Selective translation of nuclear mitochondrial respiratory proteins reprograms succinate metabolism in AML development and chemoresistance.

Mitochondrial adaptations dynamically reprogram cellular bioenergetics and metabolism and confer key properties for human cancers. However, the selective regulation of these mitochondrial responses remains largely elusive. Here, inspired by a genetic screening in acute myeloid leukemia (AML), we identify RAS effector RREB1 as a translational regulator and uncover a unique translation control system for nuclear-encoded mitochondrial proteins in human cancers. RREB1 deletion reduces mitochondrial activities and succinate metabolism, thereby damaging leukemia stem cell (LSC) function and AML development. Replenishing complex II subunit SDHD rectifies these deficiencies. Notably, inhibition of complex II re-sensitizes AML cells to venetoclax treatment. Mechanistically, a short RREB1 variant binds to a conserved motif in the 3' UTRs and cooperates with elongation factor eEF1A1 to enhance protein translation of nuclear-encoded mitochondrial mRNAs. Overall, our findings reveal a unique translation control mechanism for mitochondrial adaptations in AML pathogenesis and provide a potential strategy for targeting this vulnerability of LSCs.

Association of health behaviors in life's essential 8 and hypertension in adolescents: a cross-sectional study from the NHANES database.

BACKGROUND: Hypertension is a common condition during adolescence with increasing prevalence globally, alongside the epidemic of unhealthy lifestyles and obesity. Health behaviors have been shown to be associated with hypertension risk in adults. Life's essential 8 (LE8), as a comprehensive indicator to evaluate cardiovascular health (CVH), includes 4 health factors and 4 health behaviors. This study aims to evaluate the association between health behaviors defined in LE8 and hypertension among adolescents. METHODS: Data of this study were extracted from the National Health and Nutrition Examination Surveys (NHANES) 2007-2018. Health behaviors of LE8 including diet, physical activity and tobacco smoke exposure. The outcome was the odd of hypertension in adolescents. The weighted univariate and multivariate logistic regression was unitized to explore the relationship between CVH score and hypertension in adolescents. Subgroup analysis and sensitivity analysis were further conducted to explore the association across different populations. RESULTS: Totally 3,941 adolescents aged 12-17 years were included, with the mean aged of 14.48 ± 0.04 years. Of whom, 203 (5.15%) had hypertension. After adjusted all covariates, high CVH score was associated with the lower odds of hypertension (OR = 0.32, 95%CI: 0.17-0.61), especially in boys (OR = 0.23, 95%CI: 0.11-0.51) and adolescents with overweight/obesity (OR = 0.24, 95%CI: 0.10-0.56). Sensitivity analysis reported that the association between CVH score and the odds of hypertension was also robust after excluding self-reported hypertension and medication taking (OR = 0.37, 95%CI: 0.18-0.74). CONCLUSION: A high CVH score, indicating a greater adherence of health behaviors, was associated with a reduced odds of hypertension, especially among boys and overweight/obesity adolescents. Large-scale prospective cohort studies are needed to further explore the association between health behaviors defined in LE8 and hypertension among adolescents.

Deep Learning Model for Pathological Grading and Prognostic Assessment of Lung Cancer Using CT Imaging: A Study on NLST and External Validation Cohorts.

RATIONALE AND OBJECTIVES: To develop and validate a deep learning model for automated pathological grading and prognostic assessment of lung cancer using CT imaging, thereby providing surgeons with a non-invasive tool to guide surgical planning. MATERIAL AND METHODS: This study utilized 572 cases from the National Lung Screening Trial cohort, dividing them randomly into training (461 cases) and internal validation (111 cases) sets in an 8:2 ratio. Additionally, 224 cases from four cohorts obtained from the Cancer Imaging Archive, all diagnosed with non-small cell lung cancer, were included for external validation. The deep learning model, built on the MobileNetV3 architecture, was assessed in both internal and external validation sets using metrics such as accuracy, sensitivity, specificity, and area under the receiver operating characteristic curve (AUC). The model's prognostic value was further analyzed using Cox proportional hazards models. RESULTS: The model achieved high accuracy, sensitivity, specificity, and AUC in the internal validation set (accuracy: 0.888, macro AUC: 0.968, macro sensitivity: 0.798, macro specificity: 0.956). External validation demonstrated comparable performance (accuracy: 0.807, macro AUC: 0.920, macro sensitivity: 0.799, macro specificity: 0.896). The model's predicted signatures correlated significantly with patient mortality and provided valuable insights for prognostic assessment (adjusted HR 2.016 [95% CI: 1.010, 4.022]). CONCLUSIONS: This study successfully developed and validated a deep learning model for the preoperative grading of lung cancer pathology. The model's accurate predictions could serve as a useful adjunct in treatment planning for lung cancer patients, enabling more effective and customized interventions to improve patient outcomes.

