Expert Opin Drug Metab Toxicol. 2021 Apr 22. doi: 10.1080/17425255.2021.1921146. Online ahead of print.

ABSTRACT

INTRODUCTION: : Mitotane is the only drug registered specifically for adrenocortical carcinoma. Finding the optimal dose for a patient is difficult due to large differences in bioavailability, toxicity and effect. We therefore look to improve personalized dosing of mitotane.

AREAS COVERED: : We searched PubMed for studies related to mitotane dosing, pharmacokinetics, pharmacogenetics and combination therapy. Comparison of different dosing strategies have not resulted in an optimal advice. Several computerized pharmacokinetic models have been proposed to predict plasma levels. The current pharmacokinetic models do not explain the full variance in plasma levels. Pharmacogenetics have been proposed to find the unexplained variance. Studies on combination therapy have not yet led to a potential dose adjustment for mitotane.

EXPERT OPINION: : Computerized pharmacokinetics models are promising tools to predict plasma levels, further validation is needed. Pharmacogenetics are introduced in these models, but more research is required before clinical application. We believe that in the near future, personalized mitotane dosage will be aided by a validated web-based pharmacokinetic model with good predictive ability based primarily on clinical characteristics, adjustable for actual plasma levels and dosage.

PMID:33886381 | DOI:10.1080/17425255.2021.1921146

Soc Stud Sci. 2021 Apr 22:3063127211005539. doi: 10.1177/03063127211005539. Online ahead of print.

ABSTRACT

Personalized medicine raises the stakes of pharmaceutical market regulation. Drawing on pragmatist valuation studies and science and technology studies literature on personalized medicine and pharmaceutical markets, this article demonstrates how complex negotiations about the value of a pharmaceutical can constitute a market in various ways, while also shaping the concerned patient populations. Tracing the path of a pharmacogenetic treatment, Spinraza, from its approval by the European Medicines Agency to its adoption in the publicly funded Danish healthcare system, we show how the market was formatted through particular stratifications of the patient population. We conceptualize these seemingly technical moves as strategies of stratification, that is, the application of techniques to assemble and divide data - and what data are meant to represent - into groups delineated by certain characteristics. We argue that stakeholders' use of strategies of stratification has important implications not only for market access, but also for the delineation of diseases and patient populations. Hence, it is crucial to make intelligible the mutual constitution of pharmaceutical markets and patient populations and the political efforts of delineating and connecting the two.

PMID:33885344 | DOI:10.1177/03063127211005539

J Genet Couns. 2021 Apr 21. doi: 10.1002/jgc4.1417. Online ahead of print.

ABSTRACT

The increasing number of genetic counselors participating directly in clinical pharmacogenomic post-test counseling prompted our evaluation of pharmacogenomic education across genetic counseling training programs in North America. Thirty-one program leadership participants from both the United States (U.S.) and Canada responded to a survey assessing pharmacogenomics education and the role of genetic counselors. Eighty-five percent of respondents agreed pharmacogenomics is currently within the scope of genetic counseling practice, and 96.3% indicated their training programs currently provide education on pharmacogenomics, with the majority reporting < 7 hr of education. Lectures on pharmacogenomics were the most common method for didactics; however, some programs also included practical modalities (e.g., case studies, clinical rotations) and online resources. Barriers to expanding pharmacogenomic education included the constrained timeline of training, and lack of resources and local expertise. Moreover, participants suggested that genetic counselors ideally should be able to order pharmacogenomic tests and counsel patients on pharmacogenomics, including result interpretation, as they believe pharmacogenomics does fall within the scope of practice of genetic counseling. Our novel results also confirm that training program leadership support a pharmacogenomic service delivery model that includes a combined effort between genetic counselors and pharmacists to utilize their synergistic expertise. However, this model likely still necessitates expanding pharmacogenomic didactics in genetic counseling training programs through more practical training and/or by leveraging online pharmacogenomic courses dedicated to supporting clinical implementation.

