Crit Rev Clin Lab Sci. 2024 Aug 9:1-44. doi: 10.1080/10408363.2024.2358304. Online ahead of print.

ABSTRACT

The field of pharmacogenetics, the investigation of the influence of one or more sequence variants on drug response phenotypes, is a special case of pharmacogenomics, a discipline that takes a genome-wide approach. Massively parallel, next generation sequencing (NGS), has allowed pharmacogenetics to be subsumed by pharmacogenomics with respect to the identification of variants associated with responders and non-responders, optimal drug response, and adverse drug reactions. A plethora of rare and common naturally-occurring GPCR variants must be considered in the context of signals from across the genome. Many fundamentals of pharmacogenetics were established for G protein-coupled receptor (GPCR) genes because they are primary targets for a large number of therapeutic drugs. Functional studies, demonstrating likely-pathogenic and pathogenic GPCR variants, have been integral to establishing models used for in silico analysis. Variants in GPCR genes include both coding and non-coding single nucleotide variants and insertion or deletions (indels) that affect cell surface expression (trafficking, dimerization, and desensitization/downregulation), ligand binding and G protein coupling, and variants that result in alternate splicing encoding isoforms/variable expression. As the breadth of data on the GPCR genome increases, we may expect an increase in the use of drug labels that note variants that significantly impact the clinical use of GPCR-targeting agents. We discuss the implications of GPCR pharmacogenomic data derived from the genomes available from individuals who have been well-phenotyped for receptor structure and function and receptor-ligand interactions, and the potential benefits to patients of optimized drug selection. Examples discussed include the renin-angiotensin system in SARS-CoV-2 (COVID-19) infection, the probable role of chemokine receptors in the cytokine storm, and potential protease activating receptor (PAR) interventions. Resources dedicated to GPCRs, including publicly available computational tools, are also discussed.

PMID:39119983 | DOI:10.1080/10408363.2024.2358304

Postep Psychiatr Neurol. 2024 Jun;33(2):67-79. doi: 10.5114/ppn.2024.141056. Epub 2024 Jul 24.

ABSTRACT

PURPOSE: Stroke is the second leading cause of death worldwide with an annual mortality rate of 6.55 million, which accounts for 11.6% of the total number of deaths. Early diagnosis is crucial for improving treatment outcomes. Lean management is an approach originating in the car manufacturing process derived from the Toyota Production System, which healthcare providers have recently adapted. The objective is to examine the use of lean practices in managing AIS in hospital settings.

METHODS: A systematic literature search was performed using MEDLINE and SCOPUS databases, including publications from 1st January 2000 to 20th September 2022.

RESULTS: A total of 13 studies fulfilled the predefined inclusion criteria. The recombinant tissue plasminogen activator (rtPA) was used in 11 studies, in 2 studies in combination with mechanical thrombectomy (MT). MT alone was used in the other 2 studies. The value stream mapping was used in all included studies to analyze workflow in acute ischemic stroke (AIS) treatment. Outcome measures include mostly door-to-needle (DTN) time for rtPA treatment and door-to-puncture (DTP) time for mechanical thrombectomy. DTN time was assessed in nine studies and reached statistically significant results in five. DTP was examined in three studies; in two, statistically significant decreases in DTP were observed.

CONCLUSIONS: Lean management can be a useful method for achieving key performance indicators in AIS, consistent with current guidelines. The results of this systematic literature review show that value stream mapping may improve the process of AIS treatment by reducing in-hospital delays. The field of research that focuses on implementing lean management tools in healthcare is increasing, with more publications appearing in recent years.

PMID:39119549 | PMC:PMC11304223 | DOI:10.5114/ppn.2024.141056

Biol Cell. 2024 Aug 9:e2400073. doi: 10.1111/boc.202400073. Online ahead of print.

ABSTRACT

BACKGROUND INFORMATION: Arpin, an Arp2/3 inhibitory protein, inhibits lamellipodial protrusions and cell migration. Arpin expression is lost in tumor cells of several cancer types.

