ABCC2 Gene Research Articles

Genetic Variation in ABCC4 and CFTR and Acute Pancreatitis during Treatment of Pediatric Acute Lymphoblastic Leukemia.

Background: Acute pancreatitis (AP) is a serious, mechanistically not entirely resolved side effect of L-asparaginase-containing treatment for acute lymphoblastic leukemia (ALL). To find new candidate variations for AP, we conducted a genome-wide association study (GWAS). Methods: In all, 1,004,623 single-nucleotide variants (SNVs) were analyzed in 51 pediatric ALL patients with AP (cases) and 1388 patients without AP (controls). Replication used independent patients. Results: The top-ranked SNV (rs4148513) was located within the ABCC4 gene (odds ratio (OR) 84.1; p = 1.04 × 10−14). Independent replication of our 20 top SNVs was not supportive of initial results, partly because rare variants were neither present in cases nor present in controls. However, results of combined analysis (GWAS and replication cohorts) remained significant (e.g., rs4148513; OR = 47.2; p = 7.31 × 10−9). Subsequently, we sequenced the entire ABCC4 gene and its close relative, the cystic fibrosis associated CFTR gene, a strong AP candidate gene, in 48 cases and 47 controls. Six AP-associated variants in ABCC4 and one variant in CFTR were detected. Replication confirmed the six ABCC4 variants but not the CFTR variant. Conclusions: Genetic variation within the ABCC4 gene was associated with AP during the treatment of ALL. No association of AP with CFTR was observed. Larger international studies are necessary to more conclusively assess the risk of rare clinical phenotypes.

New deafness gene: Progress of research on ABCC1 in biological barriers

ABCC1 gene is expressed in various tissues and organs of the human body, and can transport substrates including drugs, heavy metals, toxic substances and organic anions. Previous research on ABCC1 gene has mostly focused on tumor multidrug resistance. Recently, ABCC1 has been proposed as a candidate gene for hereditary hearing impairment, which has attracted much attention. ABCC1-associated deafness may be related to its role in biological barriers. This article has summarized recent progress in the study of the role of ABCC1 in the blood-testis barrier, placental barrier, blood-brain barrier, blood-labyrinth barrier, which may provide insight into its biological functions.

BDE-209 and TCDD Modulate the Expression and Activity of ATP-Binding Cassette (ABC) Transporters in Murine Melanoma Cells (B16-F1)

Persistent organic pollutants (POPs) may alter tumor cells phenotype, possibly increasing malignancy, but there is a lack of studies investigating the mechanisms by which POPs may affect tumor cells. The ATP-Binding Cassette (ABC) transporter proteins are a widely studied component of drug resistance and tumor progression. We hypothesized that the levels of BDE-209 and TCDD detected in human serum can modulate the gene expression or activity of ATP-binding cassette (ABC) transporters in murine melanoma (B16-F1) cells. In this study, we observed an upregulation of the ABCB1 and ABCC4 (24 h) genes followed by an increased protein activity after BDE-209 15 day-exposure. We also observed that cells exposed to TCDD showed an upregulation of ABCB5, ABCC1 and ABCC4 genes (24 h) and change of protein activity after 15 days of exposure. These findings suggest that BDE-209 and TCDD can regulate the phenotype of B16-F1 cells by interfering with the expression and activity of ATP-binding cassette (ABC) transporters. This investigation revealed that environmental pollutants might intervene and modify cells’ resistance to chemotherapy and cancer prognosis.

The ABCC4 gene is associated with pyometra in golden retriever dogs

Pyometra is one of the most common diseases in female dogs, presenting as purulent inflammation and bacterial infection of the uterus. On average 20% of intact female dogs are affected before 10 years of age, a proportion that varies greatly between breeds (3–66%). The clear breed predisposition suggests that genetic risk factors are involved in disease development. To identify genetic risk factors associated with the disease, we performed a genome-wide association study (GWAS) in golden retrievers, a breed with increased risk of developing pyometra (risk ratio: 3.3). We applied a mixed model approach comparing 98 cases, and 96 healthy controls and identified an associated locus on chromosome 22 (p = 1.2 × 10–6, passing Bonferroni corrected significance). This locus contained five significantly associated SNPs positioned within introns of the ATP-binding cassette transporter 4 (ABCC4) gene. This gene encodes a transmembrane transporter that is important for prostaglandin transport. Next generation sequencing and genotyping of cases and controls subsequently identified four missense SNPs within the ABCC4 gene. One missense SNP at chr22:45,893,198 (p.Met787Val) showed complete linkage disequilibrium with the associated GWAS SNPs suggesting a potential role in disease development. Another locus on chromosome 18 overlapping the TESMIN gene, is also potentially implicated in the development of the disease.

