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PurposeFluoropyrimidines 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.MethodsThe 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).ResultsThe 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.ConclusionFour 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.

IntroductionMethotrexate is the gold-standard DMARD in rheumatoid arthritis but is often associated with “mild” adverse effects like intolerance or laboratory abnormalities. Although non-life threatening, they are responsible for drug discontinuation in 17–50%. There is limited data on clinical and genetic markers that predict their occurrence.MethodsThis prospective study enrolled patients with active rheumatoid arthritis. They were started on methotrexate at a weekly dose of 15 mg, escalated gradually to reach 25 mg which was continued till the end of the study. Intolerance (symptomatic adverse effects) was ascertained by a questionnaire at 4, 8, 16, and 24 weeks. Laboratory testing for occurrence of cytopenia and/or transaminitis was done at the same study visits. Seven SNPs in four genes involved in methotrexate handling were genotyped using real-time polymerase chain reaction.ResultsThis study included 110 patients with rheumatoid arthritis who received methotrexate for 24 weeks; the final mean weekly methotrexate dose was 22.0 ± 4.0 mg. Methotrexate intolerance occurred in 40 (37%), common being nausea (and vomiting) in 29 and anxiety (and dizziness) in 9. It was associated with lower BMI at baseline (21.5 ± 3.7, 23.8 ± 4.6 kg/m2, p = 0.01). FPGS rs10106 was significantly associated with intolerance with an allelic odds ratio (95% CI) of 2.02 (1.14–3.57) and the recessive genetic model (AA+AG versus GG) with an odds ratio of 3.8 (95% CI 1.5–9.6, p = 0.004). A model including both BMI and FPGS rs10106 could modestly predict methotrexate intolerance with an accuracy of 66.3%.ConclusionsA clinical-genetic model including BMI and SNP FPGS 10101 was found to have a modest prediction ability for methotrexate intolerance.Key Points• Methotrexate intolerance (symptomatic adverse effects) was common and occurred in 37% patients over 6 months.• SNP FPGS rs10106 and low body mass index were associated with methotrexate intolerance.• Clinico-genetic model had a modest ability of 66% for predicting intolerance.

An enzymatic route for phosphorous-carbon- bond formation is developed by discovering new promiscuous activity of lipase. This biocatalytic transformation of phosphorous-carbon- bond addition leads to biologically and pharmacologically relevant α-acyloxy phosphonates with methyl group in α-position. A series of target compounds were synthesized with yields ranging from 54% to 83% by enzymatic reaction with Candida cylindracea (CcL) lipase via Markovnikov addition of H-phosphites to vinyl esters. We carefully analyzed the best conditions for the given reaction such as the type of enzyme, temperature, and type of solvent. The developed protocol is applicable to a range of H-phosphites and vinyl esters significantly simplifying the preparation of synthetically challenging α-pivaloyloxy phosphonates. Further, the obtained compounds were validated as new potential antimicrobial drugs with characteristic E. coli bacterial strains and DNA modification recognized by the Fpg protein, N-methyl purine glycosylases as new substrates. The impact of the methyl group located in the α-position of the studied α-acyloxy phosphonates on the antimicrobial activity was demonstrated. The pivotal role of this group on inhibitory activity against selected pathogenic E. coli strains was revealed. The observed results are especially important in the case of the increasing resistance of bacteria to various drugs and antibiotics.

This work presents the successful synthesis of a library of novel peptidomimetics via Ugi multicomponent reaction. Most of these peptidomimetics contain differently substituted aminocoumarin; 7-amino-4-methylcoumarin and 7-amino-4-(trifluoromethyl) coumarin. Inspired by the biological properties of coumarin derivatives and peptidomimetics, we proposed the synthesis of coumarin incorporated peptidomimetics. We studied the potential of synthesized compounds as antimicrobial drugs on model E. coli bacterial strains (k12 and R2–R4). To highlight the importance of coumarin in antimicrobial resistance, we also synthesized the structurally similar peptidomimetics, using benzylamine. Preliminary cellular studies suggest that the compounds with coumarin derivatives have more potential as antimicrobial agents compared to the compounds without coumarin. We also analyzed the effect of aldehyde, free acid group and ester group on the course of their antimicrobial properties.

