Search Results (141)

Background/Objectives: Isocitrate dehydrogenase (IDH) mutations are hallmark features in subsets of gliomas, producing the oncometabolite D-2-hydroxyglutarate (2HG). Although IDH mutations are associated with better clinical outcomes, their relationship with tumor progression is complex. This study aimed to investigate, in vitro and in vivo, the phenotypic consequences of IDH mutation and 2HG exposure in glioblastoma (GBM) under normoxic and hypoxic conditions and under temozolomide (TMZ) and radiation exposure. Methods: Experiments were conducted using IDH-wildtype (IDH-wt) and IDH-mutant (IDH-mut) glioma cell lines under controlled oxygen conditions. Functional assays included cell viability, cell cycle analysis, apoptosis profiling, migration, and surface marker expression via flow cytometry. Orthotopic xenografts were established in immunocompromised mice to assess in vivo tumor growth and morphology, followed by MRI and histological analysis. Treatments included TMZ, radiation, and 2HG at varying concentrations. Statistical analyses were performed using SPSS and RStudio. Results:IDH-wt cells exhibited faster proliferation and greater adaptability under hypoxia, while IDH-mut cells showed cell cycle arrest and limited growth. 2HG recapitulated IDH-mut features in IDH-wt cells, including increased apoptosis under TMZ, reduced proliferation, and altered CD24/CD44 expression. In vivo, IDH-wt tumors were larger and more infiltrative, while 2HG administration reduced tumor volume and promoted compact morphology. Notably, migration was initially similar across genotypes but increased in IDH-mut and 2HG-treated IDH-wt cells over time, though suppressed under therapeutic stress. Conclusions: IDH mutation and 2HG modulate glioma cell biology, including cell cycle dynamics, proliferation rates, migration, and apoptosis. While the IDH mutation and its metabolic product confer initial growth advantages, they enhance treatment sensitivity and reduce invasiveness, highlighting potential vulnerabilities for targeted therapy. Full article

The nopal cactus, a plant from the Cactaceae family, holds significant economic and nutritional value for Mexico. This study aimed to enhance the genetic diversity and morphological traits of Opuntia velutina, a species cultivated as a vegetable nopal. A total of 1050 in vitro O. velutina explants were exposed to 15 different doses of gamma radiation from ⁶⁰Co gamma, ranging from 5 to 125 Gy. The lethal dose was above 50 Gy, with an LD₅₀ of 22.8 Gy for stimulating in vitro shoot growth. Shoots derived from doses between 5 and 50 Gy were subjected to in vitro shoot proliferation across four consecutive generations to stabilize morphological traits. Cluster analysis categorized the 178 irradiated shoots into 13 distinct morphological groups (CG1–CG13). Twenty-seven shoots exhibiting significant morphological improvements, such as a 50–100% increase in cladode length, up to a six-fold increase in shoot number, and up to a seven-fold increase in root number, were selected for molecular analysis of genetic diversity. Six primers were used with the Inter Simple Sequence Repeat (ISSR) molecular markers to examine genetic uniformity, yielding 54.5% polymorphic bands, indicating a high level of genetic variation. Both a UPGMA dendrogram and STRUCTURE-based Bayesian analysis confirmed the genetic divergence among the selected mutant lines. Overall, gamma irradiation effectively enhanced both phenotypic and genotypic diversity in O. velutina. This study corroborates that in vitro mutagenesis through gamma radiation is a viable strategy for generating novel genotypes with breeding potential within the Opuntia genus. Full article

Ultraviolet (UV)-induced mutagenesis is a cost-effective and straightforward technique for introducing random genetic variations without the use of chemical reagents or genetic engineering. It is commonly employed to enhance enzyme activity in industrial trains. In this study, Trichoderma sp. was exposed to UV radiation at varying distances (4, 9, and 13 cm) and durations (2, 4, 6, and 8 min) to induce mutations. The activities of endoglucanase (EG), β-glucosidase (BGL), and cellobiohydrolase (CBH) were assessed following treatment. The 4 cm exposure distance yielded the highest enhancement, with EG, BGL, and CBH activities increasing 1.5-, 1.3-, and 0.9-fold, respectively. When the distance was fixed at 4 cm, the optimal exposure time was identified as 4 min, yielding further enhancements of 1.9-, 1.6-, and 1.4-fold, respectively. The resulting mutant, designated Mut-4, was scaled up in a 10-L bioreactor to assess its industrial applicability. Mut-4 retained its enhanced performance, achieving 1.9-, 2.0-, and 1.4-fold enhancements in EG, BGL, and CBH activities, respectively, compared with the original strain. These findings indicate that combining UV-induced mutagenesis with basic screening is an effective strategy for enhancing cellulolytic enzyme production, representing a promising approach for lignocellulosic biomass conversion. Full article

