Search Results (749)

Paclitaxel (PTX) is a core first-line chemotherapeutic agent used to treat a broad spectrum of cancers, which remain leading causes of death worldwide. However, the emergence of intrinsic and acquired resistance critically contributes to chemotherapy failure, thereby promoting tumor recurrence and metastasis and resulting in a poor prognosis. PTX resistance is a complex biological process driven by multiple factors and cross-regulated signaling pathways. It encompasses a wide variety of mechanisms, including aberrations in microtubules and related proteins; changes in mitotic systems and chromosomal instability (CIN); epigenetic modifications including ncRNA regulation, DNA methylation, and histone modification; enhanced drug efflux and dysregulation of proliferation and apoptotic signaling pathways; enhanced protective autophagy; metabolic reprogramming; cell plasticity (increased EMT and cancer cell stemness); TME remodeling; and immune regulation. This review systematically examines the core molecular mechanisms of PTX resistance, summarizes cutting-edge strategies to reverse chemoresistance and their clinical translation, and discusses current challenges and future directions, thereby providing a theoretical framework for optimizing PTX-based regimens and overcoming clinical resistance. Full article

Background: There are limited data comparing the effect of different radiotherapy techniques on healthy cells in the same patient group. Furthermore, assessing radiotherapy-induced T-lymphocyte damage may be important given the increasing use of immunotherapy. We aimed to measure and compare DNA damage in T-lymphocytes after four types of radiotherapy for low- and intermediate-risk prostate cancer and monitor their persistence for five years. Methods: A prospective comparison of patients receiving conventional LINAC (linear accelerator) (70–78 Gy), CyberKnife teletherapy (37.5–40 Gy), low-dose-rate brachytherapy (LDR; 145 Gy) and high-dose-rate brachytherapy (HDR; 19–21 Gy was performed using the chromosome aberration technique (at 3, 6, 9, 12, 24, 36, 48, and 60 months, 192 patients). Multivariate regression analyses were conducted to assess the predictive potential of chromosome aberrations for toxicities. Results: We found that teletherapy techniques (conventional LINAC and CyberKnife therapy) caused 1.6–3.6-fold more chromosomal aberrations than brachytherapy. At three months, 4.4–13.1% of T-lymphocytes were damaged. Five years after treatment, the total aberration values of conventional LINAC and LDR brachytherapy patients were still significantly higher than those before treatment (p < 0.001 for LINAC and p = 0.011 for LDR). Significant regression models suggested that total aberrations or aberrant cell frequency might predict toxicities in addition to the biologically effective dose (BED) and the irradiated volume (V_100%) (p = 0.020 for the model including total aberrations, p = 0.010 for the model including aberrant cell frequency). Conclusions: We observed a lower chromosome aberration frequency and fewer toxicities in brachytherapy patients. We also demonstrated that long-term T-lymphocyte damage depends on the type of radiotherapy. Full article

Background and Objectives: Male factors account for approximately 30–50% of subfertile couples. Teratozoospermia is one of the major causes of male infertility; however, the genetic factors underlying many cases remain incompletely understood. This study aimed to identify potential genetic variants associated with teratozoospermia and to investigate the possible involvement of Caudal-Type Homeobox 4 (CDX4) in sperm morphogenesis. Materials and Methods: Whole-exome sequencing was performed in 44 individuals with teratozoospermia. A rare CDX4 variant (NM_005193.2, c.103G>T; NP_005184.1, Gly35Cys) was identified and confirmed by Sanger sequencing. Because CDX4 is located on the X chromosome, this variant was interpreted as hemizygous in the male patient. Sperm morphology, CDX4 localization, public GEO transcriptomic data (GSE6969), and CDX4 expression during murine spermiogenesis were analyzed. Results: The CDX4 p.Gly35Cys variant is located within the Caudal-like transactivation domain, a conserved region involved in transcriptional regulation. Spermatozoa from the patient carrying this variant exhibited severe morphological abnormalities, predominantly involving sperm-head defects, together with aberrant CDX4 localization along the midpiece and tail, in contrast to the neck- and annulus-enriched distribution observed in control spermatozoa. Reanalysis of the GEO dataset showed increased CDX4 transcript levels in teratozoospermic samples compared with normozoospermic controls. During murine spermiogenesis, CDX4 was detected in the nuclei of spermatogonia and spermatocytes and subsequently localized to the sperm head and neck/tail regions during sperm morphogenesis. Conclusions: CDX4 c.103G>T (p.Gly35Cys) is a rare hemizygous X-linked candidate variant associated with severe teratozoospermia in a single patient. Further cohort-based, segregation, and functional studies are required to clarify its role in sperm morphogenesis. Full article

