J Am Geriatr Soc. 2023 Aug 2. doi: 10.1111/jgs.18524. Online ahead of print.

NO ABSTRACT

PMID:37529936 | DOI:10.1111/jgs.18524

Pharmacogenomics. 2023 Aug 2. doi: 10.2217/pgs-2023-0098. Online ahead of print.

ABSTRACT

The Ibero-American Network of Pharmacogenetics and Pharmacogenomics (RIBEF) studies Latin American populations to benefit from the implementation of personalized medicine. Since 2006, it has studied ethnicity to apply pharmacogenetics knowledge in autochthonous populations of Latin America, considering ancestral medicine. The meeting 'Pharmacogenetics: ethnicity, Treatment and Health in Latin American Populations' was held in Mexico City, Mexico, and presented the relevance of RIBEF collaboration with Latin American researchers and the governments of Mexico, Spain and the Autonomous Community of Extremadura. The results of 17 years of uninterrupted work by RIBEF, the Declaration of Mérida/T'Hó and the call for the Dr José María Cantú Award for studies focused on the pharmacogenetics of native populations in Latin America were presented.

PMID:37529900 | DOI:10.2217/pgs-2023-0098

Ther Adv Rare Dis. 2023 Jul 29;4:26330040231188979. doi: 10.1177/26330040231188979. eCollection 2023 Jan-Dec.

ABSTRACT

BACKGROUND: The International Rare Diseases Research Consortium (IRDiRC) is an international initiative that aims to use research to facilitate rapid diagnosis and treatment of rare diseases.

OBJECTIVE: IRDiRC launched the Chrysalis Task Force to identify key financial and nonfinancial factors that make rare disease research and development attractive to companies.

METHODS: The Chrysalis Task Force was comprised of thought leaders from companies, patient advocacy groups, regulatory agencies, and research funders. The Task Force created a survey that was distributed to companies of different sizes with varied investment portfolios and interests in rare disease research. Based on the survey results, the Task Force then conducted targeted interviews.

RESULTS: The survey and interview respondents identified several factors that make rare disease research and development attractive (e.g. a good understanding of the underlying biology) as well as barriers (e.g. absence of an advocacy organization representing the affected community's needs). The concept of Return On Investment allowed the exploration of factors that were weighed differently by survey and interview respondents, depending on a number of intrinsic and extrinsic issues.

CONCLUSIONS: The Chrysalis Task Force identified factors attributable to rare disease research and development that may be of interest to and actionable by funders, academic researchers, patients and their families, companies, regulators, and payers in the medium term to short term. By addressing the identified challenges, involved parties may seek solutions to significantly advance the research and development of treatments for rare diseases.

PMID:37529076 | PMC:PMC10387802 | DOI:10.1177/26330040231188979

Psychiatr Serv. 2023 Aug 2:0. doi: 10.1176/appi.ps.20220537. Online ahead of print.

ABSTRACT

OBJECTIVE: Pharmacogenetic testing (PGx) for patients experiencing depression has been associated with modest improvements in symptoms. However, little is known about providers' use of PGx, including how and for whom providers use the test results in clinical decision making. In this article, results from qualitative interviews on the experience of providers participating in a pragmatic trial of PGx are described; implications of the providers' experiences are highlighted to inform future implementation of PGx.

METHODS: Interviews were conducted with providers participating in the trial (N=61) who treated veterans who had depression. Questions were informed by the Consolidated Framework for Implementation Research. A rapid analytic approach was used.

RESULTS: Two main themes were identified: perceptions regarding which patients would likely benefit from PGx and approaches to using the test results in prescribing. Providers generally expressed positive experiences with using PGx results. However, the providers varied in application of the test results to clinical decision making regarding medications, were uncertain about how much to rely on the results, and differed in perceptions about which patients would benefit from PGx.

CONCLUSIONS: To support future implementation, policies and procedures are needed, as well as mechanisms to support ongoing provider education on PGx.

PMID:37528698 | DOI:10.1176/appi.ps.20220537

Nicotine Tob Res. 2023 Aug 1:ntad133. doi: 10.1093/ntr/ntad133. Online ahead of print.