Effect of preoperative oral nutritional supplements on clinical outcomes in patients undergoing surgery for gastrointestinal cancer: A systematic review and meta-analysis.

BACKGROUND: The clinical benefit of preoperative oral nutritional supplements (ONS) in patients undergoing surgery for gastrointestinal cancer remains controversial. OBJECTIVE: To evaluate the effect of preoperative ONS on postoperative clinical outcomes in patients with gastrointestinal cancer. METHODS: We searched PubMed, EMBASE, Web of Science, Cochrane Library, Scopus, and the Chinese National Knowledge Infrastructure databases for randomized controlled trials evaluating preoperative ONS in patients undergoing surgery for gastrointestinal cancer from inception until April 2024. Two researchers independently assessed the quality of the included literature and performed statistical analyses using Review Manager 5.4 software. RESULTS: A total of 12 eligible studies with 1201 patients (600 ONS group and 601 control group) were included in this meta-analysis. Compared with a normal diet, preoperative ONS effectively reduced infectious complications (odds ratio = 0.63; 95% confidence interval [CI], 0.40-0.98; P = .04), white blood cell count (mean difference [MD] = -0.66; 95% CI, -1.04 to -0.28; P = .0007), C-reactive protein (MD = -0.26; 95% CI, -0.33 to -0.19; P < .00001), and markedly improved albumin levels (MD = 1.71; 95% CI, 0.97-2.46; P < .00001), prealbumin (MD = 24.80; 95% CI, 1.72-47.88; P = .04), immunoglobulin G (MD = 0.86; 95% CI, 0.44-1.28; P < .00001), CD4 T lymphocyte cells (MD = 3.06; 95% CI, 2.21-3.92; P < .00001), and CD4 T lymphocyte cells/CD8 T lymphocyte cells (MD = 0.33; 95% CI, 0.10-0.56; P = .004). However, there were no significant differences between the 2 groups in terms of noninfectious complications (odds ratio = 0.77; 95% CI, 0.39-1.53; P = .46), immunoglobulin A (MD = -0.21; 95% CI, -0.44 to 0.02; P = .08) or length of hospital stay (MD = -0.04; 95% CI, -0.71 to 0.64; P = .92). CONCLUSION: Preoperative ONS may effectively reduce postoperative infectious complications, improve postoperative nutritional status and immune function, and relieve the inflammatory response in gastrointestinal cancer patients. Therefore, we recommend that preoperative nutrition could be optimized with ONS in patients undergoing gastrointestinal cancer surgery.

Targeting Macrophage Phenotypes and Metabolism as Novel Therapeutic Approaches in Atherosclerosis and Related Cardiovascular Diseases.

PURPOSE OF THE REVIEW: Macrophage accumulation and activation function as hallmarks of atherosclerosis and have complex and intricate dynamics throughout all components and stages of atherosclerotic plaques. In this review, we focus on the regulatory roles and underlying mechanisms of macrophage phenotypes and metabolism in atherosclerosis. We highlight the diverse range of macrophage phenotypes present in atherosclerosis and their potential roles in progression and regression of atherosclerotic plaque. Furthermore, we discuss the challenges and opportunities in developing therapeutic strategies for preventing and treating atherosclerotic cardiovascular disease. RECENT FINDINGS: Dysregulation of macrophage polarization between the proinflammatory M1 and anti-inflammatory M2 phenotypealters the immuno-inflammatory response during atherosclerosis progression, leading to plaque initiation, growth, and ultimately rupture. Altered metabolism of macrophage is a key feature for their function and the subsequent progression of atherosclerotic cardiovascular disease. The immunometabolism of macrophage has been implicated to macrophage activation and metabolic rewiring of macrophages within atherosclerotic lesions, thereby shifting altered macrophage immune-effector and tissue-reparative function. Targeting macrophage phenotypes and metabolism are potential therapeutic strategies in the prevention and treatment of atherosclerosis and atherosclerotic cardiovascular diseases. Understanding the precise function and metabolism of specific macrophage subsets and their contributions to the composition and growth of atherosclerotic plaques could reveal novel strategies to delay or halt development of atherosclerotic cardiovascular diseases and their associated pathophysiological consequences. Identifying biological stimuli capable of modulating macrophage phenotypes and metabolism may lead to the development of innovative therapeutic approaches for treating patients with atherosclerosis and coronary artery diseases.