Development of adry powder for inhalation of nanoparticles codelivering cisplatin and ABCC3 siRNA in lung cancer.

Background: The current study sought to formulate a dry powder inhalant(DPI) for pulmonary delivery of lipopolymeric nanoparticles (LPNs) consisting of cisplatin and siRNA for multidrug-resistant lung cancer. siRNA against ABCC3 gene was used to silence drug efflux promoter. Results &discussion: The formulation was optimized through thequality by designsystem by nanoparticle size and cisplatin entrapment. The lipid concentration, polymer concentration and lipid molar ratio were selected as variables. The DPI was characterized by in vitro deposition study using the Anderson cascade impactor. DPI formulation showed improved pulmonary pharmacokinetic parameters of cisplatin with higher residence time in lungs. Conclusion: Local delivery of siRNA and cisplatin to the lung tissue resulted into an enhanced therapeutic effectiveness in combating drug resistance.

Predicting response to platinum and non-platinum drugs through bioluminescence resonance energy transfer (BRET) based bio-molecular interactions in platinum resistant epithelial ovarian cancer

Therapy induced rewiring of signalling networks often lead to acquirement of platinum-resistance, thereby necessitating the use of non-platinum agents as second-line treatment particularly for epithelial ovarian cancer (EOC). A prior subject-specific assessment can guide the choice of optimal non-platinum agent/s and possible targeted therapeutic/s. Assessment of protein-protein interactions are superior to simple cytotoxicity assays to determine therapeutic efficacy and associated molecular responses. Utilizing improved PIP3-AKT and ERK1/2 activation Bioluminescence Resonance Energy Transfer (BRET) sensors, we report chemotherapy-induced ERK1/2 activation predominantly in cisplatin-paclitaxel resistant EOC cells and increased activation of both ERK1/2 and AKT in malignant ascites derived cancer cells from platinum-resistant patients but not from treatment-naive or platinum-sensitive relapse patients. Further, majority of the non-platinum drugs except irinotecan increased ERK1/2 activation in platinum-taxol resistant cells as observed by live-cell BRET assessment which were associated with p90RSK1/2 and BAD activation along with upregulation of multidrug transporter gene ABCC1 and cell survival genes like cyclin D1 and Bcl2. Interestingly, only irinotecan was able to sensitize these resistant cells. Altogether, this first report of BRET based sensing of molecular pathway activations in platinum resistant cell lines and patient's derived cancer cells highlight the clinical potential of BRET sensors in management of therapy resistant cancer.

Influence of FPGS, ABCC4, SLC29A1, and MTHFR genes on the pharmacogenomics of fluoropyrimidines in patients with gastrointestinal cancer from the Brazilian Amazon.