PMID:33882174 | DOI:10.1002/jgc4.1417

Clin Pharmacol Ther. 2021 Apr 20. doi: 10.1002/cpt.2270. Online ahead of print.

ABSTRACT

Pharmacogenetics (PGx) association studies are used to discover, replicate, and validate the association between an inherited genotype and a treatment outcome. The objective of this tutorial is to provide trainees and novice PGx researchers with an overview of the major decisions that need to be made when designing and conducting a PGx association study. The first critical decision is to determine whether the objective of the study is discovery, replication, or validation. Next, the researcher must identify a patient cohort that has all of the data necessary to conduct the intended analysis. Then, the investigator must select and define the treatment outcome, or phenotype, that will be analyzed. Next, the investigator must determine what genotyping approach and genetic data will be included in the analysis. Finally, the association between the genotype and phenotype is tested using some statistical analysis methodology. This tutorial is divided into 5 sections, each section describes commonly used approaches and provides suggestions and resources for designing and conducting a PGx association study. Successful PGx association studies are necessary to discover and validate associations between inherited genetic variation and treatment outcomes, which enable clinical translation to improve efficacy and reduce toxicity of treatment.

PMID:33880756 | DOI:10.1002/cpt.2270

Biol Res. 2021 Apr 20;54(1):13. doi: 10.1186/s40659-021-00336-4.

ABSTRACT

BACKGROUND: Helicobacter pylori is detected by pathogen recognition receptors including toll-like receptors (TLR) and nucleotide-binding oligomerization domain (NOD)-like receptors, eliciting an innate immune response against this bacteria. The aim of this study was to assess if polymorphisms of TLR2, TLR4, TLR5, NOD1 and NOD2 genes are associated with gastric cancer, in particular in individuals infected with H. pylori.

RESULTS: A case-control study of 297 gastric cancer patients and 300 controls was performed to assess the association of 17 polymorphisms. Analyses performed under the allele model did not find association with gastric cancer. However, NOD1 rs2075820 (p.E266K) showed association with intestinal-type gastric cancer among H. pylori infected subjects (OR = 2.69, 95% CI 1.41-5.13, p = 0.0026). The association was not statistically significant in diffuse-type gastric cancer cases (OR = 1.26, 95% CI 0.63-2.52, p = 0.51). When the analyses were performed in patients carrying H. pylori strains harboring the cag pathogenicity island (cagPAI), we noticed significant association with NOD1 rs2075820 (OR = 4.90, 95% CI 1.80-3.36, p = 0.0019), in particular for intestinal-type gastric cancer cases (OR = 7.16, 95% CI 2.40-21.33, p = 4.1 × 10- 4) but not among diffuse-type gastric cancer cases (OR = 3.39, 95% CI 1.13-0.10, p = 0.03).

CONCLUSIONS: NOD1 rs2075820 increases the risk of intestinal-type gastric cancer among individuals infected with H. pylori, particularly in those harboring the cagPAI.

PMID:33879265 | DOI:10.1186/s40659-021-00336-4

J Chromatogr B Analyt Technol Biomed Life Sci. 2021 Apr 8;1173:122698. doi: 10.1016/j.jchromb.2021.122698. Online ahead of print.

