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Search Results (10,278)

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Keywords = epigenetics

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19 pages, 825 KiB  
Article
MicroRNA-Mediated Post-Transcriptional Regulation of Enzymes Involved in Herbicide Resistance in Echinochloa oryzicola (Vasinger) Vasinger
by Carlo Maria Cusaro, Enrica Capelli, Anna Maria Picco, Marta Guarise, Enrico Gozio, Pietro Zarpellon and Maura Brusoni
Plants 2025, 14(5), 719; https://doi.org/10.3390/plants14050719 - 26 Feb 2025
Abstract
Herbicide resistance is an emerging phytosanitary threat, causing serious yield and economic losses. Although this phenomenon has been widely studied, only recently has the role of epigenetic factors in its occurrence been considered. In the present study, we analyzed the microRNA-mediated regulation in [...] Read more.
Herbicide resistance is an emerging phytosanitary threat, causing serious yield and economic losses. Although this phenomenon has been widely studied, only recently has the role of epigenetic factors in its occurrence been considered. In the present study, we analyzed the microRNA-mediated regulation in Echinochloa oryzicola (Vasinger) Vasinger (late-watergrass) of the expression of cytochromes P450, glutathione S-transferase (GST), and eIF4B, all of which are enzymes involved in profoxydim (AURA®) detoxification. Before and after profoxydim application, the expression profiles of microRNAs (miRNAs) were selected for their ability to target the genes considered, and their targets were assessed by means of RT-qPCR. Susceptible and resistant biotypes showed different responses to this herbicide. After profoxydim application, in resistant biotypes, osa-miR2099-5p, ath-miR396b, osa-miR395f, osa-miR396a-5p, osa-miR166a-5p, osa-miR166d-5p, gra-miR8759, and gma-miR396f were not triggered, allowing the expression of CYP81A, GSTF1, and eIF4B genes and the herbicide’s detoxification. Meanwhile, the transcription of ata-miR166c-5p, ath-miR847, osa-miR5538, and gra-miR7487c was triggered, down-regulating CYP71AK2, CYP72A254, CYP72A122, and EcGST expression. In susceptible biotypes, the herbicide stimulated ata-miR166c-5p, ath-miR847, osa-miR5538, gra-miR7487c, osa-miR166a-5p, and gra-miR8759, down-regulating their respective target genes (CYP72A122, CYP71AK2, EcGST, CYP72A254, CYP81A12, and eIF4B). A better understanding of the role of miRNA-mediated epigenetic regulation in herbicide resistance will be useful in planning more targeted and sustainable methods for controlling this phytosanitary threat. Full article
(This article belongs to the Section Plant Molecular Biology)
18 pages, 2905 KiB  
Article
Effects of Exposure to Different Types of Microplastics on the Growth and Development of Rana zhenhaiensis Tadpoles
by Shimin Xiao, Hao Chen, Xiyao Gao, Xinni He, Rongzhou Jin, Yunqi Wei, Shuran Li, Lei Xie and Yongpu Zhang
Toxics 2025, 13(3), 165; https://doi.org/10.3390/toxics13030165 - 26 Feb 2025
Viewed by 1
Abstract
Microplastic (MP) pollution is a major environmental problem, but a comparative study of the toxicological effects of different MPs remains lacking. To explore the toxicological effects of three different microplastics, namely, polypropylene (PP), polystyrene (PS) and polyethylene (PE), Zhenhai brown frog (Rana [...] Read more.
Microplastic (MP) pollution is a major environmental problem, but a comparative study of the toxicological effects of different MPs remains lacking. To explore the toxicological effects of three different microplastics, namely, polypropylene (PP), polystyrene (PS) and polyethylene (PE), Zhenhai brown frog (Rana zhenhaiensis) tadpoles were used as the model animal. The results showed that exposure to PE and PS significantly reduced the metamorphosis rate of the tadpoles. Compared with the control group, the body weight of tadpoles in all MP treatments was significantly reduced compared with that of the control group. In addition, exposure to PE reduced the body length and hind limb length of tadpoles. The number of pigment cells increased and intercellular spaces expanded in the liver tissues of tadpoles receiving PS and PE treatments. The composition and function of the intestinal microbiota in the PP treatment and control groups were similar, whereas between the PS treatment and control, they differed. Liver transcriptome sequencing revealed significant alterations in key genes associated with oxidative stress, energy metabolism, immune response, and apoptosis signaling pathways with PS treatment and PP treatment. In summary, MPs may have harmed tadpoles to varying degrees by interfering with related signaling pathways. The negative effects of PE and PS were greater than those of PP. Full article
(This article belongs to the Section Ecotoxicology)
34 pages, 2945 KiB  
Review
Radiogenomic Landscape of Metastatic Endocrine-Positive Breast Cancer Resistant to Aromatase Inhibitors
by Richard Khanyile, Talent Chipiti, Rodney Hull and Zodwa Dlamini
Cancers 2025, 17(5), 808; https://doi.org/10.3390/cancers17050808 - 26 Feb 2025
Viewed by 119
Abstract
Breast cancer poses a significant global health challenge and includes various subtypes, such as endocrine-positive, HER2-positive, and triple-negative. Endocrine-positive breast cancer, characterized by estrogen and progesterone receptors, is commonly treated with aromatase inhibitors. However, resistance to these inhibitors can hinder patient outcomes due [...] Read more.
