/QALY. At a WTP threshold of C$100,000/QALY, apixaban had a higher probability of being cost-effective than PGx-based warfarin (54.6% versus 22.6%).

CONCLUSION: We found that PGx-based warfarin for patients with AF is cost-effective at a WTP threshold of C$50,000/QALY. Apixaban had a higher probability of being cost-effective (> 50%) at a WTP threshold of C$93,000/QALY.

PMID:37596504 | DOI:10.1007/s40273-023-01309-z

Cancer Epidemiol. 2023 Aug 16:102432. doi: 10.1016/j.canep.2023.102432. Online ahead of print.

ABSTRACT

INTRODUCTION: Several studies have linked increased risk of osteosarcoma with tall stature, high birthweight, and early puberty, although evidence is inconsistent. We used genetic risk scores (GRS) based on established genetic loci for these traits and evaluated associations between genetically inferred birthweight, height, and puberty timing with osteosarcoma.

METHODS: Using genotype data from two genome-wide association studies, totaling 1039 cases and 2923 controls of European ancestry, association analyses were conducted using logistic regression for each study and meta-analyzed to estimate pooled odds ratios (ORs) and 95% confidence intervals (CIs). Subgroup analyses were conducted by case diagnosis age, metastasis status, tumor location, tumor histology, and presence of a known pathogenic variant in a cancer susceptibility gene.

RESULTS: Genetically inferred higher birthweight was associated with an increased risk of osteosarcoma (OR =1.59, 95% CI 1.07-2.38, P = 0.02). This association was strongest in cases without metastatic disease (OR =2.46, 95% CI 1.44-4.19, P = 9.5 ×10-04). Although there was no overall association between osteosarcoma and genetically inferred taller stature (OR=1.06, 95% CI 0.96-1.17, P = 0.28), the GRS for taller stature was associated with an increased risk of osteosarcoma in 154 cases with a known pathogenic cancer susceptibility gene variant (OR=1.29, 95% CI 1.03-1.63, P = 0.03). There were no significant associations between the GRS for puberty timing and osteosarcoma.

CONCLUSION: A genetic propensity to higher birthweight was associated with increased osteosarcoma risk, suggesting that shared genetic factors or biological pathways that affect birthweight may contribute to osteosarcoma pathogenesis.

PMID:37596165 | DOI:10.1016/j.canep.2023.102432

Maturitas. 2023 Aug 16;176:107797. doi: 10.1016/j.maturitas.2023.107797. Online ahead of print.

ABSTRACT

OBJECTIVE: The severity of menopause-related symptoms varies considerably among women. The determinants of this variation are incompletely understood. The aim of this study was to assess the association between genetic variation in estrogen metabolism and transport pathways and the severity of menopause symptoms.

METHODS: This was a cross-sectional study of 60 peri- and postmenopausal women in the Mayo Clinic RIGHT study (which involved sequencing of genes involved in drug metabolism and transport), who had also been evaluated in the Women's Health Clinic at Mayo Clinic in Rochester, MN. All participants completed the Menopause Rating Scale (MRS) for assessment of menopause symptoms, including hot flashes. The association between severity of menopause symptoms and the variation in genes encoding 8 enzymes and transporters involved in estrogen metabolism was evaluated.

RESULTS: Lower CYP3A4 activity and higher COMT activity were associated with lower severity of somatic menopause symptoms (p = 0.04 and 0.06, respectively). These associations did not persist after adjustment for hormone therapy use. No differences in MRS scores or hot flash severity were noted among other genetic variant groups. Age at natural menopause was not affected by variations in the genes studied.

CONCLUSION: The current study did not show an association between genetic variation in estrogen metabolism and transport pathways and the severity of menopause symptoms. Further studies with larger sample sizes may be required to understand this potentially complex association.

PMID:37595497 | DOI:10.1016/j.maturitas.2023.107797

Int J Pharm Compd. 2023 Jul-Aug;27(4):284-293.

