Phytochem Anal. 2022 Jun 6. doi: 10.1002/pca.3147. Online ahead of print.

ABSTRACT

INTRODUCTION: Citri Reticulatae Pericarpium Viride (CRPV, Qing Pi in Chinese) has been widely used in traditional Chinese medicine. Polymethoxylated flavonoids (PMFs), which are a special group of flavonoids with strong antitumor activity, are broadly distributed in citrus peels. However, systematic investigation of antitumor PMFs in CRPV has received little attention to date.

OBJECTIVES: An MCF-7 cell biospecific extraction method integrated with neutral loss/diagnostic ion filtering-based HPLC-QTOF-MS/MS strategy was developed for rapid and specific profiling of antitumor PMFs and systematic identification of PMFs in CRPV.

METHODOLOGY: By incubating MCF-7 cells with CRPV extract, potential antitumor PMFs specifically bound to cells and were isolated. Then, by systematic investigation of fragmentation pathways, neutral loss and diagnostic ion filtering strategies were proposed to comprehensively and accurately identify PMFs.

RESULTS: Sixteen antitumor PMFs were unambiguously or tentatively identified. Among them, minor compound 15 (5-hydroxy-6,7,8,3',4'-pentamethoxyflavone with a free hydroxyl group at C-5) exhibited excellent antitumor activity, with an IC50 value of 2.81 ± 0.76 μg/mL, which is lower than that of 5-fluorouracil (IC50 , 4.92 ± 0.83 μg/mL). Nobiletin (12) and tangeretin (16), two major PMFs, presented moderate antitumor activities with IC50 values of 13.06 ± 1.85 and 17.07 ± 1.18 μg/mL, respectively, and their contents were sensitively and precisely determined.

CONCLUSIONS: To the best of our knowledge, this is the first report on the systematic investigation of antitumor PMFs in CRPV. The study will lay a foundation for the quality control and clinical application of CRPV.

PMID:35668040 | DOI:10.1002/pca.3147

Clin Colorectal Cancer. 2022 May 11:S1533-0028(22)00055-X. doi: 10.1016/j.clcc.2022.05.001. Online ahead of print.

ABSTRACT

BACKGROUND: Adjuvant fluoropyrimidine-based chemotherapy substantially reduces recurrence and mortality after resection of stage 3 colon cancer. While standard doses of 5-fluorouracil and capecitabine are safe for most patients, the risk of severe toxicity is increased for the approximately 6% of patients with dihydropyimidine dehydrogenase (DPD) deficiency caused by pathogenic DPYD gene variants. Pre-treatment screening for pathogenic DPYD gene variants reduces severe toxicity but has not been widely adopted in the United States.

METHODS: We conducted a cost-effectiveness analysis of DPYD genotyping prior to fluoropyrimidine-based adjuvant chemotherapy for stage 3 colon cancer, covering the c.1129-5923C>G (HapB3), c.1679T>G (*13), c.1905+1G>A (*2A), and c.2846A>T gene variants. We used a Markov model with a 5-year horizon, taking a United States healthcare perspective. Simulated patients with pathogenic DPYD gene variants received reduced-dose fluoropyrimidine chemotherapy. The primary outcome was the incremental cost-effectiveness ratio (ICER) for DPYD genotyping.

RESULTS: Compared with no screening for DPD deficiency, DPYD genotyping increased per-patient costs by $78 and improved survival by 0.0038 quality-adjusted life years (QALYs), leading to an ICER of $20,506/QALY. In 1-way sensitivity analyses, The ICER exceeded $50,000 per QALY when the cost of the DPYD genotyping assay was greater than $286. In probabilistic sensitivity analysis using a willingness-to-pay threshold of $50,000/QALY DPYD genotyping was preferred to no screening in 96.2% of iterations.

CONCLUSION: Among patients receiving adjuvant chemotherapy for stage 3 colon cancer, screening for DPD deficiency with DPYD genotyping is a cost-effective strategy for preventing infrequent but severe and sometimes fatal toxicities of fluoropyrimidine chemotherapy.

PMID:35668003 | DOI:10.1016/j.clcc.2022.05.001

Phytomedicine. 2022 May 28;102:154218. doi: 10.1016/j.phymed.2022.154218. Online ahead of print.