ABSTRACT

Tacrolimus is the cornerstone of immunosuppressive therapy in solid organ transplantation and its blood concentrations are routinely monitored. Tacrolimus is extensively metabolized into metabolites that are supposed to be nephrotoxic. Yet, few analytical methods have been described to simultaneously quantify tacrolimus and its main metabolites. We developed and validated a simple liquid chromatography-mass spectrometry method for the quantification of tacrolimus and its three desmethylated metabolites, 13-O, 15-O, and 31-O-desmethylated tacrolimus (M-I, M-III, and M-II respectively) in human whole blood. Protein precipitation of 50 µL of whole blood with 100 µL methanol and zinc sulfate was used as a single-extraction procedure. Tacrolimus and its metabolites were quantified using electrospray ionization-triple quadrupole mass spectrometry in combination with selected reaction monitoring detection in the positive ionization mode. The method was validated following FDA recommendations. This method was precise (intra- and inter-assay coefficients of variation: 2.88-7.81% and 3.96-12.10% for low and high levels of internal quality controls, respectively) and accurate (intra- and inter-assay biases: -1.67-10.30%, and -0.77--9.36%, respectively). In adult kidney transplant patients who were treated with tacrolimus prolonged release formulation, the median (10th-90th percentiles) trough concentrations (n = 16) of tacrolimus, M-I, and M-III were 5.85 (3.37-7.09), 0.100 (0.037-0.168), 0.051 (0.03-0.104), respectively. M-II was measured in only 2 trough samples. The metabolic ratios M-I/tacrolimus and M-III/tacrolimus were 0.017 (0.009-0.027) and 0.009 (0.006-0.015) when measured on trough concentration and 0.022 (0.011-0.037) and 0.008 (0.006-0.015) when measured on area under the curves 0-24 h. This method is a suitable and easy-to-perform tool for future pharmacokinetic-pharmacodynamics studies investigating the importance of tacrolimus and its metabolites blood exposure for solid organ graft survival.

PMID:33878532 | DOI:10.1016/j.jchromb.2021.122698

Pharmacogenomics. 2021 Apr 20. doi: 10.2217/pgs-2020-0193. Online ahead of print.

ABSTRACT

Aim: To evaluate the variants in the genes coding for the proteins involved in thiopurine and folate metabolism with treatment related adverse effects (TRAEs). Materials & methods: Eleven variants in seven candidate genes were genotyped in 127 pediatric acute lymphoblastic leukemia patients under 6-mercaptopurine (6-MP) treatment to infer the association of selected genotypes with TRAEs. Results: Among the genotypes inspected, NUDT15 (c.415C>T) and SLC19A1 (c.80G>A) showed a significant association with the TRAEs (odds ratio = 4.01, p = 0.002 and odds ratio = 7.78, p = 0.002). Conclusion: SLC19A1 and NUDT15 play an important role in the metabolism of 6-MP and it is necessary to spot other variants in associated pathways and investigate the factors that can impact 6-MP metabolism.

PMID:33876659 | DOI:10.2217/pgs-2020-0193

J Genet Couns. 2021 Apr 19. doi: 10.1002/jgc4.1424. Online ahead of print.

ABSTRACT

Although genetic counseling is traditionally done through in-person, one-on-one visits, workforce shortages call for efficient result return mechanisms. Studies have shown that telephone and in-person return of cancer genetic results are equivalent for patient outcomes. Few studies have been conducted with other modes, result types or racially diverse participants. This study explored participants' perspectives on receiving pharmacogenomic results by mail. Two experienced moderators facilitated six focus groups with 49 individuals who self-identified primarily as African-American and consented to participate in a genome sequencing cohort study. Participants were given a hypothetical pharmacogenomic result report (positive for c.521T>C in SLCO1B1). An accompanying letter explained that the result was associated with statin intolerance along with a recommendation to share it with one's doctor and immediate relatives. Participants reacted to the idea of receiving this type of result by mail, discussing whether the letter's information was sufficient and what they predicted they would do with the result. Two researchers coded the focus group transcripts and identified themes. Many participants thought that it was appropriate to receive the result through the mail, but some suggested a phone call alerting the recipient to the letter. Others emphasized that although a letter was acceptable for disclosing pharmacogenomic results, it would be insufficient for what they perceived as life-threatening results. Most participants found the content sufficient. Some participants suggested resources about statin intolerance and warning signs be added. Most claimed they would share the result with their doctor, yet few participants offered they would share the result with their relatives. This exploratory study advances the evidence that African-American research participants are receptive to return of certain genetic results by approaches that do not involve direct contact with a genetic counselor and intend to share results with providers. ClinSeq: A Large-Scale Medical Sequencing Clinical Research Pilot Study (NCT00410241).