The impact of substituent at phenyl ring of diethyl benzylphosphonate derivatives on cytotoxic activity was studied. The organophosphonates were obtained based on developed palladium-catalyzed α, β-homodiarylation of vinyl esters protocol. The new synthetic pathway toward 1,2-bis(4-((diethoxyphosphoryl)methyl)phenyl)ethyl acetate was proposed which significantly improves the overall yield of the final product (from 1% to 38%). Several newly synthesized organophosphonates were tested as new potential antimicrobial drugs on model Escherichia coli bacterial strains (K12 and R2-R3). All tested compounds show the highest selectivity and activity against K12 and R2 strains. Preliminary cellular studies using MIC and MBC tests and digestion of Fpg after modification of bacterial DNA suggest that selected benzylphosphonate derivatives may have greater potential as antibacterial agents than typically used antibiotics such as ciprofloxacin, bleomycin and cloxacillin. These compounds are highly specific for pathogenic E. coli strains based on the model strains used and may be engaged in the future as new substitutes for commonly used antibiotics, which is especially important due to the increasing resistance of bacteria to various drugs and antibiotics.

Not all patients with type 2 diabetes develop renal dysfunction. Identifying those at risk is problematic because even microalbuminuria, often used clinically as an indicator of future renal dysfunction, does not always precede worsening renal function. We sought to identify clinical risk factors at diagnosis of type 2 diabetes associated with later development of renal dysfunction. Of 5,102 U.K. Prospective Diabetes Study (UKPDS) participants, prospective analyses were undertaken in those without albuminuria (n = 4,031) or with normal plasma creatinine (n=5,032) at diagnosis. Stepwise proportional hazards multivariate regression was used to assess association of putative baseline risk factors with subsequent development of albuminuria (microalbuminuria or macroalbuminuria) or renal impairment (Cockcroft-Gault estimated creatinine clearance <60 ml/min or doubling of plasma creatinine). Over a median of 15 years of follow-up 1,544 (38%) of 4,031 patients developed albuminuria and 1,449 (29%) of 5,032 developed renal impairment. Of 4,006 patients with the requisite data for both outcomes, 1,534 (38%) developed albuminuria and 1,132 (28%) developed renal impairment. Of the latter, 575 (51%) did not have preceding albuminuria. Development of albuminuria or renal impairment was independently associated with increased baseline systolic blood pressure, urinary albumin, plasma creatinine, and Indian-Asian ethnicity. Additional independent risk factors for albuminuria were male sex, increased waist circumference, plasma triglycerides, LDL cholesterol, HbA(1c) (A1C), increased white cell count, ever having smoked, and previous retinopathy. Additional independent risk factors for renal impairment were female sex, decreased waist circumference, age, increased insulin sensitivity, and previous sensory neuropathy. Over a median of 15 years from diagnosis of type 2 diabetes, nearly 40% of UKPDS patients developed albuminuria and nearly 30% developed renal impairment. Distinct sets of risk factors are associated with the development of these two outcomes, consistent with the concept that they are not linked inexorably in type 2 diabetes.

This study aimed to identify sensitive and noninvasive biomarkers of early cyto-genotoxic, oxidative and inflammatory effects for exposure to volatile organic compounds (VOCs) in shipyard painters. On 17 (11 spray and 6 roller) painters (previously characterized for VOCs exposure to toluene, xylenes, ethylbenzene, ethyl acetate) and on 18 controls, we performed buccal micronucleus cytome (BMCyt) assay; Fpg-comet assay on lymphocytes; detection of urinary 8-oxoGua (8-oxo-7,8-dihydroguanine), 8-oxodGuo (8-oxo-7,8-dihydro-2′-deoxyguanosine) and 8-oxoGuo (8-oxo-7,8-dihydroguanosine), and cytokines release on serum. We found induction of cyto-genotoxicity by BMCyt assay and inflammatory effects (IL-6 and TNFα) in roller painters exposed to lower VOC concentrations than spray painters. In contrast, in both worker groups, we found direct and oxidative DNA damage by comet assay (with slightly higher oxidative DNA damage in roller) and significant increase of 8-oxoGuo and decrease of 8-oxodGuo and 8-oxoGua in respect to controls. The cyto-genotoxicity observed only on buccal cells of roller painters could be related to the task’s specificity and the different used protective equipment. Although limited by the small number of subjects, the study shows the usefulness of all the used biomarkers in the risk assessment of painters workers exposed to complex mixtures.

