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PurposeThis study compared the classification performance of normalized apparent diffusion coefficient (nADC) with percentage T2-FLAIR mismatch-volume (%T2FM-volume) for differentiating between IDH-mutant astrocytoma (IDHm-A) and other glioma molecular subtypes.MethodsA total of 105 non-enhancing gliomas were studied. T2-FLAIR digital subtraction maps were used to identify T2FM and T2-FLAIR non-mismatch (T2FNM) subregions within tumor volumes of interest (VOIs). Median nADC from the whole tumor, T2FM, and T2NFM subregions and %T2FM-volume were obtained. IDHm-A classification analyses using receiver-operating characteristic curves and multiple logistic regression were performed in addition to exploratory survival analyses.ResultsT2FM subregions had significantly higher nADC than T2FNM subregions within IDHm-A with ≥ 25% T2FM-volume (P

The 2016 and 2021 World Health Organization 2021 Classification of central nervous system tumors have resulted in a major improvement in the classification of isocitrate dehydrogenase (IDH)-mutant gliomas. With more effective treatments many patients experience prolonged survival. However, treatment guidelines are often still based on information from historical series comprising both patients with IDH wild-type and IDH-mutant tumors. They provide recommendations for radiotherapy and chemotherapy for so-called high-risk patients, usually based on residual tumor after surgery and age over 40. More up-to-date studies give a better insight into clinical, radiological, and molecular factors associated with the outcome of patients with IDH-mutant glioma. These insights should be used today for risk stratification and for treatment decisions. In many patients with IDH-mutant grades 2 and 3 glioma, if carefully monitored postponing radiotherapy and chemotherapy is safe, and will not jeopardize the overall outcome of patients. With the INDIGO trial showing patient benefit from the IDH inhibitor vorasidenib, there is a sizable population in which it seems reasonable to try this class of agents before recommending radio-chemotherapy with its delayed adverse event profile affecting quality of survival. Ongoing trials should help to further identify the patients that are benefiting from this treatment.

Glioblastoma is a clinically and molecularly heterogeneous disease, and new predictive biomarkers are needed to identify those patients most likely to respond to specific treatments. Through prospective genomic profiling of 459 consecutive primary treatment-naïve IDH-wildtype glioblastomas in adults, we identified a unique subgroup (2%, 9/459) defined by somatic hypermutation and DNA replication repair deficiency due to biallelic inactivation of a canonical mismatch repair gene. The deleterious mutations in mismatch repair genes were often present in the germline in the heterozygous state with somatic inactivation of the remaining allele, consistent with glioblastomas arising due to underlying Lynch syndrome. A subset of tumors had accompanying proofreading domain mutations in the DNA polymerase POLE and resultant "ultrahypermutation". The median age at diagnosis was 50 years (range 27-78), compared with 63 years for the other 450 patients with conventional glioblastoma (p

BackgroundThe TERT promoter mutation (TPM) is acquired in most IDH-wildtype glioblastomas (GBM) and IDH-mutant oligodendrogliomas (OD) enabling tumor cell immortality. Previous studies on TPM clonality show conflicting results. This study was performed to determine whether TPM is clonal on a tumor-wide scale.MethodsWe investigated TPM clonality in relation to presumed early events in 19 IDH-wildtype GBM and 10 IDH-mutant OD using 3-dimensional comprehensive tumor sampling. We performed Sanger sequencing on 264 tumor samples and deep amplicon sequencing on 187 tumor samples. We obtained tumor purity and copy number estimates from whole exome sequencing. TERT expression was assessed by RNA-seq and RNAscope.ResultsWe detected TPM in 100% of tumor samples with quantifiable tumor purity (219 samples). Variant allele frequencies (VAF) of TPM correlate positively with chromosome 10 loss in GBM (R = 0.85), IDH1 mutation in OD (R = 0.87), and with tumor purity (R = 0.91 for GBM; R = 0.90 for OD). In comparison, oncogene amplification was tumor-wide for MDM4- and most EGFR-amplified cases but heterogeneous for MYCN and PDGFRA, and strikingly high in low-purity samples. TPM VAF was moderately correlated with TERT expression (R = 0.52 for GBM; R = 0.65 for OD). TERT expression was detected in a subset of cells, solely in TPM-positive samples, including samples equivocal for tumor.ConclusionsOn a tumor-wide scale, TPM is among the earliest events in glioma evolution. Intercellular heterogeneity of TERT expression, however, suggests dynamic regulation during tumor growth. TERT expression may be a tumor cell-specific biomarker.