PMID:33876469 | DOI:10.1002/jgc4.1424

Sci Rep. 2021 Apr 19;11(1):8494. doi: 10.1038/s41598-021-87821-8.

ABSTRACT

Genetic risk analysis is increasingly in demand by participants. Hybrid genetic testing has the advantage over direct to consumer testing by involving a physician who guides the process and offers counseling after receiving the results. The objective of this study was to determine whether a structured physician moderated primary preventive, hybrid genetic risk assessment enhanced counseling program leads to improvement in lifestyle and does not impair quality of life. Risk genes for malignant, cardiovascular, coagulation, storage diseases and pharmacogenetics (> 100 genes) were tested. Screening, consultation and genetic counseling embedded in a primary/secondary prevention check-up program for executives of surrounding companies took place in a single center in Germany. Follow-up included established questionnaires for quality of life, nutrition and physical activity. Analysis included n = 244 participants. Median age at baseline was 49 years (interquartile range: 44-55), 93% were male, 3% (n = 7 of 136 responses) were smoker. Mean body mass index was 25.2 kg/m2. Follow-up response rate was 74% (n = 180), mean follow-up time was 6.8 months (standard deviation = 2.1). In 91 participants (37.8%, 91/241) at least one pathogenic variant was found, 60 thereof were clinically relevant (24.9%, 60/241). 238 participants (98%, 238/241) had > 1 pharmacogenetic variant, only 2 (0.8%, 2/241) took a correspondingly affected drug (56 participants took ≥ 1 drug/day). The energy expenditure significantly increased by ≈ 35% [median multiple of energy expenditure of 1.34 (confidence interval = 1.15-1.57, p < 0.001)] metabolic equivalents of task (MET)-min/week; participants spent on average 41 min (p < 0.001) less in sedentary activities per day and spent more time for lunch (≈ 2 additional minutes/day; p = 0.031). Indicators of the consumption of red meat and sweet pastries significantly decreased (both adjusted p = 0.049). Neither quality of life in general nor subgroup analysis of participants with at least one conspicuous genetic risk differed significantly over follow-up. Hybrid genetic testing and counseling exerted positive effects on health-related behavior and was not associated with major psychological adverse effects in the short-term follow-up. The approach seems to be feasible for use in preventive health care.

PMID:33875689 | DOI:10.1038/s41598-021-87821-8

Antimicrob Agents Chemother. 2021 Apr 19:AAC.00275-21. doi: 10.1128/AAC.00275-21. Online ahead of print.

ABSTRACT

Malaria remains one of the most deadly diseases in Africa, particularly for children. While successful in reducing morbidity and mortality, antimalarial treatments are also a major cause of adverse drug reactions (ADRs). Host genetic variation in genes involved in drug disposition or toxicity constitutes an important determinant of ADR risk and can prime for parasite drug resistance. Importantly however, the genetic diversity in Africa is substantial and thus genetic profiles in one population cannot be reliably extrapolated to other ethnogeographic groups. Gabon is considered a high-transmission country with more than 460,000 malaria cases per year. Yet, the pharmacogenetic landscape of the Gabonese population or its neighboring countries has not been analyzed. Using targeted sequencing, we here profiled 21 pharmacogenes with importance for antimalarial treatment in 48 Gabonese pediatric patients with severe Plasmodium falciparum malaria. Overall, we identified 347 genetic variants of which 18 were novel and each individual was found to carry 87.3±9.2 SD variants across all analyzed genes. Importantly, 16.7% of these variants were population-specific, highlighting the need for high-resolution pharmacogenomic profiling. Between one in three and one in six individuals harbored reduced activity alleles of CYP2A6, CYP2B6, CYP2D6 and CYP2C8 with important implications for artemisinin, chloroquine and amodiaquine therapy. Furthermore, one in three patients harbored at least one G6PD deficient allele, suggesting considerably increased risk of hemolytic anemia upon exposure to aminoquinolines. Combined, our results reveal the unique genetic landscape of the Gabonese population and pinpoint the genetic basis for inter-individual differences in antimalarial drug response and toxicity.