RESULTS: Here we analyzed expression levels of Arpin and various markers using Reverse Phase Protein Array (RPPA) in human mammary carcinomas. We found that Arpin protein levels were correlated with those of several DNA damage response markers. Arpin-null cells display enhanced clustering of double stand breaks (DSBs) when cells are treated with a DNA damaging agent, in line with a previously described role of the Arp2/3 complex in promoting DSB clustering for homologous DNA repair (HDR) in the nucleus. Using a specific HDR assay, we further showed that Arpin depletion increased HDR efficiency two-fold through its ability to inactivate the Arp2/3 complex.

CONCLUSIONS: Arpin regulates both cell migration in the cytosol and HDR in the nucleus.

SIGNIFICANCE: Loss of Arpin expression coordinates enhanced cell migration with up-regulated DNA repair, which is required when DNA damage is induced by active cell migration.

PMID:39118570 | DOI:10.1111/boc.202400073

Mol Genet Genomic Med. 2024 Aug;12(8):e2501. doi: 10.1002/mgg3.2501.

ABSTRACT

BACKGROUND: Non-photosensitive trichothiodystrophies (TTDs) are a diverse group of genodermatoses within the subset of conditions known as "sulphur-deficient brittle hair" syndromes. A part of them has only recently been identified, revealing novel causative genes and very rare phenotypes of these genetic skin disorders. At the same time, the molecular basis of previously published and unresolved cases has been revealed through the introduction of innovative genetic techniques. We have previously described the facial phenotype of patients with the Photosensitive form of TTD during childhood. This study marks the beginning of an effort to expand the analysis to include individuals of the same age who do not have photosensitivity.

METHODS: A total of 26 facial portraits of TTD paediatric patients with Non-photosensitivity from the literature were analysed using computer-aided technologies, and their facial features were examined through a detailed clinical review.

RESULTS: Distinct facial features were identified in both Photosensitive and Non-photosensitive TTDs.

CONCLUSION: The present study has comprehensively elucidated the facial features in TTDs, encompassing the Non-photosensitive clinical spectrum.

PMID:39118464 | DOI:10.1002/mgg3.2501

Clin Pharmacol Ther. 2024 Aug 8. doi: 10.1002/cpt.3401. Online ahead of print.

NO ABSTRACT

PMID:39115927 | DOI:10.1002/cpt.3401

JAMA Netw Open. 2024 Aug 1;7(8):e2425600. doi: 10.1001/jamanetworkopen.2024.25600.

NO ABSTRACT

PMID:39115850 | DOI:10.1001/jamanetworkopen.2024.25600

JAMA Netw Open. 2024 Aug 1;7(8):e2425593. doi: 10.1001/jamanetworkopen.2024.25593.

ABSTRACT

IMPORTANCE: Precise estimation of a patient's drug metabolism capacity is important for antiseizure dose personalization.

OBJECTIVE: To quantify the differences in plasma concentrations for antiseizure drugs associated with variants of genes encoding drug metabolizing enzymes.

DATA SOURCES: PubMed, Clinicaltrialsregister.eu, ClinicalTrials.gov, International Clinical Trials Registry Platform, and CENTRAL databases were screened for studies from January 1, 1990, to September 30, 2023, without language restrictions.

STUDY SELECTION: Two reviewers performed independent study screening and assessed the following inclusion criteria: appropriate genotyping was performed, genotype-based categorization into subgroups was possible, and each subgroup contained at least 3 participants.

DATA EXTRACTION AND SYNTHESIS: The Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines were followed for data extraction and subsequent quality, validity, and risk-of-bias assessments. The results from the included studies were pooled with random-effect meta-analysis.

MAIN OUTCOMES AND MEASURES: Plasma concentrations of antiseizure drugs were quantified with the dose-normalized area under the concentration-time curve, the dose-normalized steady state concentration, or the concentrations after a single dose at standardized dose and sampling time. The ratio of the means was calculated by dividing the mean drug plasma concentrations of carriers and noncarriers of the pharmacogenetic variant.

RESULTS: Data from 98 studies involving 12 543 adult participants treated with phenytoin, valproate, lamotrigine, or carbamazepine were analyzed. Studies were mainly conducted within East Asian (69 studies) or White or European (15 studies) cohorts. Significant increases of plasma concentrations compared with the reference subgroup were observed for phenytoin, by 46% (95% CI, 33%-61%) in CYP2C9 intermediate metabolizers, 20% (95% CI, 17%-30%) in CYP2C19 intermediate metabolizers, and 39% (95% CI, 24%-56%) in CYP2C19 poor metabolizers; for valproate, by 12% (95% CI, 4%-20%) in CYP2C9 intermediate metabolizers, 12% (95% CI, 2%-24%) in CYP2C19 intermediate metabolizers, and 20% (95% CI, 2%-41%) in CYP2C19 poor metabolizers; and for carbamazepine, by 12% (95% CI, 3%-22%) in CYP3A5 poor metabolizers.