Glioma is a highly fatal and heterogeneous brain tumor with few known risk factors. Our study examines genetically predicted variability in blood cell indices in relation to glioma risk and survival in 3418 cases and 8156 controls. We find that increased platelet to lymphocyte ratio (PLR) confers an increased risk of glioma (odds ratio (OR) = 1.25, p = 0.005), especially tumors with isocitrate dehydrogenase (IDH) mutations (OR = 1.38, p = 0.007) and IDHmut 1p/19q intact (IDHmut-intact OR = 1.53, p = 0.004) tumors. Genetically inferred increased counts of lymphocytes (IDHmut-intact OR = 0.70, p = 0.004) and neutrophils (IDHmut OR = 0.69, p = 0.019; IDHmut-intact OR = 0.60, p = 0.009) show inverse associations with risk, which may reflect enhanced immune-surveillance. Considering survival, we observe higher mortality risk in patients with IDHmut 1p/19q with genetically predicted increased counts of lymphocytes (hazard ratio (HR) = 1.65, 95% CI: 1.24–2.20), neutrophils (HR = 1.49, 1.13–1.97), and eosinophils (HR = 1.59, 1.18–2.14). Polygenic scores for blood cell traits are also differentially associated with 17 tumor immune microenvironment features in a subtype-specific manner, including signatures related to interferon signaling, PD-1 expression, and T-cell/Cytotoxic responses. Our findings highlight immune-mediated susceptibility mechanisms with potential disease management implications. Glioma is an aggressive brain tumor subtype with few known risk factors. Here, the authors utilise Mendelian Randomisation to investigate correlation of immune cell counts with subtype-specific risk and mortality in glioma patients. [ABSTRACT FROM AUTHOR]

Introduction: Precision medicine refers to managing brain tumors according to each patient's unique characteristics when it was realized that patients with the same type of tumor differ greatly in terms of survival, responsiveness to treatment, and toxicity of medication. Precision diagnostics can now be advanced through the establishment of imaging biomarkers, which necessitates quantitative image acquisition and processing. The VASARI (Visually AcceSAble Rembrandt Images) manual annotation methodology is an ideal and suitable way to determine the accurate association between genotype and imaging phenotype. Our work proposes an updated version of the VASARI score that is derived by changing the evaluation ranges of its components in an effort to increase the diagnostic accuracy of the VASARI manual annotation system and to find neuroimaging biomarkers in neuro-oncology with increasing reliability. Materials and methods: We gathered the histological grade and molecular status of 126 patients with glioma (Men/Women = 75/51; mean age: 55.30) by a retrospective analysis. Two residents and three neuroradiologists blindedly examined each patient using all 25 VASARI characteristics, after having appropriately modified the reference ranges in order to implement an innovative VASARI lexicon (VASARI 2.0). It was determined how well the observers agreed. A box plot and a bar plot were used in a statistical analysis to assess the distribution of the observations. After that, we ran a Wald test and univariate and multivariate logistic regressions. To find cutoff values that are predictive of a diagnosis, we also computed the odds ratios, confidence intervals, and evaluation matrices using receiver operating characteristic curves for each variable. Finally, we performed a Pearson correlation test to evaluate whether the variable grades and IDH were correlated. Results: An excellent Intraclass Correlation Coefficient (ICC) estimate was obtained. In this study, five features were part of the predictive model for determining glioma grade: F4, enhancement quality [area under the curve (AUC): 0.87]; F5, tumor-enhancing proportion (AUC: 0.70); F6, tumor–non-enhancing proportion (AUC: 0.89); F7, necrosis proportion (AUC: 0.79); and F17, diffusion characteristics (AUC: 0.75). Furthermore, six features were found to predict IDH mutation status: F4, enhancement quality (AUC: 0.904); F5, tumor-enhancing proportion (AUC: 0.73); F6, tumor–non-enhancing proportion (AUC: 0.91); F7, necrosis proportion (AUC: 0.84); F14, proportion of edema (AUC: 0.75); and diffusion characteristics F17 (AUC: 0.79). VASARI 2.0 models showed good performances according to the AUC values, which are also compared with traditional VASARI scores. Discussion and conclusion: Glioma grade and isocitrate dehydrogenase (IDH) status can be predicted using specific magnetic resonance imaging (MRI) features, which have significant prognostic consequences. The accuracy of texture-derived metrics from preoperative MRI gliomas and machine learning analysis for predicting grade, IDH status, and their correlation can be enhanced by the suggested new and updated VASARI manual annotation system. To help with therapy selection and enhance patient care, we intend to create prediction models that incorporate these MRI findings with additional clinical data. [ABSTRACT FROM AUTHOR]

