Search Results (323)

Background/Objectives: The advent of tyrosine kinase inhibitors (TKIs) revolutionized the management of chronic myeloid leukemia (CML), achieving survival rates near those of the general population. Despite this success, prolonged therapy presents challenges, including physical, emotional, and financial burdens. Treatment-free remission (TFR), defined as sustained deep molecular response (DMR) after discontinuing TKIs, has emerged as a viable clinical goal. This study evaluates real-world data from the Canary Islands Registry of CML (RCLMC) to explore outcomes, predictors, and the feasibility of TFR. Methods: This retrospective observational study included 393 patients diagnosed with CML-CP between 2007 and 2023. Molecular response was monitored according to international guidelines. Survival probabilities were estimated using the Kaplan–Meier method. Logistic regression analysis was performed to identify predictors of molecular relapses after TKI discontinuation. Results: Of the 383 patients who received TKI treatment, 58.3% achieved molecular response grade 2 (MR2) (BCR-ABL1 ≤ 1%), 95.05% achieved MR2, and 50.5% reached MR4 within the first year. Of the 107 patients attempting TFR, 73.2% maintained remission at 36 months. Relapses occurred in 24 patients, all regaining molecular response upon reintroduction of TKIs. No cases of disease progression were observed. Conclusions: Our findings support the feasibility and safety of TFR in a real-world clinical setting for well-selected patients, with outcomes consistent with international studies. The study underscores the importance of molecular monitoring and patient-specific strategies to optimize outcomes. Full article

Background/Objectives: This study investigated variations in DNA methylation patterns associated with chronic pain and propensity for recurrent pressure injuries (PrI) in persons with spinal cord injury (SCI). Methods: Whole blood was collected from 81 individuals with SCI. DNA methylation was quantified using Illumina genome-wide arrays (EPIC and EPICv2). Comprehensive clinical profiles collected included secondary health complications, in particular current PrI and chronic pain. Relationships between recurrent PrI and chronic pain and whether the co-occurrence of both traits was mediated by changes in DNA methylation were investigated using R packages limma, DMRcate and mCSEA. Results: Three differentially methylated positions (DMPs) (cg09867095, cg26559694, cg24890286) and one region in the micro-imprinted locus for BLCAP/NNAT are associated with chronic pain in persons with SCI. The study cohort was stratified by PrI status to identify any sites associated with chronic pain and while the same three sites and region were replicated in the group with no recurrent PrI, two novel, hypermethylated (cg21756558, cg26217441) sites and one region in the protein-coding gene FDFT1 were identified in the group with recurrent PrI. Gene enrichment and genes associated with specific promoters using MetaScape identified several shared disorders and ontology terms between independent phenotypes of pain and recurrent PrI and interactive sub-groups. Conclusions: DMR analysis using mCSEA identified several shared genes, promoter-associated regions and CGI associated with overall pain and PrI history, as well as sub-groups based on recurrent PrI history. These findings suggest that a much larger gene regulatory network is associated with each phenotype. These findings require further validation. Full article

Abiotic stress can reprogram the gametophytic pathway; the mechanisms by which floral bud pre-treatment influences microspore embryogenesis initiation remain unclear. In this study, we use bisulfite sequencing, sRNA-seq, and RNA-seq to analyze the dynamic changes in rice microspores under different cold treatment durations. Our results showed that a 10-day cold treatment is essential for CXJ microspore embryogenesis initiation. DNA methylation levels showed a slight change at CG, CHG, and CHH sites under cold treatment. The number of both hyper- and hypomethylated DMRs increased over cold treatment, with more hypermethylated DMRs at 5 and 10 dpt. Hypermethylated DMRs were more frequently in the TSS region compared to hypomethylated DMRs. The proportion of 24 nt sRNAs increased upon cold stress, with more downregulated than upregulated sRNAs at 10 dpt. The number of DMR target DEGs increased from 5 to 10 dpt. Promoter hypomethylation at the CHH site was more frequently associated with DEGs. These outcomes suggested that the RdDM pathway participates in the initiation of rice ME. GO analysis indicated that DMR target DEGs at 10 dpt were enriched in responses to chemical stimuli, biological processes, and stress responses. An auxin-related gene, OsHOX28, was further identified. Its upregulation, potentially mediated by the RdDM pathway, may play a crucial role in the initiation of rice ME. This study provides more information on epigenetic mechanisms during rice ME. Full article