ABSTRACT

BACKGROUND: Cannabis oils from FM2®, Bedica®, Bediol®, Bedrocan®, Bedrolite® and Pedanios 22/1® are largely used for medical purposes such as spasticity, chronic pain and appetite stimulating. Several studies showed cannabinoids action on CB1 and CB2 receptors reduces the hyperalgesic phase in inflammatory pain, leading to an improvement of conditions. The active compounds of these galenic preparations show a high variability making titration mandatory. For this reason, the exact oil composition knowledge is fundamental for personalizing therapy. This amis at adapting the correct dose to the patient, improving safety and efficacy of the galenic formulation, choosing the best preparation for each patient.

PURPOSE: The aim of this study was to investigate oil preparations variability among different galenic laboratories in order to highlight the importance of titration activity.

METHODS: Cannabis pharmacological active compounds titration has been performed in a large cohort of galenic laboratories in Italy. CBD, CBN, THC, THCA and CBDA quantification was carried out by a previous validated method in UHPLC-MS/MS.

RESULTS: A number of 4318 samples of Cannabis oil from 83 pharmacies between January 2021 and February 2022 were evaluated. All galenic preparation specialities showed statistically significant differences among galenic laboratories (p-value < 0.001). THCA and CBDA concentrations were investigated as percentage of the extration yelds for total THC and CBD: these compounds had different values in the same specialities among distinct galenic laboratories. Moreover, seasonal variability in analytes concentrations was observed.

CONCLUSION: This study described a wide range of oily samples from a large number of galenic laboratories, compared to published papers. In conclusion, knowledge of the exact oil composition is fundamental in the perspective of personalized therapy. Further studies aiming at the correlation between galenic composition and cannabinoids pharmacokinetics, clinical outcomes and toxic effects could be useful to improve our knowledge.

PMID:35665680 | DOI:10.1016/j.phymed.2022.154218

Front Genet. 2022 May 19;13:836970. doi: 10.3389/fgene.2022.836970. eCollection 2022.

ABSTRACT

Background: Statins are the most popular agents for the primary and secondary prevention of cardiovascular disease; however, the pharmacokinetic parameters and associated genetic factors in the Korean population have not been fully elucidated. This study explored the pharmacokinetic properties of atorvastatin and the association between genetic variations and atorvastatin pharmacokinetics in healthy Korean subjects. Methods: Atorvastatin (80 mg) was administered to 35 healthy Korean volunteers. Plasma levels of atorvastatin and its metabolites were measured sequentially using liquid chromatography-tandem mass spectrometry from 0 to 24 h after atorvastatin administration. Customized next-generation sequencing analysis was performed covering all coding exons of 15 genes, as well as 46 single-nucleotide variants in 29 genes related to statin pharmacokinetics. Results: The mean area under the concentration-time (AUC) and Cmax (maximum peak concentration) were 269.0 ng/ml∙h and 84.3 ng/ml, respectively, which were approximately two times higher than those reported in Caucasians. Genetic analysis revealed that eight genetic variants in ABCB1, ABCG2, APOA5, CETP, and CYP7A1 contributed to the AUC of atorvastatin. The atorvastatin AUC0-24 h prediction model was developed based on age and eight genetic variants using multivariate linear regression (adjusted R 2 = 0.878, p < 0.0001). Conclusion: This study shows that the pharmacokinetic properties of atorvastatin in Koreans are different from those in Caucasians and that atorvastatin AUC0-24 h could be predicted based on age and eight genetic variants of ABCB1, ABCG2, APOA5, CETP, and CYP7A1.

PMID:35664336 | PMC:PMC9160745 | DOI:10.3389/fgene.2022.836970

Front Genet. 2022 May 19;13:869160. doi: 10.3389/fgene.2022.869160. eCollection 2022.