PURPOSE: Biliary tract cancers (BTCs) include intrahepatic cholangiocarcinoma (ICC), extrahepatic cholangiocarcinoma (ECC), and gallbladder cancers. BTCs have a number of genomic alterations, including isocitrate dehydrogenase 1 (IDH1) mutations, fibroblast growth factor receptor 2 (FGFR2) rearrangements, and ERBB2 amplifications. Therapies targeting these alterations have shown clinical benefit in patients with BTCs in the United States. However, molecular differences between races in BTCs are largely unknown. In particular, the genomic profiles of African American (AA) patients with BTCs have been infrequently reported. We sought to identify key genomic differences between AA and Caucasian patients with BTCs in the United States in the Foundation Medicine and American Association for Cancer Research (AACR) GENIE databases. METHODS: BTC patients from AA and Caucasian patients from the Foundation Medicine and AACR GENIE databases were retrospectively reviewed. BTCs were divided into ICC, ECC, and GBCs in the Foundation Medicine database. BTCs were divided into cholangiocarcinomas and GBCs in the AACR GENIE database. RESULTS: The mean age of AA patients with BTCs was lower compared with Caucasians. TP53 and FGFR2 alterations were significantly more frequent in AA patients compared with Caucasian patients with BTCs. IDH1 mutations in Caucasian patients with BTCs were double that of AA patients. CONCLUSION: The results of this study suggest that significant genomic differences exist between races and warrant further investigation. [ABSTRACT FROM AUTHOR]

Purpose: While [18F]FET PET plays a complementary role in glioma imaging, it needs to be more comprehensively understood for improved characterization of glioma prior to surgery given the evolving landscape of molecular neuropathology. Thus, we investigated the utility of pre-operative dual-time-point [18F]FET PET in correlation with next-generation sequencing (NGS) data in patients with adult-type diffuse glioma (ADG). Methods: Adult patients who were suspected to have primary glioma were prospectively recruited between June 2021 and January 2024. They underwent pre-operative dual-time-point static PET/CT at 20 min (early) and 80 min (delay) after [18F]FET injection. Semi-quantitative parameters of the hottest lesion (SUVmax) of tumour and the hottest lesion-to-normal brain ratio (TBRmax) were assessed from each summed image. Furthermore, the percentage changes (△) of SUVmax and TBRmax between two images were calculated. Histopathology of glioma was determined according to the 2021 WHO classification and NGS data. Results: This study investigated a dozen genes in 76 patients, of whom 51 had isocitrate dehydrogenase (IDH)-wild-type glioblastoma, 13 had IDH-mutant astrocytoma, and 12 had IDH-mutant oligodendroglioma. Every tumour was [18F]FET-avid having TBRmax more than 1.6. Patients with CDKN2A/B loss had significantly higher values of SUVmax (5.7 ± 1.6 vs. 4.7 ± 1.3, p = 0.004; 5.0 ± 1.4 vs. 4.4 ± 1.2, p = 0.026) and TBRmax (6.5 ± 1.8 vs. 5.1 ± 1.7, p = 0.001; 5.3 ± 1.5 vs. 4.3 ± 1.3, p = 0.004) in both scans than patients without CDKN2A/B loss, even after adjustment for age, MRI enhancement, tumor grade and type of pathology. Furthermore, patients with PIK3CA mutation (16.2 ± 11.8 vs. 6.7 ± 11.6, p = 0.007) had significantly higher △SUVmax than patients without PIK3CA mutation, even after adjustment for age, MRI enhancement, tumor grade, and type of pathology. Conclusion: Among the dozen genes investigated in this prospective study in patients with ADG, we found out that CDKN2A/B loss and PIK3CA mutation status could be differentiated by pre-operative dual-time-point [18F]FET PET/CT. [ABSTRACT FROM AUTHOR]

Glioma is characterized by high heterogeneity and poor prognosis. Attempts have been made to understand its diversity in both genetic expressions and radiomic characteristics, while few integrated the two omics in predicting survival of glioma. This study was intended to investigate the connection between glioma imaging and genome, and examine its predictive value in glioma mortality risk and tumor immune microenvironment (TIME). Clinical, transcriptomics and radiomics data were obtained from public datasets and patients in our center. Correlation analysis between gene expression and radiomic feature (RF) was performed, followed by survival analysis to select RF-related genes (RFRGs) and gene expression-related RFs (GRRFs). After that, RFRGs and GRRFs were used to construct mortality risk prediction model of all glioma and isocitrate dehydrogenase (IDH) wild type (WT) glioma. The association between RFRGs and TIME was explored. Six cohorts composed of 1,754 glioma patients were included. Thirty-five genes and eighty-two RFs demonstrated high correlation with each other. Gene score based on RFRGs was independent predictor of both glioma (P < 0.05) and IDH-WT glioma (P < 0.05). Same score based on GRRFs was also able to stratify risk of both glioma (P < 0.0001) and IDH-WT glioma (P < 0.0001), with nomograms constructed separately. The TIME of gliomas predicted with RFRGs' score found mismatched risk of death with immune response. RFRGs and GRRFs were able to predict glioma mortality risk and TIME. Further studies could validate our results and explore this genome-imaging interactions. [ABSTRACT FROM AUTHOR]