Breast cancer poses a significant global health challenge and includes various subtypes, such as endocrine-positive, HER2-positive, and triple-negative. Endocrine-positive breast cancer, characterized by estrogen and progesterone receptors, is commonly treated with aromatase inhibitors. However, resistance to these inhibitors can hinder patient outcomes due to genetic and epigenetic alterations, mutations in the estrogen receptor 1 gene, and changes in signaling pathways. Radiogenomics combines imaging techniques like MRI and CT scans with genomic profiling methods to identify radiographic biomarkers associated with resistance. This approach enhances our understanding of resistance mechanisms and metastasis patterns, linking them to specific genomic profiles and common metastasis sites like the bone and brain. By integrating radiogenomic data, personalized treatment strategies can be developed, improving predictive and prognostic capabilities. Advancements in imaging and genomic technologies offer promising avenues for enhancing radiogenomic research. A thorough understanding of resistance mechanisms is crucial for developing effective treatment strategies, making radiogenomics a valuable integrative approach in personalized medicine that aims to improve clinical outcomes for patients with metastatic endocrine-positive breast cancer. Full article
(This article belongs to the Special Issue Radiomics in Cancer Imaging: Theory and Applications in Solid Tumours)
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20 pages, 3177 KiB  
Article
The Status of SOX2 Expression in Gastric Cancers with Induction of CDX2 Defines Groups with Different Genomic Landscapes
by Ioannis A. Voutsadakis
Genes 2025, 16(3), 279; https://doi.org/10.3390/genes16030279 - 26 Feb 2025
Viewed by 36
Abstract
Background: Gastric adenocarcinoma is a highly lethal neoplasm with a short survival especially when metastatic. Few effective treatments are available for the control of the disease and palliation of patients with metastatic gastric cancer. Although progress has been made in the elucidation of [...] Read more.
Background: Gastric adenocarcinoma is a highly lethal neoplasm with a short survival especially when metastatic. Few effective treatments are available for the control of the disease and palliation of patients with metastatic gastric cancer. Although progress has been made in the elucidation of molecular pathways invoked in gastric carcinogenesis, this knowledge has not yet led to major breakthroughs, in contrast to several other types of cancer. The role of stem cell transcription factors SOX2 and CDX2 is of particular interest in the pathogenesis of gastric cancer. Methods: The cohort of gastric adenocarcinomas from The Cancer Genome Atlas (TCGA) was interrogated and two groups of gastric cancers, with CDX2 induction and SOX2 suppression on the one hand and with CDX2 induction and SOX2 maintained expression on the other hand were retained. The induction of expression of the two transcription factors was defined as a mRNA expression z score compared with normal samples above zero. The two groups were compared for clinical-pathologic and genomic differences. Results: Among gastric cancers with up-regulated CDX2 mRNA, cancers with suppressed SOX2 mRNA were slightly more numerous (55.9%) than those with a maintained SOX2 expression. The SOX2 suppressed group had a higher prevalence of MSI high cancers (30.9% versus 10%) and of cases with high tumor mutation burden (35% versus 12.4%) than cancers with a SOX2 maintained expression, which presented more frequently high Chromosomal Instability (CIN). The group with SOX2 suppression had higher rates of mutations in many gastric cancer-associated genes such as epigenetic modifiers ARID1A, KMT2D, KMT2C, and KMT2B, as well as higher rates of mutations in genes encoding for receptor tyrosine kinases ERBB4 and FGFR1. On the other hand, TP53 mutations and amplifications in MYC, ERBB2, and CCNE1 were more common in the group with a maintained expression of SOX2, approaching significance for MYC. Conclusions: Notable differences are present in the genomic landscape of CDX2-induced gastric cancer depending on the level of expression of SOX2 mRNA. Despite this, SOX2 mRNA expression levels were not prognostic. Full article
(This article belongs to the Section Human Genomics and Genetic Diseases)
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17 pages, 1302 KiB  
Article
DNA Methylation and Demethylation in Triple-Negative Breast Cancer: Associations with Clinicopathological Characteristics and the Chemotherapy Response
by Kateryna Tarhonska, Mateusz Wichtowski, Thomas Wow, Agnieszka Kołacińska-Wow, Katarzyna Płoszka, Wojciech Fendler, Izabela Zawlik, Sylwia Paszek, Alina Zuchowska and Ewa Jabłońska
Biomedicines 2025, 13(3), 585; https://doi.org/10.3390/biomedicines13030585 - 26 Feb 2025
Viewed by 36
Abstract
Objectives: Triple-negative breast cancer (TNBC) is an aggressive cancer subtype with limited treatment options due to the absence of estrogen, progesterone receptors, and HER2 expression. This study examined the impact of DNA methylation and demethylation markers in tumor tissues on TNBC patients’ response [...] Read more.