Fluoropyrimidines are one of the most used drug class to treat cancer patients, although they show high levels of associated toxicity. This study analyzed 33 polymorphisms in 17 pharmacogenes involved with the pharmacogenomics of fluoropyrimidines, in gastrointestinal cancer patients undergoing fluoropyrimidine-based treatment in the Brazilian Amazon. The study population was composed of 216 patients, 92 of whom have an anatomopathological diagnosis of gastric cancer and 124 of colorectal cancer. The single nucleotide polymorphisms (SNP) were genotyped by allelic discrimination using the TaqMan OpenArray Genotyping technology, with a panel of 32 customized assays, run in a QuantStudio ™ 12K Flex Real-Time PCR System (Applied Biosystems, Life Technologies, Carlsbad USA). Ancestry analysis was performed using 61 autosomal ancestry informative markers (AIMs). The study population show mean values of 48.1% European, 31.1% Amerindian, and 20.8% African ancestries. A significant risk association for general and severe toxicity was found in the rs4451422 of FPGS (p = 0.001; OR 3.40; CI 95% 1.65-7.00 and p = 0.006; OR 4.63; CI 95% 1.56-13.72, respectively) and the rs9524885 of ABCC4 (p = 0.023; OR 2.74; CI 95% 1.14-6.65 and p = 0.024; OR 5.36; IC 95% 1.24-23.11, respectively) genes. The rs760370 in the SLC29A1 gene (p = 0.009; OR 6.71; CI 95% 1.16-8.21) and the rs1801133 in the MTHFR toxicity (p = 0.023; OR 3.09; CI 95% 1.16-8.21) gene also demonstrated to be significant, although only for severe toxicity. The results found in this study did not have statistics analysis correction. Four polymorphisms of the ABCC4, FPGS, SLC29A1, and MTHFR genes are likely to be potential predictive biomarkers for precision medicine in fluoropyrimidine-based treatments in the population of the Brazilian Amazon, which is constituted by a unique genetic background.

Aidi injection, a traditional Chinese medicine extract, reverses Gefitinib resistance in non-small cell lung cancer cells

IntroductionAidi injection is a traditional Chinese medicine containing multiple anti-tumour and immunomodulatory phytochemicals. While it synergistically enhances the efficacy of conventional chemotherapy in patients with non-small cell lung cancer (NSCLC), its effect on epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) sensitivity in NSCLC remains unclear. This study aimed to investigate the effect and mechanisms of Aidi injection on the sensitivity of human NSCLC cell lines to gefitinib. MethodsEffect of Aidi injection on gefitinib sensitivity was assessed by MTT, colony formation and apoptosis assays in three NSCLC cell lines (A549, HCC827 and H1975). The association between the expression of genes and the overall survival was analysed by accessing TCGA lung adenocarcinoma datasets. The effect of Aidi injection on multidrug resistance-associated protein 2 (MRP2, encoded by ABCC2 gene) function and gefitinib sensitivity was compared between parental HEK293 cell and HEK293 overexpressing MRP2 cells (HEK/MRP2). The principle components of Aidi injection were determined by LC-MS/MS and the interaction of Aidi components with MRP2 protein explored using molecular docking. ResultsAidi injection enhanced gefitinib sensitivity (P < 0.05) and increased gefitinib-induced apoptosis rate (P < 0.05) in three NSCLC cell lines. Analysis of TCGA lung adenocarcinoma dataset showed that patients with a high expression of ABCC2 had significantly poorer survival (P = 0.007546). Aidi injection inhibited MRP2 activity in a concentration-dependant manner in HEK/MRP2 cells (P < 0.05). The combination of gefitinib with Aidi injection gave additive or weakly synergistic growth inhibition in HEK/MRP2 cells but exhibited antagonistic cytotoxicity in HEK293 cells. There were 11 main chemical components contained in Aidi injection, including astragalosides II and IV, cantharidin, etheutheroside E, ginsenosides Rb1, Rc, Rd, Re and Rg1, isofraxidin, and syringin. Docking studies showed strong affinity of Ginsenoside_Re towards MRP2. ConclusionsAidi injection may have the potential to be an adjuvant regimen to prevent and/or reverse common gefitinib resistance in NSCLC. The in silico and principle component analyses gives insight on ginsenoside_Re being a potential MRP2 inhibitor in Aidi injection.

GWAS Hits for Bilateral Convergent Strabismus with Exophthalmos in Holstein Cattle Using Imputed Sequence Level Genotypes.