ABSTRACT

INTRODUCTION: Alaska Native and American Indian (ANAI) people have a smoking prevalence of 23%. Nicotine metabolite ratio (NMR) and genetic testing may enable tailored selection of tobacco cessation medication. The purpose of this study was to evaluate the relative contributions of NMR, cessation medication, demographics, and tobacco use history to cessation.

METHODS: Participants were recruited into an observational cohort study consisting of a baseline visit prior to their quit date and 6 week follow-up. Demographic and tobacco use surveys and blood, urine, and breath samples were collected at each visit. Electronic health records were queried for cessation medications. NMR was categorized into slow or normal nicotine metabolism phenotypes (<0.31 and ≥0.31 respectively). The main outcome was cessation at 6 weeks. Analyses consisted of descriptive statistics, medication/phenotype concordance, and estimates of relative risk of quitting.

RESULTS: We enrolled 151 ANAI adults who smoked cigarettes daily. Two-thirds had normal nicotine metabolism phenotype. Retrospective medication/phenotype concordance was 39%. The overall quit rate was 25%. No demographic factors or tobacco use history were associated with quit success. Varenicline and bupropion increased the likelihood of quitting (RR=2.93 [1.42, 6.03] and RR=2.52 [1.12, 5.64] respectively) compared to nicotine replacement therapy. Non-optimal medication/phenotype concordance decreased likelihood of quit success (RR=0.44 [0.22, 0.91]) compared to optimal concordance.

CONCLUSION: This exploratory study found associations between quit success and tobacco cessation medication as well as medication/phenotype concordance. Additional research is needed to assess use of NMR for treatment selection among ANAI people.

IMPLICATIONS: These results broadly support additional community-engaged research to improve medication/phenotype concordance in tribal health settings. Such interventional research holds promise to improve expectations, quit success, and health outcomes amongst individuals attempting to quit smoking.

PMID:37527452 | DOI:10.1093/ntr/ntad133

JAMA. 2023 Aug 1;330(5):442-453. doi: 10.1001/jama.2023.11676.

ABSTRACT

IMPORTANCE: People who smoked cigarettes may experience respiratory symptoms without spirometric airflow obstruction. These individuals are typically excluded from chronic obstructive pulmonary disease (COPD) trials and lack evidence-based therapies.

OBJECTIVE: To define the natural history of persons with tobacco exposure and preserved spirometry (TEPS) and symptoms (symptomatic TEPS).

DESIGN, SETTING, AND PARTICIPANTS: SPIROMICS II was an extension of SPIROMICS I, a multicenter study of persons aged 40 to 80 years who smoked cigarettes (>20 pack-years) with or without COPD and controls without tobacco exposure or airflow obstruction. Participants were enrolled in SPIROMICS I and II from November 10, 2010, through July 31, 2015, and followed up through July 31, 2021.

EXPOSURES: Participants in SPIROMICS I underwent spirometry, 6-minute walk distance testing, assessment of respiratory symptoms, and computed tomography of the chest at yearly visits for 3 to 4 years. Participants in SPIROMICS II had 1 additional in-person visit 5 to 7 years after enrollment in SPIROMICS I. Respiratory symptoms were assessed with the COPD Assessment Test (range, 0 to 40; higher scores indicate more severe symptoms). Participants with symptomatic TEPS had normal spirometry (postbronchodilator ratio of forced expiratory volume in the first second [FEV1] to forced vital capacity >0.70) and COPD Assessment Test scores of 10 or greater. Participants with asymptomatic TEPS had normal spirometry and COPD Assessment Test scores of less than 10. Patient-reported respiratory symptoms and exacerbations were assessed every 4 months via phone calls.

MAIN OUTCOMES AND MEASURES: The primary outcome was assessment for accelerated decline in lung function (FEV1) in participants with symptomatic TEPS vs asymptomatic TEPS. Secondary outcomes included development of COPD defined by spirometry, respiratory symptoms, rates of respiratory exacerbations, and progression of computed tomographic-defined airway wall thickening or emphysema.