Objectives: Triple-negative breast cancer (TNBC) is an aggressive cancer subtype with limited treatment options due to the absence of estrogen, progesterone receptors, and HER2 expression. This study examined the impact of DNA methylation and demethylation markers in tumor tissues on TNBC patients’ response to neoadjuvant chemotherapy (NACT) and analyzed the correlation between 5-methylcytosine (5-mC) and 5-hydroxymethylcytosine (5-hmC) and clinicopathological characteristics, offering new insights into the predictive value of these epigenetic markers. Methods: The study included 53 TNBC female patients, 19 of whom received neoadjuvant chemotherapy (NACT) before surgery. Global DNA methylation and demethylation levels were quantified using an ELISA-based method to measure 5-mC and 5-hmC content in DNA isolated from pre-treatment biopsy samples (in patients undergoing NACT) and postoperative tissues (in patients without NACT). Results: In patients who received NACT, those with disease progression had significantly higher pretreatment levels of 5-hmC (p = 0.028) and a trend toward higher 5-mC levels (p = 0.054) compared to those with pathological complete response, partial response, or stable disease. Higher 5-mC and 5-hmC levels were significantly associated with higher tumor grade (p = 0.039 and p = 0.017, respectively). Additionally, a positive correlation was observed between the Ki-67 proliferation marker and both 5-mC (rS = 0.340, p = 0.049) and 5-hmC (rS = 0.341, p = 0.048) levels in postoperative tissues. Conclusions: Our study highlights the potential of global DNA methylation and demethylation markers as predictors of tumor aggressiveness and chemotherapy response in TNBC. Further research in larger cohorts is necessary to validate these markers’ prognostic and predictive value. Full article
(This article belongs to the Special Issue Molecular Research in Breast Cancer)
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21 pages, 3570 KiB  
Article
Isothiocyanates Enhance the Anti-Melanoma Effect of Zebularine Through Modulation of Apoptosis and Regulation of DNMTs’ Expression, Chromatin Configuration and Histone Posttranslational Modifications Associated with Altered Gene Expression Patterns
by Ioannis Anestopoulos, Ioannis Paraskevaidis, Sotiris Kyriakou, Louiza Potamiti, Dimitrios T. Trafalis, Sotiris Botaitis, Rodrigo Franco, Aglaia Pappa and Mihalis I. Panayiotidis
Epigenomes 2025, 9(1), 7; https://doi.org/10.3390/epigenomes9010007 - 25 Feb 2025
Viewed by 144
Abstract
Background: In the present study, we aimed to characterize the cytotoxic efficacy of Zebularine either as a single agent or in combination with various isothiocyanates in an in vitro model consisting of human melanoma (A375, Colo-679) as well as non-tumorigenic immortalized keratinocyte (HaCaT) [...] Read more.