Antrodia cinnamomea (AC) is a medicinal mushroom native to Taiwan. This study evaluated the genotoxicity and toxicity of red quinoa and barley-based solid-state fermented AC mycelium (RQBACM). The safety of RQBACM was evaluated via a 90-day repeated-dose oral toxicity study in rats and a battery of genotoxicity assays, including the Ames, CHO-K1 chromosomal aberration, and in vivo micronucleus tests. RQBACM exhibited no mutagenicity in the Ames test, regardless of S9 metabolic activation, nor did it induce chromosomal aberrations in CHO-K1 cells. In mice, no significant changes in reticulocyte or micronucleus frequency were observed at doses up to 5000 mg/kg. In the 90-day study, Sprague–Dawley rats receiving up to 3000 mg/kg/day showed no treatment-related adverse effects, except for a slight reduction in body weight in high-dose males. No significant changes were found in hematology, serum biochemistry, urinalysis, organ weights, or histopathology. The no-observed-adverse-effect level (NOAEL) was determined to be 3000 mg/kg/day, supporting the safety of RQBACM for potential human consumption. Full article

Background/Objectives: A complex karyotype (CK) in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDSs) is defined as the presence of three or more unrelated chromosomal abnormalities in the absence of defining core-binding factor translocations. Losses/Deletions on chromosomes 5, 7 and 17 are frequently observed. It is heavily associated with TP53 mutations, with 70–80% of CK cases in MDS/AML harboring TP53 mutations. Methods: An extensive literature search of the studies carried out in the last two decades has shown a consistent development of experimental and clinical studies aiming to characterize the biological properties and clinical features of AML and MDS bearing CK and TP53 mutations. Results: These studies have greatly contributed to identifying as separate entities AML and MDS bearing CK and or TP53 alterations. Particularly, the improvement in the methods of detection of chromosome aberrations has contributed to defining the specific nature of the various chromosome abnormalities and to deciphering the mechanisms of catastrophic events leading to gene rearrangements. Two types of CK were identified in AML and MDS, one more frequently associated with TP53 mutations (with poor prognosis) and another less frequently without TP53 mutations (with relatively better prognosis). Conclusions: The treatment of AML and MDS with CK and/or TP53 mutations alterations remains extremely challenging, and the prognosis of these patients is dismal. The main aim of the various induction treatments explored in these patients is to bridge patients to allo-HSCT, the only therapeutic approach able to improve the survival of at least a part of these patients. Full article

Refractory celiac disease (RCeD) is a rare but severe complication of celiac disease characterized by persistent or recurrent malabsorptive symptoms and villous atrophy despite a strict gluten-free diet, after exclusion of ongoing gluten exposure, alternative enteropathies, and overt lymphoma. RCeD comprises two biologically distinct entities. RCeD-I is associated with phenotypically normal, polyclonal intraepithelial lymphocytes and generally reflects persistent gluten-independent mucosal inflammation with a relatively favorable prognosis. RCeD-II is defined by expansion of aberrant clonal intraepithelial lymphocytes lacking normal surface T-cell markers and is increasingly regarded as a low-grade intraepithelial lymphoma or in situ lymphomatous disorder, with substantial risk of progression to enteropathy-associated T-cell lymphoma (EATL). Mechanistic studies identify epithelial stress, IL-15-driven IEL survival, stromal and innate immune amplification, and cytotoxic epithelial injury as central drivers of refractory mucosal damage. In RCeD-II, aberrant IELs acquire a hybrid T/NK-like phenotype, persist through anti-apoptotic IL-15/JAK–STAT signaling, and induce enterocyte killing, while molecular alterations involving JAK1, STAT3, JAK/STAT regulators, NF-κB signaling, epigenetic regulators, and chromosomal abnormalities support stepwise lymphomagenesis. Recent single-cell multiomic studies further reveal genetically altered intestinal lymphocyte clones and intratumoral heterogeneity across the RCeD-II–EATL continuum. From a nutritional immunology perspective, RCeD illustrates a setting in which removal of the initiating dietary antigen is insufficient to restore mucosal immune homeostasis. This review summarizes the pathogenic processes that distinguish RCeD-I from RCeD-II and link failed mucosal recovery after gluten withdrawal to persistent immune-mediated epithelial injury, aberrant IEL expansion, clonal evolution, and lymphoma progression. Full article