RESULTS: Of 1397 study participants, 226 had symptomatic TEPS (mean age, 60.1 [SD, 9.8] years; 134 were women [59%]) and 269 had asymptomatic TEPS (mean age, 63.1 [SD, 9.1] years; 134 were women [50%]). At a median follow-up of 5.76 years, the decline in FEV1 was -31.3 mL/y for participants with symptomatic TEPS vs -38.8 mL/y for those with asymptomatic TEPS (between-group difference, -7.5 mL/y [95% CI, -16.6 to 1.6 mL/y]). The cumulative incidence of COPD was 33.0% among participants with symptomatic TEPS vs 31.6% among those with asymptomatic TEPS (hazard ratio, 1.05 [95% CI, 0.76 to 1.46]). Participants with symptomatic TEPS had significantly more respiratory exacerbations than those with asymptomatic TEPS (0.23 vs 0.08 exacerbations per person-year, respectively; rate ratio, 2.38 [95% CI, 1.71 to 3.31], P < .001).

CONCLUSIONS AND RELEVANCE: Participants with symptomatic TEPS did not have accelerated rates of decline in FEV1 or increased incidence of COPD vs those with asymptomatic TEPS, but participants with symptomatic TEPS did experience significantly more respiratory exacerbations over a median follow-up of 5.8 years.

PMID:37526720 | DOI:10.1001/jama.2023.11676

BMC Cancer. 2023 Jul 31;23(1):714. doi: 10.1186/s12885-023-11121-9.

ABSTRACT

BACKGROUND: Precise prognostication is the key to optimum and effective treatment planning for early-stage hormone receptor (HR) positive, HER2/neu negative breast cancer patients. Differences in the breast cancer incidence and tumor anatomical features at diagnosis, pharmacogenomics data between Western and Indian women along with the vast diversity in the economic status and differences in insurance policies of these regions; suggest recommendations put forward for Western women might not be applicable to Indian/Asian women. Opinions from oncologists through a voting survey on various prognostic factors/tools to be considered for planning adjuvant therapy are consolidated in this report for the benefit of oncologists of the sub-continent, SAARC and Asia's LMIC (low and middle-income countries).

METHODS: A three-phase DELPHI survey was conducted to collect opinions on prognostic factors considered for planning adjuvant therapy in early-stage HR+/HER2/neu negative breast cancer patients. A panel of 25 oncologists with expertise in breast cancer participated in the survey conducted in 2021. The experts provided opinions as 'agree' or disagree' or 'not sure' in phases-1 and 2 which were conducted virtually; in the final phase-3, all the panel experts met in person and concluded the survey.

RESULTS: Opinions on 41 statements related to prognostic factors/tools and their implications in planning adjuvant endocrine/chemotherapy were collected. All the statements were supported by the latest data from the clinical trials (prospective/retrospective). The statements with opinions of consensus less than 66% were disseminated in phase-2, and later in phase-3 with supporting literature. In phase-3, all the opinions from panelists were consolidated and guidelines were framed.

CONCLUSIONS: This consensus guideline will assist oncologists of India, SAARC and LMIC countries in informed clinical decision-making on adjuvant treatment in early HR+/HER2/neu negative breast cancer patients.

PMID:37525142 | DOI:10.1186/s12885-023-11121-9

Proc Natl Acad Sci U S A. 2023 Aug 8;120(32):e2303402120. doi: 10.1073/pnas.2303402120. Epub 2023 Jul 31.

ABSTRACT

The endoplasmic reticulum (ER) and mitochondria form a unique subcellular compartment called mitochondria-associated ER membranes (MAMs). Disruption of MAMs impairs Ca2+ homeostasis, triggering pleiotropic effects in the neuronal system. Genome-wide kinase-MAM interactome screening identifies casein kinase 2 alpha 1 (CK2A1) as a regulator of composition and Ca2+ transport of MAMs. CK2A1-mediated phosphorylation of PACS2 at Ser207/208/213 facilitates MAM localization of the CK2A1-PACS2-PKD2 complex, regulating PKD2-dependent mitochondrial Ca2+ influx. We further reveal that mutations of PACS2 (E209K and E211K) associated with developmental and epileptic encephalopathy-66 (DEE66) impair MAM integrity through the disturbance of PACS2 phosphorylation at Ser207/208/213. This, in turn, causes the reduction of mitochondrial Ca2+ uptake and the dramatic increase of the cytosolic Ca2+ level, thereby, inducing neurotransmitter release at the axon boutons of glutamatergic neurons. In conclusion, our findings suggest a molecular mechanism that MAM alterations induced by pathological PACS2 mutations modulate Ca2+-dependent neurotransmitter release.