Numerous protocols have emerged to address the energy depletion problem in Wireless Sensor Networks (WSNs). Among these protocols, the Dynamic Multi-Hop Routing (DMR) protocol adopts a dynamic technique for routing data across the network. The use of the DMR protocol has shown promising results in reducing energy consumption, prolonging the network lifetime, and increasing throughput. To improve the performance of WSNs, this paper proposes the Enhanced Dynamic Multi-Hop Routing (EDMR) protocol as a modification of the DMR protocol. The EDMR protocol introduces an effective sleeping mechanism that selectively deactivates clusters that do not generate significantly updated data for a specific duration. This mechanism reduces redundant transmissions, thereby saving energy and prolonging the network lifetime. The EDMR protocol incorporates static and dynamic approaches to support two major categories of applications: monitoring and event-driven applications. The proposed protocol is evaluated against the DMR protocol, the Enhanced Dynamic Multi-Hop Technique (EMDHT-LEACH) protocol, and the Low-Energy Adaptive Clustering Hierarchy (LEACH) protocol. The simulation results demonstrate that the EDMR protocol mitigates energy depletion, extends the network lifetime, increases stability, and improves network throughput toward the Base Station (BS), while reducing packet redundancy compared with the other protocols. Full article

Background/Objectives: Prostate cancer (PCa) is diagnosed at an earlier median age, more advanced stage, and has worse clinical outcomes in African American (AA) men compared to European Americans (EA). Methods: To investigate the role of aberrant DNA methylation in tumor-adjacent stroma (TAS), methyl binding domain sequencing (MBD-seq) was performed on AA (n = 17) and EA (n = 15) PCa patients. This was independently confirmed using the long interspersed nuclear element-1 (LINE-1) assay. Pathway analysis was performed on statistically significantly differentially methylated genes for AA and EA TAS. DNA methylation profiles of primary cultured AA and EA carcinoma-associated fibroblasts (CAFs) were compared with AA and EA TAS. AA and EA CAFs were treated with demethylating agent 5-Azacytidine (5-AzaC). Results: AA TAS exhibited higher global DNA methylation than EA TAS (p-value < 0.001). Of the 3268 differentially methylated regions identified (DMRs, p-value < 0.05), 85% (2787 DMRs) showed increased DNA methylation in AA TAS, comprising 1648 genes, of which 1379 were protein-coding genes. Based on DNA methylation levels, two AA subgroups were identified. Notably, AA patients with higher DNA methylation were predominantly those with higher Gleason scores. Pathway analysis linked methylated genes in AA TAS to several key signaling pathways (p-value < 0.05), including immune response (e.g., IL-1, IL-15, IL-7, IL-8, IL-3, and chemokine), Wnt/β-catenin, androgen, PTEN, p53, TGF-β, and circadian clock regulation. A total of 168 concordantly methylated genes were identified, with 109 genes (65%) showing increased methylation in AA CAFs and TAS (p-value < 0.05). Treatment with 5-AzaC significantly reduced DNA methylation of concordant genes in AA CAFs (p-value < 0.001). Conclusions: These findings suggest a distinct stromal methylome in AA, providing a foundation for integrating demethylating agents into standard therapies. This approach targets the tumor microenvironment, potentially addressing PCa disparities in AA men. Full article

This study evaluated the effects of different doses of limonene essential oil (LEO) and a blend of cinnamaldehyde and carvacrol (BCC) on the fermentative quality and chemical–bromatological composition of total mixed ration (TMR) silages. Two independent trials were conducted, each focused on one additive, using a completely randomized design with four treatments (0, 200, 400, and 600 mg/kg of dry matter), replicated across two seasons (summer and autumn), with five replicates per treatment per season. The silages were assessed for their chemical composition, fermentation profile, aerobic stability (AS), and storage losses. In the LEO trial, the dry matter (DM) content increased significantly by 0.047% for each mg/kg added. Dry matter recovery (DMR) peaked at 97.9% at 473 mg/kg (p < 0.01), while lactic acid (LA) production reached 5.87% DM at 456 mg/kg. Ethanol concentrations decreased to 0.13% DM at 392 mg/kg (p = 0.04). The highest AS value (114 h) was observed at 203.7 mg/kg, but AS declined slightly at the highest LEO dose (600 mg/kg). No significant effects were observed for the pH, neutral detergent fiber (NDF), acid detergent fiber (ADF), crude protein (CP), or non-fiber carbohydrates (NFCs). In the BCC trial, DMR reached 98.2% at 548 mg/kg (p < 0.001), and effluent losses decreased by approximately 20 kg/ton DM. LA production peaked at 6.41% DM at 412 mg/kg (p < 0.001), and AS reached 131 h at 359 mg/kg. BCC increased NDF (from 23.27% to 27.73%) and ADF (from 35.13% to 41.20%) linearly, while NFCs and the total digestible nutrients (TDN) decreased by 0.0007% and 0.039% per mg of BCC, respectively. In conclusion, both additives improved the fermentation efficiency by increasing LA and reducing losses. LEO was more effective for DM retention and ethanol reduction, while BCC improved DMR and AS, with distinct effects on fiber and energy fractions. Full article