Background: In the present study, we aimed to characterize the cytotoxic efficacy of Zebularine either as a single agent or in combination with various isothiocyanates in an in vitro model consisting of human melanoma (A375, Colo-679) as well as non-tumorigenic immortalized keratinocyte (HaCaT) cells. Methods: In this model, we have evaluated the anti-melanoma effect of Zebularine (in single and combinatorial protocols) in terms of cell viability, apoptotic induction and alterations in ultrastructural chromatin configuration, protein expression levels of DNA methyltransferases (DNMTs) and associated histone epigenetic marks capable of mediating gene expression. Results: Exposure to Zebularine resulted in dose- and time-dependent cytotoxicity through apoptotic induction in malignant melanoma cells, while neighboring non-tumorigenic keratinocytes remained unaffected. A more profound response was observed in combinational protocols, as evidenced by a further decline in cell viability leading to an even more robust apoptotic induction followed by a differential response (i.e., activation/de-activation) of various apoptotic genes. Furthermore, combined exposure protocols caused a significant decrease of DNMT1, DNMT3A and DNMT3B protein expression levels together with alterations in ultrastructural chromatin configuration and protein expression levels of specific histone modification marks capable of modulating gene expression. Conclusions: Overall, we have developed a novel experimental approach capable of potentiating the cytotoxic efficacy of Zebularine against human malignant melanoma cells while at the same time maintaining a non-cytotoxic profile against neighboring non-tumorigenic keratinocyte (HaCaT) cells. Full article
(This article belongs to the Collection Epigenetics of Melanoma)
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19 pages, 3777 KiB  
Article
Sustained Epigenetic Reactivation in Fragile X Neurons with an RNA-Binding Small Molecule
by Christina W. Kam, Jason G. Dumelie, Gabriele Ciceri, Wang-Yong Yang, Matthew D. Disney, Lorenz Studer and Samie R. Jaffrey
Genes 2025, 16(3), 278; https://doi.org/10.3390/genes16030278 - 25 Feb 2025
Viewed by 273
Abstract
Background/Objectives: Fragile X syndrome (FXS) is a disease of pathologic epigenetic silencing induced by RNA. In FXS, an expanded CGG repeat tract in the FMR1 gene induces epigenetic silencing during embryogenesis. FMR1 silencing can be reversed with 5-aza-deoxyctidine (5-aza-dC), a nonspecific epigenetic reactivator; [...] Read more.
Background/Objectives: Fragile X syndrome (FXS) is a disease of pathologic epigenetic silencing induced by RNA. In FXS, an expanded CGG repeat tract in the FMR1 gene induces epigenetic silencing during embryogenesis. FMR1 silencing can be reversed with 5-aza-deoxyctidine (5-aza-dC), a nonspecific epigenetic reactivator; however, continuous administration of 5-aza-dC is problematic due to its toxicity. We describe an approach to restore FMR1 expression in FXS neurons by transient treatment with 5-aza-dC, followed by treatment with 2HE-5NMe, which binds the CGG repeat expansion in the FMR1 mRNA and could block the resilencing of the FMR1 gene after withdrawal of 5-aza-dC. Methods: This study uses immunofluorescence and fluorescent in situ hybridization (FISH) to measure whether FMR1 expression is maintained in FXS post-mitotic neurons treated with 2HE-5NMe. Genome-wide profiling of histone marks was used to monitor epigenetic changes and drug selectivity in response to 5-aza-dC followed by 2HE-5NMe treatment. Changes to dendritic morphology were visualized using confocal microscopy. Results: In this study, we find that 2HE-5Nme maintains FMR1 in a reactivated state after reactivation using 5-aza-dC in post-mitotic neurons. FMR1 reactivation in neurons results in the re-expression of FMRP and reversal of FXS-associated dendritic spine defects. Conclusions: These results demonstrate that an RNA-binding small molecule can achieve gene-specific epigenetic control and provide an approach for the restoration of FMRP in FXS neurons. Full article
(This article belongs to the Section Epigenomics)
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16 pages, 2030 KiB  
Article
Sonidegib Inhibits the Adhesion of Acute Myeloid Leukemia to the Bone Marrow in Hypoxia: An Optical Tweezer Study
by Katarzyna Gdesz-Birula, Sławomir Drobczyński, Krystian Sarat and Kamila Duś-Szachniewicz
Biomedicines 2025, 13(3), 578; https://doi.org/10.3390/biomedicines13030578 - 25 Feb 2025
Viewed by 175
Abstract
Background: Acute myeloid leukemia (AML) is a heterogeneous disease highly resistant to chemotherapeutic agents. Leukemia stem cells (LSCs) can enter a dormant state and avoid apoptosis in the protective niche of the bone marrow (BM) microenvironment. Moreover, bone marrow stromal cells protect leukemia [...] Read more.