ABSTRACT

Omeprazole is extensively used to manage gastroesophageal reflux disease (GERD). It is primarily metabolized by CYP2C19. The CYP2C19*17 (rs12248560) allele and the recently described CYP2C:TG haplotype (rs11188059 and rs2860840) are associated with increased enzymatic activity, and may reduce omeprazole exposure. This observational study aimed to investigate the association between these genetic variants and omeprazole treatment failure in GERD. We recruited predominantly New Zealand European GERD patients who either did not respond to omeprazole or experienced breakthrough heartburn symptoms despite at least 8 weeks of omeprazole (≥40 mg/day). The GerdQ score was used to gauge symptomatic severity. A total of 55 cases were recruited with a median age (range) of 56 years (19-82) and GerdQ score of 11 (5-17). Of these, 19 (34.5%) were CYP2C19*17 heterozygotes and two (3.6%) were CYP2C19*17 homozygotes. A total of 30 (27.3%) CYP2C:TG haplotypes was identified in our cohort, with seven (12.7%) CYP2C:TG homozygotes, and 16 (29%) CYP2C:TG heterozygotes. No significant differences were observed for overall CYP2C19*17 alleles, CYP2C19*17/*17, overall CYP2C:TG haplotypes, and CYP2C:TG heterozygotes (p > 0.05 for all comparisons). Gastroscopy and 24-h esophageal pH/impedance tests demonstrated objective evidence of GERD in a subgroup of 39 (71%) cases, in which the CYP2C:TG/TG was significantly enriched (p = 0.03) when compared with the haplotype frequencies in a predominantly (91%) New Zealand European reference population, but not the CYP2C19*17/*17 (p > 0.99), when compared with the allele frequencies for the non-Finnish European subset of gnomAD. We conclude that omeprazole treatment failure in GERD is associated with CYP2C:TG/TG, but not CYP2C19*17.

PMID:35664313 | PMC:PMC9160307 | DOI:10.3389/fgene.2022.869160

Front Pharmacol. 2022 May 18;13:885259. doi: 10.3389/fphar.2022.885259. eCollection 2022.

ABSTRACT

The implementation of pharmacogenetic testing into clinical practice has been a slow process so far. Here, we review the implementation of pre-treatment testing of dihydropyrimidine dehydrogenase gene (DPYD) risk variants to prevent early-onset fluoropyrimidine (FP)-related toxicity in cancer patients in Switzerland based on data of a large Swiss diagnostic center. In January 2017, the Swiss Federal Office of Public Health introduced the reimbursement of DPYD testing by the compulsory health insurance in Switzerland based on evidence for the clinical relevance of DPYD-risk variants and the cost-effectiveness of pre-treatment testing, and on the availability of international guidelines. However, we did not observe a strong increase in DPYD testing at our diagnostic center from 2017 to 2019. Only a low number of DPYD-testing requests (28-42 per year), concerning mostly retrospective investigations of suspected FP-toxicity, were received. In contrast, we observed a 14-fold increase in DPYD testing together with a strong shift from retrospective to pre-treatment test requests upon the release of recommendations for DPYD testing prior to FP-treatment in April 2020 by the European Medicines Agency. This increase was mainly driven by three geographic regions of Switzerland, where partner institutions of previous research collaborations regarding FP-related toxicity are located and who acted as early-adopting institutions of DPYD testing. Our data suggest the important role of early adopters as accelerators of clinical implementation of pharmacogenetic testing by introducing these policies to their working environment and educating health workers from their own and nearby institutions.

PMID:35662713 | PMC:PMC9159275 | DOI:10.3389/fphar.2022.885259

Contemp Clin Trials. 2022 Jun 1:106813. doi: 10.1016/j.cct.2022.106813. Online ahead of print.

ABSTRACT

RATIONALE AND OBJECTIVE: APOL1 risk alleles are associated with increased cardiovascular and chronic kidney disease (CKD) risk. It is unknown whether knowledge of APOL1 risk status motivates patients and providers to attain recommended blood pressure (BP) targets to reduce cardiovascular disease.

STUDY DESIGN: Multicenter, pragmatic, randomized controlled clinical trial.

SETTING AND PARTICIPANTS: 6650 individuals with African ancestry and hypertension from 13 health systems.

INTERVENTION: APOL1 genotyping with clinical decision support (CDS) results are returned to participants and providers immediately (intervention) or at 6 months (control). A subset of participants are re-randomized to pharmacogenomic testing for relevant antihypertensive medications (pharmacogenomic sub-study). CDS alerts encourage appropriate CKD screening and antihypertensive agent use.

OUTCOMES: Blood pressure and surveys are assessed at baseline, 3 and 6 months. The primary outcome is change in systolic BP from enrollment to 3 months in individuals with two APOL1 risk alleles. Secondary outcomes include new diagnoses of CKD, systolic blood pressure at 6 months, diastolic BP, and survey results. The pharmacogenomic sub-study will evaluate the relationship of pharmacogenomic genotype and change in systolic BP between baseline and 3 months.

RESULTS: To date, the trial has enrolled 3423 participants.

