Gefitinib-Induced Severe Dermatological Adverse Reactions: A Case Report and Pharmacogenetic Profile.

Gefitinib is a selective inhibitor of the epidermal growth factor receptor that is used to treat advanced and metastatic non-small cell lung cancer (NSCLC). Dermatological adverse reactions are most commonly associated with gefitinib treatment. The cause of adverse reactions in individuals is multifactorial. Pharmacogenetics is an effective tool to detect such adverse reactions. This case report describes a female patient with NSCLC who was administered gefitinib at a dose of 250 mg/day. However, due to severe adverse dermatological reactions, the treatment was interrupted for 15 d and antibiotic therapy was administered to manage the skin rashes, maculopapular rashes, and hyperpigmentation. Treatment adherence was adequate, and no drug interactions were detected. A pharmacogenetic analysis revealed homozygosity in the ATP-binding cassette (ABC)-B1 rs1128503 (c.1236A>G), heterozygosity in ABCG2 rs2231142 (c.421G>T) and rs2622604 (c.-20+614T>C), and a non-functional variant of the cytochrome P450 family 3, subfamily A, member 5 (CYP3A5). The relationship between altered genetic variants and the presence of adverse reactions induced by gefitinib is still controversial. Overall, this case report highlights the importance of continuing to study pharmacogenetics as predictors of adverse drug reactions.

Genetic Variants in the ABCB1 and ABCG2 Gene Drug Transporters Involved in Gefitinib-Associated Adverse Reaction: A Systematic Review and Meta-Analysis.

This systematic review and meta-analysis aimed to verify the association between the genetic variants of adenosine triphosphate (ATP)-binding cassette subfamily B member 1 (ABCB1) and ATP-binding cassette subfamily G member 2 (ABCG2) genes and the presence and severity of gefitinib-associated adverse reactions. We systematically searched PubMed, Virtual Health Library/Bireme, Scopus, Embase, and Web of Science databases for relevant studies published up to February 2024. In total, five studies were included in the review. Additionally, eight genetic variants related to ABCB1 (rs1045642, rs1128503, rs2032582, and rs1025836) and ABCG2 (rs2231142, rs2231137, rs2622604, and 15622C>T) genes were analyzed. Meta-analysis showed a significant association between the ABCB1 gene rs1045642 TT genotype and presence of diarrhea (OR = 5.41, 95% CI: 1.38-21.14, I2 = 0%), the ABCB1 gene rs1128503 TT genotype and CT + TT group and the presence of skin rash (OR = 4.37, 95% CI: 1.51-12.61, I2 = 0% and OR = 6.99, 95%CI: 1.61-30.30, I2= 0%, respectively), and the ABCG2 gene rs2231142 CC genotype and presence of diarrhea (OR = 3.87, 95% CI: 1.53-9.84, I2 = 39%). No ABCB1 or ABCG2 genes were positively associated with the severity of adverse reactions associated with gefitinib. In conclusion, this study showed that ABCB1 and ABCG2 variants are likely to exhibit clinical implications in predicting the presence of adverse reactions to gefitinib.

FRAX486, a PAK inhibitor, overcomes ABCB1-mediated multidrug resistance in breast cancer cells

The overexpression of P-glycoprotein (P-gp/ABCB1) is a leading cause of multidrug resistance (MDR). Hence, it is crucial to discover effective pharmaceuticals that counteract ABCB1-mediated multidrug resistance. FRAX486 is a p21-activated kinase (PAK) inhibitor. The objective of this study was to investigate whether FRAX486 can reverse ABCB1-mediated multidrug resistance, while also exploring its mechanism of action. The CCK8 assay demonstrated that FRAX486 significantly reversed ABCB1-mediated multidrug resistance. Furthermore, western blotting and immunofluorescence experiments revealed that FRAX486 had no impact on expression level and intracellular localization of ABCB1. Notably, FRAX486 was found to enhance intracellular drug accumulation and reduce efflux, resulting in the reversal of multidrug resistance. Docking analysis also indicated a strong affinity between FRAX486 and ABCB1. This study highlights the ability of FRAX486 to reverse ABCB1-mediated multidrug resistance and provides valuable insights for its clinical application.

