Search Results (130)

Eukaryotic cells double their mass and divide at the same rate, allowing cells to maintain a uniform cell size over many cell divisions. We hypothesize that aneuploid cancer cells are more sensitive to forced overgrowth, more than doubling their mass during a single longer-duration cell division cycle, relative to healthy diploid cells. This hypothesis stems from the observation that cancer cells are under proteotoxic stress, during which heat-shock proteins become rate-limiting and the unfolded-protein response network has a growth-suppressive phenotype. Forced overgrowth will lead to the production of more individual proteins per cell division cycle and increase the duration of time during which any mis-folded or aggregated proteins might disrupt the function of properly folded proteins. To induce these potential forced overgrowth effects, we suggest targeting the cell division cycle regulatory enzyme, the anaphase-promoting complex/cyclosome (APC/C), to suppress—but not inhibit—its activity. We conclude by proposing experiments to test this hypothesis in which an APC/C inhibitor, such as a low level of proTAME, is combined with the clinically approved heat-shock protein 90 (HSP90)-inhibitor pimitespib (TAS-116) or the pre-clinical molecule tanespimycin, which, to the best of our knowledge, are combinations that have not been investigated before. Full article

Background/Objectives: Aneuploidy is near-ubiquitous in cancer and can decrease chemotherapy efficacy while also sensitizing cells to other drugs. Methods: To systematically identify treatment strategies that target aneuploid cancers, data were integrated from The Cancer Genome Atlas (TCGA; 10,967 samples, 16,948 aneuploidy events) and the Broad Institute’s Profiling Relative Inhibition Simultaneously in Mixtures (PRISM) screen of 578 cancer cell lines and 4518 compounds. Results: Our analyses uncovered 37,720 significant positive and negative associations linking specific aneuploidies and treatments with patient prognosis or cell viability. Within TCGA data, 22 treatments correlated with improved 5-year survival for specific aneuploid cancers, whereas 46 were linked to worse outcomes. A complementary analysis of PRISM identified 17,946 compound–aneuploidy associations and 16,189 mechanism of action (MOA)–aneuploidy associations. Pathway-altering compounds that selectively reduce viability in cells with aneuploidy profiles were discovered, including an unexpectedly prominent number of glucocorticoid receptor agonists. Conclusions: This integrated dataset provides a resource for designing therapeutic decision hypotheses, identifying drug-repurposing opportunities, and informing future studies aimed at targeting aneuploidy-induced vulnerabilities in cancer. Full article

This study investigated the effects of oryzalin treatments on the induction of polyploids and variants, as well as their subsequent morphological and physiological characteristics, in Lysimachia xiangxiensis, a perennial herbaceous plant belonging to the Primulaceae family that is known for its ornamental value. A total of 52 of the 162 treated stem segments survived after treatments and further developed into plantlets, and significant morphological changes in leaf color and growth status were observed. Using flow cytometry and chromosome counting, plants are categorized into the three variant types (VT1, VT2, and VT3), that is, VT1 and VT2 were diploid aneuploids, while VT3 was triploid. The optimized polyploid induction scheme involved treatment with 0.001% oryzalin for 4 days, resulting in an induction rate of up to 100%. Higher concentrations and longer exposure durations resulted in lower survival and polyploid induction rates of all stem segments during the above-mentioned processing. Observation of morphological features indicated that triploid VT3 vines were longer, with larger and thicker leaves and more guard cells, but lower stomatal density, compared with diploid aneuploids or the wild type. Polyploids outperformed other types in terms of chlorophyll content, net photosynthesis rate, stomatal conductance, and intercellular CO₂ concentration, but had a lower flavonoid content. The results demonstrate that oryzalin can effectively induce polyploidy and variants in L. xiangxiensis, resulting in beneficial changes in morphology and physiological characteristics; this should provide valuable insight into the improvement of excellent varieties in plants. Full article