CONCLUSIONS: The effect of patient and provider knowledge of APOL1 genotype on systolic blood pressure has not been well-studied. GUARDD-US addresses whether blood pressure improves when patients and providers have this information. GUARDD-US provides a CDS framework for primary care and specialty clinics to incorporate APOL1 genetic risk and pharmacogenomic prescribing in the electronic health record.

TRIAL REGISTRATION: ClinicalTrials.govNCT04191824.

PMID:35660539 | DOI:10.1016/j.cct.2022.106813

Adv Pharmacol. 2022;94:141-182. doi: 10.1016/bs.apha.2022.04.001. Epub 2022 May 24.

ABSTRACT

The idea of personalized medicine came to fruition with sequencing the human genome; however, aside from a few cases, the genetic revolution has yet to materialize. Cardiovascular diseases are the leading cause of death globally, and hypertension is a common prelude to nearly all cardiovascular diseases. Thus, hypertension is an ideal candidate disease to apply tenants of personalized medicine to lessen cardiovascular disease. Herein is a survey that visually depicts the polymorphisms in the top eight antihypertensive targets. Although there are numerous genome-wide association studies regarding cardiovascular disease, few studies look at the effects of receptor polymorphisms on drug treatment. With 17,000+ polymorphisms in the combined target proteins examined, it is expected that some of the clinical variability in the treatment of hypertension is due to polymorphisms in the drug targets. Recent advances in techniques and technology, such as high throughput examination of single mutations, structure prediction, computational power for modeling, and CRISPR models of point mutations, allow for a relatively rapid and comprehensive examination of the effects of known and future polymorphisms on drug affinity and effects. As hypertension is easy to measure and has a plethora of clinically viable ligands, hypertension makes an excellent disease to study pharmacogenomics in the lab and the clinic. If the promises of personalized medicine are to materialize, a concerted effort to examine the effects polymorphisms have on drugs is required. A clinician with the knowledge of a patient's genotype can then prescribe drugs that are optimal for treating that specific patient.

PMID:35659371 | DOI:10.1016/bs.apha.2022.04.001

Front Aging Neurosci. 2022 May 17;14:896371. doi: 10.3389/fnagi.2022.896371. eCollection 2022.

NO ABSTRACT

PMID:35656536 | PMC:PMC9152086 | DOI:10.3389/fnagi.2022.896371

Front Pharmacol. 2022 May 17;13:909504. doi: 10.3389/fphar.2022.909504. eCollection 2022.

ABSTRACT

Cancer cell lysosomes contain various hydrolases and non-degraded substrates that are corrosive enough to destroy cancer cells. However, many traditional small molecule drugs targeting lysosomes have strong side effects because they cannot effectively differentiate between normal and cancer cells. Most lysosome-based research has focused on inducing mild lysosomal membrane permeabilization (LMP) to release anticancer drugs from lysosomal traps into the cancer cell cytoplasm. In fact, lysosomes are particularly powerful "bombs". Achieving cancer cell-selective LMP induction may yield high-efficiency anticancer effects and extremely low side effects. Nanodrugs have diverse and combinable properties and can be specifically designed to selectively induce LMP in cancer cells by taking advantage of the differences between cancer cells and normal cells. Although nanodrugs-induced LMP has made great progress recently, related reviews remain rare. Herein, we first comprehensively summarize the advances in nanodrugs-induced LMP. Next, we describe the different nanodrugs-induced LMP strategies, namely nanoparticles aggregation-induced LMP, chemodynamic therapy (CDT)-induced LMP, and magnetic field-induced LMP. Finally, we analyze the prospect of nanodrugs-induced LMP and the challenges to overcome. We believe this review provides a unique perspective and inspiration for designing lysosome-targeting drugs.

PMID:35656308 | PMC:PMC9152002 | DOI:10.3389/fphar.2022.909504

Nat Chem Biol. 2022 Jun 2. doi: 10.1038/s41589-022-01044-0. Online ahead of print.