CONCLUSIONS AND RELEVANCE: This systematic review and meta-analysis found that CYP2C9 and CYP2C19 genotypes encoding low enzymatic capacity were associated with a clinically relevant increase in phenytoin plasma concentrations, several pharmacogenetic variants were associated with statistically significant but only marginally clinically relevant changes in valproate and carbamazepine plasma concentrations, and numerous pharmacogenetic variants were not associated with statistically significant differences in plasma concentrations of antiseizure drugs.

PMID:39115847 | DOI:10.1001/jamanetworkopen.2024.25593

Pharmacogenomics. 2024 Aug 8:1-6. doi: 10.1080/14622416.2024.2375188. Online ahead of print.

ABSTRACT

In 2021, the Clinical Pharmacology Department of Hospital Universitario de La Princesa launched the PriME-PGx initiative (Multidisciplinary Initiative of the Hospital Universitario de La Princesa for the Implementation of Pharmacogenetics) to promote the expansion of pharmacogenetics in hospitalized patients. We establish seven pharmacogenetic profiles based on the specific needs of seven departments: Oncology, Pain Unit, Neuropsychiatry, Internal or Infectious Medicine, Cardiology, Gastroenterology and Immunosuppressants. The experience of the last 3 years reflects a total of 1421 reports (37.4% being oncology profiles), with a gradual increase in the number of requests each year. With this project, we aim to expand the availability and utility of pharmacogenetic biomarkers to achieve personalised therapy that avoids adverse drug reactions and therapeutic failure.

PMID:39115196 | DOI:10.1080/14622416.2024.2375188

Front Pharmacol. 2024 Jul 24;15:1463384. doi: 10.3389/fphar.2024.1463384. eCollection 2024.

NO ABSTRACT

PMID:39114360 | PMC:PMC11303329 | DOI:10.3389/fphar.2024.1463384

Pharmacogenomics J. 2024 Aug 7;24(5):24. doi: 10.1038/s41397-024-00346-x.

ABSTRACT

This study utilized Mendelian randomization (MR) analysis and genome-wide association study (GWAS) data to investigate the association between commonly prescribed drugs and bladder cancer (BLCA) risk. Our results revealed that HMG CoA reductase (HMGCR) inhibitors, specifically simvastatin, are significantly associated with reduced BLCA risk. We further showed that simvastatin could significantly inhibit BLCA proliferation and epithelial-mesenchymal transition in animal models, with transcriptomic data identifying several pathways associated with these processes. Higher expression of HMGCR were linked with BLCA development and progression, and certain blood lipids, such as lipoprotein particles and very low density lipoprotein (VLDL) cholesterol, might influence BLCA risk. These findings suggested that HMGCR inhibitors, particularly simvastatin, could be potential treatment options or adjuvant therapies for BLCA.

PMID:39112450 | DOI:10.1038/s41397-024-00346-x

Pharmacogenomics. 2024 Aug 7:1-13. doi: 10.1080/14622416.2024.2382078. Online ahead of print.

ABSTRACT

Aim: To explore general practitioners' (GPs) views on implementing pharmacogenomic testing in Australian general practice. Methods: Semi-structured interviews were conducted with nine GPs in Australia, recruited from primary care networks. Interviews were analyzed using thematic analysis. Themes were mapped onto the Consolidated Framework for Implementation Research domains. Results: Barriers to implementation included lack of knowledge, education, standardized pharmacogenomic reports and national clinical guidelines and financial inaccessibility. Facilitators included positive exposure to pharmacogenomics, peer influences, interdisciplinary collaboration and proven clinical utility. Current uptake was minimal; however, GPs shared positive perceptions of clinical use. Conclusion: Recommendations for successful implementation include building and disseminating clinical evidence, developing national guidelines and standardized reports, incorporation into formal education and increasing financial accessibility.