Association of variants in the ABCB1, CYP2C19 and CYP2C9 genes for Juvenile Myoclonic Epilepsy.

Juvenile myoclonic epilepsy (JME) is the most common of the generalized genetic epilepsies, with multiple causal and susceptibility genes; however, its etiopathogenesis is mainly unknown. The toxic effects caused by xenobiotics in cells occur during their metabolic transformation, mainly by enzymes belonging to cytochrome P450. The elimination of these compounds by transporters of the ABC type protects the central nervous system, but their accumulation causes neuronal damage, resulting in neurological diseases. The present study has sought the association between single nucleotide genetic variants of the CYP2C9, CYP2C19, and ABCB1 genes and the development of JME in patients compared to healthy controls. The CC1236 and GG2677 genotypes of ABCB1 in women; allele G 2677, genotypes GG 2677 and CC 3435 in men; the CYP2C19*2A allele, and the CYP2C19*3G/A genotype in both sexes were found to be risk factors for JME. Furthermore, carriers of the TTGGCC genotype combination of the ABCB1 gene (1236/2677/3435) have a 10.5 times higher risk of developing JME than non-carriers. Using the STRING database, we found an interaction between the proteins encoded by these genes and other possible proteins. These findings indicate that the CYP450 system and ABC transporters could interact with other genes in the JME.

Glycolipids from Sargassum filipendula, a Natural Alternative for Overcoming ABC Transporter-Mediated MDR in Cancer.

Chemotherapy is a widely used strategy to treat cancer, a disease that causes millions of deaths each year. However, its efficacy is reduced by the overexpression of ABC transporters, which are proteins that expel the drugs used in chemotherapy and involved in the multidrug resistance (MDR). Glycolipids have been identified as potential inhibitors of ABC transporters. Algae of the genus Sargassum contain high levels of glycolipids, making them a promising therapeutic alternative against the MDR phenotype. Sargassum filipendula glycolipids were obtained by exhaustive maceration with chloroform/methanol, purified by column and thin layer chromatography, and then characterized by FTIR, NMR, and LC-MS. Cell viability by PI labeling and inhibition of ABC transporters were analyzed by flow cytometry. Assessment of resistance reversal was determined by MTT assay. Ten sulfoquinovosylglycerol-type compounds were found, and six of them are reported for the first time. In particular, moiety 4 (GL-4) showed strong and moderate inhibitory activity against ABCC1 and ABCB1 transporters respectively. Treatment of GL-4 in combination with the antineoplastic drug vincristine sensitized Lucena-1 cell model to drug and reversed the MDR phenotype. This is the first report of glycolipids isolated from S. filipendula capable of inhibiting ABC transporters and thus overcoming acquired drug resistance.

An Improved Technique for Genotyping the ABCB1 Gene Variant of Exon 21.

The Multidrug Resistance protein (ABCB1, MDR1) is involved in the transport of xenobiotics and antiretroviral drugs. Some variants of the ABCB1 gene are of clinical importance; among them, exon 12 (c.1236C>T, rs1128503), 21 (c.2677G>T/A, rs2032582), and 26 (c.3435C>T, rs1045642) have a high incidence in Caucasians. Several protocols have been used for genotyping the exon 21 variants, such as allele-specific PCR-RFLP using adapted primer to generate a digestion site for several enzymes and automatic sequencing to detect the SNVs, TaqMan Allele Discrimination assay and High-Resolution Melter analysis (HRMA). The aim was to describe a new approach to genotype the three variants c.2677G>T/A for the exon 21 doing only one PCR with the corresponding primers and the digestion of the PCR product with two restriction enzymes: BrsI to identify A allele and BseYI to differentiate between G or T. An improvement of this methodology was also described. The proposal technique here described is demonstrated to be very efficient, easy, fast, reproducible, and cost-effective.

Effects of chemotherapeutic drugs on the antioxidant capacity of human erythroleukemia cells with MDR phenotype.