ABSTRACT

The growing appreciation of immune cell-cell interactions within disease environments has led to extensive efforts to develop immunotherapies. However, characterizing complex cell-cell interfaces in high resolution remains challenging. Thus, technologies leveraging therapeutic-based modalities to profile intercellular environments offer opportunities to study cell-cell interactions with molecular-level insight. We introduce photocatalytic cell tagging (PhoTag) for interrogating cell-cell interactions using single-domain antibodies (VHHs) conjugated to photoactivatable flavin-based cofactors. Following irradiation with visible light, the flavin photocatalyst generates phenoxy radical tags for targeted labeling. Using this technology, we demonstrate selective synaptic labeling across the PD-1/PD-L1 axis in antigen-presenting cell-T cell systems. In combination with multiomics single-cell sequencing, we monitored interactions between peripheral blood mononuclear cells and Raji PD-L1 B cells, revealing differences in transient interactions with specific T cell subtypes. The utility of PhoTag in capturing cell-cell interactions will enable detailed profiling of intercellular communication across different biological systems.

PMID:35654846 | DOI:10.1038/s41589-022-01044-0

Endocrinol Metab (Seoul). 2022 Jun 3. doi: 10.3803/EnM.2021.1349. Online ahead of print.

ABSTRACT

Vitamin D has received considerable optimistic attention as a potentially important factor in many pathological states over the past few decades. However, the proportion of the active form of vitamin D metabolites responsible for biological activity is highly questionable in disease states due to flexible alterations in the enzymes responsible for their metabolism. For instance, CYP3A4 plays a crucial role in the biotransformation of vitamin D and other drug substances. Food-drug and/or drug-drug interactions, the disease state, genetic polymorphism, age, sex, diet, and environmental factors all influence CYP3A4 activity. Genetic polymorphisms in CYP450-encoding genes have received considerable attention in the past few decades due to their extensive impact on the pharmacokinetic and dynamic properties of drugs and endogenous substances. In this review, we focused on CYP3A4 polymorphisms and their interplay with vitamin D metabolism and summarized the role of vitamin D in calcium homeostasis, bone diseases, diabetes, cancer, other diseases, and drug substances. We also reviewed clinical observations pertaining to CYP3A4 polymorphisms among the aforementioned disease conditions. In addition, we highlighted the future perspectives of studying the pharmacogenetics of CYP3A4, which may have potential clinical significance for developing novel diagnostic genetic markers that will ascertain disease risk and progression.

PMID:35654576 | DOI:10.3803/EnM.2021.1349

Eur J Clin Pharmacol. 2022 Jun 2. doi: 10.1007/s00228-022-03345-8. Online ahead of print.

ABSTRACT

PURPOSE: Imatinib is a substrate of CYP3A4, ABCB1 and ABCG2, and is known to have wide variability in pharmacokinetics (PK). At the same time, a clear relationship between drug levels and response also exists for imatinib in chronic myeloid leukaemia (CML). Therefore, pharmacogenetic-based dosing of imatinib is an attractive proposition. This study aims to characterize the population pharmacokinetics of imatinib in order to identify significant covariates including pharmacogenetic variants.

METHODS: Forty-nine patients with CML were enrolled in the study after being on imatinib for at least 4 consecutive weeks. Steady-state pharmacokinetic sampling was performed either in a sparse (4 samples each, n = 44) or intensive manner (9 samples each, n = 5). An additional pharmacogenetic sample was also collected from all patients. Plasma imatinib levels were estimated using a validated HPLC method. Pharmacogenetic variants were identified using the PharmacoScan array platform. Population pharmacokinetic analysis was carried out using NONMEM v7.2. Seven SNPs within CYP3A4, ABCB1 and ABCG2 genes were evaluated for covariate effect on the clearance of imatinib.

RESULTS: Imatinib PK was well characterized using a one-compartment model with zero-order absorption. The clearance and volume of distribution were found to be 10.2 L/h and 389 L respectively. Only SNP rs1128503 of the ABCB1 gene had a small but insignificant effect on imatinib clearance, with a 25% reduction in clearance observed in patients carrying the polymorphism. Twenty-three out of forty-nine patients (47%) carried the polymorphic allele, of whom 17 were heterozygous and six were homozygous.

CONCLUSION: Our study conclusively proves that genetic polymorphisms in the CYP3A4 and ABC family of transporters do not have any role in the personalized dosing of imatinib in CML.

PMID:35652931 | DOI:10.1007/s00228-022-03345-8

Eur Heart J Qual Care Clin Outcomes. 2022 Jun 2:qcac031. doi: 10.1093/ehjqcco/qcac031. Online ahead of print.

