Search Results (223)

Background: Tyrosine kinase inhibitors (TKIs) have significantly improved outcomes in non-small cell lung cancer (NSCLC), especially among patients with actionable genetic mutations. However, the influence of family and personal medical history (FPMH) on clinical and treatment outcomes with TKI therapy remains underexplored. Methods: We conducted a retrospective cohort study involving 136 NSCLC patients receiving TKIs, categorized into two groups based on the presence or absence of documented FPMH. Clinical variables assessed included demographic data, comorbidities, Eastern Cooperative Oncology Group (ECOG) performance status, tumor characteristics, genetic mutations (EGFR, ALK, ROS1), treatment responses, toxicity profiles, and survival outcomes. Statistical analyses included Chi-square tests, t-tests, Mann–Whitney U tests, Spearman correlation, and univariate logistic regression (p < 0.05 threshold for significance). Results: Patients with FPMH (n = 34) had a significantly higher burden of chronic diseases (58.8% vs. 15.7%), poorer ECOG scores (≥3: 8.8% vs. 1.0%), increased recurrence (41.2% vs. 20.6%), and greater chemotherapy-related toxicity (50.0% vs. 28.4%) compared to those without FPMH (n = 102). However, there were no significant differences in survival duration or mutation status between the two groups. Conclusions: FPMH may be a predictive factor for treatment complications and recurrence in NSCLC patients receiving TKIs, although it does not appear to influence survival or genetic mutation status. These findings support the need for personalized clinical monitoring strategies based on medical history. Full article

Background: Methotrexate (MTX) remains the most commonly prescribed drug used to treat rheumatoid arthritis (RA). Polymorphisms in solute carrier organic anion transporter family member 1B3 (SLCO1B3) and SLCO1B1 may play a critical role in MTX pharmacokinetics and patient outcomes. However, research on these polymorphisms in Saudi Arabia remains limited. We evaluated the association of SLCO1B3 (rs4149117, rs7311358) and SLCO1B1 (rs2306283, rs4149056) polymorphisms with MTX efficacy and safety in Saudi patients with RA. Methods: This multicenter, case-control study included patients diagnosed with RA in Jeddah and Taif. Demographic and clinical data were collected and analyzed. Genotyping of SLCO1B3 (rs4149117, rs7311358) and SLCO1B1 (rs2306283, rs4149056) polymorphisms was performed using Sanger sequencing. Statistical analyses, including logistic regression and haplotype analysis, were conducted to evaluate associations between these polymorphisms, MTX efficacy, and toxicity. Results: The study cohort comprised 100 patients with RA, with 46 showing a good response to MTX and 54 showing a poor response. Clinical predictors of MTX response were significantly higher in patients with poor response. Both SLCO1B3 polymorphisms (rs4149117, rs7311358) were significantly associated with anemia. Significant associations were found between SLCO1B1 (rs2306283) and gastrointestinal disturbances and anemia. The GAAT haplotype was significantly more prevalent among good responders, while the TGGT haplotype was significantly associated with poor responders. Conclusions: These results highlight the importance of genetic testing in predicting MTX treatment outcomes and tailoring personalized treatment plans for patients with RA to improve efficacy and minimize adverse effects. Full article

Efficient new methods are needed to support initiatives to reduce, refine, and/or replace toxicity testing in vertebrates. 5-fluorouracil (5FU), hydroxyurea (HU), and ribavirin (RV) are mammalian teratogens. Skeletal, endocrine organ, and cardiac effects are often associated with teratogenesis, and a simple nematode like C. elegans lacks these systems. However, many genetic pathways required for mammalian morphogenesis have at least some conserved elements in this small, invertebrate model. The C. elegans lifecycle is 3 days. The effects of 5FU, HU, and RV on the C. elegans morphology were evaluated on day 4 post-initiation of the feeding after hatching for continuous and 24 h (early-only) developmental exposures. Continuous exposures to 5FU and HU induced increases in the incidences of abnormal gonadal structures that were significantly reduced in early-only exposure groups. The incidence of prolapse increased with continuous 5FU and HU exposures and was further increased in early-only exposure groups. Intestinal prolapse through the vulval muscle in C. elegans may be related to reported 5FU and HU effects on skeletal muscle and the gastrointestinal tract in mammals. Continuous RV exposures induced a phenotype lacking a uterus and gonad arms, as well as vulval anomalies that were largely, but not completely, reversed with early-only exposures, which is consistent with reported reversible reproductive tract anomalies after an RV exposure in mammals. These findings suggest that C. elegans can be used to detect the hazard risk from chemicals that adversely affect conserved pathways involved in organismal morphogenesis, but to determine the fit-for-purpose use of this model in chemical safety evaluations, further studies using larger and more diverse chemical test panels are needed. Full article