PMID:37523531 | DOI:10.1073/pnas.2303402120

JAMA Netw Open. 2023 Jul 3;6(7):e2326445. doi: 10.1001/jamanetworkopen.2023.26445.

ABSTRACT

IMPORTANCE: Although the clinical utility of genome sequencing for critically ill children is well recognized, its utility for proactive pediatric screening is not well explored.

OBJECTIVE: To evaluate molecular findings from screening ostensibly healthy children with genome sequencing compared with a gene panel for medically actionable pediatric conditions.

DESIGN, SETTING, AND PARTICIPANTS: This case series study was conducted among consecutive, apparently healthy children undergoing proactive genetic screening for pediatric disorders by genome sequencing (n = 562) or an exome-based panel of 268 genes (n = 606) from March 1, 2018, through July 31, 2022.

EXPOSURES: Genetic screening for pediatric-onset disorders using genome sequencing or an exome-based panel of 268 genes.

MAIN OUTCOMES AND MEASURES: Molecular findings indicative of genetic disease risk.

RESULTS: Of 562 apparently healthy children (286 girls [50.9%]; median age, 29 days [IQR, 9-117 days]) undergoing screening by genome sequencing, 46 (8.2%; 95% CI, 5.9%-10.5%) were found to be at risk for pediatric-onset disease, including 22 children (3.9%) at risk for high-penetrance disorders. Sequence analysis uncovered molecular diagnoses among 32 individuals (5.7%), while copy number variant analysis uncovered molecular diagnoses among 14 individuals (2.5%), including 4 individuals (0.7%) with chromosome scale abnormalities. Overall, there were 47 molecular diagnoses, with 1 individual receiving 2 diagnoses; of the 47 potential diagnoses, 22 (46.8%) were associated with high-penetrance conditions. Pathogenic variants in medically actionable pediatric genes were found in 6 individuals (1.1%), constituting 12.8% (6 of 47) of all diagnoses. At least 1 pharmacogenomic variant was reported for 89.0% (500 of 562) of the cohort. In contrast, of 606 children (293 girls [48.3%]; median age, 26 days [IQR, 10-67 days]) undergoing gene panel screening, only 13 (2.1%; 95% CI, 1.0%-3.3%) resulted in potential childhood-onset diagnoses, a significantly lower rate than those screened by genome sequencing (P < .001).

CONCLUSIONS AND RELEVANCE: In this case series study, genome sequencing as a proactive screening approach for children, due to its unrestrictive gene content and technical advantages in comparison with an exome-based gene panel for medically actionable childhood conditions, uncovered a wide range of heterogeneous high-penetrance pediatric conditions that could guide early interventions and medical management.

PMID:37523181 | DOI:10.1001/jamanetworkopen.2023.26445

J Biomed Mater Res B Appl Biomater. 2023 Jul 31. doi: 10.1002/jbm.b.35306. Online ahead of print.

ABSTRACT

Porous NiTi (pNiTi) is a promising biomaterial for functional long-term implantation that has been produced using various manufacturing techniques and tested for biocompatibility. pNiTi produced using a more recent technology of Metal Injection Molding (MIM) has shown better physical and mechanical properties than those produced by earlier manufacturing methods, but its biocompatibility has yet to be determined. Hence, extracts from pNiTi dental implants produced by MIM were tested for cytotoxicity and genotoxicity in this work. Its toxicity was evaluated at the cellular and in vitro levels using elution and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assays. Short-term testing revealed that pNiTi extract was cytocompatible with L-929 fibroblast and V79-4 lung cells, with no cell lysis or reactivity observed, respectively (USP grade 0). Following exposure to varied extract concentrations, good cell viability was observed where the lowest concentration showed the highest optical density (OD) and cell viability (2.968 ± 0.117 and 94%, respectively), and the highest concentration had the least OD and cell viability (2.251 ± 0.054 and 71%, respectively). pNiTi extracts demonstrated genocompatibility in two independent assays: mutagenic potential using a bacterial reverse mutation test and a clastogenic effect on chromosomes using the micronucleus test. Similar to the negative control reactions, there was no significant increase in revertant colonies following exposure to 100% pNiTi extract with and without metabolic activation (p = .00). No DNA clastogenic activity was caused by pNiTi at varied extract concentrations as compared to the negative control when tested with and without metabolic activation (p = .00). As a result, both cytotoxic and genotoxic investigations have confirmed that pNiTi dental implants utilizing the MIM process are cytocompatible and genocompatible in the short term, according to the International Standard, ISO 10993 - Parts 3, 5, and 33.