Common buckwheat (Fagopyrum esculentum Moench), a valuable plant, is characterized by a highly unstable seed yield. The objective of the present study was to ascertain whether seed treatment with gamma radiation of 30 or 40 Gy would enhance yield and the content of amino acids. Plants obtained from irradiated seeds were named M0 generation. Subsequently, the mutants were subjected to cross-pollination under isolation conditions within groups, contingent upon the radiation dose, to yield the M1, M2, and M3 generations. To estimate the extent of mutation changes, genotyping by sequencing analysis was performed on selected M0 plants. Each year, the selection of plants was based on their seed yield. The amino acid composition in the seeds of the M2 and M3 generations was determined. The number of unique heterozygote variants identified for the 40 Gy plants was found to be less than that observed in remaining plants. The M0 and M1 plants of 40 Gy group exhibited an augmented seed yield; however, this characteristic did not reoccur in the M2 generation. In the M2, the control seeds exhibited the highest amino acid content compared to the mutants. In the M3 generation, only one accession of the 40 Gy group demonstrated higher amino acid content than the other plants. The findings suggest that irradiating seeds with 40 Gy can enhance seed yield and amino acid content. Full article

Background: Chondrosarcoma is the second most common bone tumor in adults with an average incidence of 0.1–0.3 individuals per 100,000 per year. These tumors are often resistant to chemotherapy and radiation, and surgical excision is a mainstay of current treatment. However, survival in the setting of metastatic disease is still poor, and research is needed to identify prognostic biomarkers and potential therapeutic targets. Several studies have examined the role of IDH mutations in chondrosarcoma, but the results vary widely. The goal of this analysis was to aggregate individual patient data from these studies and conduct a high-powered analysis of the impact of IDH mutations on survival outcomes in chondrosarcoma. Methods: Chondrosarcoma studies that included data on the IDH mutation status of tumors were queried, and the individual datasets reporting patient and tumor variables were extracted. The data from these studies were added to the internal dataset from the authors’ home institution. Two-sample tests for equality of proportions were used to assess the distribution of sample characteristics between groups. Univariate Kaplan–Meier (KM) curves and multivariate Cox Proportional Hazards (CPH) models were used to assess the relationship between tumor IDH mutations and five and ten-year patient overall survival (OS). Results: The final cohort included 1152 patients sourced from 21 studies and the authors’ internal dataset. IDH mutations were more common in higher grade tumors and were more likely to be found in individuals over 60 years old. Patients with IDH mutant tumors had shorter five-year OS in univariate KM analysis when analyzing all chondrosarcomas combined. However, multivariate CPH models accounting for age and tumor grade, found that the effect of IDH mutation was isolated to patients with dedifferentiated tumors only. Patients with IDH mutant dedifferentiated tumors displayed significantly shorter five-year OS (HR: 1.99, p = 0.02) relative to patients with IDH wild-type (WT) dedifferentiated tumors. The primary predictor of five-year OS in the conventional chondrosarcoma cohort was tumor grade, regardless of IDH mutation status (HR: 2.72, p < 0.005). Discussion: IDH mutations are relatively common in cartilaginous neoplasms (including benign tumors), with the literature reporting rates as high as 50% in chondrosarcomas. Prior studies have investigated the link between IDH1/2 mutation status, tumor grade and overall survival, with mixed results on the effect of IDH mutation on survival. Vuong et al. performed a meta-analysis in 2021 and found that IDH mutation was associated with older patient age, larger tumor size, higher tumor grade, and increased risk of death compared to WT tumors. Our analysis, which builds on the Vuong et al. study, indicates that IDH status itself is not independently predictive of overall survival in conventional chondrosarcoma, however, it does correlate with survival in dedifferentiated tumors. Further analysis is needed to investigate the potential correlation of IDH mutations in higher grade tumors and patients of older age. Full article