Bilateral convergent strabismus with exophthalmos (BCSE) is a malformation of the eyes and is recognized as a mild but progressive disorder that affects cattle in the first two years of life. This most likely inherited disorder is rarely described in cattle resembling autosomal dominantly inherited forms of human progressive external ophthalmoplegia (PEO). In German Braunvieh cattle, two linked genome regions were found that could be responsible for the development and/or progression of BCSE. The goal of this study was to phenotypically characterize BCSE in Holstein cattle from Germany and Switzerland as well as to identify associated genome regions by GWAS. The clinicopathological phenotype of 52 BCSE-affected Holstein cattle was in accordance with the phenotype described in German Braunvieh cattle, but in addition, signs of degeneration and cellular infiltration in the eye muscles were found. By using imputed sequence level genotype data, three genome-wide significant GWAS hits were revealed on different chromosomes that were not detected by initial GWAS based on high density SNP array data highlighting the usefulness of this approach for mapping studies. The associated genome regions include the ABCC4 gene as well as markers adjacent to the NCOR2 and DNAJC3 genes all illustrating possible functional candidate genes. Our results challenge a monogenic mode of inheritance and indicate a more complex inheritance of BCSE in Holstein cattle. Furthermore, in comparison to previous results from German Braunvieh cattle, it illustrates an obvious genetic heterogeneity causing BSCE in cattle. Subsequent whole genome sequencing (WGS)-based analyses might elucidate pathogenic variants in the future.

Abstract 346: Tumoral expression of folate-associated genes is associated with progression-free survival of patients with advanced colorectal cancer

Abstract Background - 5-fluorouracil (5-FU) in combination with the folate leucovorin (LV) has formed the backbone of chemotherapy for advanced colorectal cancer for several decades. A number of genes encode proteins that participate in transportation of LV into the cells, as well as in subsequent metabolic action. We previously reported that high tumoral expression of genes involved in folate transport, polyglutamation, and metabolism was associated with decreased risk of recurrent disease in patients with stage III colorectal cancer treated with 5-FU + LV (FLV) alone, or in combination with oxaliplatin (FLOX) according to the Nordic bolus regimen. The aim of the present study was to determine the association between expression of the folate-associated genes ABCC3, MTHFD2, SLC19A1, SLC25A32, SLC46A1, and TYMS and outcome of patients with metastatic colorectal cancer subjected to palliative chemotherapy. Patients and Methods - A total of 290 patients treated with FLV (n = 113), FLOX (n = 102) or FLV + irinotecan (FLIRI, n = 75) were included. Relative gene expression (ΔCt) was determined in primary tumors by quantitative PCR and analyzed in relation to clinical benefit, based on RECIST criteria and 3-year progression-free survival (PFS). Analyses were conducted on the whole study group, and on subgroups based on tumor stage at primary surgery (subgroup 1, stage I-III; subgroup 2, stage IV). An ANOVA test was used to assess the relationship between expression and clinical benefit. A multivariate Cox proportional hazard model was applied to assess potential associations between genetic markers, clinical variables and PFS. A Stepwise model selection was used to identify a minimal set of variables associated with PFS. Results - Low expression of TYMS and MTHFD2, and high expression of ABCC3 was significantly associated with a clinical benefit in the whole group (p&amp;lt;0.0001, p=0.017, and p=0.028, respectively). The association between TYMS expression and clinical benefit was seen in both sub-groups, whereas ABCC3 expression was significant in subgroup 2 (p=0.041). Multivariate models showed that low TYMS and high SLC25A32 expression in subgroup 1 and high ABCC3 expression in subgroup 2 correlated significantly with better PFS (Hazard Ratio (HR) = 0.75 (95% CI = 0.57-1.0), HR = 2.21 (95% CI = 1.37-3.6), and HR = 1.34 (95% CI = 1.08 -1.7), respectively). Conclusion - Expression of TYMS, the target enzyme of 5-FU, was strongly associated with clinical benefit in the whole group, whereas expression of TYMS and the folate transporters SLC25A32, and ABCC3 was associated with PFS in the subgroups (stage I-III and stage IV), respectively. The prospective global phase III study AGENT is presently conducted on patients with advanced colorectal cancer, to determine whether expression of these genes can predict response to 5-FU-based chemotherapy that includes LV or the novel folate arfolitixorin. Citation Format: Yvonne Wettergren, Elisabeth Odin, Göran Carlsson, Pushpa Saksena, Anders Edsjö, Alessandro Di Cara, Roger Tell, Bengt Gustavsson. Tumoral expression of folate-associated genes is associated with progression-free survival of patients with advanced colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 346.