PMID:37522375 | DOI:10.1002/jbm.b.35306

Front Pharmacol. 2023 Jul 13;14:1217516. doi: 10.3389/fphar.2023.1217516. eCollection 2023.

ABSTRACT

Background: The relationship between HLA-B*15:02 and Severe Cutaneous Adverse Reactions was rigorously examined in Japanese, Han Chinese, Thais, and Caucasians. However, the number of studies about this topic in Vietnamese population is still limited and mostly focuses on the North of Vietnam. Objective: This study aims to clarify the genetic culprit of SCARs in Vietnamese population, particularly in the South of Vietnam, and to validate our result by a meta-analysis about this topic in Vietnamese. Method: A retrospective case-control study with 37 patients treated with carbamazepine monotherapy. Statistical calculation and meta-analysis were performed by R software. Result: HLA-B*15:02 increases the risk of SJS 12.5 times higher in CBZ-treated patients (p-value = 0.017). However, this allele has no impact on MCARs (Mild Cutaneous Adverse Reactions) of CBZ. The number needed to test and the number needed to genotype is two and nine patients respectively. Conclusion: This study recommends more investigations about the cost-effectiveness of this test to accelerate the protection of Southern Vietnamese from SCARs.

PMID:37521485 | PMC:PMC10374328 | DOI:10.3389/fphar.2023.1217516

Stat Methods Med Res. 2023 Jul 31:9622802231188519. doi: 10.1177/09622802231188519. Online ahead of print.

ABSTRACT

In the era of precision medicine, many biomarkers have been discovered to be associated with drug efficacy and safety responses, which can be used for patient stratification and drug response prediction. Due to the small sample size and limited power of randomized clinical studies, meta-analysis is usually conducted to aggregate all available studies to maximize the power for identifying prognostic and predictive biomarkers. However, it is often challenging to find an independent study to replicate the discoveries from the meta-analysis (e.g. meta-analysis of pharmacogenomics genome-wide association studies (PGx GWAS)), which seriously limits the potential impacts of the discovered biomarkers. To overcome this challenge, we develop a novel statistical framework, MAJAR (meta-analysis of joint effect associations for biomarker replicability assessment), to jointly test prognostic and predictive effects and assess the replicability of identified biomarkers by implementing an enhanced expectation-maximization algorithm and calculating their posterior-probability-of-replicabilities and Bayesian false discovery rates (Fdr). Extensive simulation studies were conducted to compare the performance of MAJAR and existing methods in terms of Fdr, power, and computational efficiency. The simulation results showed improved statistical power with well-controlled Fdr of MAJAR over existing methods and robustness to outliers under different data generation processes. We further demonstrated the advantages of MAJAR over existing methods by applying MAJAR to the PGx GWAS summary statistics data from a large cardiovascular randomized clinical trial. Compared to testing main effects only, MAJAR identified 12 novel variants associated with the treatment-related low-density lipoprotein cholesterol reduction from baseline.

PMID:37519295 | DOI:10.1177/09622802231188519

Chin J Nat Med. 2023 Jul;21(7):516-526. doi: 10.1016/S1875-5364(23)60427-3.