LRG1 promotes atherosclerosis by inducing macrophage M1-like polarization.

Atherosclerosis is a chronic inflammatory disease of the arterial wall characterized by the accumulation of cholesterol-rich lipoproteins in macrophages. How macrophages commit to proinflammatory polarization under atherosclerosis conditions is not clear. Report here that the level of a circulating protein, leucine-rich alpha-2 glycoprotein 1 (LRG1), is elevated in the atherosclerotic tissue and serum samples from patients with coronary artery disease (CAD). LRG1 stimulated macrophages to proinflammatory M1-like polarization through the activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK) pathways. The LRG1 knockout mice showed significantly delayed atherogenesis progression and reduced levels of macrophage-related proinflammatory cytokines in a high-fat diet-induced Apoe-/- mouse atherosclerosis model. An anti-LRG1 neutralizing antibody also effectively blocked LRG1-induced macrophage M1-like polarization in vitro and conferred therapeutic benefits to animals with ApoE deficiency-induced atherosclerosis. LRG1 may therefore serve as an additional biomarker for CAD and targeting LRG1 could offer a potential therapeutic strategy for CAD patients by mitigating the proinflammatory response of macrophages.

Comparable efficacy and safety of generic and branded imatinib for patients with chronic myeloid leukemia in China.

Background: Generics imatinib became an alternative treatment option for chronic myeloid leukemia (CML) patients in China. However, clinicians and patients alike harbor concerns regarding the long-term safety of generic imatinib. Objectives: Patients with chronic phase CML receiving frontline imatinib treatment. Design: A retrospective study was used to evaluate the blood concentration, effectiveness, and safety of generic in 170 CML patients. Methods: Imatinib plasma concentrations were detected by high-performance liquid chromatography-tandem mass spectrometry. Results: Among the 170 patients, 73 (42.9%) patients treated with branded imatinib as first-line therapy, while 22 (12.9%) switched to generic imatinib during treatment due to economic considerations. No significant differences in trough concentrations between branded and generic imatinib (1549.9 ± 648.8 ng/mL vs 1479.0 ± 507.0 ng/mL; p = 0.95). During the 2-year follow-up, there were no significant differences in molecular response rates (major molecular response (MMR): 33.3% vs 37.0%; deep molecular response: 56.9% vs 42.9%, p = 0.17) between the branded and generic imatinib. Both groups showed similar rates of switching to second-generation tyrosine kinase inhibitor (11.8% vs 15.1%, p = 0.56). Furthermore, there were no significant differences in event-free survival or failure-free survival between branded and generic imatinib. Twenty-two (12.9%) switched to generic imatinib during treatment, 68.2% maintained their level of response, 27.3% improved, and only one patient (4.5%) lost MMR. There were no significant differences in the incidence of various adverse events. Conclusion: Generic imatinib are equally effective and safe compared to branded molecules, both for newly diagnosed patients and those who switch from branded.

No difference in oncological outcomes and perioperative complications between patients with ESRD with unilateral and bilateral UTUC receiving radical nephroureterectomy.

Patients with end stage renal disease (ESRD) are at high risk of developing upper tract urothelial carcinoma (UTUC). Due to high recurrence rate of UTUC in contralateral kidney and ureter, and high risk of complications related to surgery and anesthesia, whether it's necessary to remove both kineys and ureters at one time remains in debate. We utilized Taiwanese UTUC Registry Database to valuate the difference of oncological outcomes and perioperative complications between patients with ESRD with unilateral and bilateral UTUC receiving surgical resection. Patients with ESRD and UTUC were divided into three groups, unilateral UTUC, previous history of unilateral UTUC with metachronous contralateral UTUC, and concurrent bilatetral UTUC. Oncological outcomes, perioperative complications, and length of hospital stays were investiaged. We found that there is no diffence of oncological outcomes including overall survival, cancer specific survival, disease free survival and bladder recurrence free survival between these three groups. Complication rate and length of hospital stay are similar. Adverse oncological features such as advanced tumor stage, lymph node involvement, lymphovascular invasion, and positive surgical margin would negatively affect oncological outcomes.

A predictive model for therapy failure in chronic myeloid leukemia patients receiving tyrosine kinase inhibitor therapy.