Aim: The management of low-grade gliomas (LGGs) is evolving with new insights into disease biology. Furthermore, recently, the phase III INDIGO¹ study highlighted the benefits of an IDH inhibitor, vorasidenib, in treating residual or recurrent grade 2 IDH-mutant gliomas following surgery alone. We aimed to characterise the current patterns of care for patients with LGGs in Australia and New Zealand, including the role of vorasidenib. Methods: An online survey examining respondents’ practice setting, caseload, and preferred treatment approach to three clinical scenarios was distributed through the Cooperative Trials Group for Neuro-Oncology, New Zealand Aotearoa Neuro-Oncology Society, and the Australian and New Zealand Society for Neuropathology in December 2023 with three reminders in April, June, and September of 2024. Results: The survey response rate was 19.6% (57/291), 87.7% from Australia, and 12.3% from New Zealand, spanning medical oncology (45.7%), pathology (22.8%), radiation oncology (17.5%), and neurosurgery (14.0%). Case 1 examined an IDH-mutant grade 2 astrocytoma following gross total resection. Observation alone was recommended by 93%. Case 2 examined an incompletely resected IDH-mutant grade 2 astrocytoma. If feasible, 38% recommended further surgery and 83% adjuvant chemotherapy and radiotherapy. After 12 months of disease stability, 53% of the respondents preferred vorasidenib over the existing therapies. Case 3 examined an incompletely resected IDH-mutant grade 3 oligodendroglioma. No respondents recommended observation alone, with 26% recommending salvage surgery and 97% recommending further chemotherapy and radiotherapy. Conclusions: This study describes current management practices for LGGs in Australia and New Zealand, showing ongoing variation and a cautious approach to integrating IDH inhibitors. This highlights the critical role of multidisciplinary team-based decision-making in increasingly complex clinical situations. Full article

The prolyl-hydroxylase inhibitor (PHI), used effectively in several countries for the treatment of renal anemia, activates the multifunctional hypoxia-inducible factors (HIFs). While hypoxic conditions in tumors are known to affect the response to radiation therapy, the effect of PHI on the radiation response of cancer cells has not been determined. Hypoxic pretreatment increased the radiation sensitivity of A549 lung adenocarcinoma cells, whereas hypoxic culture after irradiation decreased the radiation sensitivity of HSC2 oral squamous cell carcinoma cells. Treatment of PC9 lung adenocarcinoma and HSC2 cells with the PHI FG-4592 significantly increased radiation resistance, whereas A549 and TIG3 lung fibroblast cells tended to be sensitized, suggesting cell type-specific differential effects of PHI. Quantitative RT-PCR analyses revealed that the basal and radiation-inducible expressions of DEC2, BAX, and BCL2 may be related to PHI-mediated radiation responses. Knock-down experiments showed that silencing of DEC2 sensitized both A549 and PC9 cells under PHI-treated conditions. On the other hand, silencing of p53, which regulates BAX/BCL2, desensitized A549 cells expressing wild-type p53, but not PC9 cells, with mutant-type p53, to irradiation, regardless of whether PHI was treated or not. Taken together, PHI modifies radiation responses in a cell type-specific manner, possibly through DEC2 signaling. Full article

The prevalence and deaths from esophageal cancer (EC) have recently increased. Although therapeutic strategies depend on the EC stage and recurrence, such as surgical intervention, chemotherapy, radiation therapy, chemoradiation therapy, targeted therapy, and immunotherapy, a more effective and novel treatment for EC is still required. This review briefly describes and summarizes some insightful oncotargets involved in the metabolic modulation of EC, including (1) cancer stem cells (CSCs) for EC progression, poor prognosis, tumor recurrence, and therapy resistance; (2) retinoic acid receptors (RARs) for esophageal carcinogenesis and regeneration; (3) phosphofructokinase (PFK) for EC-reprogrammed glycolysis; (4) lactate dehydrogenase (LDH) as an EC peripheral blood biomarker; and (5) hypoxia-inducible factor-1 alpha (HIF-1α) for the tumor microenvironment under hypoxic conditions. Moreover, the aforementioned oncotargets can be modulated by mutant TP53 and have their own features in the carcinogenesis, differentiation, proliferation, and metastasis of EC. Thus, the clarification of pharmacological mechanisms regarding the interaction between mutant TP53 and the abovementioned oncotargets could provide precise and perspective opinions for minimizing prediction errors, reducing therapy resistance, and developing novel drugs against EC. Full article

Mutagenesis breeding, combined with the application of corresponding herbicides to develop herbicide-resistant rice germplasm, provides great promise for the management of weeds and weedy rice. In this study, a topramezone-resistant rice mutant, TZR1, was developed from the indica rice line Chuangyu 9H (CY9H) through radiation mutagenesis and topramezone selection. Dose–response curves revealed that the resistance index of TZR1 to topramezone was 1.94-fold compared to that of CY9H. The resistance mechanism of TZR1 was not due to target-site resistance. This resistance could be reversed by a specific inhibitor of glutathione S-transferase (GST). The activity of antioxidant enzymes was analyzed. SNPs and Indels were detected using whole-genome resequencing; differentially expressed genes were identified through RNA sequencing. Then, they underwent Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. Key candidate genes associated with topramezone resistance were validated via a real-time quantitative PCR assay. Five GST genes, two UDP-glycosyltransferase genes, and three ATP-binding cassette transporter genes were identified as potential contributors to topramezone detoxification in TZR1. Overall, these findings suggest that GST enzymes possibly play an important role in TZR1 resistance to topramezone. This study will provide valuable information for the scientific application of 4-hydroxyphenylpyruvate dioxygenase inhibitors in paddy fields in future. Full article