Preimplantation genetic testing for aneuploidy (PGT-A) is widely used to select euploid embryos for in vitro fertilization (IVF), but its accuracy in predicting the implantation potential for full segmental aneuploid (Seg-A) embryos remains unclear. In this study, we investigated chromosomal concordance between clinically biopsied trophectoderm (TE) and inner cell mass (ICM) in 175 donated blastocysts, which comprised those clinically diagnosed as euploid (13), Seg-A (36), segmental mosaicism (Seg-M) (60), whole-chromosome aneuploid (Who-A) (52), and whole-chromosome mosaicism (14). Using next-generation sequencing (NGS), we found that TE–ICM concordance rates were higher for euploid (85%) and Who-A (94%) embryos but significantly lower for Seg-A (25%) and Seg-M embryos (33%). For Seg-A, the euploidy rate in the ICM was 19% and the euploidy rate in the ICM was 63% for Seg-M. These low concordance rates may be due to technical and biological artifacts of PGT-A for Seg-A. Despite the significant discordance between TE and ICM, a subset of Seg-A embryos demonstrated euploidy. While clinically diagnosed euploid embryos remain the preferred choice, Seg-A embryos should be considered as having implantation potential. In particular, Seg-A results should be clearly distinguished from Who-A results and not routinely categorically discarded. Further research is required to refine the selection criteria, aided by parental karyotyping or re-biopsy, and to develop more reliable embryo assessment methods to ensure the accurate evaluation of reproductive potential and support shared decision making between doctors and patients. Full article

Background: Given the common occurrence of mosaicism and aneuploidy in IVF embryos, our study aimed to retrospectively identify whether specific chromosomal regions or individual chromosomes are predominantly affected in our clinic. Understanding these patterns can improve embryo selection, reduce miscarriage risks, and enhance genetic counseling. At the same time, due to the limited data on potential comorbidities in affected children, our findings aim to support both clinicians and patients in making informed decisions. Methods: The retrospective clinical study included 461 PGT-A biopsies from our clinic database (September 2023–December 2024) to determine whether specific chromosome regions or individual chromosomes (C) are more likely to be mosaic or aneuploid. Results: Among the 461 embryos analyzed in our clinic, the incidence rate of mosaicism was 16.70% whereas the aneuploidy rate was 32.10%. Our results showed that mosaicism tends to target a specific chromosomal region in embryos, namely the chromosome 1 to 9 region, in particular chromosomes 7, 1, 9. On the other hand, aneuploidy targets the chromosomal region chromosome 16 to 22, particularly chromosomes 16, 19, and 22. Conclusions: Our data suggest that mosaicism and aneuploidy affect the genome in an uneven manner and are often concentrated in specific chromosomal regions, with mosaicism primarily affecting the C1–C9 region and aneuploidy targeting the C16–C22 region. These data highlight the need for further research to understand these patterns and the impact of IVF methods on chromosomal targeting. Comparative studies could also be helpful in genetic counseling by clarifying the implications of the levels of mosaicism in the newborn. Full article

Aneuploidy-related disruptions are generally tolerated in polyploid plants, which exhibit a greater capacity for genomic compensation. In this study, we utilize allotetraploid Brassica napus as a model and generated three aneuploid variants (NC1, NC2, and NC8) to investigate the phenotypic and transcriptional consequences of chromosome loss. Significant phenotypic variations were observed, with the most notable being a marked dwarfing phenotype in the aneuploid materials compared to the euploid Oro. Transcriptomic analysis revealed widespread alterations in gene expression across the entire genome in the deficient variants. Notably, most of the differentially expressed genes (DEGs) were attributed to trans-acting effects resulting from the deletion of C chromosomes. Deletion of the C chromosomes induced gene expression changes not only on the corresponding chromosomes, but also on the affected genes across other chromosomes. Specifically, in the C1-deleted variant, the average gene expression of the A1 chromosome increased, while the number of expressed genes on other chromosomes decreased. In contrast, for C2 and C8 deletions, the average expression levels of homologous genes decreased, but the number of expressed genes on other chromosomes increased. These findings shed light on the complex compensatory mechanisms that underlie aneuploidy in polyploid plants and provide valuable insights into how plants maintain genomic stability despite chromosomal loss. Full article