Radon (Rn) exposure has a strong association with lung cancer risk and is influenced by epigenetic modifications. To investigate the characterization of DNA methylation (DNAm) episignatures for radon-induced lung cancer, we detected the specific changes in DNAm in blood and lung tissues using reduced representation bisulfite sequencing (RRBS). We identified the differentially methylated regions (DMRs) induced by radon exposure. The bioinformatics analysis of the DMR-mapped genes revealed that pathways in cancer were affected by radon exposure. Among them, the DNAm episignatures of MAPK10, PLCG1, PLCβ3 and PIK3R2 were repeated between lung tissue and blood, and validated by the MassArray. In addition, radon exposure promoted lung cancer development in the genetic engineering mouse model (GEMM), accompanied by decreased MAPK10 and increased PLCG1, PLCβ3, and PIK3R2 with mRNA and protein levels. Conclusively, radon exposure significantly changes the genomic DNAm patterns in lung tissue and blood. The DNAm episignatures of MAPK10, PLCG1, PLCβ3 and PIK3R2 have a significant influence on radon-induced lung cancer. This brings a new perspective to understanding the pathways involved in radon-induced lung cancer and offers potential targets for developing blood-based biomarkers and epigenetic therapeutics. Full article

While prime editing offers improved precision compared to traditional CRISPR-Cas9 systems, concerns remain regarding potential off-target effects, including epigenetic changes such as DNA methylation. In this study, we investigated whether prime editing induces aberrant CpG methylation patterns. Whole-genome bisulfite sequencing revealed overall methylation similarity between Cas9-edited, and PE2-edited cells. However, localized epigenetic changes were observed, particularly in CpG islands and exon regions. The PE2-edited group showed a higher proportion of differentially methylated regions (DMRs) in some coding sequences compared to controls and Cas9-edited samples. Notably, CpG island methylation reached 0.18% in the PE2 vs. Cas9 comparison, indicating a higher susceptibility of these regulatory elements to epigenetic alterations by prime editing. Molecular function analyses including Gene Ontology and KEGG pathway analyses further revealed enrichment in molecular functions related to transcriptional regulation and redox activity in PE2-edited cells. These findings suggest that prime editing, while precise, may introduce subtle but functionally relevant methylation changes that could influence gene expression and cellular pathways. In summary, prime editing can induce localized DNA methylation changes in human cells, particularly within regulatory and coding regions. Understanding these epigenetic consequences is critical for the development of safer and more effective therapeutic applications of genome editing technologies. Full article

High-altitude pulmonary edema (HAPE) is a severe condition associated with high-altitude environments, and its molecular mechanism has not been fully elucidated. This study systematically analyzed the DNA methylation status of HAPE patients and healthy controls using reduced-representation bisulfite sequencing (RRBS) and 850K DNA methylation chips, identifying key differentially methylated regions (DMRs). Targeted bisulfite sequencing (TBS) revealed significant abnormalities in DMRs of five genes, azurocidin 1 (AZU1), growth factor receptor bound protein 7 (GRB7), mannose receptor C-type 2 (MRC2), RUNX family transcription factor 3 (RUNX3), and septin 9 (SEPT9). The abnormal expression of AZU1 was validated using peripheral blood leukocytes from HAPE patients and normal controls, as well as rat lung tissue, indicating its potential importance in the pathogenesis of HAPE. To further validate the function of AZU1, we conducted experimental studies using a hypobaric hypoxia injury model in Human Umbilical Vein Endothelial Cells (HUVEC). The results showed that AZU1 was significantly upregulated under hypobaric hypoxia. Knocking down AZU1 mitigates the reduction in HUVEC proliferation, angiogenesis, and oxidative stress damage induced by acute hypobaric hypoxia. AZU1 induces cellular oxidative stress via the p38/mitogen-activated protein kinase (p38/MAPK) signaling pathway. This study is the first to elucidate the mechanism of AZU1 in HAPE via the p38/MAPK pathway, offering novel insights into the molecular pathology of HAPE and laying a foundation for future diagnostic and therapeutic strategies. Full article