In this work, we identified that different chemotherapeutic drugs may select cells with different antioxidant capacities. For this, we evaluated the sensitivity of two multidrug-resistant (MDR) erythroleukemia cell lines: Lucena (resistant to vincristine, VCR) and FEPS (resistant to daunorubicin, DNR) derived from the same sensitive cell K562 (non-MDR) to hydrogen peroxide. In addition, we evaluated how the cell lines respond to the oxidizing agent in the absence of VCR/DNR. In absence of VCR, Lucena drastically decreases cell viability when exposed to hydrogen peroxide, while FEPS is not affected even without DNR. To analyze whether selection by different chemotherapeutic agents may generate altered energetic demands, we analyzed the production of reactive oxygen species (ROS) and the relative expression of the glucose transporter 1 gene (glut1). We observed that the selection through DNR apparently generates a higher energy demand than VCR. High levels of transcription factors genes expression (nrf2, hif-1α, and oct4) were kept even when the DNR is withdrawn from the FEPS culture for one month. Together, these results indicate that DNR selects cells with greater ability to express the major transcription factors related to the antioxidant defense system and the main extrusion pump (ABCB1) related to the MDR phenotype. Taking into account that the antioxidant capacity of tumor cells is closely related to resistance to multiple drugs, it is evident that endogenous antioxidant molecules may be targets for the development of new anticancer drugs.

Pharmacogenetics of ABCB1, CDA, DCK, GSTT1, GSTM1 and outcomes in a cohort of pediatric acute myeloid leukemia patients from Colombia.

BACKGROUND AND AIM: Different studies have shown pharmacogenetic variants related to drug toxicity in acute myeloid leukemia (AML) patients. Our aim was to identify the association between ABCB1, CDA, DCK, GSTT1, and GSTM1 variants with clinical outcomes and toxicity in pediatric patients with AML. METHODS: Fifty-one confirmed de novo AML pediatric patients were included. A SNaPshot™ assay and conventional PCR were used to evaluate ABCB1, CDA, DCK, GSTT1, and GSTM1 variants. Clinical outcomes and toxicity associations were evaluated using odds ratios and Chi-square analysis. RESULTS: Patients carrying ABCB1 (1236C > T, rs1128503) GG genotype in had a 6.8 OR (CI 95% 1.08-42.73, p = .044) for cardiotoxicity as compared to patients carrying either AA or GA genotypes 0.14 OR (CI 95% 0.023-0.92, p = .044). For ABCB1 (1236G > A rs1128503/2677C > A/T rs2032582/3435G > A rs1045642) AA/AA/AA combined genotypes had a strong association with death after HSTC OR 13.73 (CI 95% 1.94-97.17, p = .009). Combined genotypes GG/CC/GG with CDA (79A > C, rs2072671) CA genotype or CDA (-451G > A, rs532545) CT genotype, had a 4.11 OR (CI 95% 2.32-725, p = .007) and 3.8 OR (CI 95% 2.23-6.47, p = .027) with MRD >0.1% after first chemotherapy cycle, respectively. CONCLUSION: Our results highlight the importance of pharmacogenetic analysis in pediatric AML, particularly in populations with a high degree of admixture, and might be useful as a future tool for patient stratification for treatment.

Infection and disruption of placental multidrug resistance (MDR) transporters: Implications for fetal drug exposure.

P-glycoprotein (P-gp, encoded by the ABCB1 gene) and breast cancer resistance protein (BCRP/ABCG2) are efflux multidrug resistance (MDR) transporters localized at the syncytiotrophoblast barrier of the placenta and protect the conceptus from drug and toxin exposure throughout pregnancy. Infection is an important modulator of MDR expression and function. This review comprehensively examines the effect of infection on the MDR transporters, P-gp and BCRP in the placenta. Infection PAMPs such as bacterial lipopolysaccharide (LPS) and viral polyinosinic-polycytidylic acid (poly I:C) and single-stranded (ss)RNA, as well as infection with Zika virus (ZIKV), Plasmodium berghei ANKA (modeling malaria in pregnancy - MiP) and polymicrobial infection of intrauterine tissues (chorioamnionitis) all modulate placental P-gp and BCRP at the levels of mRNA, protein and or function; with specific responses varying according to gestational age, trophoblast type and species (human vs. mice). Furthermore, we describe the expression and localization profile of Toll-like receptor (TLR) proteins of the innate immune system at the maternal-fetal interface, aiming to better understand how infective agents modulate placental MDR. We also highlight important gaps in the field and propose future research directions. We conclude that alterations in placental MDR expression and function induced by infective agents may not only alter the intrauterine biodistribution of important MDR substrates such as drugs, toxins, hormones, cytokines, chemokines and waste metabolites, but also impact normal placentation and adversely affect pregnancy outcome and maternal/neonatal health.