Cover Caption

The fall armyworm, Spodoptera frugiperda, is a major pest native to the Americas that has recently invaded the Old World. A whole‐genome sequencing (WGS) approach was used to identify mutations associated with resistance to insecticides and Bt proteins in 150 individuals of S. frugiperda collected from China, Malawi, Uganda and Brazil. This approach revealed three amino acid substitutions (A201S, G227A and F290V) of the acetylcholinesterase‐1 (ace‐1) in the four geographical populations of S. frugiperda, which are known to be associated with organophosphate resistance. A novel Cry1F resistance allele in the ABCC2 gene was identified from the Brazilian population but absent in the invasive populations (see pages 627‐638). Photo provided by Prof. Run‐Zhi Zhang.

Polymorphisms in the CYP2A6 and ABCC4 genes are associated with a protective effect on chronic myeloid leukemia in the Brazilian Amazon population.

BackgroundSusceptibility to Chronic Myeloid Leukemia (CML) may be modulated by genetic variables. However, the majority of previous investigations have focused on genetically homogeneous populations, resulting in a lack of evidence on how genetic factors may influence the development of CML in miscegenated populations. We analyzed 30 polymorphisms in genes related to DNA repair, folate metabolism, transmembrane transport, xenobiotic metabolism, and pyrimidine synthesis in relation to their potential role in the susceptibility of the individual to CML.MethodsThis case‐control study included 126 healthy individuals and 143 patients diagnosed with CML from the admixed population of the Brazilian Amazon. The samples were genotyped by real‐time PCR and the genetic ancestry analysis was based on a panel of 61 ancestry informative markers.ResultsThe results indicated a protective effect against the development of CML in carriers of the C allele of the rs28399433 (CYP2A6) gene and the CC genotype of the rs3742106 (ABCC4) gene.ConclusionOur findings suggest that the rs3742106 (ABCC4) and rs28399433 (CYP2A6) polymorphisms may modulate susceptibility to CML in a population of the Brazilian Amazon region.

Neonatal Dubin-Johnson syndrome: biochemical parameters, characteristics, and genetic variants study.

The clinical characteristics and gene mutation characteristics of children with Dubin-Johnson syndrome (DJS) need in-depth study. The clinical and genomic data of neonatal Dubin-Johnson syndrome (NDJS) and 155 cases with idiopathic cholestasis (IC) were analyzed from June 2016 to August 2020 RESULTS: ABCC2 gene variants were identified in eight patients, including one patient with homozygous variants and seven patients with compound heterozygous variants. A total of 13 different ABCC variants were detected in the NDJS patients, including three nonsense variants, six missense variants, three frameshift variants, and a splice site variant. The variant c.2443C > T (p.R815X), c.4237_4238insCT (p.H1414Lfs*17), c.960_961insGT (p.L322Cfs*3), c.4250delC (p.S1417Ffs*14), c.2224G > A (p.D742N), c.4020G > C (p.K1340N), and c.2439 + 5G > A were not reported in the Human Gene Variant Database. There was no significance in the sex, birth weight, and onset age between the NDJS and IC groups. Compared with the IC group, the NDJS group had significantly higher levels of total bilirubin (TB), but a significantly lower level of alanine transaminase and a ratio of direct bilirubin (DB) to TB. There is no significance in total bile acid, gamma-glutamyl-transpeptidase, albumin, or international normalized ratio between the two groups. NDJS should be considered in prolonged neonatal intrahepatic cholestasis, especially in infants with normal or slightly elevated transaminase levels. Explore the biochemical parameters, characteristics, and genetic profile of NDJS. By summarizing the characteristics of biochemical indicators, seven new mutation types of the ABCC2 gene were detected, which expanded the mutation spectrum of the ABCC2 gene. NDJS should be considered in prolonged neonatal intrahepatic cholestasis, especially in infants with normal or slightly elevated transaminase levels.