Obesity is a major global health challenge associated with significant metabolic and gastrointestinal comorbidities. While metabolic and bariatric surgery remains the gold standard for durable weight loss, the desire for additional options has fueled the development of endoscopic bariatric therapies (EBTs) as another tool for weight loss. This review examines established EBTs, including endoscopic sleeve gastroplasty (ESG), intragastric balloons (IGBs), and transoral outlet reduction (TORe), alongside emerging therapies such as duodenal mucosal resurfacing (DMR), incisionless anastomosis creation, and fully automated endoscopic gastric remodeling systems. ESG has demonstrated durable weight loss, favorable safety, and superior cost-effectiveness compared to pharmacotherapy alone, while combination strategies using EBTs and anti-obesity medications (AOMs), particularly GLP-1 receptor agonists, have resulted in greater total-body weight loss than either modality alone. Genetic variation, particularly within the leptin–melanocortin pathway, may predict response to endoscopic interventions and guide personalized treatment selection. Novel investigational procedures such as DMR, automated or robotic gastric remodeling, and magnetic or ultrasound-assisted gastric bypass show promising early results. Endoscopic therapies are poised to become increasingly central to the personalized, scalable management of obesity and related metabolic diseases. Full article

Background: Ovarian cancer remains the most lethal gynecological cancer, primarily due to its asymptomatic nature in early stages and consequent late diagnosis. Early detection improves survival, but current biomarkers lack sensitivity and specificity. Cell-free DNA (cfDNA) released from tumor cells captures tumor-associated epigenetic alterations and represents a promising source for minimally invasive biomarkers. Among these, aberrant DNA methylation occurs early in tumorigenesis and may reflect underlying disease biology. This study aimed to investigate genome-wide cfDNA methylation profiles in patients with ovarian cancer, benign ovarian conditions, and healthy controls to identify cancer-associated methylation patterns that may inform future biomarker development. Results: We performed genome-wide cfDNA methylation profiling using cell-free methylated DNA immunoprecipitation sequencing (cfMeDIP-seq) on plasma samples from 40 patients with high-grade serous ovarian carcinoma, 38 patients with benign ovarian conditions, and 38 healthy postmenopausal women. A total of 536 differentially methylated regions (DMRs) were identified between ovarian cancer and controls (n = 76), with 97% showing hypermethylation in ovarian cancer. DMRs were enriched in CpG islands and gene bodies and depleted in repetitive elements, consistent with known cancer-associated methylation patterns. Fifteen genes showed robust hypermethylation across analyses. These genes exhibited methylation across intronic, exonic, and upstream regulatory regions. Separate comparisons of ovarian cancer to each control group (benign and healthy) supported the reproducibility of these findings. Gene Ontology enrichment analysis revealed enrichment in gland development, embryonic morphogenesis, and endocrine regulation, suggesting biological relevance to ovarian tumorigenesis. Conclusions: This study identifies consistent cfDNA hypermethylation patterns in ovarian cancer, affecting genes involved in developmental regulation and hormone-related processes. Our findings underscore the potential of cfMeDIP-seq for detecting tumor-specific methylation signatures in plasma and highlight these 15 hypermethylated genes as biologically relevant targets for future studies on cfDNA methylation in ovarian cancer. Full article

Chicken semen cryopreservation is crucial for utilizing high-quality cockerel genetics, but semen is highly sensitive to cryoinjury, leading to poor preservation outcomes. This study aimed to establish a theoretical foundation for selecting cockerels for semen cryopreservation through serum testing and to improve semen quality via DNA methylation editing. Semen and serum samples were collected from 102 Xiaoshan cockerels, with semen cryopreserved and thawed following standardized protocols. Post-thaw semen quality and serum testosterone (T) levels were assessed. Eight cockerels were selected based on motile sperm quality, and whole-genome bisulfite sequencing (WGBS) was used to analyze sperm DNA methylation. The results showed a significant positive correlation between serum T levels and sperm motility. There were notable differences in sperm motility and serum T levels between high-quality and low-quality semen groups but no differences in estradiol (E₂), superoxide dismutase (SOD), or glutathione peroxidase (GSH-Px) levels. A total of 217 differentially methylated regions (DMRs) and 116 differentially methylated genes (DMGs) were identified. Key genes such as PRKACB (protein kinase, cAMP-dependent, catalytic, beta) and ACSL1 (long-chain-fatty-acid--CoA ligase 1) were associated with sperm motility. These findings provide important insights for improving semen cryopreservation and contribute to breeding practices and the development of cryoprotectants. Full article