PMID:33875422 | DOI:10.1128/AAC.00275-21

Front Genet. 2021 Apr 1;12:658983. doi: 10.3389/fgene.2021.658983. eCollection 2021.

ABSTRACT

Background: The goal of the study was to assess the relationship between single nucleotide variants (SNVs) in calcineurin inhibitor (CNI) pharmacokinetic and pharmacodynamic genes and renal dysfunction in adult heart transplant (HTx) recipients. Methods: This retrospective analysis included N = 192 patients receiving a CNI at 1-year post-HTx. Using a candidate gene approach, 93 SNVs in eight pharmacokinetic and 35 pharmacodynamic genes were chosen for investigation. The primary outcome was renal dysfunction 1-year after HTx, defined as an estimated glomerular filtration rate (eGFR) <45 ml/min/1.73m2. Results: Renal dysfunction was present in 28.6% of patients 1-year after HTx. Two SNVs [transforming growth factor beta 1 (TGFB1) rs4803455 C > A and phospholipase C beta 1 (PLCB1) rs170549 G > A] were significantly associated with renal dysfunction after accounting for a false discovery rate (FDR) of 20%. In a multiple-SNV adjusted model, variant A allele carriers of TGFB1 rs4803455 had lower odds of renal dysfunction compared to C/C homozygotes [odds ratio (OR) 0.28, 95% CI 0.12-0.62; p = 0.002], whereas PLCB1 rs170549 variant A allele carriers had higher odds of the primary outcome vs. patients with the G/G genotype (OR 2.66, 95% CI 1.21-5.84, p = 0.015). Conclusion: Our data suggest that genetic variation in TGFB1 and PLCB1 may contribute to the occurrence of renal dysfunction in HTx recipients receiving CNIs. Pharmacogenetic markers, such as TGFB1 rs4803455 and PLCB1 rs170549, could help identify patients at increased risk of CNI-associated renal dysfunction following HTx, potentially allowing clinicians to provide more precise and personalized care to this population.

PMID:33868389 | PMC:PMC8047196 | DOI:10.3389/fgene.2021.658983

Front Pharmacol. 2021 Mar 25;12:638882. doi: 10.3389/fphar.2021.638882. eCollection 2021.

ABSTRACT

Although the mood stabilizer lithium is a first-line treatment in bipolar disorder, a substantial number of patients do not benefit from it and experience side effects. No clinical tool is available for predicting lithium response or the occurrence of side effects in everyday clinical practice. Multiple genetic research efforts have been performed in this field because lithium response and side effects are considered to be multifactorial endophenotypes. Available results from linkage and segregation, candidate-gene, and genome-wide association studies indicate a role of genetic factors in determining response and side effects. For example, candidate-gene studies often report GSK3β, brain-derived neurotrophic factor, and SLC6A4 as being involved in lithium response, and the latest genome-wide association study found a genome-wide significant association of treatment response with a locus on chromosome 21 coding for two long non-coding RNAs. Although research results are promising, they are limited mainly by a lack of replicability and, despite the collaboration of consortia, insufficient sample sizes. The need for larger sample sizes and "multi-omics" approaches is apparent, and such approaches are crucial for choosing the best treatment options for patients with bipolar disorder. In this article, we delineate the mechanisms of action of lithium and summarize the results of genetic research on lithium response and side effects.

PMID:33867988 | PMC:PMC8044839 | DOI:10.3389/fphar.2021.638882

Front Pharmacol. 2021 Apr 1;12:635345. doi: 10.3389/fphar.2021.635345. eCollection 2021.