ABCB1 gene variants as risk factors and modulators of age of onset of demyelinating disease in Mexican patients.

INTRODUCTION: The C1236T, G2677T/A, and C3435T variants of the ABCB1 gene alter the functioning of P-glycoprotein and the transport of endogenous and exogenous substances across the blood-brain barrier, and act as risk factors for some neurodegenerative diseases. This study aimed to determine the association between demyelinating disease and the C1236T, G2677T/A, and C3435T variants of ABCB1 and its haplotypes and combinations of genotypes. METHODS: Polymerase chain reaction with restriction fragment length polymorphism analysis (PCR-RFLP) and Sanger sequencing were used to genotype 199 patients with demyelinating disease and 200 controls, all Mexicans of mixed race; frequencies of alleles, genotypes, haplotypes, and genotype combinations were compared between patients and controls. We conducted a logistic regression analysis and calculated chi-square values and 95% confidence intervals (CI); odds ratios (OR) were calculated to evaluate the association with demyelinating disease. RESULTS: The TTT and CGC haplotypes were most frequent in both patients and controls. The G2677 allele was associated with demyelinating disease (OR: 1.79; 95% CI, 1.12-2.86; P =  .015), as were the genotypes GG2677 (OR: 2.72; 95% CI, 1.11-6.68; P =  .025) and CC3435 (OR: 1.82; 95% CI, 1.15-2.90; P =  .010), the combination GG2677/CC3435 (OR: 2.02; 95% CI, 1.17-3.48; P =  .010), and the CAT haplotype (OR: 0.21; 95% CI, 0.05-0.66; P =  .001). TTTTTT carriers presented the earliest age of onset (23.0 ±â€¯7.7 years, vs 31.6 ±â€¯10.7; P =  .0001). CONCLUSIONS: The GG2677/CC3435 genotype combination is associated with demyelinating disease in this sample, particularly among men, who may present toxic accumulation of P-glycoprotein substrates. In our study, the G2677 allele of ABCB1 may differentially modulate age of onset of demyelinating disease in men and women.

P-glycoprotein and cancer: what do we currently know?

Acquired resistance during cancer treatment is unfortunately a frequent event. There are several reasons for this, including the ability of the ATP-binding cassette transporters (ABC transporters), which are integral membrane proteins, to export chemotherapeutic molecules from the interior of the tumor cells. One important member of this family is the protein known as Permeability Glycoprotein (P-Glycoprotein, P-gp or ABCB1). Its clinical relevance relies mainly on the fact that the inhibition of P-gp and other ABC transporters could result in the reversal of the multidrug resistance (MDR) phenotype in some patients. Recently, other roles apart from being a key player in MDR, have emerged for P-gp. Therefore, this review discusses the relationship between P-gp and MDR, in addition to the possible role of this protein as a biomarker in cancer.

Colon Cancer Pharmacogenetics: A Narrative Review.

Currently, metastatic colon cancer is treated with monotherapeutic regimens such as folinic acid, fluorouracil, and oxaliplatin (FOLFOX), capecitabine and oxaliplatin (CapeOX), and leucovorin, fluorouracil, and irinotecan hydrochloride (FOLFIRI). Other treatments include biological therapies and immunotherapy with drugs such as bevacizumab, panitumumab, cetuximab, and pembrolizumab. After the research, it was found that some mutations make those treatments not as effective in all patients. In this bibliographic review, we investigated the pharmacogenetic explanations for how mutations in the genes coding for rat sarcoma virus (RAS) and rapidly accelerated fibrosarcoma (RAF) reduce the effectiveness of these treatments and allow the continued proliferation of tumors. Furthermore, we note that patients with mutations in the dihydropyrimidine dehydrogenase (DPDY) gene usually require lower doses of therapies such as 5-fluorouracyl (5-FU) and capecitabine to avoid severe adverse effects. Some other mutations in the thymidylate synthase gene (TSYM), methylenetetrahydrofolate reductase gene (MTHFR), and ATP binding cassette transporter B (ABCB1 and ABCB2) affect efficacy and security of the treatments. It is important to address the clinical implication of the oncologist in the study of gene mutations than can influence in the antitumoral response and safety of colon cancer treatments.