ABSTRACT

People infected by severe acute respiratory coronavirus 2 (SARS-CoV-2) risk the development of not only acute coronavirus- disease-2019 (COVID-19) - the signs and symptoms of which range from none to severe illness that requires intensive treatment - but also long COVID (i.e., chronic COVID), a cyclical, progressive, multiphasic illness characterized by myriad debilitating conditions that persist long term. In some patients, those sequelae result in psychiatric disorders that can lead to suicide or other forms of self-harm, incidences of which have increased exponentially since before the COVID pandemic. It has been suggested that long COVID develops in an estimated 10% to 35% of people diagnosed as having COVID-19. Because the success of therapy for either form of COVID can be complicated by each patient's pharmacogenomic profile, personal treatment preferences, medical needs, and/or dosing requirements, we have found that in some people so afflicted, manufactured medications are ineffective or intolerable, and that for those individuals, a customized compound often provides relief and promotes recovery. The primary focus of this article is long COVID. The pathogenesis of that disease is reviewed, therapies for the signs and symptoms it engenders are examined, and 2 compounded formulations effective in treating both acute and chronic COVID-19 are presented.

PMID:37595172

Clin Orthop Relat Res. 2023 Aug 18. doi: 10.1097/CORR.0000000000002797. Online ahead of print.

NO ABSTRACT

PMID:37594407 | DOI:10.1097/CORR.0000000000002797

Clin Orthop Relat Res. 2023 Aug 18. doi: 10.1097/CORR.0000000000002767. Online ahead of print.

ABSTRACT

BACKGROUND: Pharmacogenomics is an emerging and affordable tool that may improve postoperative pain control. One challenge to successful pain control is the large interindividual variability among analgesics in their efficacy and adverse drug events. Whether preoperative pharmacogenomic testing is worthwhile for patients undergoing TKA is unclear.

QUESTIONS/PURPOSES: (1) Are the results of preoperative pharmacogenetic testing associated with lower postoperative pain scores as measured by the Overall Benefit of Analgesic Score (OBAS)? (2) Do the results of preoperative pharmacogenomic testing lead to less total opioids given? (3) Do the results of preoperative pharmacogenomic testing lead to changes in opioid prescribing patterns?

METHODS: Participants of this randomized trial were enrolled from September 2018 through December 2021 if they were aged 18 to 80 years and were undergoing primary TKA under general anesthesia. Patients were excluded if they had chronic kidney disease, a history of chronic pain or narcotic use before surgery, or if they were undergoing robotic surgery. Preoperatively, patients completed pharmacogenomic testing (RightMed, OneOME) and a questionnaire and were randomly assigned to the experimental group or control group. Of 99 patients screened, 23 were excluded, one before randomization; 11 allocated patients in each group did not receive their allocated interventions for reasons such as surgery canceled, patients ultimately undergoing spinal anesthesia, and change in surgery plan. Another four patients in each group were excluded from the analysis because they were missing an OBAS report. This left 30 patients for analysis in the control group and 38 patients in the experimental group. The control and experimental groups were similar in age, gender, and race. Pharmacogenomic test results for patients in the experimental group were reviewed before surgery by a pharmacist, who recommended perioperative medications to the clinical team. A pharmacist also assessed for clinically relevant drug-gene interactions and recommended drug and dose selection according to guidelines from the Clinical Pharmacogenomics Implementation Consortium for each patient enrolled in the study. Patients were unaware of their pharmacogenomic results. Pharmacogenomic test results for patients in the control group were not reviewed before surgery; instead, standard perioperative medications were administered in adherence to our institutional care pathways. The OBAS (maximum 28 points) was the primary outcome measure, recorded 24 hours postoperatively. A two-sample t-test was used to compare the mean OBAS between groups. Secondary measures were the mean 24-hour pain score, total morphine milligram equivalent, and frequency of opioid use. Postoperatively, patients were assessed for pain with a VAS (range 0 to 10). Opioid use was recorded preoperatively, intraoperatively, in the postanesthesia care unit, and 24 hours after discharge from the postanesthesia care unit. Changes in perioperative opioid use based on pharmacogenomic testing were recorded, as were changes in prescription patterns for postoperative pain control. Preoperative characteristics were also compared between patients with and without various phenotypes ascertained from pharmacogenomic test results.

RESULTS: The mean OBAS did not differ between groups (mean ± SD 4.7 ± 3.7 in the control group versus 4.2 ± 2.8 in the experimental group, mean difference 0.5 [95% CI -1.1 to 2.1]; p = 0.55). Total opioids given did not differ between groups or at any single perioperative timepoint (preoperative, intraoperative, or postoperative). We found no difference in opioid prescribing pattern. After adjusting for multiple comparisons, no difference was observed between the treatment and control groups in tramadol use (41% versus 71%, proportion difference 0.29 [95% CI 0.05 to 0.53]; nominal p = 0.02; adjusted p > 0.99).