Background: Acute myeloid leukemia (AML) is a heterogeneous disease highly resistant to chemotherapeutic agents. Leukemia stem cells (LSCs) can enter a dormant state and avoid apoptosis in the protective niche of the bone marrow (BM) microenvironment. Moreover, bone marrow stromal cells protect leukemia cells by promoting pro-survival signaling pathways and drug resistance. Therefore, attenuating interactions between leukemia cells and BM cells may have a positive therapeutic effect. Objectives: In this work, we hypothesized that sondages may inhibit the adhesion of leukemia cells to the bone marrow by inhibiting the Hedgehog (Hh) signaling pathway. The Hedgehog pathway is a key therapeutic target in AML due to its role in leukemic cell growth and survival. Methods: We investigated the effects of sonidegib on the adhesion of individual OCI-AML3 cells to a bone marrow stromal spheroid derived from the HS-5 cell line. For this purpose, we precisely determined the minimum cell-to-cell adhesion time using optical tweezers under normoxic (21% of O2) and hypoxic (1% of O2) conditions. Results: Our results demonstrated that sonidegib significantly increased the minimum cell-to-cell adhesion time necessary for leukemic cells to establish adhesive bonds with bone marrow stromal cells, thereby indicating a reduction in their adhesive properties. Additionally, we showed that sonidegib is particularly effective at hypoxic oxygen concentrations. Conclusions: The results obtained in this study suggest that sonidegib, through its modulation of the Hedgehog signaling pathway, holds promise as a potential therapeutic approach to target leukemic cell adhesion within the bone marrow microenvironment. Full article
(This article belongs to the Special Issue 3D Cell Culture Systems for Biomedical Research)
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35 pages, 2905 KiB  
Review
Mechanisms and Strategies to Overcome Drug Resistance in Colorectal Cancer
by Jennifer Haynes and Prasath Manogaran
Int. J. Mol. Sci. 2025, 26(5), 1988; https://doi.org/10.3390/ijms26051988 - 25 Feb 2025
Viewed by 80
Abstract
Colorectal cancer (CRC) is a major cause of cancer-related mortality worldwide, with a significant impact on public health. Current treatment options include surgery, chemotherapy, radiotherapy, molecular-targeted therapy, and immunotherapy. Despite advancements in these therapeutic modalities, resistance remains a significant challenge, often leading to [...] Read more.
Colorectal cancer (CRC) is a major cause of cancer-related mortality worldwide, with a significant impact on public health. Current treatment options include surgery, chemotherapy, radiotherapy, molecular-targeted therapy, and immunotherapy. Despite advancements in these therapeutic modalities, resistance remains a significant challenge, often leading to treatment failure, poor progression-free survival, and cancer recurrence. Mechanisms of resistance in CRC are multifaceted, involving genetic mutations, epigenetic alterations, tumor heterogeneity, and the tumor microenvironment. Understanding these mechanisms at the molecular level is crucial for identifying novel therapeutic targets and developing strategies to overcome resistance. This review provides an overview of the diverse mechanisms driving drug resistance in sporadic CRC and discusses strategies currently under investigation to counteract this resistance. Several promising strategies are being explored, including targeting drug transport, key signaling pathways, DNA damage response, cell death pathways, epigenetic modifications, cancer stem cells, and the tumor microenvironment. The integration of emerging therapeutic approaches that target resistance mechanisms aims to enhance the efficacy of current CRC treatments and improve patient outcomes. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Inhibition of Colorectal Cancer)
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31 pages, 2346 KiB  
Review
Non-Invasive Biomarkers in the Era of Big Data and Machine Learning
by Konstantinos Lazaros, Styliani Adam, Marios G. Krokidis, Themis Exarchos, Panagiotis Vlamos and Aristidis G. Vrahatis
Sensors 2025, 25(5), 1396; https://doi.org/10.3390/s25051396 - 25 Feb 2025
Viewed by 81
Abstract
Invasive diagnostic techniques, while offering critical insights into disease pathophysiology, are often limited by high costs, procedural risks, and patient discomfort. Non-invasive biomarkers represent a transformative alternative, providing diagnostic precision through accessible biological samples or physiological data, including blood, saliva, breath, and wearable [...] Read more.