Although tyrosine kinase inhibitor (TKI) therapy has markedly improved the survival of people with chronic-phase chronic myeloid leukemia (CML), 20-30% of people still experienced therapy failure. Data from 1,955 consecutive subjects with chronic-phase CML diagnosed by the European LeukemiaNet (ELN) recommendations from 1 center receiving initial TKI imatinib or a second-generation (2G-) TKI therapy were interrogated to develop a clinical prediction model for TKI therapy failure. This model was subsequently validated in 3,454 subjects from 76 other centers. Using the predictive clinical co-variates associated with TKI therapy failure, we developed a model that stratified subjects into low-, intermediate- and high-risk subgroups with significantly different cumulative incidences of therapy failure (p < 0.001). There was good discrimination and calibration in the external validation dataset, and the performance was consistent with that of the training dataset. Our model had the better prediction discrimination than the Sokal and ELTS scores did, with the greater time-dependent area under the receiver-operator characteristic curve (AUROC) values and a better ability to re-defined the risk of therapy failure. Our model could help physicians estimate the likelihood of initial imatinib or 2G-TKI therapy failure in people with chronic-phase CML.

Safety and efficacy of flumatinib as later-line therapy in patients with chronic myeloid leukemia.

To evaluate the efficacy and safety of flumatinib in the later-line treatment of Chinese patients with Philadelphia chromosome-positive chronic-phase chronic myeloid leukemia (CP-CML previously treated with tyrosine kinase inhibitors (TKIs). Patients with CML-CP were evaluated for the probabilities of responses including complete hematologic response (CHR), cytogenetic response, and molecular response (MR) and adverse events (AEs) after the later-line flumatinib therapy. Of 336 enrolled patients with median age 50 years, median duration of treatment with flumatinib was 11.04 (2-25.23) months. Patients who achieved clinical responses at baseline showed maintenance of CHR, complete cytogenetic response (CCyR)/2-log molecular response (MR2), major molecular response (MMR), and 4-log molecular response or deep molecular response (MR4/DMR) in 100%, 98.9%, 98.6%, and 92.9% patients, respectively. CHR, CCyR/MR2, MMR, and MR4/DMR responses were achieved in 86.4%, 52.7%, 49.6%, and 23.5% patients respectively, which showed the lack of respective clinical responses at baseline. The patients without response at baseline, treated with flumatinib as 2L TKI, having no resistance to prior TKI or only resistance to imatinib, with response to last TKI, and with BCR::ABL ≤10% had higher CCyR/MR2, MMR, or MR4/DMR. The AEs observed during the later-line flumatinib treatment were tolerable and consistent with those reported with the first-line therapy. Flumatinib was effective and safe in patients who are resistant or intolerant to other TKIs. In particular, 2L flumatinib treatment induced high response rates and was more beneficial to patients without previous 2G TKI resistance, thus serving as a probable treatment option for these patients.

Palmitic acid reduces the methylation of the FOXO1 promoter to suppress the development of diffuse large B-cell lymphoma via modulating the miR-429/DNMT3A axis.

Diffuse large B-cell lymphoma (DLBCL) is characterized by significant treatment resistance. Palmitic acid (PA) has shown promising antitumor properties. This study aims to elucidate the molecular mechanisms by which PA influences DLBCL progression. We quantified the expression levels of microRNAs (miRNAs), Forkhead box protein O1 (FOXO1), and DNA methyltransferase 3A (DNMT3A) in both untreated and PA-treated DLBCL tumors and cell lines. Assessments were made of cell viability, apoptosis, and autophagy-related protein expression following PA administration. Interaction analyses among miR-429, DNMT3A, and FOXO1 were conducted using luciferase reporter assays and methylation-specific (MSP) Polymerase chain reaction (PCR). After transfecting the miR-429 inhibitor, negative control (NC) inhibitor, shRNA against DNMT3A (sh-DNMT3A), shRNA negative control (sh-NC), overexpression vector for DNMT3A (oe-DNMT3A), or overexpression negative control (oe-NC), we evaluated the effects of miR-429 and DNMT3A on cell viability, mortality, and autophagy-related protein expression in PA-treated DLBCL cell lines. The efficacy of PA was also tested in vivo using DLBCL tumor-bearing mouse models. MiR-429 and FOXO1 expression levels were downregulated, whereas DNMT3A was upregulated in DLBCL compared to the control group. PA treatment was associated with enhanced autophagy, mediated by the upregulation of miR-429 and downregulation of DNMT3A. The luciferase reporter assay and MSP confirmed that miR-429 directly inhibits DNMT3A, thereby reducing FOXO1 methylation. Subsequent experiments demonstrated that PA promotes autophagy and inhibits DLBCL progression by upregulating miR-429 and modulating the DNMT3A/FOXO1 axis. In vivo PA significantly reduced the growth of xenografted tumors through its regulatory impact on the miR-429/DNMT3A/FOXO1 axis. Palmitic acid may modulate autophagy and inhibit DLBCL progression by targeting the miR-429/DNMT3A/FOXO1 signaling pathway, suggesting a novel therapeutic target for DLBCL management.