Background/Objectives: The base excision repair (BER) pathway repairs oxidative DNA damage, a common and detrimental form of damage to the genome. Although biochemical steps in BER have been well defined, little is understood about how the pathway is regulated. Such regulation is critical, as cells must respond rapidly to DNA damage while avoiding aberrant activation of repair proteins that can produce DNA damage as intermediates in the repair pathway. Indeed, overexpression of the human BER protein NTHL1, a DNA N-glycosylase, can cause genomic instability and early cellular hallmarks of cancer. Methods: We developed a Saccharomyces cerevisiae model to explore how overexpression of NTHL1 may impair cellular function. Results: Overexpression of Ntg1, the budding yeast orthologue of NTHL1, impairs cell growth. To dissect mechanisms underlying this growth defect, we overexpressed either wild-type Ntg1 or a catalytically inactive variant of Ntg1 (ntg1_catdead). Consistent with results obtained for NTHL1, both variants of Ntg1 impair cell growth, but only the wild-type protein causes accumulation of double-strand breaks and chromosome loss. We screened a panel of DNA repair mutants for resistance/sensitivity to overexpression of wild-type Ntg1 or ntg1_catdead. This analysis identified several cellular pathways that protect cells from Ntg1-induced damage, providing insight into the interplay between DNA repair pathways. Finally, we identified a link to SUMOylation and probed into how this post-translational modification could contribute to regulation of Ntg1 function. Conclusions: This study describes a budding yeast system to understand how cells regulate and respond to dysregulation of the BER pathway. Full article

Fanconi anemia (FA) is a rare disease with a deficient homologous recombination DNA repair pathway and high sensitivity to mitomycin C (MMC). In FA cells, hydroxyurea (HU), when applied in the G2 phase of the cell cycle, exacerbates the chromosomal aberrations (CAs) induced by MMC. Here, we study how exposure to HU in the G2 phase results in an increased CAs frequency in FA cells with or without prior treatment with MMC. We performed chromosome aberration analysis, flow cytometry, and mRNA and protein expression in lymphoblastoid cell lines. We found that HU alone induces post-replicative DNA damage in the form of DNA double-strand breaks (DSBs) in both wild-type and FA cells and a similar increase in the activation of DSBs marker ɣH2AX. HU potentiates the amount of CAs only in MMC-treated FA cells by multiple mechanisms, including (1) hindering the ɣH2AX signal, (2) impairing the translocation of ribonucleotide reductase (RNR) into the cell nucleus, and (3) promoting the activity of WIP1 phosphatase. Concomitantly, increased levels of cell death were observed in FA cell cultures. HU induces DNA damage and potentiates pre-existent damage in FA cells by preventing the translocation of the RNR component p53R2 into the nucleus and activating checkpoint recovery, thus allowing the survival of a proportion of FA cells that have adapted to DNA damage. Full article

Due to the advanced plans for the development of nuclear power plants in Poland, those who are to live around nuclear facilities may have unjustified doubts about their own radiation safety. Moreover, when future power plant workers will be potentially exposed to low, cumulative doses of ionizing radiation, it seems important to develop cytogenetic methods for showing the actual genotoxic effects of environmental or occupational nuclear influences. The method of analyzing the frequency of chromosomal type aberrations in peripheral blood lymphocytes remains one of the most significant possibilities in achieving this goal. Three techniques are used to monitor aberration frequency, i.e., most commonly, Giemsa staining (FPG), FISH, or M-FISH. The types of aberrations determined by Giemsa-staining preparation will be described in detail, and issues with the nomenclature of these aberrations will be discussed. To effectively explore small changes in aberration yields, studies of aberration rates in non-exposed populations are needed. Such a dataset has been generated at the Institute of Nuclear Chemistry and Technology (INCT), Warsaw, Poland. This database would allow for the assessment of the genotoxic impact of planned nuclear facilities, the impact of radon in areas within its increased concentration, or the impact of such a working environment on, for example, medical workers working with radiation. Full article