Background: Oxidative stress, defined as an imbalance between reactive oxygen species and antioxidant defenses, plays a pivotal role in the pathogenesis of sex chromosome aneuploidies (SCAs), such as Turner syndrome (TS) and Klinefelter syndrome (KS). Pediatric patients with SCAs are particularly susceptible due to hormonal deficiencies, metabolic disturbances, and systemic complications. Methods: A comprehensive literature search was conducted in November 2024 using PubMed, Scopus, and Web of Science. Keywords included “antioxidants”, “oxidative stress”, “pediatrics”, “Turner syndrome”, “Klinefelter syndrome”, and “sex chromosome aneuploidies”. English-language articles were included without publication year restrictions. Relevant data on oxidative stress mechanisms and antioxidant interventions were systematically extracted. Results: The relationship between oxidative stress and SCAs can be described as bidirectional, where oxidative stress both contributes to and is exacerbated by aneuploidies. TS is marked by estrogen deficiency, cardiovascular anomalies, and metabolic dysfunction, all linked to heightened oxidative stress. KS is associated with hypogonadism, metabolic syndrome, and neurocognitive challenges, further exacerbated by oxidative damage. The aneuploid condition predisposes to increased oxidative stress in other SCAs, including 47,XXX and 47,XYY, as well as in high-grade aneuploidies. Emerging evidence highlights the therapeutic potential of antioxidants, including vitamin C, vitamin E, glutathione precursors, polyphenols, and melatonin. These interventions, when combined with hormonal therapies such as estrogen replacement in TS or testosterone replacement in KS, demonstrate synergistic effects in restoring redox balance and mitigating systemic complications. Conclusions: Oxidative stress significantly impacts the progression of SCAs in pediatric populations, amplifying risks across metabolic, cardiovascular, and neurocognitive domains. Early, tailored antioxidant strategies, integrated with syndrome-specific hormonal therapies, could reduce long-term complications and improve patient outcomes. Future research should focus on standardizing protocols to optimize these interventions for pediatric patients with SCAs. Full article

The chromosome numbers of 56 populations belonging to 25 species and 4 varieties of Artemisia L. (Asteraceae) from China were examined, and those of 13 species and four varieties are reported here for the first time. The karyotypes of 39 populations in 23 species and four varieties were also studied. Among them, twelve species and one variety were found to be diploid, with 2n = 16 or 18; nine species and three varieties were found to be tetraploid, with 2n = 32 or 36; and two species were found to have both diploid and tetraploid cytotypes. Two species were found to have aneuploid cytotypes. The karyotypes of Artemisia are similar, with most chromosomes belonging to median-centromeric (m) and a few belonging to submedian-centromeric (sm) or subterminal-centromeric (st). The high level of polyploids in Artemisia from the Qinghai–Tibetan Plateau indicates that polyploidy has played an important role in the evolutionary speciation of this highly diversified genus in this region. Full article

Supernumerary (B) chromosomes are widespread in numerous plants, including the Lilium genus. However, their origin remains unclear. This study used traditional and modern cytogenetics to analyze the triploid lily cultivar ‘Eyeliner’ (LAA) to identify the microsporogenesis, fertility, and chromosome composition of its progeny and record a case of potential B chromosome formation. The results indicated anomalous meiosis of LAA in all processes. In microspores, different cells had different numbers of chromosomes and fragments. Moreover, the fluorescence in situ hybridization (FISH) results showed that some fragments contained telomere signals at both ends. The LAA × AA progenies were aneuploid, with one progeny containing a small aberrant chromosome (potential B chromosome). The genomic in situ hybridization (GISH) results showed that the aberrant chromosome originated from the L genome. In contrast, the FISH results showed that the aberrant chromosome contained two telomere signals. This suggests that the anomalous meiosis of the triploid lily forms chromosome bridges, fragments, and small aberrant chromosomes (isochromosome), which eventually form aneuploid gametes containing small aberrant chromosomes passed on to the progeny. This study provides a case in which the potential B chromosomes are derived from the A chromosomes. Full article

Alpha-fetoprotein (AFP) is measured during pregnancy in maternal serum to screen for, and in amniotic fluid to test for, neural tube defects. This study aimed to determine whether or not AFP is expressed in blastocoel fluid-conditioned media (BFCM) at the blastocyst stage of embryonic development. For this in vitro study, BFCM was obtained from blastocyst stage embryos following standard embryology laboratory processes. Good quality blastocysts (n = 40) had trophectoderm biopsy for preimplantation genetic testing for aneuploidy (PGT-A) with subsequent blastocyst vitrification and BFCM collection. BFCM samples (n = 40) were analyzed for human AFP protein via an AFP Human ELISA Kit. Statistical analysis was performed with Fisher’s exact test. AFP was expressed in 12.5% (5/40) of BFCM samples (range = 1.69–20.5 pg/mL). Of blastocysts with AFP in BFCM, 80% (4/5) had aneuploid PGT-A results; of blastocysts with no AFP in BFCM, 57% (20/35) had aneuploid PGT-A results, with no difference between groups (p = 0.63). Our study demonstrates AFP expression in BFCM. To our knowledge, this is the first study to report the detection of AFP at the embryonic blastocyst stage in vitro. Future studies are needed and underway to determine whether assessment of AFP at the embryonic stage can improve embryo transfer outcomes. Full article