P671 Effect of genetic polymorphisms in the folate pathway on the efficacy and safety of methotrexate in Crohn’s disease

Abstract Background Methotrexate (MTX) is currently used in steroid-dependent patients with moderate-to-severe Crohn’s disease (CD) when thiopurines have failed or are contraindicated. Although its efficacy has been proved for both induction and maintenance of remission, its use is limited due to the rate of associated adverse events. Polymorphisms in the folate pathway might predict the efficacy and toxicity of MTX. Our aims were to evaluate the predictive value of these polymorphisms of MTX efficacy and safety in CD. Methods Patients from ENEIDA registry of GETECCU who were treated with MTX on monotherapy and of whom genomic DNA was available, were identified. Clinical efficacy and MTX-related toxicity were collected, and 10 variants from ATIC, DHFR, MTHFR, RFC1, ABCB1 and ABCC3 genes were genotyped with TaqMan assays. Results One hundred and twenty nine patients were included, 55% were female and 31% active smokers. MTX was used as first and second-line therapy in 10% and 60% of patients, respectively, at a mean dose of 22 mg and for a median time of 14 months. Thirty-seven per cent of patients achieved clinical remission, whereas 34% were non-responders (MTX failure). Forty patients (30%) developed MTX-related toxicity, with nausea and vomiting, myelotoxicity and hepatotoxicity as the most frequent adverse events (37%, 15% and 15%, respectively). MTX was discontineud in 19% of the patients due to toxicity. In the multivariable analysis, patients with the AA genotype for the rs408626 DHFR variant was predictive of a higher efficacy as compared to the G allele carriers (RR 0.372, p=0.026), and smoking was associated with a higher risk of MTX therapy failure (RR 2.676, p=0.015). Moreover, the CC genotype for the rs1476413 MTHFR variant and the TT genotype for the rs4793665 ABCC3 variant were independently associated with a higher risk of MTX toxicity (RR 2.357, p=0.038 and RR 2.368, p=0.044, respectively). Conclusion Genetic polymorphisms related to the folate pathway (mainly the variant rs408626 of DHFR, rs1476413 of MTHFR and rs4793665 of ABCC3) seem to impact on MTX efficacy and toxicity in CD. Smoking could also influence MTX efficacy.

Geographic Monitoring of Insecticide Resistance Mutations in Native and Invasive Populations of the Fall Armyworm.

Simple SummaryThe moth fall armyworm (Spodoptera frugiperda) is a major agricultural pest insect damaging a wide range of crops, especially corn. Field evolved resistance against Bacillus thuringiensis (Bt) toxins and synthetic insecticides has been repeatedly reported. While the fall armyworm is native to the Americas, its biological invasion was first reported from West Africa in 2016. Since then, this pest has been detected across sub-Saharan and North Africa, Asia, and Oceania. Here, we examine the geographical distribution of mutations causing resistance against Bt or synthetic insecticides to test if the invasion was accompanied by the spread of resistance mutations using 177 individuals collected from 12 geographic populations including North and South America, West and East Africa, India, and China. We observed that Bt resistance mutations generated in Puerto Rico or Brazil were found only from their native populations, while invasive populations had higher copy numbers of cytochrome P450 genes and higher proportions of resistance mutations at AChE, which are known to cause resistance against synthetic insecticides. This result explains the susceptibility to Bt insecticides and the resistance against synthetic insecticides in invasive Chinese populations. This information will be helpful in investigating the cause and consequence associated with insecticide resistance.Field evolved resistance to insecticides is one of the main challenges in pest control. The fall armyworm (FAW) is a lepidopteran pest species causing severe crop losses, especially corn. While native to the Americas, the presence of FAW was confirmed in West Africa in 2016. Since then, the FAW has been detected in over 70 countries covering sub-Saharan Africa, the Middle East, North Africa, South Asia, Southeast Asia, and Oceania. In this study, we tested whether this invasion was accompanied by the spread of resistance mutations from native to invasive areas. We observed that mutations causing Bt resistance at ABCC2 genes were observed only in native populations where the mutations were initially reported. Invasive populations were found to have higher gene numbers of cytochrome P450 genes than native populations and a higher proportion of multiple resistance mutations at acetylcholinesterase genes, supporting strong selective pressure for resistance against synthetic insecticides. This result explains the susceptibility to Bt insecticides and resistance to various synthetic insecticides in Chinese populations. These results highlight the necessity of regular and standardized monitoring of insecticide resistance in invasive populations using both genomic approaches and bioassay experiments.