CONCLUSION: Routine use of pharmacogenomic testing for patients undergoing TKA did not lead to better pain control or decreased opioid consumption. Future studies might focus on at-risk populations, such as patients with chronic pain or those undergoing complex, painful surgical procedures, to test whether pharmacogenomic results might be beneficial in certain circumstances.

LEVEL OF EVIDENCE: Level I, therapeutic study.

PMID:37594401 | DOI:10.1097/CORR.0000000000002767

Eur Respir J. 2023 Aug 17:2300441. doi: 10.1183/13993003.00441-2023. Online ahead of print.

ABSTRACT

Studies suggest a harmful pharmacogenomic interaction exists between short leukocyte telomere length (LTL) and immunosuppressants in idiopathic pulmonary fibrosis (IPF). It remains unknown if a similar interaction exists in non-IPF interstitial lung disease (ILD).A retrospective, multi-centre cohort analysis was performed in fibrotic hypersensitivity pneumonitis, unclassifiable ILD, and connective tissue disease ILD patients from five centres. LTL was measured by qPCR for discovery and replication cohorts and expressed as age-adjusted percentiles of normal. Inverse probability of treatment weights based on propensity scores were used to assess the association between mycophenolate or azathioprine exposure and age-adjusted LTL on two-year transplant-free survival using weighted Cox proportional hazards regression incorporating time-dependent immunosuppressant exposure.The discovery and replication cohorts included 613 and 325 patients, respectively. In total, 40% of patients were exposed to immunosuppression and 22% had LTL <10th percentile of normal. Fibrotic hypersensitivity pneumonitis and unclassifiable ILD patients with LTL <10th percentile experienced reduced survival when exposed to either mycophenolate or azathioprine in the discovery cohort (mortality HR 4.97, 95% CI 2.26-10.92, p<0.001) and replication cohort (mortality HR 4.90, 95% CI 1.74-13.77, p=0.003). Immunosuppressant exposure was not associated with differential survival in patients with LTL ≥10th percentile. There was a significant interaction between LTL <10th percentile and immunosuppressant exposure (Discovery p-interaction=0.013; Replication p-interaction=0.011). Low event rate and prevalence of LTL <10th percentile precluded subgroup analyses for connective tissue disease ILD.Similar to IPF, fibrotic hypersensitivity pneumonitis and unclassifiable ILD patients with age-adjusted LTL <10th percentile may experience reduced survival when exposed to immunosuppression.

PMID:37591536 | DOI:10.1183/13993003.00441-2023

Curr Biol. 2023 Aug 10:S0960-9822(23)00970-3. doi: 10.1016/j.cub.2023.07.031. Online ahead of print.

ABSTRACT

Balancing the competing demands of phagolysosomal degradation and autophagy is a significant challenge for phagocytic tissues. Yet how this plasticity is accomplished in health and disease is poorly understood. In the retina, circadian phagocytosis and degradation of photoreceptor outer segments by the postmitotic retinal pigment epithelium (RPE) are essential for healthy vision. Disrupted autophagy due to mechanistic target of rapamycin (mTOR) overactivation in the RPE is associated with blinding macular degenerations; however, outer segment degradation is unaffected in these diseases, indicating that distinct mechanisms regulate these clearance mechanisms. Here, using advanced imaging and mouse models, we identify optineurin as a key regulator that tunes phagocytosis and lysosomal capacity to meet circadian demands and helps prioritize outer segment clearance by the RPE in macular degenerations. High-resolution live-cell imaging implicates optineurin in scissioning outer segment tips prior to engulfment, analogous to microglial trogocytosis of neuronal processes. Optineurin is essential for recruiting light chain 3 (LC3), which anchors outer segment phagosomes to microtubules and facilitates phagosome maturation and fusion with lysosomes. This dynamically activates transcription factor EB (TFEB) to induce lysosome biogenesis in an mTOR-independent, transient receptor potential-mucolipin 1 (TRPML1)-dependent manner. RNA-seq analyses show that expression of TFEB target genes temporally tracks with optineurin recruitment and that lysosomal and autophagy genes are controlled by distinct transcriptional programs in the RPE. The unconventional plasma membrane-to-nucleus signaling mediated by optineurin ensures outer segment degradation under conditions of impaired autophagy in macular degeneration models. Independent regulation of these critical clearance mechanisms would help safeguard the metabolic fitness of the RPE throughout the organismal lifespan.