Delaying mitotic cell cycle progression has been proposed as a strategy to potentiate the effects of anti-mitotic anti-cancer drugs that induce multipolar mitotic spindles. Toward this end, we have performed an in silico docking screen targeting anaphase-promoting complex/cyclosome subunit 1 (APC1) at a conserved 10-amino acid surface site that was modeled to interact via a single hydrogen bond with the essential mitotic anaphase-promoting complex/cyclosome (APC/C) co-factor cell division cycle 20 (CDC20). Five molecules were identified after screening 15,000 small molecules. As a secondary in cellulo bioactivity screening, MDA-MB-231 genomically unstable aneuploid breast cancer cells were exposed to each compound in the absence and presence of 10 nM paclitaxel or 1 nM eribulin, the likely clinically relevant doses of these drugs in these cells. Two of the five compounds, which share a common 2-(trifluoromethyl)quinazolin-4-amine chemical structure, induced elevated levels of cell death in combination with paclitaxel, as observed by fluorescence-activated cell sorting (FACS). These two compounds will now serve as a starting point for further optimization and target validation experiments and for additional in silico screens in search of other chemically related small molecules that display more potent but specific anti-cancer cell effects. Full article

Objective: Abnormally fertilized embryos are often discarded during in vitro fertilization due to the fact that known chromosomal ploidy abnormalities lead to implantation failure or pregnancy loss. The objective of this study was to determine if pronuclear numeration (PN) observed at fertilization check is representative of the true ploidy status of the subsequent developing blastocyst in order to maximize the number of viable embryos available for infertility patients and increase their chances of conception. Methods: Upon successful fertilization, pronuclear numeration was noted, and zygotes were cultured to the blastocyst stage. Biopsied trophectoderm cells were then lysed, and the isolated DNA was whole-genome amplified followed by library preparation. Next-generation sequencing was performed for PGT-A, and excess whole-genome amplified DNA was utilized for single nucleotide polymorphism beadchip array analysis. Results: At the time of fertilization check on day 1 of embryo development, when there were no visible pronuclei (n = 291), 56% of these 0PN blastocysts were confirmed to be diploid and normally fertilized. The remaining 41.9% were aneuploid, and 2.1% of the 0PN blastocysts contained only 23 haploid chromosomes. Upon analysis of the 1PN blastocysts (n = 217), just over a third (36.4%) only contained 23 haploid chromosomes (23XO), with another third (31.8%) identified as aneuploid, and surprisingly, the remaining third (31.8%) confirmed to be diploid and normally fertilized. In contrast, 50% of the 3PN blastocysts (n = 172) showed the presence of a third set of 23 parental chromosomes and were confirmed to be triploid (69XXY = 59.3% and 69XXX = 40.7%), with 41.9% identified as aneuploid and, interestingly, a small percentage (8.1%) confirmed to be diploid with normal fertilization. A very small proportion of biopsied blastocysts (0.63%) displaying the correct number of pronuclei for normal fertilization (2PN) were also identified as triploid with a third set of 23 parental chromosomes. To date, there have been 74 euploid embryo transfers from zygotes originally identified with an alternate pronuclear numeration, resulting in 16 ongoing pregnancies and 32 healthy live births, rates that match those typically observed with normally fertilized 2PN zygotes (>60%). Conclusions: A surprising number of blastocysts that were identified to have alternate pronuclear numeration at fertilization check on day 1 of embryo development were actually determined to be diploid with normal fertilization after molecular analysis. Accurate identification of haploid and tripoid zygotes is critical to prevent implantation failure and pregnancy loss and allows for the identification of all euploid embryos in a cohort, which has the potential to increase cumulative live birth rates for infertility patients. Full article