Development and external validation of a multimodal integrated feature neural network (MIFNN) for the diagnosis of malignancy in small pulmonary nodules (≤10 mm).

Objectives. Current lung cancer screening protocols primarily evaluate pulmonary nodules, yet often neglect the malignancy risk associated with small nodules (≤10 mm). This study endeavors to optimize the management of pulmonary nodules in this population by devising and externally validating a Multimodal Integrated Feature Neural Network (MIFNN). We hypothesize that the fusion of deep learning algorithms with morphological nodule features will significantly enhance diagnostic accuracy.Materials and Methods. Data were retrospectively collected from the Lung Nodule Analysis 2016 (LUNA16) dataset and four local centers in Beijing, China. The study includes patients with small pulmonary nodules (≤10 mm). We developed a neural network, termed MIFNN, that synergistically combines computed tomography (CT) images and morphological characteristics of pulmonary nodules. The network is designed to acquire clinically relevant deep learning features, thereby elevating the diagnostic accuracy of existing models. Importantly, the network's simple architecture and use of standard screening variables enable seamless integration into standard lung cancer screening protocols.Results. In summary, the study analyzed a total of 382 small pulmonary nodules (85 malignant) from the LUNA16 dataset and 101 small pulmonary nodules (33 malignant) obtained from four specialized centers in Beijing, China, for model training and external validation. Both internal and external validation metrics indicate that the MIFNN significantly surpasses extant state-of-the-art models, achieving an internal area under the curve (AUC) of 0.890 (95% CI: 0.848-0.932) and an external AUC of 0.843 (95% CI: 0.784-0.891).Conclusion. The MIFNN model significantly enhances the diagnostic accuracy of small pulmonary nodules, outperforming existing benchmarks by Zhanget alwith a 6.34% improvement for nodules less than 10 mm. Leveraging advanced integration techniques for imaging and clinical data, MIFNN increases the efficiency of lung cancer screenings and optimizes nodule management, potentially reducing false positives and unnecessary biopsies.Clinical relevance statement. The MIFNN enhances lung cancer screening efficiency and patient management for small pulmonary nodules, while seamlessly integrating into existing workflows due to its reliance on standard screening variables.

Eosinophilic pulmonary disease with ulcerative colitis: A case report.

RATIONALE: Eosinophilic pulmonary disease (EPD) is a general term for a large group of diseases with complex etiology. Ulcerative colitis is an inflammatory bowel disease (IBD). Patients with IBD may have pulmonary involvement. We herein present a case of ulcerative colitis complicated with EPD. PATIENT CONCERNS: A 34-year-old woman with ulcerative colitis presented with dry cough. She had peripheral eosinophilia and apical ground glass opacities on CT (computed tomography) of her chest. Antibiotic treatment was ineffective. DIAGNOSES: Lung biopsy revealed eosinophil infiltration in the alveolar space and interstitial space, so EPD was considered. INTERVENTIONS: After oral administration of prednisone, the lung shadow on CT disappeared when the cough symptoms resolved. However, the symptoms recurred after drug withdrawal, and the lung shadow reappeared on imaging. The cough symptoms and lung shadow disappeared after oral prednisone was given again. Prednisone was slowly discontinued after 6 months of treatment. OUTCOMES: The patient stopped prednisone for half a year. No recurrence or abnormal CT findings were detected during the half-year follow-up. LESSONS: The clinical manifestations of EPD are atypical, laboratory and imaging findings are not specific, and it is difficult to make a definite diagnosis before lung biopsy. The diagnosis depends on pathological examination. Glucocorticoid treatment is effective, but some patients may relapse after drug withdrawal. Active follow-up after glucocorticoid treatment is very important for identifying disease recurrence. Patients with IBD are relatively prone to developing EPD. The etiology of EPD is complex. In clinical practice, we need to make a diagnosis and differential diagnosis to clarify its etiology.

NTRK3 exhibits a pro-oncogenic function in upper tract urothelial carcinomas.