PMID:39109497 | DOI:10.1080/14622416.2024.2382078

Pharmacogenomics. 2024 Aug 7:1-13. doi: 10.1080/14622416.2024.2370761. Online ahead of print.

ABSTRACT

Calcineurin inhibitors (CNIs) are the mainstay of immunosuppression in kidney transplantation. Interpatient variability in the disposition of calcineurin inhibitors is a well-researched phenomenon and has a well-established genetic contribution. There is great diversity in the makeup of African genomes, but very little is known about the pharmacogenetics of CNIs and transplant outcomes. This review focuses on genetic variants of calcineurin inhibitors' metabolizing enzymes (CYP3A4, CYP3A5), related molecules (POR, PPARA) and membrane transporters involved in the metabolism of calcineurin inhibitors. Given the genetic diversity across the African continent, it is imperative to generate pharmacogenetic data, especially in the era of personalized medicine and emphasizes the need for studies specific to African populations. The study of allelic variants in populations where they have greater frequencies will help answer questions regarding their impact. We aim to fill the knowledge gaps by reviewing existing research and highlighting areas where African research can contribute.

PMID:39109483 | DOI:10.1080/14622416.2024.2370761

J Endocr Soc. 2024 Jul 16;8(9):bvae135. doi: 10.1210/jendso/bvae135. eCollection 2024 Jul 26.

ABSTRACT

OBJECTIVE: Testosterone concentrations, albeit rarely, may be in the normal range (>3.0 ng/mL) in men with a prolactin-secreting pituitary adenoma (PSPA-nt). The evolution of total, bioavailable testosterone, gonadotropin levels, and that of graded symptoms of testosterone deficiency (TD) are uncertain in these patients.

DESIGN: Retrospective case-control longitudinal study at a tertiary referral center.

METHODS: From 287 men, we selected 25 PSPA-nt men undergoing prolactin normalization (<20.0 ng/mL) during the follow-up. Graded symptoms of TD were investigated by structured interviews. Biochemical changes and TD symptoms were compared to those of a matched cohort of 61 men with pituitary neoplasms and normal testosterone levels (PA-nt).

RESULTS: Baseline testosterone levels were similar between PSPA-nt and PA-nt subjects. The prevalence of specific and suggestive symptoms of TD was higher in PSPA-nt (20% and 68%) than in PAnt (3.3 and 29.5%; P = .02 and P = .0015, respectively). At the follow-up, total and bioavailable testosterone levels increased in PSPA-nt but not in PA-nt patients (Δ change: 1.28 ± 2.1 vs0.03 ± 1.5 ng/mL, + 0.33 ± 0.55 vs-0.26 ± 0.60 ng/mL; P = .0028 and P = .0088, respectively). LH and FSH levels also increased in PSPA-nt men (P < .05). Specific and suggestive, but not nonspecific symptoms of TD, improved only in PSPA-nt men (P < .05 for both). Baseline testosterone and LH were the strongest predictors of testosterone improvement in PSPA-nt patients.

CONCLUSION: Despite having normal testosterone levels at baseline, patients with PSPA-nt experience a relief of TD symptoms and an improvement of their pituitary-gonadal axis function following prolactin normalization, especially when baseline TT and LH levels are in the low-normal range.

PMID:39109291 | PMC:PMC11301044 | DOI:10.1210/jendso/bvae135

Front Pharmacol. 2024 Jul 23;15:1404370. doi: 10.3389/fphar.2024.1404370. eCollection 2024.

ABSTRACT

BACKGROUND: Pharmacogenomics (PGx) is a well-established concept of how genes impact medication response, with many studies demonstrating reductions in medication side effects, improved efficacy and cost effectiveness. Despite these benefits, implementation of PGx in daily practice remains limited. Studies on the implementation of PGx in clinical practice have previously found that inadequate knowledge is one of the main barriers. Details regarding specifically which educational needs exist among family medicine clinicians requires further study.

OBJECTIVE: The aim of this study was to identify both the perceived role that pharmacogenomics (PGx) could play in primary care practice, the knowledge gaps that family medicine clinicians experience, and the skills they require to use PGx in their daily practice.