ABSTRACT

The response to medications in children differs not only in comparison to adults but also between children of the different age groups and according to the disease. This is true for anti-infectives that are widely prescribed in children with malignancy. In the absence of pharmacokinetic/pharmacodynamic paediatric studies, dosage is frequently based on protocols adapted to adults. After a short presentation of the drugs, we reviewed the population pharmacokinetic studies available for glycopeptides (vancomycin and teicoplanin, n = 5) and antifungals (voriconazole, posaconazole, and amphotericin B, n = 9) currently administered in children with onco-hematological malignancies. For each of them, we reported the main study characteristics including identified covariates affecting pharmacokinetics and proposed paediatric dosage recommendations. This review highlighted the very limited amount of data available, the lack of consensus regarding PK/PD targets used for dosing optimization and regarding dosage recommendations when available. Additional PK studies are urgently needed in this specific patient population. In addition to pharmacokinetics, efficacy may be altered in immunocompromised patients and prospective clinical evaluation of new dosage regimen should be provided as they are missing in most cases.

PMID:33867986 | PMC:PMC8048069 | DOI:10.3389/fphar.2021.635345

Front Pharmacol. 2021 Mar 19;12:620043. doi: 10.3389/fphar.2021.620043. eCollection 2021.

NO ABSTRACT

PMID:33867983 | PMC:PMC8044957 | DOI:10.3389/fphar.2021.620043

EBioMedicine. 2021 Apr 14:103339. doi: 10.1016/j.ebiom.2021.103339. Online ahead of print.

ABSTRACT

BACKGROUND: Patients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for the coronavirus disease 2019 (COVID-19), exhibit a wide spectrum of disease behaviour. Since DNA methylation has been implicated in the regulation of viral infections and the immune system, we performed an epigenome-wide association study (EWAS) to identify candidate loci regulated by this epigenetic mark that could be involved in the onset of COVID-19 in patients without comorbidities.

METHODS: Peripheral blood samples were obtained from 407 confirmed COVID-19 patients ≤ 61 years of age and without comorbidities, 194 (47.7%) of whom had mild symptomatology that did not involve hospitalization and 213 (52.3%) had a severe clinical course that required respiratory support. The set of cases was divided into discovery (n = 207) and validation (n = 200) cohorts, balanced for age and sex of individuals. We analysed the DNA methylation status of 850,000 CpG sites in these patients.

FINDINGS: The DNA methylation status of 44 CpG sites was associated with the clinical severity of COVID-19. Of these loci, 23 (52.3%) were located in 20 annotated coding genes. These genes, such as the inflammasome component Absent in Melanoma 2 (AIM2) and the Major Histocompatibility Complex, class I C (HLA-C) candidates, were mainly involved in the response of interferon to viral infection. We used the EWAS-identified sites to establish a DNA methylation signature (EPICOVID) that is associated with the severity of the disease.

INTERPRETATION: We identified DNA methylation sites as epigenetic susceptibility loci for respiratory failure in COVID-19 patients. These candidate biomarkers, combined with other clinical, cellular and genetic factors, could be useful in the clinical stratification and management of patients infected with the SARS-CoV-2.

FUNDING: The Unstoppable campaign of the Josep Carreras Leukaemia Foundation, the Cellex Foundation and the CERCA Programme/Generalitat de Catalunya.

PMID:33867313 | DOI:10.1016/j.ebiom.2021.103339

Expert Rev Proteomics. 2021 Apr 19:1-8. doi: 10.1080/14789450.2021.1915775. Online ahead of print.