Impact of the ABCB1 Drug Resistance Gene on the Risk Factors of Patients with COVID-19 and Its Relationship with the Drugs Used.

Objective: In the last two years progress was made in molecular, physio pathological understanding and the form of transmission of COVID-19, and different therapeutic strategies have been explored to deal with the situation of the pandemic. However, the evaluation of certain genes that participate in the metabolism and transport of these drugs has not been fully explored. A lack of response to treatment and a lower survival have been observed that may be due to the presence of the ABCB1 drug resistance gene. Our research group analyzed whether the expression levels of the ABCB1 gene are associated with comorbidities, treatments, overall survival and risk of death in patients with severe COVID-19. Methods: The expression levels of the ABCB1 gene were analyzed by RT-qPCR in 61 patients diagnosed with COVID-19. The association between the levels of expression, the risk variables and different treatments were determined by the Chi-Square test and the Fisher's exact test. Global Survival (GS) was determined by the Kaplan-Meier method. The impact of high levels of expression and the risk of death was performed by odds ratio. Results: The different risk variables showed that patients with either high or absent levels of ABCB1 gene expression presented a greater risk of death (OR 3.08, 95%, CI 1.02-9.26) as well as need for ventilatory support (OR 2.8, 95%, CI 0.98 -8.5). Patients with diabetes and COVID-19, treated with metformin, were associated with a lower risk of death (OR 1.11, 95%, CI 0.38-3.22). OS with respect to high or absent levels of expression of the ABCB1 gene was lower. Conclusion: High levels or null expression of the ABCB1 gene are associated with a higher risk of death or progression of the disease, the use of metformin in patients with COVID-19 confers a lower risk of death.

Pharmacogenetic studies in Alzheimer disease.

INTRODUCTION: Alzheimer disease (AD) is the most common cause of dementia and is considered one of the main causes of disability and dependence affecting quality of life in elderly people and their families. Current pharmacological treatment includes acetylcholinesterase inhibitors (donepezil, galantamine, rivastigmine) and memantine; however, only one-third of patients respond to treatment. Genetic factors have been shown to play a role in this inter-individual variability in drug response. DEVELOPMENT: We review pharmacogenetic reports of AD-modifying drugs, the pharmacogenetic biomarkers included, and the phenotypes evaluated. We also discuss relevant methodological considerations for the design of pharmacogenetic studies into AD. A total of 33 pharmacogenetic reports were found; the majority of these focused on the variability in response to and metabolism of donepezil. Most of the patients included were from Caucasian populations, although some studies also include Korean, Indian, and Brazilian patients. CYP2D6 and APOE are the most frequently studied biomarkers. The associations proposed are controversial. CONCLUSIONS: Potential pharmacogenetic biomarkers for AD have been identified; however, it is still necessary to conduct further research into other populations and to identify new biomarkers. This information could assist in predicting patient response to these drugs and contribute to better treatment decision-making in a context as complex as ageing.

Pharmacogenetic predictors of variability in efavirenz pharmacokinetics in an admixed Brazilian HIV cohort.