METHODS: To achieve this aim, the attitudes, knowledge, barriers, skills needed, and preferred educational program were explored in a family medicine clinician focus group study via a semi-structured interview and knowledge quiz. Second, multidisciplinary focus groups provided information on the level of knowledge and necessary skills to use PGx in patient care. After gathering key recorded information from both focus groups, the perceived role pharmacogenomics could possibly play in primary care, the predominant knowledge gaps, and the most appropriate educational program was determined by qualitative analysis.

RESULTS: Four themes emerged regarding the PGx educational needs and the role of PGx in family medicine: 1) need for PGx competences, 2) insight into the roles and responsibilities of PGx services, 3) optimization of PGx workflow through artificial intelligence integrated in the electronic health record, and 4) the ethical dilemmas and psychological effects related to PGx. These themes reflect a shift in the role of PGx in family medicine with implications for education.

CONCLUSION: The results obtained from this study will help improve the implementation of PGx in daily practice, and consequently, may result in increased utilization of PGx, thereby resulting in improved medication efficacy and reduced side effects.

PMID:39108762 | PMC:PMC11300371 | DOI:10.3389/fphar.2024.1404370

Iran J Pharm Res. 2024 May 14;23(1):e143898. doi: 10.5812/ijpr-143898. eCollection 2024 Jan-Dec.

ABSTRACT

BACKGROUND: Warfarin is the only approved anticoagulant for antithrombotic treatment in patients with mechanical prosthetic heart valves (MPHV). However, dosing warfarin is challenging due to its narrow therapeutic window and highly variable clinical outcomes. Both low and high doses of warfarin can lead to thrombotic and bleeding events, respectively, with these complications being more severe in individuals with sensitive genetic polymorphisms. Incorporating genetic testing could enhance the accuracy of warfarin dosing and minimize its adverse events.

OBJECTIVES: This study aims to evaluate the utilities and cost-effectiveness of pharmacogenomics-guided versus standard dosing of warfarin in patients with MPHV in Iran.

METHODS: In this economic evaluation study, a cost-effectiveness analysis was conducted to compare pharmacogenomics-guided versus standard warfarin dosing. Data related to quality of life (QoL) were collected through a cross-sectional study involving 105 randomly selected MPHV patients using the EuroQol-5D (EQ-5D) Questionnaire. Costs were calculated with input from clinical experts and a review of relevant guidelines. Additional clinical data were extracted from published literature. The pharmacoeconomic threshold set for medical interventions within Iran's healthcare system was $1,500. A decision tree model was designed from the perspective of Iran's healthcare system with a one-year study horizon. Sensitivity analyses were also performed to assess the uncertainty of input parameters.

RESULTS: The utility scores derived from the questionnaire for standard and pharmacogenomics-guided warfarin treatments were 0.68 and 0.76, respectively. Genotype-guided dosing of warfarin was more costly compared to the standard dosing ($246 vs $69), and the calculated incremental cost-effectiveness ratio (ICER) was $2474 per quality-adjusted life year (QALY) gained. One-way sensitivity analyses showed that our model is sensitive to the percentage of time in the therapeutic range (PTTR), the cost of genetic tests, and the utility of both pharmacogenomics-guided and standard dosing arms. However, the probabilistic sensitivity analysis demonstrates the robustness of our model.

CONCLUSIONS: Warfarin dosing with pharmacogenomics testing is currently not cost-effective. However, if the cost of genotyping tests decreases to $118, the ICER would become cost-effective.

PMID:39108643 | PMC:PMC11302438 | DOI:10.5812/ijpr-143898

Acta Anaesthesiol Scand. 2024 Aug 6. doi: 10.1111/aas.14508. Online ahead of print.

ABSTRACT

BACKGROUND: Treatment with opioids is a mainstay in perioperative pain management. While the leading treatment paradigm has been procedure-specific pain management, efforts regarding personalized pain treatment are increasing. The OPI•AID project aims to develop personalized algorithms for perioperative pain management, taking demographic, surgical, and anaesthesiologic factors into account. We will undertake five parallel reviews to illuminate current evidence on different aspects of individual responses to perioperative opioid treatment.

METHODS: Inclusion of adult populations in English-written studies. Review-specific searches are developed for the following databases: CENTRAL, MEDLINE, Embase, clinicaltrials.gov, and clinicaltrial.eu. Two authors will independently screen citations, extract data, and assess the risks of bias in each review (QUIPS, PROBAST and RoB2, as relevant).