PMID:37586372 | DOI:10.1016/j.cub.2023.07.031

Pharmacogenomics J. 2023 Aug 16. doi: 10.1038/s41397-023-00314-x. Online ahead of print.

ABSTRACT

The pharmacological management of musculoskeletal pain starts with NSAIDs, followed by weak or strong opioids until the pain is under control. However, the treatment outcome is usually unsatisfying due to inter-individual differences. To investigate the genetic component of treatment outcome differences, we performed a genome-wide association study (GWAS) in ~23,000 participants with musculoskeletal pain from the UK Biobank. NSAID vs. opioid users were compared as a reflection of the treatment outcome of NSAIDs. We identified one genome-wide significant hit in chromosome 4 (rs549224715, P = 3.88 × 10-8). Suggestive significant (P < 1 × 10-6) loci were functionally annotated to 18 target genes, including four genes linked to neuropathic pain processes or musculoskeletal development. Pathway and network analyses identified immunity-related processes and a (putative) central role of EGFR. However, this study should be viewed as a first step to elucidate the genetic background of musculoskeletal pain treatment.

PMID:37587271 | DOI:10.1038/s41397-023-00314-x

Res Social Adm Pharm. 2023 Jul 31:S1551-7411(23)00342-X. doi: 10.1016/j.sapharm.2023.07.012. Online ahead of print.

ABSTRACT

BACKGROUND: The field of pharmacogenomics is rapidly advancing, but its adoption and implementation remain slow and lacking. Lack of pharmacogenomics knowledge among healthcare professionals is the most frequently cited barrier to adopting and implementing pharmacogenomics in clinical settings.

OBJECTIVES: This study aimed to critically evaluate and determine the effectiveness of educational interventions in improving pharmacogenomics knowledge and practice.

METHODS: Four electronic databases were searched: MEDLINE, EMBASE, CENTRAL, and PsycINFO. Studies on pharmacogenomics educational interventions for health care professionals and students with pre- and post-intervention assessments and results were included. No restrictions were placed on time, language, or educational contexts. The educational outcomes measured include both objective and subjective outcomes. The pharmacogenomics competency domains used to judge educational interventions are based on the competency domains listed by the American Association of Colleges of Pharmacies (AACP). The National Heart, Lung, and Blood Institute of the National Institutes of Health was used for the quality assessment of pre-post studies with no control group and the controlled intervention studies. No meta-analysis was conducted; the data were synthesized qualitatively. The systematic review was reported in accordance with the PRISMA statement.

RESULTS: Fifty studies were included in this review. All included studies integrated the AACP pharmacogenomics competency domains into their educational interventions. Most of the studies had educational interventions that integrated clinical cases (n = 44; 88%). Knowledge was the most frequently evaluated outcome (n = 34; 68%) and demonstrated significant improvement after the educational intervention that integrated AACP pharmacogenomics competency domains and employed active learning with clinical case inclusion.

CONCLUSION: This review provided evidence of the effectiveness of educational interventions in improving pharmacogenomics knowledge and practice. Incorporating pharmacogenomics competency domains into education and training, with patient cases for healthcare professionals and students, dramatically improved their pharmacogenomics knowledge, attitudes, and confidence in practice.

PMID:37586945 | DOI:10.1016/j.sapharm.2023.07.012

Annu Rev Pharmacol Toxicol. 2023 Aug 16. doi: 10.1146/annurev-pharmtox-032023-121106. Online ahead of print.

ABSTRACT

Pharmacogenomics (PGx) enables personalized treatment for the prediction of drug response and to avoid adverse drug reactions. Currently, PGx mainly relies on the genetic information of absorption, distribution, metabolism, and excretion (ADME) targets such as drug-metabolizing enzymes or transporters to predict differences in the patient's phenotype. However, there is evidence that the phenotype-genotype concordance is limited. Thus, we discuss different phenotyping strategies using exogenous xenobiotics (e.g., drug cocktails) or endogenous compounds for phenotype prediction. In particular, minimally invasive approaches focusing on liquid biopsies offer great potential to preemptively determine metabolic and transport capacities. Early studies indicate that ADME phenotyping using exosomes released from the liver is reliable. In addition, pharmacometric modeling and artificial intelligence improve phenotype prediction. However, further prospective studies are needed to demonstrate the clinical utility of individualized treatment based on phenotyping strategies, not only relying on genetics. The present review summarizes current knowledge and limitations. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 64 is January 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

PMID:37585662 | DOI:10.1146/annurev-pharmtox-032023-121106