This article is devoted to a novel class of antimicrobial agents: nanocomposites composed of spherical silica and silver ions located at the silica’s surface with the assumed distribution. Such materials are in high demand due to the increasing threat from bacterial strains that are becoming resistant to currently known antibiotics. In particular, we focus on materials that make it possible to limit the growth of bacterial colonies on a variety of tactile surfaces. In this paper, we present a method for preparing a silica-based nanocomposite containing silver ions and the analysis of their antimicrobial properties. Our research revealed that the presence of tested nanocomposite induces very high oxidative stress in the bacteria cell, damaging and modifying bacterial DNA, creating oxidized guanines, cytosines, or adenines, which causes its very rapid destruction, leading to cell death.

Introduction Whereas fasting plasma glucose (FPG) is cheaper, the glycated haemoglobin (HBA1c) test, which does not require fasting, is more convenient for diabetes screening and could be available to patients throughout the day. In this study, we compared the cost effectiveness of the HBA1c test to that of the FPG test when used for point-of-care (POC) screening of type 2 diabetes in a low-resource setting in Uganda. Methods A cost-effectiveness analysis from a societal perspective was conducted for a single screening cycle of 1659 adults aged 35–70 years receiving care at the outpatient department of a general hospital. We constructed a decision analysis model using TreeAge Pro Healthcare v2023, with the cost estimated using an ingredient approach and the effectiveness measured based on the proportion of patients correctly diagnosed with diabetes. Results The unit cost was US$ 6.48 for the HBA1c test and US$ 8.39 for the FPG test. However, a marginally greater percentage of patients were correctly diagnosed according to the FPG test (96.3%) than the HBA1c test (96.2%). The cost-effectiveness ratio was $6.74 for the HBA1c test and $8.39 for the FPG test. The incremental cost effectiveness ratio was $989.06 per additional patient correctly diagnosed with diabetes. Conclusion HBA1c POC testing could be a more cost-effective alternative to the FPG POC test for the screening of diabetes in under-served outpatient populations in Uganda and similar contexts.

Background Methotrexate (MTX) eradicates leukemic cells by disrupting de novo nucleotide biosynthesis and DNA replication, resulting in cell death. Since its introduction in 1947, MTX-containing chemotherapeutic regimens have proven instrumental in achieving curative effects in acute lymphoblastic leukemia (ALL). However, drug resistance phenomena pose major obstacles to efficacious ALL chemotherapy. Moreover, clinically relevant molecular mechanisms underlying chemoresistance remain largely obscure. Several alterations in MTX metabolism, leading to impaired accumulation of this cytotoxic agent in tumor cells, have been classified as determinants of MTX resistance. However, the relation between MTX resistance and long-term clinical outcome of ALL has not been shown previously. Methods We have collected clinical data for 235 childhood ALL patients, for whom samples taken at the time of diagnosis were also broadly characterized with respect to MTX resistance. This included measurement of concentrations of MTX polyglutamates in leukemic cells, mRNA expression of enzymes involved in MTX metabolism (FPGS, FPGH, RFC, DHFR, and TS), MTX sensitivity as determined by the TS inhibition assay, and FPGS activity. Results Herein we demonstrate that higher accumulation of long-chain polyglutamates of MTX is strongly associated with better overall (10-year OS: 90.6 vs 64.1 %, P = 0.008) and event-free survival (10-year EFS: 81.2 vs 57.6 %, P = 0.029) of ALL patients. In addition, we assessed both the association of several MTX resistance-related parameters determined in vitro with treatment outcome as well as clinical characteristics of pediatric ALL patients treated with MTX-containing combination chemotherapy. High MTX sensitivity was associated with DNA hyperdiploid ALL ( P < 0.001), which was linked with increased MTX accumulation ( P = 0.03) and elevated reduced folate carrier (RFC) expression ( P = 0.049) in this subset of ALL patients. TEL-AML1 fusion was associated with increased MTX resistance ( P = 0.023). Moreover, a low accumulation of MTX polyglutamates was observed in MLL -rearranged and TEL-AML1 rearranged ALL ( P < 0.05). Conclusions These findings emphasize the central role of MTX in ALL treatment thereby expanding our understanding of the molecular basis of clinical differences in treatment response between ALL individuals. In particular, the identification of patients that are potentially resistant to MTX at diagnosis may allow for tailoring novel treatment strategies to individual leukemia patients.