ABSTRACT

Lignans derived from Eucommia ulmoides Oliver (Eucommia lignans) inhibit the progression of inflammatory diseases, while their effect on the progression of diabetic nephropathy (DN) remained unclear. This work was designed to assess the function of Eucommia lignans in DN. The major constituents of Eucommia lignans were analyzed by UPLC-Q-TOF-MS/MS. The binding between Eucommia lignans and aldose reductase (AR) was predicted by molecular docking. Eucommia lignans (200, 100, and 50 mg·kg-1) were used in model animals to evaluate their renal function changes. Rat glomerular mesangial cells (HBZY-1) were transfected with sh-AR, sh-AMPK, and oe-AR in the presence of high glucose (HG) or HG combined with Eucommia lignans to evaluate whether Eucommia lignans affected HG-induced cell injury and mitochondrial dysfunction through the AR/Nrf2/HO-1/AMPK axis. Eucommia lignans significantly attenuated the progression of DN in vivo. Eucommia lignans notably reversed HG-induced upregulation of inflammatory cytokines and mitochondrial injury, while downregulating the levels of Cyto c, caspase 9, AR, and NOX4 in HBZY-1 cells. In contrast, HG-induced downregulation of Nrf2, HO-1 and p-AMPKα levels were abolished by Eucommia lignans. Meanwhile, knockdown of AR exerted similar therapeutic effect of Eucommia lignans on DN progression, and AR overexpression reversed the effect of Eucommia lignans. Eucommia lignans alleviated renal injury through the AR/Nrf2/HO-1/AMPK axis. Thus, these findings might provide evidence for the use of Eucommia lignans in treating DN.

PMID:37517819 | DOI:10.1016/S1875-5364(23)60427-3

Therapie. 2023 Jul 17:S0040-5957(23)00103-8. doi: 10.1016/j.therap.2023.07.002. Online ahead of print.

ABSTRACT

Although French genomic medicine is reaching a turning point in its history and the implementation of genome sequencing in routine is being implemented as part of the France Genomic Medicine 2025 Plan (FGMP), many questions about secondary data management remain to be addressed. In particular, the use of pharmacogenetic (PGx) information that can be extracted from genome data is a concern. We sought to analyze the opinion of French health professionals on their desire to have access to this information. For this purpose, we created a 22-item questionnaire on the experiences, attitudes, expectations, and knowledge of French physicians and pharmacists about PGx. We collected the responses in different groups and determined a knowledge score with the last 3 questions of the questionnaire. Then, we built a prediction model for this score and determined which factors may influence it. Half of the responders were physicians (158/311) and the other half were pharmacists (153/311), and the majority of them worked in a hospital (265/311). Almost two third (62.7%, 195/311) of the responders thought that pharmacogenetic data should be communicated with genomic results for the primary indication within the framework of FGMP, and 89.1% (277/311) of them that PGx tests could be an interesting tool to optimize patients' drug therapy in the future. Only 11.2% (35/311) of the responders reached the maximum knowledge score, while 25.4% (76/311) had already prescribed or recommended a PGx test. This study identified a need for training for French physicians and pharmacists in PGx, particularly given the interest of health professionals in it.

PMID:37516659 | DOI:10.1016/j.therap.2023.07.002

Vaccines (Basel). 2023 Jul 19;11(7):1257. doi: 10.3390/vaccines11071257.

ABSTRACT

The COVID-19 mRNA vaccine is the first mRNA vaccine approved for human administration by both the U.S. Food and Drug Administration and the European Medicines Agency. Studies have shown that the immune response and the decay of immunity after vaccination with the COVID-19 vaccines are variable within a population. Host genetic factors probably contribute to this variability. In this study, we investigated the effect of the single-nucleotide polymorphisms rs12252 and rs34481144 in the interferon-induced transmembrane protein (IFITM) 3 gene on the humoral immune response after vaccination against COVID-19 with mRNA vaccines. Blood samples were collected from 1893 healthcare workers and medical students at multiple time points post-vaccination and antibody titers against the SARS-CoV-2 S1 protein receptor binding domain were determined at all time points. All participants were genotyped for the rs34481144 and rs12252 polymorphisms in the IFITM3 gene. After the second and third vaccinations, antibody titer levels increased at one month and decreased at six months (p < 0.0001) and were higher after the booster vaccination than after the basic immunization (p < 0.0001). Participants vaccinated with mRNA-1273 had a higher humoral immune response than participants vaccinated with BNT162b2. rs12252 had no effect on the antibody response. In contrast, carriers of the GG genotype in rs34481144 vaccinated with BNT162b2 had a lower humoral immune response compared to A allele carriers, which reached statistical significance on the day of the second vaccination (p = 0.03) and one month after the second vaccination (p = 0.04). Further studies on the influence of rs12252 and rs34481144 on the humoral immune response after vaccination against COVID-19 are needed.

PMID:37515072 | DOI:10.3390/vaccines11071257

Pharmaceutics. 2023 Jul 20;15(7):1995. doi: 10.3390/pharmaceutics15071995.