Invasive diagnostic techniques, while offering critical insights into disease pathophysiology, are often limited by high costs, procedural risks, and patient discomfort. Non-invasive biomarkers represent a transformative alternative, providing diagnostic precision through accessible biological samples or physiological data, including blood, saliva, breath, and wearable health metrics. They encompass molecular and imaging approaches, revealing genetic, epigenetic, and metabolic alterations associated with disease states. Furthermore, advances in breathomics and gut microbiome profiling further expand their diagnostic scope. Even with their strengths in terms of safety, cost-effectiveness, and accessibility, non-invasive biomarkers face challenges in achieving monitoring sensitivity and specificity comparable to traditional clinical approaches. Computational advancements, particularly in artificial intelligence and machine learning, are addressing these limitations by uncovering complex patterns in multi-modal datasets, enhancing diagnostic accuracy and facilitating personalized medicine. The present review integrates recent innovations, examines their clinical applications, highlights their limitations and provides a concise overview of the evolving role of non-invasive biomarkers in precision diagnostics, positioning them as a compelling choice for large-scale healthcare applications. Full article
(This article belongs to the Special Issue Sensors-Based Biomarker Detection and Bioinformatics Analysis)
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50 pages, 17383 KiB  
Review
Untangling the Role of MYC in Sarcomas and Its Potential as a Promising Therapeutic Target
by Fabio Sias, Stefano Zoroddu, Rossana Migheli and Luigi Bagella
Int. J. Mol. Sci. 2025, 26(5), 1973; https://doi.org/10.3390/ijms26051973 - 25 Feb 2025
Viewed by 143
Abstract
MYC plays a pivotal role in the biology of various sarcoma subtypes, acting as a key regulator of tumor growth, proliferation, and metabolic reprogramming. This oncogene is frequently dysregulated across different sarcomas, where its expression is closely intertwined with the molecular features unique [...] Read more.
MYC plays a pivotal role in the biology of various sarcoma subtypes, acting as a key regulator of tumor growth, proliferation, and metabolic reprogramming. This oncogene is frequently dysregulated across different sarcomas, where its expression is closely intertwined with the molecular features unique to each subtype. MYC interacts with critical pathways such as cell cycle regulation, apoptosis, and angiogenesis, amplifying tumor aggressiveness and resistance to standard therapies. Furthermore, MYC influences the tumor microenvironment by modulating cell–extracellular matrix interactions and immune evasion mechanisms, further complicating therapeutic management. Despite its well-established centrality in sarcoma pathogenesis, targeting MYC directly remains challenging due to its “undruggable” protein structure. However, emerging therapeutic strategies, including indirect MYC inhibition via epigenetic modulators, transcriptional machinery disruptors, and metabolic pathway inhibitors, offer new hope for sarcoma treatment. This review underscores the importance of understanding the intricate roles of MYC across sarcoma subtypes to guide the development of effective targeted therapies. Given MYC’s central role in tumorigenesis and progression, innovative approaches aiming at MYC inhibition could transform the therapeutic landscape for sarcoma patients, providing a much-needed avenue to overcome therapeutic resistance and improve clinical outcomes. Full article
(This article belongs to the Collection Feature Papers in Molecular Oncology)
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30 pages, 2199 KiB  
Review
Molecular Abnormalities and Carcinogenesis in Barrett’s Esophagus: Implications for Cancer Treatment and Prevention
by Thaís Cabral de Melo Viana, Eric Toshiyuki Nakamura, Amanda Park, Kaique Flávio Xavier Cardoso Filardi, Rodrigo Moisés de Almeida Leite, Luiz Fernando Sposito Ribeiro Baltazar, Pedro Luiz Serrano Usón Junior and Francisco Tustumi
Genes 2025, 16(3), 270; https://doi.org/10.3390/genes16030270 - 25 Feb 2025
Viewed by 140
Abstract
Background: Barrett’s esophagus (BE) is described by the transformation of the normal squamous epithelium into metaplastic columnar epithelium, driven by chronic gastroesophageal reflux disease (GERD). BE is a recognized premalignant condition and the main precursor to esophageal adenocarcinoma (EAC). Understanding the molecular mechanisms [...] Read more.