Background/Objectives: To assess the ploidy status of embryos via preimplantation genetic testing for aneuploidy (PGT-A), a biopsy of trophectoderm (TE) cells can be performed. However, this approach is considered invasive, and therefore the aim of this study was to identify the optimal sample type and sampling day for non-invasive or minimally invasive PGT-A (ni/miPGT-A) in terms of data quality and concordance rates with TE biopsies derived from the same embryos. Methods: This study was performed using 239 embryo cultures. After optimization using 96 embryos, non-invasive spent culture media (SCM) and a minimally invasive combination of blastocoel fluid and SCM (BF+SCM), along with the corresponding TE samples, were collected from 143 embryos cultured for 5 days (n = 70) or 6 days (n = 73), and all were subjected to ni/miPGT-A with whole-genome amplification followed by next-generation sequencing. Results: The amplification failure rate was lower for SCM samples than for BF+SCM (SCM: 0.7%, 1/143 vs. BF+SCM: 7.7%, 11/143; p = 0.005). The rate of ploidy concordance with TE was significantly higher for SCM samples than for BF+SCM samples (SCM: 83.7%, 118/141 vs. BF+SCM: 58%, 76/131; p < 0.001). Among SCM samples, concordance rates were higher for samples derived from embryos cultured for 6 days (87.5%, 63/72) than for 5 days (79.7%, 55/69). In the embryos cultured for 6 days, discordant cases included five (6.9%) SCM samples with falsely negative (euploid) results that were deemed to be mosaic according to TE and four (5.6%) samples falsely found to be aneuploid. Conclusions: SCM samples derived from embryos cultured for 6 days can be applied in niPGT-A with subsequent verification of aneuploid samples using TE biopsy. Full article

The increasing use of Cannabis sativa products for medicinal, dietary, and recreational purposes has raised concerns about mycotoxin contamination in cannabis and hemp. Mycotoxins persist in these products’ post-processing, posing health risks via multiple exposure routes. This study investigated cytotoxic and genotoxic interactions between cannabidiol (CBD) and the mycotoxin citrinin (CIT) using human cell models: SH-SY5Y, HepG2, HEK293, and peripheral blood lymphocytes. IC₅₀ values and membrane disruption were initially assessed, followed by an evaluation of genotoxicity in lymphocytes using the Comet Assay and Cytokinesis Blocked Micronucleus Cytome Assay. Obtained findings demonstrate that cell-type sensitivity varied across treatments, with combined CBD and CIT exposure exhibiting distinct interactions. Lactate dehydrogenase (LDH) release remained minimal, suggesting cytotoxicity did not stem from membrane disruption but likely involved intracellular pathways. In lymphocytes, CBD alone produced negligible cyto/genotoxic effects and weak antiproliferative responses, whereas CIT displayed clear toxic impacts. DNA damage indicates that CIT may induce genome instability through indirect mechanisms rather than direct DNA interaction, with evidence of potential aneuploidic effects from the CBMN Cyt Assay. Combined exposure led to a reduction in CIT-induced DNA and cytogenetic damage, suggesting CIT’s potential interference with the beneficial properties of CBD. These results provide a foundation for further toxicological assessments and highlight the necessity of standardized mycotoxin monitoring in cannabis-derived products. Full article

Aneuploidy is highly detrimental to organisms due to genomic imbalance. However, the influence of parental unbalanced genome conditions on gene expression of their offspring remains unclear, particularly in animals. To further explore the molecular regulatory mechanisms, we firstly analyzed the expression patterns of aneuploid Drosophila offspring from different parents with unbalanced genomes via reciprocal crosses and studied the potential functions of male-specific lethal 2 (MSL2) in this process. The results showed that the ectopic expression of MSL2 in aneuploidy resulted in gene expression patterns closer to those of diploidy, including MSL2 target genes, maternal genes, mitochondrial genes, and transposable elements. In addition, it was also found that ERp60, the key target gene of MSL2, played a crucial role in regulating endoplasmic reticulum (ER) Ca²⁺ homeostasis through its interaction with the STIM1 protein. When it was overexpressed, ER Ca²⁺ levels and the survival of aneuploid females were significantly increased. Furthermore, we observed upregulated ER Ca²⁺ levels identified in aneuploid brains, which suggested that Ca²⁺ homeostasis may be involved in the regulation mediated by MSL2 in aneuploid genomes. Full article