ABSTRACT

Diabetic kidney disease (DKD) is a severe and common complication and affects a quarter of patients with type 2 diabetes mellitus (T2DM). Oxidative stress and inflammation related to hyperglycemia are interlinked and contribute to the occurrence of DKD. It was shown that sodium-glucose cotransporter-2 (SGLT2) inhibitors, a novel yet already widely used therapy, may prevent the development of DKD and alter its natural progression. SGLT2 inhibitors induce systemic and glomerular hemodynamic changes, provide metabolic advantages, and reduce inflammatory and oxidative stress pathways. In T2DM patients, regardless of cardiovascular diseases, SGLT2 inhibitors may reduce albuminuria, progression of DKD, and doubling of serum creatinine levels, thus lowering the need for kidney replacement therapy by over 40%. The molecular mechanisms behind these beneficial effects of SGLT2 inhibitors extend beyond their glucose-lowering effects. The emerging studies are trying to explain these mechanisms at the genetic, epigenetic, transcriptomic, and proteomic levels.

PMID:37514181 | DOI:10.3390/pharmaceutics15071995

Pharmaceutics. 2023 Jul 11;15(7):1923. doi: 10.3390/pharmaceutics15071923.

ABSTRACT

The relevance of race and ethnicity to genetics and medicine has long been a matter of debate. An emerging consensus holds that race and ethnicity are social constructs and thus poor proxies for genetic diversity. The goal of this study was to evaluate the relationship between race, ethnicity, and clinically relevant pharmacogenomic variation in cosmopolitan populations. We studied racially and ethnically diverse cohorts of 65,120 participants from the United States All of Us Research Program (All of Us) and 31,396 participants from the United Kingdom Biobank (UKB). Genome-wide patterns of pharmacogenomic variation-6311 drug response-associated variants for All of Us and 5966 variants for UKB-were analyzed with machine learning classifiers to predict participants' self-identified race and ethnicity. Pharmacogenomic variation predicts race/ethnicity with averages of 92.1% accuracy for All of Us and 94.3% accuracy for UKB. Group-specific prediction accuracies range from 99.0% for the White group in UKB to 92.9% for the Hispanic group in All of Us. Prediction accuracies are substantially lower for individuals who identified with more than one group in All of Us (16.7%) or as Mixed in UKB (70.7%). There are numerous individual pharmacogenomic variants with large allele frequency differences between race/ethnicity groups in both cohorts. Frequency differences for toxicity-associated variants predict hundreds of adverse drug reactions per 1000 treated participants for minority groups in All of Us. Our results indicate that race and ethnicity can be used to stratify pharmacogenomic risk in the US and UK populations and should not be discounted when making treatment decisions. We resolve the contradiction between the results reported here and the orthodoxy of race and ethnicity as non-genetic, social constructs by emphasizing the distinction between global and local patterns of human genetic diversity, and we stress the current and future limitations of race and ethnicity as proxies for pharmacogenomic variation.

PMID:37514109 | DOI:10.3390/pharmaceutics15071923

Pharmaceutics. 2023 Jul 5;15(7):1887. doi: 10.3390/pharmaceutics15071887.

ABSTRACT

Hepatocellular carcinoma (HCC) is a prevalent and high-mortality cancer worldwide, and its complexity necessitates novel strategies for drug selection and design. Current approaches primarily focus on reducing gene expression, while promoting gene overexpression remains a challenge. In this work, we studied the effect of cytoplasmic polyadenylation element binding protein 2 (CPEB2) in HCC by constructing tissue microarrays (TAMs) from 90 HCC cases and corresponding para-cancerous tissues. Our analysis showed that CPEB2 expression was significantly reduced in HCC tissues, and its low expression was associated with a higher recurrence risk and poorer prognosis in patients with head and neck cancer. CPEB2 was found to regulate HCC epithelial-mesenchymal transition (EMT) and metastasis through the HIF-1α/miR-210-3p/CPEB2 feedback circuit. Using the RNA binding protein immunoprecipitation (RIP) assay, we demonstrated that miR-210 directly governs the expression of CPEB2. The inverse relationship between CPEB2 expression and miR-210-3p in HCC tissues suggested that this regulatory mechanism is directly linked to HCC metastasis, EMT, and clinical outcomes. Moreover, utilizing the SM2miR database, we identified drugs that can decrease miR-210-3p expression, consequently increasing CPEB2 expression and providing new insights for drug development. In conclusion, our findings illustrated a novel HIF-1α/miR-210-3p/CPEB2 regulatory signaling pathway in HCC and highlighted the potential of enhancing CPEB2 expression through targeting miR-210-3p as a novel predictive biomarker and therapeutic strategy in HCC, as it is modulated by the HIF-1α/miR-210-3p/CPEB2 feedback circuit.