Background: Barrett’s esophagus (BE) is described by the transformation of the normal squamous epithelium into metaplastic columnar epithelium, driven by chronic gastroesophageal reflux disease (GERD). BE is a recognized premalignant condition and the main precursor to esophageal adenocarcinoma (EAC). Understanding the molecular mechanisms underlying BE carcinogenesis is crucial for improving prevention, surveillance, and treatment strategies. Methods: This narrative review examines the molecular abnormalities associated with the progression of BE to EAC. Results: This study highlights inflammatory, genetic, epigenetic, and chromosomal alterations, emphasizing key pathways and biomarkers. BE progression follows a multistep process involving dysplasia and genetic alterations such as TP53 and CDKN2A (p16) mutations, chromosomal instability, and dysregulation of pathways like PI3K/AKT/mTOR. Epigenetic alterations, including aberrant microRNA expression or DNA methylation, further contribute to this progression. These molecular changes are stage-specific, with some alterations occurring early in BE during the transition to high-grade dysplasia or EAC. Innovations in chemoprevention, such as combining proton pump inhibitors and aspirin, and the potential of antireflux surgery to halt disease progression are promising. Incorporating molecular biomarkers into surveillance strategies and advancing precision medicine may enable earlier detection and personalized treatments. Conclusions: BE is the primary preneoplastic condition for EAC. A deeper understanding of its molecular transformation can enhance surveillance protocols, optimize the management of gastroesophageal reflux inflammation, and refine prevention and therapeutic strategies, ultimately contributing to a reduction in the global burden of EAC. Full article
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37 pages, 2498 KiB  
Review
Antibody-Based and Other Novel Agents in Adult B-Cell Acute Lymphoblastic Leukemia
by Clifford M. Csizmar, Mark R. Litzow and Antoine N. Saliba
Cancers 2025, 17(5), 779; https://doi.org/10.3390/cancers17050779 - 25 Feb 2025
Viewed by 160
Abstract
Despite notable progress in managing B-cell acute lymphoblastic leukemia (B-ALL) over recent decades, particularly in pediatric cohorts where the 5-year overall survival (OS) reaches 90%, outcomes for the 10–15% with relapsed and refractory disease remain unfavorable. This disparity is further accentuated in adults, [...] Read more.
Despite notable progress in managing B-cell acute lymphoblastic leukemia (B-ALL) over recent decades, particularly in pediatric cohorts where the 5-year overall survival (OS) reaches 90%, outcomes for the 10–15% with relapsed and refractory disease remain unfavorable. This disparity is further accentuated in adults, where individuals over the age of 40 years undergoing aggressive multiagent chemotherapy continue to have lower survival rates. While the adoption of pediatric-inspired treatment protocols has enhanced complete remission (CR) rates among younger adults, 20–30% of these patients experience relapse, resulting in a subsequent 5-year OS rate of 40–50%. For relapsed B-ALL in adults, there is no universally accepted standard salvage therapy, and the median OS is short. The cornerstone of B-ALL treatment continues to be the utilization of combined cytotoxic chemotherapy regimens to maximize early and durable disease control. In this manuscript, we go beyond the multiagent chemotherapy medications developed prior to the 1980s and focus on the incorporation of antibody-based therapy for B-ALL with an eye on existing and upcoming approved indications for blinatumomab, inotuzumab ozogamicin, other monoclonal antibodies, and chimeric antigen receptor (CAR) T cell products in frontline and relapsed/refractory settings. In addition, we discuss emerging investigational therapies that harness the therapeutic vulnerabilities of the disease through targeting apoptosis, modifying epigenetics, and inhibiting the mTOR pathway. Full article
(This article belongs to the Special Issue Drug Development for Acute Lymphoblastic Leukemia)
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17 pages, 3839 KiB  
Article
Epigenetic Perspectives and Their Prognostic Value in Early Recurrence After Hepatocellular Carcinoma Resection
by Chang-Yi Lu, Ching-Pin Lin, Hsiang-Lin Lee, Pey-Jey Peng, Shao-Chang Huang, Meng-Rong Chuang and Yih-Jyh Lin
Cancers 2025, 17(5), 769; https://doi.org/10.3390/cancers17050769 - 24 Feb 2025
Viewed by 81
Abstract
Background/Objectives: The post-hepatectomy survival of patients with hepatocellular carcinoma (HCC) faces challenges due to high recurrence rates, especially early recurrence (ER). We investigated DNA methylation in HCC and developed a methylation-based model for ER prediction (MER). Methods: We studied HCC patients with ER [...] Read more.