Colchicine and ⁶⁰Co-γ radiation are commonly used breeding techniques for kiwifruit, offering advantages such as low cost, rapid execution, and high efficiency. The buds of red-fleshed kiwifruit (Actinidia chinensis) cv. ‘Donghong’ were used as experimental material and subjected to different concentrations of colchicine and different doses of ⁶⁰Co-γ radiation, respectively. Then, the buds were grafted on rootstock, and the ploidy, leaf size, and fruit quality of mutant fruit were evaluated, and principal component analysis (PCA) and simple sequence repeat markers were used to comprehensively assess and detect genetic variations, respectively. The results indicated that a total of 19 buds successfully germinated, with 13 branches successfully bearing fruit. Significant changes were observed in both leaf and fruit morphology following the mutation treatments. Most of the mutant materials showed significant increases in fruit weight, flesh firmness, and soluble sugar content, while titratable acidity and ascorbic acid content significantly decreased. Notably, the 25Gy ⁶⁰Co-γ radiation (25d) treatment demonstrated outstanding results, with fruit weight increasing by 256.10%, soluble sugar content rising by 88.29%, titratable acidity decreasing by 29.86%, and ascorbic acid content increasing by 35.60%. PCA results showed that the 25d mutant had the best comprehensive traits. And, except for the 0.4c mutant, all other mutant materials exhibited significant genetic changes at the DNA level. Full article

Glioblastoma, the most common and aggressive primary brain tumor in adults, presents a formidable challenge due to its rapid progression, treatment resistance, and poor survival outcomes. Standard care typically involves maximal safe surgical resection, followed by fractionated external beam radiation therapy and concurrent temozolomide chemotherapy. Despite these interventions, median survival remains approximately 12–15 months, with a five-year survival rate below 10%. Prognosis is influenced by factors such as patient age, molecular characteristics, and the extent of resection. Patients with IDH-mutant tumors or methylated MGMT promoters generally have improved survival, while recurrent glioblastoma is associated with a median survival of only six months, as therapies in these cases are often palliative. Innovative treatments, including TTFields, add incremental survival benefits, extending median survival to around 20.9 months for eligible patients. Symptom management—addressing seizures, headaches, and neurological deficits—alongside psychological support for patients and caregivers is essential to enhance quality of life. Emerging targeted therapies and immunotherapies, though still limited in efficacy, show promise as part of an evolving treatment landscape. Continued research and clinical trials remain crucial to developing more effective treatments. This multidisciplinary approach, incorporating diagnostics, personalized therapy, and supportive care, aims to improve outcomes and provides a hopeful foundation for advancing glioblastoma management. Full article

Background: Cancer remains a leading cause of mortality globally. Conventional treatment modalities, including radiation and chemotherapy, often fall short of achieving complete remission, highlighting the critical need for novel therapeutic strategies. One promising approach involves the oncolytic potential of Group A Streptococcus (GAS) strains for tumor treatment. This study aimed to investigate the oncolytic efficacy of S. pyogenes GUR and its M protein knockout mutant, S. pyogenes strain GURSA1, which was genetically constructed to minimize overall toxicity, against mouse hepatoma 22A, pancreatic cancer PANC02, and human glioma U251 cells, both in vitro and in vivo, using the C57BL/6 mouse model. Methods: The in vitro oncolytic cytotoxic activity of GAS strains was studied against human glioma U251, pancreatic cancer PANC02, murine hepatoma 22a, and normal skin fibroblast cells using the MTT assay and the real-time xCELLigence system. A syngeneic mouse model of hepatoma and pancreatic cancer was used to evaluate the in vivo oncolytic effect of GAS strains. Statistical analysis was conducted using Student’s t-test and Mann–Whitney U-test with GraphPad Prism software. Results: The in vitro model showed that the live S. pyogenes GUR strain had a strong cytotoxic effect (67.4 ± 1.9%) against pancreatic cancer PANC02 cells. This strain exhibited moderate (38.0 ± 1.8%) and weak (16.3 ± 5.4%) oncolytic activities against glioma and hepatoma cells, respectively. In contrast, the S. pyogenes GURSA1 strain demonstrated strong (86.5 ± 1.6%) and moderate (36.5 ± 1.8%) oncolytic activities against glioma and hepatoma cells. Additionally, the S. pyogenes GURSA1 strain did not exhibit cytotoxic activity against healthy skin fibroblast cells (cell viability 104.2 ± 1.3%, p = 0.2542). We demonstrated that tumor treatment with S. pyogenes GURSA1 significantly increased the lifespan of C57BL/6 mice with hepatoma (34 days, p = 0.040) and pancreatic cancer (32 days, p = 0.039) relative to the control groups (24 and 28 days, respectively). Increased lifespan was accompanied by a slowdown in tumor progression, as evidenced by a reduction in the growth of hepatoma and pancreatic cancer tumors under treatment with GAS strains in mice. Conclusions: Both S. pyogenes GUR and S. pyogenes GURSA1 strains demonstrated strong oncolytic activity against murine hepatoma 22a, pancreatic cancer PANC02, and human U251 glioma cells in vitro. In contrast, S. pyogenes GUR and GURSA1 did not show toxicity against human normal skin fibroblasts. The overall survival rate and lifespan of mice treated with S. pyogenes GURSA1, a strain lacking the M protein on its surface, were significantly higher compared to the control and S. pyogenes GUR strain groups. Full article