PMID:37514073 | DOI:10.3390/pharmaceutics15071887

Pharmaceuticals (Basel). 2023 Jul 3;16(7):954. doi: 10.3390/ph16070954.

ABSTRACT

The long-term use of psychopharmacology medications in autism spectrum disorder (ASD) hitherto remains controversial due to a lack of evidence about safety and tolerability. In this regard, genotyping the metabolizing enzyme cytochrome P450 (CYP) 2D6, especially its extreme phenotypes, could help to prevent drug-related adverse reactions or adverse events (AEs). There are several medications warranting CYP2D6 screening that are consumed by people with ASD, such as risperidone and aripiprazole to name a few. A naturalistic observational study was carried out in participants with ASD to analyze the influence of the CYP2D6 phenotype in drug tolerability using a local pharmacovigilance system created for this study. In this case, AEs were identified from participants' electronic health records (EHRs) and paper registries. Other variables were collected: socio-demographic information, comorbidities, and psychopharmacology prescriptions (polypharmacy defined as ≥4 simultaneous prescriptions) and doses. The genetic analysis included allelic discrimination (CYP2D6*1, *2, *3, *4, *5, *6, *10, *17, and *41) and copy number variations. All of these were used to determine theoretical phenotypes of the metabolic profiles: poor (PM); intermediate (IM); normal (NM); and ultra-rapid (UM). Sex differences were analyzed. A total of 71 participants (30 ± 10 years old, 82% male, 45% CYP2D6 NM phenotype (32 participants)) with a median of 3 (IQR 2-4) comorbidities per person, mainly urinary incontinence (32%) and constipation (22%), were included. CYP2D6 UM showed the highest rate of polypharmacy, whilst, IM participants had the highest rates of neurological and psychiatric AEs, even worse if a CYP2D6 inhibitor drug was prescribed simultaneously. CYP2D6 pharmacogenomics and the monitoring of new antipsychotic prescriptions may make a difference in medication safety in adults with ASD. Particularly in those with psychopharmacology polymedication, it can help with AE avoidance and understanding.

PMID:37513866 | DOI:10.3390/ph16070954

Life (Basel). 2023 Jul 10;13(7):1532. doi: 10.3390/life13071532.

ABSTRACT

BACKGROUND: AKT1 is a serine/threonine kinase necessary for the mediation of apoptosis, angiogenesis, metabolism, and cell proliferation in both normal and cancerous cells. The mutations in the AKT1 gene have been associated with different types of cancer. Further, the AKT1 gene mutations are also reported to be associated with other diseases such as Proteus syndrome and Cowden syndromes. Hence, this study aims to identify the deleterious AKT1 missense SNPs and predict their effect on the function and structure of the AKT1 protein using various computational tools.

METHODS: Extensive in silico approaches were applied to identify deleterious SNPs of the human AKT1 gene and assessment of their impact on the function and structure of the AKT1 protein. The association of these highly deleterious missense SNPs with different forms of cancers was also analyzed. The in silico approach can help in reducing the cost and time required to identify SNPs associated with diseases.

RESULTS: In this study, 12 highly deleterious SNPs were identified which could affect the structure and function of the AKT1 protein. Out of the 12, four SNPs-namely, G157R, G159V, G336D, and H265Y-were predicted to be located at highly conserved residues. G157R could affect the ligand binding to the AKT1 protein. Another highly deleterious SNP, R273Q, was predicted to be associated with liver cancer.

CONCLUSIONS: This study can be useful for pharmacogenomics, molecular diagnosis of diseases, and developing inhibitors of the AKT1 oncogene.

PMID:37511907 | DOI:10.3390/life13071532