Background/Objectives: The post-hepatectomy survival of patients with hepatocellular carcinoma (HCC) faces challenges due to high recurrence rates, especially early recurrence (ER). We investigated DNA methylation in HCC and developed a methylation-based model for ER prediction (MER). Methods: We studied HCC patients with ER within a year post-hepatectomy, comparing them to those who remained recurrence-free (RF) for 5 years. In a testing set, we examined genome-wide methylation profiles to identify differences between ER and RF. Validation in an independent cohort confirmed candidate markers using real-time quantitative methylation-specific PCR (qMSP). We constructed MER by incorporating identified gene methylation, clinical information, and serum protein marker, and evaluated its predictive performance using ROC analysis and Cox regression. Results: Distinct signatures of hypermethylation and hypomethylation were observed between ER and RF, as well as between cirrhotic and non-cirrhotic groups. Significant aberrant methylation pathways, including FGFR signaling, the PI3K network, and the MAPK pathway, were observed in non-cirrhotic ER patients. Conversely, cirrhotic ER patients showed notable associations with Wnt/β-catenin signaling, cell adhesion, and migration mechanisms. Through qMSP analysis, we identified ER-associated genes, including BDNF, FOXL2, LMO7, NCAM1, NEIS3, PLA2G7, and LTB4R. MER demonstrated strong predictive ability for ER, with an AUC of 0.855, surpassing current indicators such as AFP, tumor size, and BCLC stage. Combining different predictors resulted in heightened AUC values. Importantly, the inclusion of MER yielded to the highest AUC of 0.952, underscoring the substantial contribution of MER to predictive accuracy. Conclusions: This study discovered the involvement of aberrant DNA methylation in HCC with early recurrence. The MER outperforms clinicopathological predictors and achieves robust prediction capabilities in identifying patients at risk of ER. Full article
(This article belongs to the Section Cancer Pathophysiology)
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19 pages, 5703 KiB  
Article
Establishment and Molecular Characterization of a Human Stem Cell Line from a Primary Cell Culture Obtained from an Ectopic Calcified Lesion of a Tumoral Calcinosis Patient Carrying a Novel GALNT3 Mutation
by Simone Donati, Gaia Palmini, Cinzia Aurilia, Irene Falsetti, Francesca Marini, Gianna Galli, Roberto Zonefrati, Teresa Iantomasi, Lorenzo Margheriti, Alessandro Franchi, Giovanni Beltrami, Laura Masi, Arcangelo Moro and Maria Luisa Brandi
Genes 2025, 16(3), 263; https://doi.org/10.3390/genes16030263 - 24 Feb 2025
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Abstract
Background/Objectives: Tumoral calcinosis (TC) is an extremely rare inherited disease characterized by multilobulated, dense ectopic calcified masses, usually in the periarticular soft tissue regions. In a previous study, we isolated a primary cell line from an ectopic lesion of a TC patient carrying [...] Read more.
Background/Objectives: Tumoral calcinosis (TC) is an extremely rare inherited disease characterized by multilobulated, dense ectopic calcified masses, usually in the periarticular soft tissue regions. In a previous study, we isolated a primary cell line from an ectopic lesion of a TC patient carrying a previously undescribed GALNT3 mutation. Here, we researched whether a stem cell (SC) subpopulation, which may play a critical role in TC progression, could be present within these lesions. Methods: A putative SC subpopulation was initially isolated by the sphere assay (marked as TC1-SC line) and characterized for its stem-like phenotype through several cellular and molecular assays, including colony forming unit assay, immunofluorescence staining for mesenchymal SC (MSC) markers, gene expression analyses for embryonic SC (ESC) marker genes, and multidifferentiation capacity. In addition, a preliminary expression pattern of osteogenesis-related pathways miRNAs and genes were assessed in the TC1-SC by quantitative Real-Time PCR (qPCR). Results: These cells were capable of differentiating into both the adipogenic and the osteogenic lineages. Moreover, they showed the presence of the MSC and ESC markers, confirmed respectively by using immunofluorescence and qualitative reverse transcriptase PCR (RT-PCR), and a good rate of clonogenic capacity. Finally, qPCR data revealed a signature of miRNAs (i.e., miR-21, miR-23a-3p, miR-26a, miR-27a-3p, miR-27b-3p, and miR-29b-3p) and osteogenic marker genes (i.e., ALP, RUNX2, COLIA1, OPG, OCN, and CCN2) characteristic for the established TC1-SC line. Conclusions: The establishment of this in vitro cell model system could advance the understanding of mechanisms underlying TC pathogenesis, thereby paving the way for the discovery of new diagnostic and novel gene-targeted therapeutic approaches for TC. Full article
(This article belongs to the Special Issue MicroRNA in Cancers)
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