Prostate cancer is one of the most prevalent malignancies in men, posing a significant public health challenge due to its high incidence and long-term treatment-related toxicities. Long-lived patients often experience prolonged side effects that can severely diminish their quality of life. Despite advancements in radiotherapy techniques like IMRT and VMAT, some patients still experience acute and late side effects. Current treatment protocols do not account for individual variability in normal-tissue radiosensitivity, highlighting the need for predictive tools and a personalised treatment approach. Genetic factors and molecular regulators like microRNAs (miRNAs) contribute to these variations by influencing DNA repair, inflammation, and apoptosis. This review explores potential biomarkers of radiotoxicity, focusing on immune-related factors such as IL-6 and TGF-β1, SNPs influencing radiosensitivity, miRNAs involved in radiation responses, and functional assays including the radiation-induced lymphocyte apoptosis (RILA) test. These approaches offer promising tools for identifying radiosensitive patients and enabling risk-adapted radiotherapy. Full article

Sediments are key players in the optimum functioning of ecosystems; however, they also represent the largest known repository of harmful contaminants. The vast variety of these sediment-associated contaminants may exert harmful effects on marine communities and can impair ecosystem functioning. Whole-cell biosensors are a rapid and biologically relevant tool for assessing environmental toxicity. Therefore, in this study, we developed a bioassay-based toxicity measurement system using genetically modified bacteria to create a whole-cell optical biosensor. Briefly, reporter bacteria were integrated and immobilized using a calcium alginate matrix on fiber-optic tips connected to a photon counter placed inside a light-proof, portable case. The calcium alginate matrix acts as a semi-permeable membrane that protects the reporter-encapsulated optical fiber tips and allows the inward passage of toxicant(s) to induce a dose-dependent response in the bioreporter. The samples were tested by directly submerging the fiber tip with immobilized bacteria into vials containing either water or suspended sediment samples, and the subsequent bioluminescent responses were acquired. In addition to bioavailable sediment toxicity assessments, conventional chemical methods, such as liquid chromatography–mass spectroscopy (LC-MS) and inductively coupled plasma optical emission spectroscopy (ICP-OES), were used for comprehensive evaluation. The results demonstrated the efficacy of the biosensor in detecting various toxicity levels corresponding to identified contaminants, highlighting its potential integration into environmental monitoring frameworks for enhanced sediment and water quality assessments. Despite its utility, this study notes the system’s operational challenges in field conditions, recommending future enhancements for improved portability and usability in remote locations. Full article

Background/Objectives: Radiotherapy is a cornerstone in the treatment of breast cancer, yet its use is frequently accompanied by skin toxicities that vary in severity and timing among patients. The objective of this meta-analysis is to systematically evaluate the pooled impact of genetic variations on the risk and severity of acute and late skin side effects from radiotherapy in breast cancer patients. Materials and Methods: A systematic literature search was conducted across PubMed, Embase, and Scopus to identify studies published between 2014 and 2024 that examined associations between genetic polymorphisms and radiotherapy-induced skin toxicity. Studies were selected based on predefined inclusion and exclusion criteria, and data were synthesized using a random-effects meta-analysis model. The risk of bias was evaluated using the ROBINS-I tool, and publication bias was assessed through funnel plots and Egger’s test. Results: A total of 11 studies involving breast cancer patients were included, identifying associations between various gene polymorphisms and skin toxicity. The pooled analysis revealed that patients with specific genetic variants had a 53% increased risk of acute skin side effects and a 44% increased risk of late effects. Notable implicated genes included XRCC2, IFNG, ATM, TGFB1, and PER3. Significant heterogeneity and publication bias were noted across studies, warranting cautious interpretation. Conclusions: This meta-analysis highlights the role of genetic variation in predicting radiotherapy-induced skin toxicity in breast cancer patients. These findings support the future development of predictive biomarkers and personalized radiotherapy strategies to minimize treatment-related toxicity. Full article