Clinical Relevance of ABCB1, ABCG2, and ABCC2 Gene Polymorphisms in Chronic Myeloid Leukemia Patients Treated With Nilotinib.

Tyrosine kinase inhibitors (TKIs) have radically changed the outcome of chronic myeloid leukemia (CML) patients in the last 20 years. Moreover, the advent of second generation TKIs, namely nilotinib and dasatinib, have largely increased the number of CML patients achieving deep and sustained molecular responses. However, the possible mechanisms capable of influencing the maintenance of the long-term molecular response are not yet fully known and understood. In this light, polymorphisms in MDR-ABC transporters may influence the efficacy and safety of TKIs. In this study, we examined seven single nucleotide polymorphisms (SNPs) in four ABC transporter genes: ABCC1 rs212090 (5463T>A), ABCC2 rs3740066 (3972C>T), ABCC2 rs4148386 G>A, ABCC2 rs1885301 (1549G>A), ABCG2 rs2231137 (34G>A), ABCG2 rs2231142 G>C, ABCB1 rs1045642 (3435C>T), to determine their effect on the achievement and/or loss of molecular response in 90 CML patients treated with nilotinib. We found that ABCC2 rs3740066 CC and CT as well as the ABCB1 rs1045642 TT genotypes correlated with a higher probability to achieve MR3 in a shorter time (p=0.02, p=0.004, and p=0.01), whereas ABCG2 rs2231137 GG was associated with lower probability of MR3 achievement (p=0.005). Moreover, ABCC2 rs3740066 CC genotype, the ABCB1 rs1045642 CC and TT genotypes were positively correlated with MR4 achievement (p=0.02, p=0.007, and p=0.003). We then generated a predictive model incorporating the information of four genotypes, to evaluate the combined effect of the SNPs. The combination of SNPs present in the model affected the probability and the time to molecular response. This model had a high prognostic significance for both MR3 and MR4 (p=0.005 and p=0.008, respectively). Finally, we found ABCG2 rs2231142 GG genotype to be associated with a decrease risk of MR3 loss. In conclusion, MDR-transporters SNPs may significantly affect the achievement and loss of molecular response in CML patients treated with nilotinib.

Association between ABCB1 Polymorphisms and Artesunate-Mefloquine Treatment Responses of Patients with Falciparum Malaria on the Thailand-Myanmar Border.

A decrease in the clinical efficacy of a 3-day artesunate-mefloquine combination treatment was reported in the areas of multidrug-resistant Plasmodium falciparum along the Thailand-Myanmar border. The current study investigated the possible contribution of genetic polymorphisms of the three major genes encoding drug efflux transporters, ABCB1, ABCG2, and ABCC1, to responses to the aforementioned treatment in 91 patients with acute uncomplicated falciparum malaria residing along the Thailand-Myanmar border. Patients carrying homozygous mutant genotype ABCB1 c.1236C>T (TT) were found to have a three-times higher chance of successful treatment with this combination compared with other genotypes (CC and CT). Furthermore, whole blood mefloquine concentrations in these patients with the TT genotype were significantly lower than those of patients carrying the CC genotype. Patients with heterozygous mutant genotype (CT), however, were three-times more likely to experience treatment failure. No significant association was found with the ABCG2 and ABCC1 gene polymorphisms. The results suggest that ABCB1 c.1236C>T polymorphisms could be useful genetic markers for predicting responses to the 3-day artesunate-mefloquine treatment; however, studies using larger sample sizes in different malaria-endemic areas are necessary to confirm this finding. This study highlights the impact of pharmacogenetic factors on antimalarial treatment responses and the basis for the application of control policies in various malaria-endemic areas.

Methyl jasmonate ameliorates lead toxicity in Oryza sativa by modulating chlorophyll metabolism, antioxidative capacity and metal translocation.