ABSTRACT

AIM: CYP2C19-guided P2Y12 inhibitor selection can reduce cardiovascular events and bleeding in patients with acute coronary syndromes (ACS) post-percutaneous coronary intervention (PCI). The 12-month cost-effectiveness of CYP2C19-guided P2Y12 inhibitor selection for Veterans post-ACS/PCI was evaluated from the Veteran Health Administration's (VHA) perspective.

METHODS AND RESULTS: Using average annualized PCI volumes and P2Y12 inhibitor use from VA data, a decision-analytic model simulated CYP2C19 testing versus no testing outcomes in 2800 hypothetical Veterans receiving PY212 inhibitor for 12 months post-ACS/PCI (74% clopidogrel, 5% prasugrel, 21% ticagrelor use at baseline without testing). CYP2C19 loss-of-function (LOF) carrier prevalence was 28%. Model inputs were from studies (bleeding/ischemic events, CYP2C19-guided therapy effect, health state utilities, CYP2C19 LOF carrier prevalence) and VHA administrative data (costs of events, drugs, CYP2C19 testing; PCI volumes, P2Y12 inhibitor prescriptions). The primary outcome was cost (2020 US${\$}$) per quality-adjusted life year (QALY) gained. Base-case scenario, probabilistic sensitivity analyses, and scenario analyses were completed. CYP2C19-guided therapy resulted in 496 (24%) escalations (clopidogrel to prasugrel/ticagrelor) and 465 (65%) de-escalations (prasugrel/ticagrelor to clopidogrel). CYP2C19 testing averted 1 stroke, 27 myocardial infarctions, 8 cardiovascular-related deaths, and caused 3 bleeds. CYP2C19 testing (vs no testing) was dominant in base-case scenario (0.0027 QALYs gained, ${\$}$527 saved/person) and in 97.1% of simulations, making it cost-effective and high-value. In scenario analyses, de-escalation in conjunction with escalation is required for CYP2C19 testing to be cost-effective and high-value.

CONCLUSIONS: In Veterans post-ACS/PCI, CYP2C19-guided P2Y12 inhibitor selection can improve cardiovascular outcomes and lower costs for the VHA within 12 months of implementation.

PMID:35652783 | DOI:10.1093/ehjqcco/qcac031

Expert Opin Drug Metab Toxicol. 2022 Jun 1. doi: 10.1080/17425255.2022.2085552. Online ahead of print.

ABSTRACT

INTRODUCTION: Opioids play a fundamental role in chronic pain, especially considering when 1 of 5 Europeans adults, even more in older females, suffer from it. However, half of them do not reach an adequate pain relief. Could pharmacogenomics help to choose the most appropriate analgesic drug?

AREAS COVERED: The objective of the present narrative review was to assess the influence of cytochrome P450 2D6 (CYP2D6) phenotypes on pain relief, analgesic tolerability and potential opioid misuse. Until December 2021, a literature search was conducted through the MEDLINE, PubMed database, including papers from the last 10 years. CYP2D6 plays a major role in metabolism that directly impacts on opioid (tramadol, codeine or oxycodone) concentration with differences between sexes, with a female trend towards poorer pain control. In fact, CYP2D6 gene variants are the most actionable to be translated into clinical practice according to regulatory drug agencies and international guidelines.

EXPERT OPINION: CYP2D6 genotype can influence opioids' pharmacokinetics, effectiveness, side effects, and average opioid dose. This knowledge needs to be incorporated in pain management. Environmental factors, psychological together with genetic factors, under a sex perspective, must be considered when you are selecting the most personalized pain therapy for your patients.

PMID:35649041 | DOI:10.1080/17425255.2022.2085552

Cancer. 2022 Jun 1. doi: 10.1002/cncr.34269. Online ahead of print.

ABSTRACT

BACKGROUND: Pancreatic adenocarcinoma (PDAC) remains a refractory disease; however, modern cytotoxic chemotherapeutics can induce tumor regression and extend life. A blood-based, pharmacogenomic, chemosensitivity assay using gene expression profiling of circulating tumor and invasive cells (CTICs) to predict treatment response was previously developed. The combination regimen of 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) and gemcitabine/nab-paclitaxel (G/nab-P) are established frontline approaches for treating advanced PDAC; however, there are no validated biomarkers for treatment selection. A similar unmet need exists for choosing second-line therapy.

METHODS: The chemosensitivity assay was evaluated in metastatic PDAC patients presenting for frontline treatment. A prospective study enrolled patients (n = 70) before receiving either FOLFIRINOX or G/nab-P at a 1:1 ratio. Six milliliters of peripheral blood was collected at baseline and at time of disease progression. CTICs were isolated, gene-expression profiling was performed, and the assay was used to predict effective and ineffective chemotherapeutic agents. Treating physicians were blinded to the assay prediction results.