Background/Objectives: Pharmacogenetic (PGx) testing can predict drug efficacy, toxicity, and risk of adverse drug reactions (ADRs). However, PGx-guided prescribing for pediatric chronic pain is underutilized. Methods: We evaluated the rate of deviance from standard drug dosing regimens in children and adolescents with chronic pain based on PGx testing of drug-metabolizing genes. We also assessed the acceptability and feasibility of PGx testing and implementation of PGx-guided recommendations from patient, caregiver, and prescriber perspectives. Finally, we explored whether PGx results could predict self-reported therapeutic responses and/or ADRs to medications. Results: Forty-eight participants aged 8–17 years with chronic pain provided DNA via buccal swab. Genetic variant data for CYP2D6, CYP2C9, and CYP2C19 metabolism genes and associated metabolizer status were analyzed with respect to clinical PGx guidelines for dosing recommendations of analgesics and psychotropic medications. Participants, their caregivers, and their prescribers also completed quantitative questionnaires evaluating their experience with PGx testing. Twenty-three (50%) participants were predicted to benefit from non-standard dosing for medications with clinical PGx guidelines. Participants expressed satisfaction with the PGx testing process and felt it was safe and worthwhile. Prescribers also reported that PGx results were relevant for medication choices in 42 (91%) participants. Seven (15%) participants had genotyping results which may have predicted their self-reported therapeutic responses and/or ADRs to specific medications. Conclusions: Though further research on pharmacodynamic associations is required to sufficiently address the complexity of interpatient responses to medications for the treatment of pediatric pain and mental health conditions, PGx testing may be used to inform individualized medication choices based on genetic make-up. Full article

Background: Statin intolerance is a serious therapeutic dilemma in secondary cardiovascular prevention (e.g., ESC/EAS Guidelines 2023). This is especially true when confirmed by genetic predisposition and complicated by rhabdomyolysis. Although several non-statin agents have become available in recent years, evidence regarding their combined use in high-risk statin-intolerant patients remains limited. Furthermore, the pharmacokinetics of statins in toxic concentrations are poorly characterized in clinical settings. Case Presentation: We present two cases of genetically confirmed statin-induced rhabdomyolysis, both accompanied by severe acute kidney injury requiring renal replacement therapy. In both patients, serial measurements of rosuvastatin plasma concentrations revealed markedly delayed elimination, with detectable levels persisting for several weeks despite ongoing dialysis. Estimated half-lives exceeded 7 days in both cases, far beyond the known therapeutic range. Genetic testing identified SLCO1B1, ABCB1, and CYP2C9 polymorphisms linked to reduced hepatic uptake and impaired drug clearance. Following biochemical recovery, both patients were initiated on a triple non-statin lipid-lowering regimen consisting of ezetimibe, bempedoic acid, and inclisiran. The combination was well tolerated, with no recurrence of muscle-related symptoms or biochemical toxicity. LDL-C levels were reduced from 3.05 to 1.59 mmol/L and from 4.99 to 1.52 mmol/L, respectively, with sustained response over 12 and 40 weeks. Full lipid profiles demonstrated favorable changes across all parameters. Conclusions: These two cases suggest that the combination of ezetimibe, inclisiran, and bempedoic acid may serve as a safe and effective therapeutic option in patients with severe statin intolerance. Pharmacogenetic testing and serial pharmacokinetic assessment may guide personalized lipid-lowering strategies and improve outcomes in this challenging patient population. Full article

Background/Objectives: Pharmacogenomic screening plays a crucial role in optimizing chemotherapy outcomes and minimizing toxicity. Characterizing the baseline distribution of genetic variants in specific populations is essential to inform the prioritization of drug–gene combinations for clinical implementation. The objective of this study was to investigate the distribution of pharmacogenetic variants in 36 genes related to the fluoropyrimidine (FP) pathway among healthy Omani individuals, forming a foundation for future studies in cancer patients receiving FP-based chemotherapy. Methods: Ninety-eight healthy Omani participants aged ≥18 years were recruited at the Sultan Qaboos Comprehensive Cancer Care and Research Center. Whole-blood samples were collected, and genomic DNA was extracted. Targeted next-generation sequencing was performed using a custom Ion AmpliSeq panel covering coding exons and splice-site regions of 36 genes involved in FP metabolism and response. Results: A total of 999 variants were detected across the 36 genes, with 63.3% being heterozygous. The ABCC4 gene had the highest mutation frequency (76 mutations), while DHFR and SMUG1 had the lowest (<10 mutations). In DPYD, four functionally significant variants were found at frequencies ranging from 1 to 8.2% of the population. Missense mutations were also observed in MTHFR and UGT1A1. Three actionable variants in DPYD and MTHFR, associated with 5-fluorouracil and/or capecitabine response, were identified. Additionally, 27 novel single-nucleotide polymorphisms of unknown clinical significance were detected. Conclusions: This study reveals key pharmacogenetic variants in the Omani population, underscoring the importance of integrating pharmacogenomic testing into routine care to support safer, more personalized chemotherapy in the region. Full article