CONCLUSION: These reviews will evaluate various aspects of perioperative opioid treatment, including individualized treatment strategies, selection of specific opioids, and individual patient responses. These will guide future development of a personalized perioperative opioid treatment algorithm (OPI•AID) that will be validated and tested clinically against standard of care.

PMID:39107975 | DOI:10.1111/aas.14508

Br J Clin Pharmacol. 2024 Aug 6. doi: 10.1111/bcp.16196. Online ahead of print.

ABSTRACT

AIMS: Sunitinib exhibits considerable interindividual variability in exposure. While the target total plasma concentration of sunitinib and its active metabolite is 50-87.5 ng/mL for the intermittent dosing schedule, ~10-21% of patients experience higher exposures (>87.5 ng/mL), correlated with an increased risk for toxicity. Previous research identified single nucleotide variants (SNVs) in genes from the sunitinib pharmacokinetic pathway to be associated with efficacy and toxicity. However, significant interindividual variability in exposure remains unexplained. Our aim was to identify genetic variants associated with supratherapeutic exposure of sunitinib.

METHODS: This was a genome-wide association study. Cases were identified during routine therapeutic drug monitoring and consisted of patients with dose-normalized sunitinib plasma concentrations >87.5 ng/mL (intermittent dosing) or >75 ng/mL (continuous dosing). Controls were sampled from the historical cohort EuroTARGET who tolerated the standard dose of 50 mg in an intermittent schedule. SNVs were tested for an association with sunitinib exposure. A P-value ≤5 × 10-8 was considered significant and a P-value between 5 × 10-8 and 5 × 10-6 was considered suggestive.

RESULTS: Sixty-nine cases and 345 controls were included for association analysis. One SNV (rs6923761), located on the gene glucagon-like peptide 1 receptor, was significantly associated with increased sunitinib exposure (P = 7.86 × 10-19). Twelve SNVs were suggestive for an association with sunitinib exposure (P ≤ 5 × 10-6).

CONCLUSIONS: While rs6923671 is associated with high sunitinib exposure, the underlying mechanism is not yet clarified and warrants further investigation. We could not confirm the earlier found associations between SNVs in candidate genes involved in the pharmacokinetic pathway of sunitinib and its efficacy and toxicity.

PMID:39107874 | DOI:10.1111/bcp.16196

Transl Psychiatry. 2024 Aug 6;14(1):322. doi: 10.1038/s41398-024-02998-6.

ABSTRACT

In the past two decades, significant progress has been made in the development of polygenic scores (PGSs). One specific application of PGSs is the development and potential use of pharmacogenomic- scores (PGx-scores) to identify patients who can benefit from a specific medication or are likely to experience side effects. This systematic review comprehensively evaluates published PGx-score studies in psychiatry and provides insights into their potential clinical use and avenues for future development. A systematic literature search was conducted across PubMed, EMBASE, and Web of Science databases until 22 August 2023. This review included fifty-three primary studies, of which the majority (69.8%) were conducted using samples of European ancestry. We found that over 90% of PGx-scores in psychiatry have been developed based on psychiatric and medical diagnoses or trait variants, rather than pharmacogenomic variants. Among these PGx-scores, the polygenic score for schizophrenia (PGSSCZ) has been most extensively studied in relation to its impact on treatment outcomes (32 publications). Twenty (62.5%) of these studies suggest that individuals with higher PGSSCZ have negative outcomes from psychotropic treatment - poorer treatment response, higher rates of treatment resistance, more antipsychotic-induced side effects, or more psychiatric hospitalizations, while the remaining studies did not find significant associations. Although PGx-scores alone accounted for at best 5.6% of the variance in treatment outcomes (in schizophrenia treatment resistance), together with clinical variables they explained up to 13.7% (in bipolar lithium response), suggesting that clinical translation might be achieved by including PGx-scores in multivariable models. In conclusion, our literature review found that there are still very few studies developing PGx-scores using pharmacogenomic variants. Research with larger and diverse populations is required to develop clinically relevant PGx-scores, using biology-informed and multi-phenotypic polygenic scoring approaches, as well as by integrating clinical variables with these scores to facilitate their translation to psychiatric practice.