AIMS: To investigate the influence of pharmacogenetic polymorphisms on efavirenz (EFV) exposure and metabolism in HIV-infected Brazilians under treatment with EFV-containing antiretroviral (ART) regimens. METHODS: HIV-positive adults (n = 82) on stable ART regimens containing 600 mg EFV once daily for at least 6 months were recruited at 2 university hospitals. Blood samples collected at mid-dose interval were used to quantify the plasma concentrations of EFV (denoted [EFV]), its major metabolite 8-OH-EFV ([8-OH-EFV]) and [8-OH-EFV]/[EFV] metabolic ratio, and to genotype single nucleotide polymorphisms in CYP2B6 (rs3745274, c.516G > T; rs28399499, c.983 T > C) and ABCB1 (rs3842, c.4036G > A). CYP2B6 metabolic phenotypes were inferred from the CYP2B6 diplotypes. Linear regression modelling was applied to identify sociodemographic, clinical and pharmacogenetic predictors of [EFV] and [8-OH-EFV]/[EFV] metabolic ratio. RESULTS: Wide (50-fold) interindividual variation in [EFV], [8-OH-EFV] and [8-OH-EFV]/[EFV] was observed; 69.5% of participants had [EFV] within the nominal therapeutic range (1000-4000 ng/mL), while 19.5 and 11.0% had [EFV] below and above this range, respectively. Multiple regression modelling retained only CYP2B6 metabolic phenotypes or the combined rs3745274 and rs28399499 genotypes, as significant predictors of [EFV] and [8-OH-EFV]/[EFV]. CONCLUSION: EFV exposure and disposition varied widely among HIV-infected Brazilians under stable treatment with EFV-containing ART regimens. About 1/10 of the participants had [EFV] exceeding nominal supratherapeutic concentration (4000 ng/mL), but reported tolerance to the ARV regimens, while 1/5 of participants had nominal subtherapeutic [EFV] (<1000 ng/mL) but adequate virological response. Genotype for the 2 CYP2B6 single nucleotide polymorphisms studied explained 48% of variation in [EFV] and 35% of variation in [8-OH-EFV]/[EFV].

P-Glycoprotein and Androgen Receptor Expression Reveals Independence of Canine Prostate Cancer from Androgen Hormone Stimulation.

Canine prostate cancer (PC) is an aggressive disease, and dogs can be considered comparative models for human PC. In recent years, canine PC has been shown to resemble human castrate-resistant prostate cancer. The influx and efflux of testosterone in prostatic luminal cells are regulated by P-glycoprotein (P-gp). Therefore, human PC generally lacks P-gp expression and maintains the expression of androgen receptors (ARs). However, this co-expression has not previously been investigated in dogs. Therefore, this study aimed to evaluate AR and P-gp co-expression to elucidate these protein patterns in canine prostate samples. We identified AR/P-gp double immunofluorescence co-expression of both proteins in normal luminal cells. However, in canine PC, cells lack AR expression and exhibit increased P-gp expression. These results were confirmed by gene expression analyses. Overall, our results strongly suggest that normal canine prostate testosterone influx may be regulated by P-gp expression, and that during progression to PC, prostatic cells lack AR expression and P-gp overexpress. P-gp expression in canine PC may be related to a phenotype of multiple drug resistance.

Stress hormone norepinephrine incites resistance of oral cancer cells to chemotherapy.

This study investigated whether norepinephrine (NE) and epinephrine (E) interfere in the response of head and neck squamous cell carcinoma (SCC) cell lines to cisplatin and explored the mechanisms of chemoresistance. Head and neck SCC-derived cell lines SCC-9, Cal27, SCC-25, and FaDu were stimulated with NE or E and treated with the inhibitory concentration of cisplatin for 24 h. As for adrenergic receptors (ADRB) inhibition, cells were treated with propranolol. The results showed that, when combined with NE, cisplatin effectiveness against SCC-9 and Cal27 but not SCC-25 and FaDu cells were notably reduced. E did not affect the response of the cells to cisplatin. Further experiments were performed with the responsive SCC-9 and SCC-25 cell lines and the hormone NE. The time course assay showed that stimulation of oral SCC cells with NE decreased the cleavage of caspase-3 and expression of multidrug resistance protein 1 (MDR-1) but only transiently affected ATP-binding cassette (ABC) subfamily G, isoform 2 protein (ABCG2) expression. The expression of cleaved caspase-3 and Bcl-2 were, respectively, decreased and increased by the combination of NE and cisplatin in SCC-9 and Cal27 cells. NE-induced resistance was reverted by previous treatment with propranolol. Expressions of ABCG2, and p-Akt but not of MDR-1, were enhanced by NE plus cisplatin when compared to cisplatin only in both cell lines. Migratory activity of oral SCC cells challenged with cisplatin was not affected by NE. These findings reveal for the first time that stress hormone NE induces resistance of oral cancer cells to cisplatin in vitro through the ADRB/Akt/ABCG2 pathway, pumping the drug out of the cell and inhibiting apoptosis.