Glioblastoma multiforme (GBM) is a malignant primary brain tumor categorized as a Grade 4 astrocytic glioma by the World Health Organization (WHO). Some of the established risk factors of GBM include inherited genetic syndromes, body mass index, alcohol consumption, use of non-steroidal anti-inflammatory drugs (NSAIDs), and therapeutic ionizing radiation. Vascular anomalies, including local and peripheral thrombosis, are common features of GBM. Podoplanin (PDPN), a ligand of the C-type lectin receptor (CLEC-2), promotes platelet activation, aggregation, venous thromboembolism (VTE), lymphatic vessel formation, and tumor metastasis in GBM patients. It is regulated by Prox1 and is expressed in developing and adult mammalian brains. It was initially identified on lymphatic endothelial cells (LECs) as the E11 antigen and on fibroblastic reticular cells (FRCs) of lymphoid organs and thymic epithelial cells as gp38. In recent research studies, its expression has been linked with prognosis in GBM. PDPN-expressing cancer cells are highly pernicious, with a mutant aptitude to form stem cells. Such cells, on colocalization to the surrounding tissues, transition from epithelial to mesenchymal cells, contributing to the malignant carcinogenesis of GBM. PDPN can be used as an independent prognostic factor in GBM, and this review provides strong preclinical and clinical evidence supporting these claims. Full article

This review delves into the significant cellular and molecular responses triggered by UVR exposure in human skin, emphasizing the pivotal role of mutant p53 (mutp53) in the carcinogenic process elicited by radiation. By underlining the role of a functional p53 in safeguarding skin cells from UVR-induced damage, this work underscores the potential significance of targeting mutp53, aiming to restore its wild-type-like activity (reactivation), as a protective strategy against skin cancer (SC), particularly NMSC. Most importantly, an interesting crosstalk between p53 and its vitamin D receptor (VDR) transcriptional target is also highlighted in the suppression of skin carcinogenesis, which opens the way to promising chemopreventive strategies involving synergistic combinations between mutp53 reactivators and vitamin D. Collectively, this review not only opens new avenues for future research, but also offers promising prospects for the development of novel beneficial approaches in the field of SC. Full article

Adjuvant radiation therapy (ART) for macroscopic regional nodal cutaneous melanoma has evolved. A significant step was the discovery of targeted therapies, particularly towards V600E-mutated melanoma, and immunotherapy under its different kinds. Prior to this, the defining trial was the Australia and New Zealand Melanoma Trials Group (ANZMTG) 01.02/Trans-Tasman Radiation Oncology Group (TROG) 02.01 phase III trial that showed that ART using three-dimensional conformal radiotherapy (3DCRT) decreased in-field recurrence by 50% (48 Gray (Gy) in 20 fractions). After the advent of systemic therapies, a trial of the combination targeted therapy of dabrafenib plus trametinib toward BRAF V600-mutant nodal cutaneous melanoma showed that all 35 patients achieved a pathological response. Radiotherapy (RT) was found to be safe to give with concurrent combination therapy. A retrospective immunotherapy study found that in 71 patients that received ART after a first recurrence, further in-field recurrence significantly decreased (p = 0.01). For those tumours that do recur in-field, there are now competing therapies like Talimogene laherparepvec or T-VEC. Generally, ART is now used at the first recurrence. The challenge now is to find which melanomas are truly radiosensitive if ART is to have any future role in this scenario. Full article