ABSTRACT

Elucidating the dysregulated metabolic pathways in cancer cells and their relevance to cisplatin resistance could yield new insights into cancer therapy. We previously reported that eight metabolites involved in the tricarboxylic acid (TCA) cycle and glutamine metabolism were associated with platinum-based chemotherapy efficacy in human lung cancer. Here, we investigated the metabolic differences upon cisplatin treatment in lung cancer in vitro and in vivo. A simple and partially validated standard addition method was applied for the quantification of five metabolites involved in the TCA cycle and glutamine metabolism using amide hydrophilic interaction liquid chromatography-tandem mass spectrometry (HILIC-MS/MS). The present study investigated the levels of these biomarkers in A549 cells and the cisplatin-resistant A549-DDP cells, as well as in the plasma before and after cisplatin treatment in A549 xenograft mice. Levels of five metabolites, including 2-hydroxyglutaric acid (2-HG), α-ketoglutarate (α-KG), succinate, glutamine, and glutamate, showed a decreasing trend in A549-DDP cells. In addition, 2-HG and glutamine were the most significantly altered metabolites in cisplatin-treated A549 xenograft mice. These data indicate that the TCA cycle and glutamine metabolism play important roles in cisplatin-based chemotherapy resistance in lung cancer. Our results provide a new angle for exploring the molecular mechanisms underlying cisplatin resistance.

PMID:33866908 | DOI:10.1080/14789450.2021.1915775

Semin Arthritis Rheum. 2021 Mar 4;51(3):513-522. doi: 10.1016/j.semarthrit.2021.03.004. Online ahead of print.

ABSTRACT

The incidence of autoimmune diseases is increasing worldwide, thus stimulating studies on their etiopathogenesis, derived from a complex interaction between genetic and environmental factors. Genetic association studies have shown the PTPN22 gene as a shared genetic risk factor with implications in multiple autoimmune disorders. By encoding a protein tyrosine phosphatase expressed by the majority of cells belonging to the innate and adaptive immune systems, the PTPN22 gene may have a fundamental role in the development of immune dysfunction. PTPN22 polymorphisms are associated with rheumatoid arthritis, type 1 diabetes, systemic lupus erythematosus, and many other autoimmune conditions. In this review, we discuss the progress in our understanding of how PTPN22 impacts autoimmunity in both humans and animal models. In addition, we highlight the pathogenic significance of the PTPN22 gene, with particular emphasis on its role in T and B cells, and its function in innate immune cells, such as monocytes, dendritic and natural killer cells. We focus particularly on the complexity of PTPN22 interplay with biological processes of the immune system. Findings highlight the importance of studying the function of disease-associated PTPN22 variants in different cell types and open new avenues of investigation with the potential to drive further insights into mechanisms of PTPN22. These new insights will reveal important clues to the molecular mechanisms of prevalent autoimmune diseases and propose new potential therapeutic targets.

PMID:33866147 | DOI:10.1016/j.semarthrit.2021.03.004

Asian Pac J Allergy Immunol. 2021 Apr 18. doi: 10.12932/AP-110920-0955. Online ahead of print.

ABSTRACT

BACKGROUND: Severe cutaneous adverse drug reactions (SCARs) are rare but deadly drug reactions with severe damages to patients. One of the most well-known SCARs risk factors is the human leukocyte antigen (HLA) genes polymorphism. Among the HLA polymorphic alleles, the HLA-A*33:03 allele has been found in association with SCARs induced by various drugs, especially in Asian people. There has not been any report on the specific detection protocol of the HLA-A*33:03 allele.

OBJECTIVE: This study aimed to design a nested AS-PCR protocol for detecting and distinguishing diplotype genotype of the HLA-A*33:03 allele.

METHODS: A nested allele-specific (AS)-PCR protocol with four primer sets was designed. The method was compared with the Sanger sequencing method on 100 samples of unknown genotypes of unrelated Vietnamese people.

RESULTS: The nested AS-PCR method could identify the HLA-A*33:03 allele and the HLA-A*33:03 diplotype genotypes. Comparison with the Sanger sequencing method showed an absolute agreement (κ = 1.00, p < 0.001). The nested ASPCR protocol had a sensitivity of 100% (95%CI: 92.13-100%) and a specificity of 100% (95%CI: 93.51-100%). The protocol was used for the determination of HLA-A*33:03 allele distribution in 810 unrelated Vietnamese Kinh people, showing a frequency of HLA-A*33:03 carriers of 19.6% and an allele frequency of 10.55%.