Prevalence of ABCB1 3435C>T polymorphism in the Cuban population.

OBJECTIVES: ABCB1 gene polymorphisms can modify P-glycoprotein function with clinical consequences. METHODS: The 3435C>T polymorphism prevalence was analyzed using oligonucleotide probes and next-generation sequencing in 421 unrelated healthy individuals living in Cuba. Data were stratified by gender, ethnic background and residence. The genotype and allelic frequencies were determined. RESULTS: The genotype distribution met the Hardy-Weinberg equilibrium assumption. The allelic frequency was 63.5% for the 3435C variant. The genotype frequencies were 41.1% for CC, 44.9% for CT and 14.0% for TT. The allele and genotype distributions differed between individuals living in La Habana and Santiago de Cuba (p<0.05) when ethnic background was analyzed. The allelic distribution was similar among Admixed and Black subjects, and they differed from Caucasians. The CC genotype was equally distributed among Admixed and Black subjects, and they differed from Caucasians. The TT genotype frequency differed between Caucasians and Admixed. The CT genotype was distributed differently among the three groups. Similar distribution was obtained in Brazilians, whereas some similarities were observed in African, Spanish and Chinese populations, consistent with the mixed Cuban ethnic origin. CONCLUSIONS: This is the first report on allele and genotype frequencies of the 3435C>T polymorphism in Cuba, which may support personalized medicine programs.

High expression levels and the C3435T SNP of the ABCB1 gene are associated with lower survival in adult patients with acute myeloblastic leukemia in Mexico City.

BACKGROUND: Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by different genetic alterations that cause changes in the normal mechanisms of differentiation, which are associated with chemoresistance. The ABCB1 gene is part of a family of ATP-binding cassette (ABC) transporter genes involved in the progression of various types of cancer. The following work aimed to evaluate the expression levels of the ABCB1 gene and the C3435T SNP with the response to first-line treatment and survival in patients with AML. METHODS: In total 135 samples were taken to isolate total RNA and DNA at the beginning of the treatment. Expression analysis by RT-qPCR and SNP C3435T assessment method were performed for real-time Polymerase chain reaction (qPCR). RESULTS: The expression levels impact on the survival of patients with AML compared to low or absent levels; the CC genotype was found in 22.9%, the CT genotype was found in 47.4%, and the TT genotype was found in 29.6%, the presence of the C3435T SNP, the TT genotype also impacts with a lower survival compared to CT and CC genotypes. In addition, it was shown that the dominant model significantly impacts survival. CONCLUSION: In conclusion, we have found that the overexpression of the ABCB1 gene, as well as the presence of the TT genotype of the C3435T SNP, contributes to a worse prognosis in AML.

Pharmacogenetics Approach for the Improvement of COVID-19 Treatment.

The treatment of coronavirus disease 2019 (COVID-19) has been a challenge. The efficacy of several drugs has been evaluated and variability in drug response has been observed. Pharmacogenetics could explain this variation and improve patients' outcomes with this complex disease; nevertheless, several disease-related issues must be carefully reviewed in the pharmacogenetic study of COVID-19 treatment. We aimed to describe the pharmacogenetic variants reported for drugs used for COVID-19 treatment (remdesivir, oseltamivir, lopinavir, ritonavir, azithromycin, chloroquine, hydroxychloroquine, ivermectin, and dexamethasone). In addition, other factors relevant to the design of pharmacogenetic studies were mentioned. Variants in CYP3A4, CYP3A5, CYP2C8, CY2D6, ABCB1, ABCC2, and SLCO1B1, among other variants, could be included in pharmacogenetic studies of COVID-19 treatment. Besides, nongenetic factors such as drug-drug interactions and inflammation should be considered in the search for personalized therapy of COVID-19.