Breast cancer is the most common cancer in women worldwide. Anthracyclines (doxorubicin, epirubicin, daunorubicin, idarubicin) are among the most used drugs for the treatment of breast cancer. Unfortunately, anthracyclines cause cardiotoxicity, which is a limiting factor for its use, and the lifetime cumulative dose of anthracyclines is the major risk factor for cardiotoxicity. In our study, we focused on acute and subacute heart damage. One of the main factors is a genetic predisposition, which determines individual susceptibility to anthracycline cardiotoxicity. The main idea of this study was, for the first time, to evaluate drug metabolism-related genes as a risk factor for developing cardiovascular toxicity in breast cancer patients. The main objective of our study was to identify the impact of drug metabolism-related gene SNPs on the development of subclinical heart damage during and/or after doxorubicin-based chemotherapy in breast cancer patients. The data of 81 women with breast cancer treated with doxorubicin-based chemotherapy in an outpatient clinic were analyzed, and SNP RT-PCR tests were performed. The drug metabolism-related gene variants SULT2B1 rs10426377, UGT1A6 rs17863783, CBR1 rs9024, CBR3 rs1056892, NCF4 rs1883112, and CYBA rs1049255 did not reach a statistically important impact on ABCC in multivariate logistic regression analysis. However, we identified that NCF4 rs1883112 had a risk reduction tendency for ABCC (OR = 0.49, 95% CI 0.27–0.87, p = 0.015). Our findings suggest that some SNPs, such as NCF4 rs1883112, may be associated with a reduced risk of cardiotoxicity, while no variants in this study showed a statistically significant increased risk. Even though, NCF4 rs1883112 showed a risk reduction tendency, suggesting the potential for personalized risk stratification. We can conclude that multiple genes are involved in ABCC, with different impacts, and it is unlikely that there is a single driver gene in ABCC pathogenesis. Full article

Metachromatic leukodystrophy (MLD) is a rare inherited disorder of lysosomal storage, caused by a deficiency in the arylsulfatase A (ARSA) enzyme, leading to toxic accumulation of sulfatides, which progressively impair motor and cognitive function. MLD is a candidate for inclusion in newborn screening (NBS) programs, due to the narrow pre-symptomatic window for effective therapeutic intervention. We set up a prospective pilot NBS program for MLD in Tuscany, based on a two-step approach. The first-tier test quantified four sulfatides; if levels exceeded the cut-off, we performed the second-tier test by measuring ARSA activity on the same neonatal dried blood spot (DBS). We performed the first-tier test on 42,262 newborns over two years and the second-tier test on residual neonatal DBS from 90 of them (0.21%). We recalled 10 newborns (0.02%) for an additional DBS, due to insufficient residual material for a second-tier test (n = 4) or to low ARSA activity (n = 6). We found normal ARSA activity in all new DBS and identified no new cases of MLD. Retrospective analysis of eight neonatal and fifteen non-neonatal DBS from patients with genetically confirmed MLD showed that the algorithm accurately identified MLD patients. This diagnostic algorithm proved feasible and accurate for early detection of MLD in prospective NBS. Full article

Aluminum toxicity in acidic soils represents a significant environmental stressor that affects yields worldwide and is only expected to worsen. Breeding resistant varieties remains the most viable solution; however, fast and robust procedures to determine cultivar viability must be developed and applied to promising genotypes. This study explored historical and modern Lithuanian-bred barley cultivars using morphometrical and biochemical markers for Al resistance and sequence and expression analyses of potential candidate genes. Morphometric seedling measurements (relative root length reduction −13.65 ± 0.33% (p < 0.001) and root tolerance index 0.86 ± 0.44 after 72 h at 8 mM Al stress) revealed the modern cv. ‘Ema DS’ to be the most Al resistant, while biochemical assays offered a poor distinction between the Al-resistant and sensitive cultivars. Thus, we determined that morphometric parameters were more effective in the early screening for barley Al resistance. The genetic screening of well-established Al resistance markers in the barley citrate transporter HvAACT1 revealed a mismatch between the observed barley phenotypes and genotypes. Further testing was conducted through expression analyses of HvAACT1 and seven aquaporin family genes, which revealed a correlation between the best empirical performance in cv. ‘Ema DS’ and a high HvAACT1 (2.02 fold change, p < 0.05) expression, despite the lack of established genetic markers, as well as a stress-induced significant upregulation of aquaporin TIP4;1 (2.45 fold change, p < 0.05), suggesting previously undiscovered regulatory mechanisms of external and internal detoxification influencing Al resistance in Lithuanian barley cultivars, as well as potential future candidates for Al-resistant barley breeding programs. Full article