Objectives: New generations of annuloplasty rings are designed to combine structural support with enhanced flexibility, allowing for better adaptation to the dynamic nature of the mitral annulus. This study investigated the early clinical and echocardiographic outcomes of minimally invasive mitral valve repair (MI-MVr) with a new semi-rigid open ring (PhysioFlex, annuloplasty ring, Edwards Lifesciences, Irvine, CA, USA). Methods: A total of 150 consecutive patients who underwent MI-MVr for severe degenerative mitral regurgitation (DMR) using the PhysioFlex annuloplasty ring between June 2021 and April 2024 were included in the study. Preoperative, intraoperative, and postoperative data were collected for the entire population. A three-dimensional mitral valve reconstruction analysis was performed across the entire cohort using a semi-automated software package (4D Mitral Valve Analysis; Tomtec Imaging Systems, Munich, Germany). Results: The median age was 59 (50–67) years and 25.3% patients were female. The median Euroscore II and left ventricular ejection fraction were 0.72 (0.56–0.99) and 60% (55–65), respectively. The median implanted ring size was 34 mm (32–36). The entire cohort was discharged with no residual mitral regurgitation greater than mild and a median mean transmitral pressure gradient of 2.4 mmHg (2–3). The median hospitalization time was 7 days (6–11) and in-hospital mortality occurred in 1 (0.7%) patient. Conclusions: MI-MVr was safely performed using the novel semi-rigid partial PhysioFlex ring in the DMR patient cohort with favorable early results. The PhysioFlex annuloplasty ring may be used as an alternative to complete rings in MI-MVr. Further research is needed to conduct comparisons with other currently available annuloplasty rings. Full article

Breast cancer remains a leading cause of cancer-related deaths among women worldwide, highlighting the urgent need for early detection. While mammography is the gold standard, it faces cost and accessibility barriers in resource-limited areas. Infrared thermography is a promising cost-effective, non-invasive, painless, and radiation-free alternative that detects tumors by measuring their thermal signatures through thermal infrared radiation. However, challenges persist, including limited clinical validation, lack of Food and Drug Administration (FDA) approval as a primary screening tool, physiological variations among individuals, differing interpretation standards, and a shortage of specialized radiologists. This survey uniquely focuses on integrating texture analysis and machine learning within infrared thermography for breast cancer detection, addressing the existing literature gaps, and noting that this approach achieves high-ranking results. It comprehensively reviews the entire processing pipeline, from image preprocessing and feature extraction to classification and performance assessment. The survey critically analyzes the current limitations, including over-reliance on limited datasets like DMR-IR. By exploring recent advancements, this work aims to reduce radiologists’ workload, enhance diagnostic accuracy, and identify key future research directions in this evolving field. Full article

Genomic imprinting is critical for mammalian development, but its regulation varies across species. The insulin-like growth factor 2 receptor (IGF2R), which is a maternally expressed imprinted gene critical for cell proliferation and differentiation, as well as embryonic and placental development, is classically regulated by differentially methylated regions (DMRs) and lncRNA-Airn in mice. However, studies on this in equus are scarce, especially in terms of mechanistic studies. In the present study, heart, liver, spleen, lung, kidney, brain, and muscle samples were obtained from horses, donkeys, and hybrids, and gene expression and imprinting state were tested to investigate the imprinting regulation of Igf2r in these animals. Bisulfite sequencing combined with an allele-specific expression analysis revealed a tissue-specific loss of imprinting in the mule liver and hybrid brain tissues. Strikingly, we found that the maternal-specific expression of equine Igf2r did not rely on the canonical DMRs or lncRNA-Airn. Surprisingly, DNA methylation of a specific region called CpG island 2 (CpGI2) in the Igf2r promoter showed cis-acting inheritance, meaning that the DNA methylation patterns of the parental alleles are retained in hybrid tissues. Notably, the DNA methylation of CpGI2 correlated negatively with Igf2r expression in the spleen (R² = 0.8797, p = 6.46 × 10⁻⁶), lung (R² = 0.8569, p = 1.57 × 10⁻⁵), and kidney (R² = 0.8650, p = 3.85 × 10⁻⁶). Our findings suggest that imprinting may work differently in other species. This study provides a framework for understanding imprinting diversity in hybrids and shows that equine hybrids can be used to study how epigenetic inheritance works. Full article