Objectives: This study compared controlled ovarian hyperstimulation (COH) outcomes and chromosomal euploidy results between the Utrogestan-based progesterone-primed ovarian stimulation (PPOS) and gonadotropin-releasing hormone antagonist (GnRH-Ant) protocols in preimplantation genetic testing for monogenic disorders (PGT-M) cycles, and assessed the efficacy and safety of the Utrogestan-based PPOS protocol. Methods: In this retrospective single-center cohort study, 176 PGT-M cycles managed with the Utrogestan-based PPOS protocol were compared with 176 GnRH-Ant cycles using 1:1 direct caliper matching without replacement. Embryos were classified as euploid, mosaic, aneuploid, or no-call according to next-generation sequencing results. The primary outcomes were euploidy rate and chromosomal aberration patterns; secondary outcomes included COH outcomes and pregnancy outcomes. Results: Baseline characteristics were comparable after matching. The total gonadotropin (Gn) dose was significantly lower in the Utrogestan-based PPOS group (2100 (1500–3000) vs. 2250 (1800–3000), p = 0.035). PGT analysis revealed comparable rates of euploidy, aneuploidy, mosaicism, and “No-call” between the Utrogestan-based PPOS (n = 586) and GnRH-Ant (n = 605) groups. The unadjusted difference in euploidy rate per MII oocyte between groups (18.98% vs. 16.36%, p = 0.045) was no longer statistically significant after multivariable adjustment (p = 0.194). In addition, patterns of aneuploidy and chromosomal involvement were similar between groups. The Utrogestan-based PPOS group showed numerically higher clinical pregnancy rate (70.67% vs. 63.22%) and live birth rate (62.67% vs. 51.72%), and a lower early abortion rate (5.66% vs. 12.73%), but none of these differences were statistically significant. Conclusions: Compared with the GnRH-Ant protocol, the Utrogestan-based PPOS protocol required a significantly lower total Gn dose while exhibiting comparable euploidy rate, analogous chromosomal abnormality spectrums, and pregnancy outcomes. The Utrogestan-based PPOS protocol may be a feasible alternative ovarian stimulation strategy in PGT-M cycles. Full article

Iron oxide-based nanomaterials have attracted considerable interest owing to their unique magnetic properties and potential biomedical and environmental applications. In this study, starch-coated superparamagnetic Fe₃O₄ nanoparticles (Sta-MNP) were synthesized and comprehensively characterized using electron microscopy (TEM, SEM), energy-dispersive X-ray spectroscopy (EDS), X-ray diffraction (XRD), vibrating sample magnetometry (VSM), attenuated total reflectance Fourier-transform infrared spectroscopy (ATR-FTIR), and nanoparticle tracking analysis (NTA). The results confirmed the formation of a magnetite-based iron oxide nanoparticles sample with a median physical diameter of 12.24 nm, superparamagnetic behavior with a saturation magnetization of 59.81 emu/g, and effective starch coating on the nanoparticle surface. The biological effects of Sta-MNP were assessed in Triticum aestivum L. using the mitotic index (MI) and aberration index (AI) as cytogenetic endpoints, respectively. Exposure-induced concentration-dependent increases in both parameters across the tested volume fractions (0–200 µL/L), suggesting a significant interaction between Sta-MNP and dividing cells. Overall, this study provides a comprehensive physicochemical profile of starch-coated magnetite nanoparticles and demonstrates their potential cytogenetic impact in a plant model system, supporting further investigation of their environmental interactions and potential agricultural applications. Full article