Plant growth and its interaction with microorganisms change yearly. High temperature and humidity have characterized recent seasons in the north of Italy and around the world, increasing the parasitic ability of Aspergillus flavus to colonize maize kernels and aflatoxin levels. These molecules have the highest acute and chronic toxicity of all mycotoxins; the maximal concentration in agricultural food and feed products, and their commodities, are regulated worldwide. In this study we suggest a simple methodology to test the susceptibility of candidate maize varieties to A. flavus before their release onto the market. A panel of 92 inbred lines and 14 hybrids were analysed, disease phenotypes were scored on artificially inoculated kernels using a rolled towel assay, and therefore we observed different responses to fungal infection on the kernels, outlining a high variability among the tested lines characterized by a different effect of the pathogen on seedling development. Even the hybrids responded differently on a statistical basis to A. flavus with regard to the development of coleoptile, allowing their categorization into classes of susceptibility to be used for the varietal registration. Interestingly, the hybrid 6a-A was less susceptible to A. flavus compared to its reciprocal in terms of the length of the coleoptile. The comparison of breeding lines released on the market in different years suggested a poor improvement in genetic resistance against A. flavus in maize so far, opening up a possible topic for future research aimed at mitigating the impact of climate change on agriculture. Full article

Pharmacogenomics, the study of how genetic variations influence drug response, has become integral to cancer treatment as personalized medicine evolves. This review aims to explore key pharmacogenomic biomarkers relevant to cancer therapy and their clinical implications, providing an updated and comprehensive perspective on how genetic variations impact drug metabolism, efficacy, and toxicity in oncology. Genetic heterogeneity among oncology patients significantly impacts drug efficacy and toxicity, emphasizing the importance of incorporating pharmacogenomic testing into clinical practice. Genes such as CYP2D6, DPYD, UGT1A1, TPMT, EGFR, KRAS, and BRCA1/2 play pivotal roles in influencing the metabolism, efficacy, and adverse effects of various chemotherapeutic agents, targeted therapies, and immunotherapies. For example, CYP2D6 polymorphisms affect tamoxifen metabolism in breast cancer, while DPYD variants can result in severe toxicities in patients receiving fluoropyrimidines. Mutations in EGFR and KRAS have significant implications for the use of targeted therapies in lung and colorectal cancers, respectively. Additionally, BRCA1/2 mutations predict the efficacy of PARP inhibitors in breast and ovarian cancer. Ongoing research in polygenic risk scores, liquid biopsies, gene–drug interaction networks, and immunogenomics promises to further refine pharmacogenomic applications, improving patient outcomes and reducing treatment-related adverse events. This review also discusses the challenges and future directions in pharmacogenomics, including the integration of computational models and CRISPR-based gene editing to better understand gene–drug interactions and resistance mechanisms. The clinical implementation of pharmacogenomics has the potential to optimize cancer treatment by tailoring therapies to an individual’s genetic profile, ultimately enhancing therapeutic efficacy and minimizing toxicity. Full article

Insecticide resistance surveillance systems for vector-borne diseases are crucial for early detection of resistance and the implementation of evidence-based resistance management strategies. While insecticide susceptibility bioassays are typically conducted under controlled laboratory conditions, mosquitoes in the field experience varying environmental conditions, with temperature being a key determinant. Understanding the relationship between temperature and insecticide toxicity is essential for interpreting and extrapolating assay results across different climate zones or more locally across days with different weather conditions. In this study, we examined Aedes aegypti mosquitoes with different genetic backgrounds of insecticide resistance. Mosquitoes were homozygous for the knockdown resistance (kdr) F1534C mutation, plus either (1) homozygous for the kdr 1016V wildtype allele, (2) homozygous for the kdr V1016I mutant allele, or (3) heterozygous genetic crosses. These three genotypes were exposed to deltamethrin using WHO tube tests at three temperatures (22 °C, 27 °C, and 32 °C) and varying dosages. LC50 values were determined for each genotype and temperature combination. A negative temperature coefficient was observed exclusively in female mosquitoes homozygous for the 1016V wildtype allele, indicating reduced pyrethroid toxicity at higher temperatures. No temperature–toxicity relationship was found in males of this genotype or in other genotypes of either sex. These findings suggest that temperature may interact with kdr mutations and possibly even sex, highlighting the complex interactions between genetic mutations and environmental factors, such as temperature, in determining the insecticide resistance phenotype. Given the wide distribution of Ae. aegypti, understanding how local climate conditions influence insecticide performance will help improve control strategies and slow resistance evolution, protecting public health efforts against mosquito-borne diseases Full article