CONCLUSIONS: A novel nested AS-PCR method with a hundred-percent sensitivity and a specificity for the HLA-A*33:03 allele detection was reported. The protocol can be applied for the stratification of patients at SCAR risks with various drugs.

PMID:33865300 | DOI:10.12932/AP-110920-0955

Neuro Oncol. 2021 Apr 17:noab095. doi: 10.1093/neuonc/noab095. Online ahead of print.

ABSTRACT

BACKGROUND: The transcription factor NFκB drives neoplastic progression of many cancers including primary brain tumors (glioblastoma; GBM). Precise therapeutic modulation of NFκB activity can suppress central oncogenic signalling pathways in GBM, but clinically applicable compounds to achieve this goal have remained elusive.

METHODS: In a pharmacogenomics study with a panel of transgenic glioma cells we observed that NFκB can be converted into a tumor suppressor by the non-psychotropic cannabinoid Cannabidiol (CBD). Subsequently, we investigated the anti-tumor effects of CBD, which is used as an anticonvulsive drug (Epidiolex) in pediatric neurology, in a larger set of human primary GBM stem-like cells (hGSC). For this study we performed pharmacological assays, gene expression profiling, biochemical and cell-biological experiments. We validated our findings using orthotopic in vivo models and bioinformatics analysis of human GBM-datasets.

RESULTS: We found that CBD promotes DNA binding of the NFκB subunit RELA and simultaneously prevents RELA-phosphorylation on serine-311, a key residue which permits genetic transactivation. Strikingly, sustained DNA binding by RELA lacking phospho-serine 311 was found to mediate hGSC cytotoxicity. Widespread sensitivity to CBD was observed in a cohort of hGSC defined by low levels of reactive oxygen-species (ROS), while high ROS-content in other tumors blocked CBD induced hGSC death. Consequently, ROS levels served as predictive biomarker for CBD-sensitive tumors.

CONCLUSIONS: This evidence demonstrates how a clinically approved drug can convert NFκB into a tumor suppressor and suggests a promising repurposing option for GBM-therapy.

PMID:33864076 | DOI:10.1093/neuonc/noab095

Mol Cancer Res. 2021 Apr 16:molcanres.MCR-21-0099-A.2021. doi: 10.1158/1541-7786.MCR-21-0099. Online ahead of print.

ABSTRACT

NF-κB activation has been linked to prostate cancer (PCa) progression and is commonly observed in castrate-resistant disease. It has been suggested that NF-κB-driven resistance to androgen deprivation therapy (ADT) in PCa cells may be mediated by aberrant androgen receptor (AR) activation and AR splice variant production. Preventing resistance to ADT may therefore be achieved by utilizing NF-κB inhibitors. However, low oral bioavailability and high toxicity of NF-κB inhibitors is a major challenge for clinical translation. Dimethylaminoparthlide (DMAPT) is an oral NF-κB inhibitor in clinical development and has already shown favorable pharmacokinetic and pharmacodyanamic data in patients with heme malignancies including decrease of NF-κB in circulating leuchemic blasts. Here we report that activation of NF-κB/p65 by castration in mouse and human PCa models resulted in a significant increase in AR variant-7 (AR-V7) expression and modest upregulation of AR. In vivo castration of VCaP-CR tumors resulted in significant upregulation of phosphorylated-p65 and AR-V7, which was attenuated by combination with DMAPT and DMAPT increased the efficacy of AR inhibition. We further demonstrate that the effects of DMAPT sensitizing PCa cells to castration were dependent on the ability of DMAPT to inhibit phosphorylated-p65 function. Implications: Our study shows that DMAPT, an oral NF-κB inhibitor in clinical development, inhibits phosphorylated-p65 upregulation of AR-V7 and delays PCa castration resistance. This provides rationale for the development of DMAPT as a novel therapeutic strategy to increase durable response in patients receiving AR targeted therapy.

PMID:33863813 | DOI:10.1158/1541-7786.MCR-21-0099