RESULTS: Patients receiving an effective regimen as predicted by the chemosensitivity assay experienced significantly longer median progression-free survival (mPFS; 7.8 months vs. 4.2 months; hazard ratio [HR], 0.35; p = .0002) and median overall survival (mOS; 21.0 months vs. 9.7 months; HR, 0.40; p = .005), compared with an ineffective regimen. Assay prediction for effective second-line therapy was explored. The entire study cohort experienced favorable outcomes compared with historical controls, 7.1-month mPFS and 12.3-month mOS.

CONCLUSIONS: Chemosensitivity assay profiling is a promising tool for guiding therapy in advanced PDAC. Further prospective validation is under way (clinicaltrials.gov NCT03033927).

PMID:35647938 | DOI:10.1002/cncr.34269

Am Heart J Plus. 2022 Mar;15:100136. doi: 10.1016/j.ahjo.2022.100136. Epub 2022 Apr 27.

ABSTRACT

BACKGROUND: Filipino Americans (FAs) are the third-largest Asian American subgroup in the United States (US). Some studies showed that FAs experience more cardiometabolic diseases (CMDs) than other Asian subgroups and non-Hispanic Whites. The increased prevalence of CMD observed in FAs could be due to genetics and social/dietary lifestyles. While FAs are ascribed as an Asian group, they have higher burdens of CMD, and adverse social determinants of health compared to other Asian subgroups. Therefore, studies to elucidate how FAs might develop CMD and respond to medications used to manage CMD are warranted. The ultimate goals of this study are to identify potential mechanisms for reducing CMD burden in FAs and to optimize therapeutic drug selection. Collectively, these investigations could reduce the cardiovascular health disparities among FAs.

RATIONALE AND DESIGN: This is a cross-sectional epidemiological design to enroll 300 self-identified Filipino age 18 yrs. or older without a history of cancer and/or organ transplant from Virginia, Washington DC, and Maryland. Once consented, a health questionnaire and disease checklist are administered to participants, and anthropometric data and other vital signs are collected. When accessible, we collect blood samples to measure basic blood biochemistry, lipids, kidney, and liver functions. We also extract DNA from the blood or saliva for genetic and pharmacogenetic analyses. CMD prevalence in FAs will be compared to the US population. Finally, we will conduct multivariate analyses to ascertain the role of genetic and non-genetic factors in developing CMD in FAs. Virginia Commonwealth University IRB approved all study materials (Protocol HM20018500).

SUMMARY: This is the first community-based study to involve FAs in genomics research. The study is actively recruiting participants. Participant enrollment is ongoing. At the time of this publication, the study has enrolled 97 participants. This ongoing study is expected to inform future research to reduce cardiovascular health disparities among FAs.

PMID:35647570 | PMC:PMC9139029 | DOI:10.1016/j.ahjo.2022.100136

AIMS Mol Sci. 2022;9(2):66-78. doi: 10.3934/molsci.2022004. Epub 2022 Apr 28.

ABSTRACT

Clopidogrel is a purinergic receptor P2Y12 (P2RY12)-blocking pro-drug used to inhibit platelet aggregation in patients at risk for major adverse cardiac events (MACE), such as coronary artery disease and stroke. Despite clopidogrel therapy, some patients may still present with recurrent cardiovascular events. One possible cause of recurrence are variants in the cytochrome P450 2C19 (CYP2C19) gene. CYP2C19 is responsible for the metabolism of many drugs including clopidogrel. Recent studies have associated pharmacogenetics testing of CYP2C19 variants to guide clopidogrel therapy with a decreased risk of certain recurrent MACEs. Through a different mechanism, diabetes mellitus (DM) and obesity are also associated with clopidogrel treatment failure. We describe the case of a 64-year-old Caucasian woman with a history of acute coronary syndrome (ACS) and percutaneous coronary intervention (PCI), and DM/obesity, who presented to University of Texas Medical Branch (UTMB) in 2019 with a transient ischemic attack (TIA) while on clopidogrel/aspirin dual anti-platelet therapy. After CYP2C19 genetic testing revealed that she was an intermediate metabolizer with a heterozygous *2 genotype, ticagrelor replaced the clopidogrel treatment regimen. No future MACEs were documented in the two-year patient follow-up. Thus, ACS patients with DM/obesity who have undergone PCI and are intermediate CYP2C19 metabolizers may yield better treatment outcomes if prescribed ticagrelor instead of clopidogrel. Whether this improvement was due to genotype-guided therapy or the differing interactions of clopidogrel/ticagrelor in DM/obese patients is unknown based on available data. Regardless, CYP2C19 genotype-guided treatment of ACS/PCI patients, with consideration of DM/obesity status, may provide effective individualized therapy compared to standard treatment. The inclusion of DM/obesity in this study is clinically relevant because DM/obesity has become a major health issue in the United States and worldwide.