PMID:39107294 | DOI:10.1038/s41398-024-02998-6

ERJ Open Res. 2024 Aug 5;10(4):00909-2023. doi: 10.1183/23120541.00909-2023. eCollection 2024 Jul.

ABSTRACT

INTRODUCTION: Type 2 (T2) asthma is often associated with chronic rhinosinusitis with nasal polyposis (CRSwNP). Additionally, nonsteroidal anti-inflammatory drug (NSAID) intolerance leads to NSAID-exacerbated respiratory disease (N-ERD). Previous transcriptomic data in non-CRSwNP T2 asthma patients showed differentially expressed genes. We focused on ALOX15, CLC, CYSLTR2, HRH4 and SMPD3 to investigate their role in T2 asthma.

METHODS: The study included 100 healthy controls and 103 T2 asthma patients, divided into patients with asthma (n=54), patients with asthma and CRSwNP (n=29) and patients with N-ERD (n=20). Quantitative PCR analysis was performed on blood-derived RNA samples first to validate the five differentially expressed genes. The data were further analysed to find potential associations and biomarkers.

RESULTS: Patients, regardless of stratification, exhibited significantly higher gene expression than healthy controls. The patterns of association revealed that ALOX15 was exclusively present in the non-comorbidity group, SMPD3 and CLC in the comorbidity groups, and HRH4 in all patient groups. ALOX15, CYSLTR2 and SMPD3 expression showed potential as biomarkers to confirm the diagnosis of T2 asthma using peripheral blood eosinophils as the initial criterion. Peripheral blood eosinophils combined with gene expression, especially SMPD3, may improve the diagnosis. CLC and CYSLTR2 expression play a specific role in discriminating N-ERD.

DISCUSSION: We validated the transcriptomic data of five differentially expressed genes in T2 asthma. Different patterns of association were identified in patient stratification, suggesting that different molecular mechanisms underlie the spectrum of T2 asthma. Potential biomarkers were also found and used to design an algorithm with practical diagnostic utility for T2 asthma, including risk stratification for N-ERD.

PMID:39104947 | PMC:PMC11299009 | DOI:10.1183/23120541.00909-2023

J Clin Oncol. 2024 Aug 5:JCO2400500. doi: 10.1200/JCO.24.00500. Online ahead of print.

ABSTRACT

PURPOSE: Acute lymphoblastic leukemia (ALL) can occur across all age groups, with a strikingly higher cure rate in children compared with adults. However, the pharmacological basis of age-related differences in ALL treatment response remains unclear.

METHODS: Studying 767 children and 309 adults with newly diagnosed B-cell ALL enrolled on frontline trials at St Jude Children's Research Hospital, MD Anderson Cancer Center, the Alliance for Clinical Trials in Oncology, and the ECOG-ACRIN Cancer Research Group, we determined the ex vivo sensitivity of leukemia cells to 21 drugs. Twenty-three ALL molecular subtypes were identified using RNA sequencing. We systematically characterized the associations between drug response and ALL genomics in children, adolescents and young adults, and elderly adults. We evaluated the effect of age-related gene expression signature on ALL treatment outcomes.

RESULTS: Seven ALL drugs (asparaginase, prednisolone, mercaptopurine, dasatinib, nelarabine, daunorubicin, and inotuzumab ozogamicin) showed differential activity between children and adults, of which six were explained by age-related differences in leukemia molecular subtypes. Adolescents and young adults showed similar patterns of drug resistance as older adults, relative to young children. Mercaptopurine exhibited subtype-independent greater sensitivity in children. Transcriptomic profiling uncovered subclusters within CRLF2-, DUX4-, and KMT2A-rearranged ALL that were linked to age and cytotoxic drug resistance. In particular, a subset of children had adult-like ALL on the basis of leukemia gene expression patterns across subtypes, despite their chronological age. Resistant to cytotoxic drugs, children with adult-like ALL exhibited poor prognosis in pediatric ALL trials, even after adjusting for age and minimal residual diseases.

CONCLUSION: Our results provide pharmacogenomic insights into age-related disparities in ALL cure rates and identify leukemia prognostic features for treatment individualization across age groups.

PMID:39102629 | DOI:10.1200/JCO.24.00500