Lead (Pb) not only negatively alters plant growth and yield but may also have potentially toxic risks to human health. Nevertheless, the interaction between rice (Oryza sativa L.) plants and the molecular cell dynamics induced by lead-methyl jasmonate (MJ) remains unknown. Here, plants were hydroponically exposed to Pb (150 and 300µM) alone or in combination with 0.5 and 1µMMJ. The application of MJ modulated the expression of the HMAs, PCS1, PCS2 and ABCC1 genes, thereby immobilizing the Pb in the roots and lessening its translocation to the aerial parts of the rice plant. The supplementation of MJ improved the growth and yield of Pb-stressed rice by adjusting the proline and chlorophyll metabolism, increasing the phytochelatins (PCs) accumulation and diminishing the accumulation of Pb in the shoots. the application of MJ alleviated the oxidative stress of rice plants exposed to Pb toxicity by enhancing the activity of antioxidant enzymes and enzymes of the glyoxalase system (glyoxalase I and II) and decreasing the endogenous levels of malondialdehyde (MDA), hydrogen peroxide (H2O2) and methylglyoxal (MG). Therefore, the results of the present study could provide a molecular insight and cellular interplay scheme for the development of a promising strategy in Pb-contaminated areas to produce healthy food.

PCA062, a P-cadherin Targeting Antibody-Drug Conjugate, Displays Potent Antitumor Activity Against P-cadherin-expressing Malignancies.

The cell surface glycoprotein P-cadherin is highly expressed in a number of malignancies, including those arising in the epithelium of the bladder, breast, esophagus, lung, and upper aerodigestive system. PCA062 is a P-cadherin specific antibody-drug conjugate that utilizes the clinically validated SMCC-DM1 linker payload to mediate potent cytotoxicity in cell lines expressing high levels of P-cadherin in vitro, while displaying no specific activity in P-cadherin-negative cell lines. High cell surface P-cadherin is necessary, but not sufficient, to mediate PCA062 cytotoxicity. In vivo, PCA062 demonstrated high serum stability and a potent ability to induce mitotic arrest. In addition, PCA062 was efficacious in clinically relevant models of P-cadherin-expressing cancers, including breast, esophageal, and head and neck. Preclinical non-human primate toxicology studies demonstrated a favorable safety profile that supports clinical development. Genome-wide CRISPR screens reveal that expression of the multidrug-resistant gene ABCC1 and the lysosomal transporter SLC46A3 differentially impact tumor cell sensitivity to PCA062. The preclinical data presented here suggest that PCA062 may have clinical value for treating patients with multiple cancer types including basal-like breast cancer.

ABCC4 single-nucleotide polymorphisms as markers of tenofovir disoproxil fumarate-induced kidney impairment.

Recently, the use of antiretroviral drug tenofovir disoproxil fumarate (TDF) is increased, thanks to the new co-formulation with doravirine, the availability of booster-free regimens, and its advantageous lipid-lowering effect. The aim of our study was to identify genetic markers that contribute to assess the risk of TDF-related renal toxicity. We have retrospectively investigated, in 179 HIV positive patients treated with TDF, the association between the main variants in ABCC2, ABCC4, and ABCC10 genes and four safety endpoints, three clinically relevant as renal outcomes and a higher tenofovir plasma concentration. In patients with an annual eGFR decline >5 mL/min/1.73 m2 a difference in genotype frequencies was observed for ABCC10 c.1875 + 526 G>A (3 subjects AA vs. 44 GG + GA, p = 0.045). In patients with an eGFR decrement >25%, plus a decline in GFR category and TDF discontinuation, a difference was observed for ABCC4 c.*38T>G (35 subjects TG + GG vs. 18 TT, p = 0.052). At univariate analysis OR was 1.39 [(95% CI 1.00-1.96) p = 0.054] and at multivariate analysis OR was 1.49 [(95% CI 1.00-2.22) p = 0.049]. The stronger associations were found between the tenofovir accumulation and ABCC4 c.*38T>G and c.3348G>A: the percentage of these patients was higher in the TG + GG (p = 0.011) and in the AA (p = 0.004) genotype, respectively. The logistic regression analysis confirmed these significant relationships. No significant association was observed in patients with eGFR < 60 mL/min/1.73m2 and with the studied ABCC2 polymorphisms. Our results show a major role for a combined determination of ABCC4/ABCC10 variants as an indicator of tenofovir toxicity in the clinical practice.