PMID:35647265 | PMC:PMC9140224 | DOI:10.3934/molsci.2022004

Front Cell Dev Biol. 2022 May 12;10:868465. doi: 10.3389/fcell.2022.868465. eCollection 2022.

ABSTRACT

Mitochondrial repair is essential to metabolic homeostasis. Outer mitochondrial membrane mitofusin (MFN) proteins orchestrate mitochondrial fusion that opposes mitochondrial degeneration caused by senescence. Depending upon physiological context, MFN2 can either mediate mitochondrial fusion or recruit cytosolic Parkin to initiate mitophagic elimination. Because it is not clear how these events are counter-regulated we engineered and expressed MFN2 mutants that mimic phosphorylated or non-phosphorylatable MFN2 at its PINK1 phosphorylation sites: T111, S378, and S442. By interrogating mitochondrial fusion, polarization status, and Parkin binding/mitophagy as a function of inferred MFN2 phosphorylation, we discovered that individual MFN2 phosphorylation events act as a biological "bar-code", directing mitochondrial fate based on phosphorylation site state. Experiments in Pink1 deficient cells supported a central role for PINK1 kinase as the pivotal regulator of MFN2 functionality. Contrary to popular wisdom that Parkin-mediated ubiquitination regulates MFN-mediated mitochondrial fusion, results in Prkn null cells demonstrated the dispensability of Parkin for MFN2 inactivation. These data demonstrate that PINK1-mediated phosphorylation is necessary and sufficient, and that Parkin is expendable, to switch MFN2 from fusion protein to mitophagy effector.

PMID:35646911 | PMC:PMC9133611 | DOI:10.3389/fcell.2022.868465

Front Oncol. 2022 May 11;12:842200. doi: 10.3389/fonc.2022.842200. eCollection 2022.

ABSTRACT

Multiple myeloma (MM) is an incurable plasma cell malignancy with dose-limiting toxicities and inter-individual variation in response/resistance to the standard-of-care/primary drugs, proteasome inhibitors (PIs), and immunomodulatory derivatives (IMiDs). Although newer therapeutic options are potentially highly efficacious, their costs outweigh the effectiveness. Previously, we have established that clofazimine (CLF) activates peroxisome proliferator-activated receptor-γ, synergizes with primary therapies, and targets cancer stem-like cells (CSCs) in drug-resistant chronic myeloid leukemia (CML) patients. In this study, we used a panel of human myeloma cell lines as in vitro model systems representing drug-sensitive, innate/refractory, and clonally-derived acquired/relapsed PI- and cereblon (CRBN)-negative IMiD-resistant myeloma and bone marrow-derived CD138+ primary myeloma cells obtained from patients as ex vivo models to demonstrate that CLF shows significant cytotoxicity against drug-resistant myeloma as single-agent and in combination with PIs and IMiDs. Next, using genome-wide transcriptome analysis (RNA-sequencing), single-cell proteomics (CyTOF; Cytometry by time-of-flight), and ingenuity pathway analysis (IPA), we identified novel pathways associated with CLF efficacy, including induction of ER stress, autophagy, mitochondrial dysfunction, oxidative phosphorylation, enhancement of downstream cascade of p65-NFkB-IRF4-Myc downregulation, and ROS-dependent apoptotic cell death in myeloma. Further, we also showed that CLF is effective in killing rare refractory subclones like side populations that have been referred to as myeloma stem-like cells. Since CLF is an FDA-approved drug and also on WHO's list of safe and effective essential medicines, it has strong potential to be rapidly re-purposed as a safe and cost-effective anti-myeloma drug.

PMID:35646666 | PMC:PMC9130773 | DOI:10.3389/fonc.2022.842200