(1) Background: KMT2A (alias MLL) is located at chromosome 11q23 and encodes histone methyltransferase 2A which activates target genes via chromatin methylation of histone H3 lysine K4. Mutations of KMT2A, including partial tandem duplication (PTD) and fusion with partner genes, are present in both lymphoid and myeloid acute leukemia. More than 100 various KMT2A fusion genes have been described, with only a minority represented by cell line models. (2) Methods: Cytogenetic and genomic copy number analyses, PCR, Western blot and RNA-sequencing were performed to characterize aberrations in acute myeloid leukemia (AML) cell line KOPM-88. Bioinformatic analysis of public AML patient data revealed differentially expressed genes. Functional analyses were performed by siRNA-mediated knockdown and live-cell imaging. (3) Results: The AML cell line KOPM-88 is derived from a boy at relapse and has been reported to carry t(X;11)(q24;q23), albeit with uncharacterized breakpoints. In KOPM-88 we identified fusion gene KMT2A::SEPTIN6 generated by this translocation, but excluded KMT2A-PTD. KMT2A::SEPTIN6 activated bone morphogenetic protein (BMP)-signalling and inhibited expression of HOXA7 and HOXA9. BMP signalling in turn activated cell proliferation and inhibited CDKN2B expression. (4) Conclusions: KOPM-88 contains fusion gene KMT2A::SEPTIN6, representing the only cell line model for this rare type of KMT2A rearrangement. KOPM-88 may serve to advance novel therapeutic treatments for KMT2A::SEPTIN6-positive AML. Full article

Background/Objectives: Absent or hypoplastic nasal bone is strongly associated with Trisomy 21 and other common aneuploidies. Nevertheless, there is a growing body of literature that has associated absence or hypoplasia of the nasal bone with underlying genetic aberrations, other than Trisomy 21. While karyotyping effectively identifies substantial structural mutations, it is limited by its inability to detect submicroscopic copy number variants, thereby constraining the identification of pathological submicroscopic DNA gains or losses. The main objective of our study was to conduct a systematic literature review and a meta-analysis to evaluate the incremental yield of chromosomal microarray analysis compared to karyotyping in cases of isolated absence/hypoplasia of the fetal nasal bone. Methods: Our review was designed according to the PRISMA guidelines. It included all observational studies that reported the results of CMA testing in fetuses diagnosed with absent or hypoplastic nasal bone without additional structural abnormalities or findings that would not qualify as structural abnormalities (soft signs) (isolated absent/hypoplastic nasal bone). Results: The study included 15 studies with a total of 1328 cases of affected fetuses that met the inclusion criteria for analysis. Combined data from these studies revealed an overall 3% incremental yield of CMA over karyotyping (95% CI 1–4%, I² = 62%) in isolated cases. Conclusions: Our findings may be beneficial in clinical practice to provide management strategies and counsel couples, personalizing, as such, patient care and assisting clinicians when encountering this prevalent clinical entity. Full article

Acute myeloid leukemia (AML) is one of the most common types of hematological malignancies and a leading cause of cancer deaths. It is characterized by the rapid accumulation of typically immature myeloid cells that serve to disrupt the production of mature cells, leading to a range of clinical sequelae. The role of recurrent chromosomal aberrations has long been appreciated in this disease, but a myriad of gene mutations have been increasingly acknowledged as having important roles. This review provides a comprehensive overview of the mutational landscape of AML, discussing the various genetic lesions in terms of their function, classification, etiological role, prognostic value, therapeutic impact, detection, and monitoring, with a particular focus on gene mutations. Full article

Recurrent genetic and chromosomal aberrations drive multiple myeloma (MM) pathogenesis. Among these, the t(4;14) translocation leads to overexpression of fibroblast growth factor receptor 3 (FGFR3) and is associated with poor prognosis. However, therapeutic approaches directly targeting FGFR3-driven myeloma progression remain limited. Here, we investigated the single-agent activity of ponatinib, a multikinase inhibitor, in MM. KMS18 and U266 myeloma cell lines were treated with ponatinib, and apoptosis induction, as well as VEGF and IL-6 secretion, was assessed. RNA sequencing of MM cells revealed pathway alterations induced by ponatinib treatment, which were subsequently validated by Western blot analysis. In vivo, mice inoculated with 5T33 myeloma cells received ponatinib, and survival was monitored. Notably, ponatinib exerted potent single-agent antimyeloma activity in an FGFR3-dependent manner by inducing apoptosis and suppressing VEGF and IL-6 secretion through inhibition of JAK/STAT, PI3K/AKT, and MAPK signaling. In vivo administration prolonged survival in myeloma-bearing mice. Collectively, our findings demonstrate the therapeutic efficacy of ponatinib in FGFR3-expressing MM beyond selective FGFR3 inhibition, suggesting that concurrent suppression of multiple signaling pathways is a critical mechanism of action. These results highlight the therapeutic potential of combined FGFR3-targeted strategies in multiple myeloma and provide a rationale for further clinical investigation. Full article