Neurotrophic receptor tyrosine kinase 3 (NTRK3) has pleiotropic functions: it acts not only as an oncogene in breast and gastric cancers but also as a dependence receptor in tumor suppressor genes in colon cancer and neuroblastomas. However, the role of NTRK3 in upper tract urothelial carcinoma (UTUC) is not well documented. This study investigated the association between NTRK3 expression and outcomes in UTUC patients and validated the results in tests on UTUC cell lines. A total of 118 UTUC cancer tissue samples were examined to evaluate the expression of NTRK3. Survival curves were generated using Kaplan-Meier estimates, and Cox regression models were used for investigating survival outcomes. Higher NTRK3 expression was correlated with worse progression-free survival, cancer-specific survival, and overall survival. Moreover, the results of an Ingenuity Pathway Analysis suggested that NTRK3 may interact with the PI3K-AKT-mTOR signaling pathway to promote cancer. NTRK3 downregulation in BFTC909 cells through shRNA reduced cellular migration, invasion, and activity in the AKT-mTOR pathway. Furthermore, the overexpression of NTRK3 in UM-UC-14 cells promoted AKT-mTOR pathway activity, cellular migration, and cell invasion. From these observations, we concluded that NTRK3 may contribute to aggressive behaviors in UTUC by facilitating cell migration and invasion through its interaction with the AKT-mTOR pathway and the expression of NTRK3 is a potential predictor of clinical outcomes in cases of UTUC.

New infundibulopelvic angle measurement method can predict stone-free rates following retrograde intrarenal surgery.

To enhance the accuracy of predicting stone-free rates after retrograde intrarenal surgery, we devised a novel approach to assess the renal infundibulopelvic angle. We conducted a retrospective review of patient records for those who underwent retrograde intrarenal surgery for renal stones between April 2018 and August 2019. Patient demographics, stone characteristics, and perioperative data were recorded. Subsequently, we introduced a modified angle measurement called the pelvic stone angle and evaluated its predictive performance for stone-free rates by comparing it with the traditional method in scoring systems. A total of 43 individuals were included in this study. Notable differences in stone burden and Hounsfield unit measurements were found between stone-free and non-stone-free patients. The pelvic stone angle demonstrated a good model fit when used in scoring systems, performing equally well as the conventional approach. The area under the receiver operating characteristic curve for the R.I.R.S. scoring system using the pelvic stone angle and the conventional approach did not show a significant difference. In conclusion, the predictive ability of the pelvic stone angle for stone-free rates was comparable to the old measurement method. Moreover, scoring systems using the pelvic stone angle exhibited a better model fit than those using the conventional approach.

Influence of genetic polymorphisms on imatinib concentration and therapeutic response in patients with chronic-phase chronic myeloid leukemia.

BACKGROUND: Diminished bioavailability of imatinib in leukemic cells contributes to poor clinical response. We examined the impact of genetic polymorphisms of imatinib on the pharmacokinetics and clinical response in 190 patients with chronic myeloid leukaemia (CML). METHODS: Single nucleotide polymorphisms were genotyped using pyrophosphate sequencing. Plasma trough levels of imatinib were measured using liquid chromatography-tandem mass spectrometry. RESULTS: Patients carrying the TT genotype for ABCB1 (rs1045642, rs2032582, and rs1128503), GG genotype for CYP3A5-rs776746 and AA genotype for ABCG2-rs2231142 polymorphisms showed higher concentration of imatinib. Patients with T allele for ABCB1 (rs1045642, rs2032582, and rs1128503), A allele for ABCG2-rs2231142, and G allele for CYP3A5-rs776746 polymorphisms showed better cytogenetic response and molecular response. In multivariate analysis, carriers of the CYP3A5-rs776746 G allele exhibited higher rates of complete cytogenetic response (CCyR) and major molecular response (MMR). Similarly, patients with the T allele of ABCB1-rs1045642 and rs1128503 demonstrated significantly increased CCyR rates. Patients with the A allele of ABCG2-rs2231142 were associated with higher MMR rates. The AA genotype for CYP3A5-rs776746, and the CC genotype for ABCB1-rs104562, and rs1128503 polymorphisms were associated with a higher risk of imatinib failure. Patients with the G allele for CYP3A5-rs776746 exhibited a higher incidence of anemia, and T allele for ABCB1-rs2032582 demonstrated an increased incidence of diarrhea. CONCLUSIONS: Genotyping of ABCB1, ABCG2, and CYP3A5 genes may be considered in the management of patients with CML to tailor therapy and optimize clinical outcomes.