Context: Central nervous system tumors are a major cause of morbidity and mortality worldwide. The most prevalent type of primary brain tumor is glioma. The exploration of significant genetic, epigenetic, and transcriptional abnormalities has not only improved our understanding of glioma pathogenesis but has also revealed that these molecular alterations can serve as useful diagnostic markers for more precise classification and are linked to better treatment response and prognosis. Hence, incorporating molecular markers into routine tumor classification is a major priority in modern glioma diagnostics. Aim: The aim is to assess the mutation status of isocitrate dehydrogenase (IDH)-1, alpha-thalassemia/mental retardation syndrome X-linked (ATRX), and tumor protein 53 in glioma, and look for their association with various clinicopathological features. Methodology: A single-center prospective cohort study, where all biopsies of glioma (January 2019 to July 2020) were evaluated, and immunohistochemistry was performed to assess the expression of IDH-1, ATRX, p53, and Ki-67 index. The data were analyzed using IBM SPSS-24 software. Results: Immunohistochemistry was performed in 123 consecutive cases of glioma. IDH-1 mutation was noted in 54 (43.9%) cases and these patients frequently presented with "seizures" (P = 0.006). The expression was maximum in World Health Organization (WHO) grade 2 tumors (65.4%) (P < 0.001), with the highest frequency in oligodendrogliomas (100% in WHO grade 2 and 3). Furthermore, these tumors showed lower proliferative indices (P = 0.001). ATRX mutation was noted in 59 (48%) and p53 overexpression was noted in 76 (61.8%) cases. These mutations were significantly associated with astrocytic phenotype (P = 0.03). Conclusions: Molecular characterization of glioma is an important step in modern glioma diagnostics and immunohistochemistry can play an important role. IDH-1 mutation is commonly observed in adults, frontal lobe location, patients presenting with seizures, and WHO grade 2 tumors with the highest frequencies in oligodendrogliomas. ATRX and p53 can be used as surrogate markers for tumors of astrocytic lineage. [ABSTRACT FROM AUTHOR]

In this study, the effects of calcium levels on structure and function of mitochondria under high glucose environment were studied. In the high glucose environment, yeast growth capacity was inhibited, and intracellular reactive oxygen species (ROS) content was increased from 6 h to 12 h, while ROS content was reduced in group with 1 × 10−1 and 1 g/L CaCl2 level from 24 h to 36 h. Exogenous calcium addition had a significant effect on the elevation of intracellular Ca2+ and cytochrome C content in yeast from 6 h to 12 h; mitochondrial membrane potential decreased with the increase of CaCl2 level under high glucose levels. Mitochondrial swelling of yeast was influenced by high glucose levels and showed a regulatory dynamic change by Ca2+ levels. Isocitrate dehydrogenase activity increased in 1 × 10−3 g/L CaCl2 level from 6 h to 12 h, α-ketoglutarate dehydrogenase activity increased with an increase in CaCl2 level from 6 h to 24 h. Calcium affected the structure and function of mitochondria by regulating the intracellular signal, enzymes in tricarboxylic acid cycle, and cytochrome system of yeast under high glucose stress. [ABSTRACT FROM AUTHOR]

Enriched iron metabolic features such as high transferrin receptor (TfR) expression and high iron content are commonly observed in aggressive gliomas and can be associated with poor clinical responses. However, the underlying question of how iron contributes to tumor aggression remains elusive. Gliomas harboring isocitrate dehydrogenase (IDH) mutations account for a high percentage (>70 %) of recurrent tumors and cells with an acquired IDH mutation have been reported to have increased motility and invasion. This study aims to investigate how an acquired IDH mutation modulates iron metabolism and the implication(s) of iron on tumor cell growth. IDH mutant cells (U87R132H) grow significantly faster which is accompanied with increased TfR expression and iron uptake in vitro compared to wild-type U87 cells. This phenotype is retained in vivo. Biomechanically, U87R132H cells are significantly less stiff and supplementation with ferrous ammonium sulfate (Fe2+) augments membrane fluidity to drive U87R132H cells into a super motile state. These findings provide insight into how an acquired IDH mutation may be able to modulate iron metabolism, allowing iron to serve as a biomechanical driver of tumor progression. [Display omitted] • Isocitrate dehydrogenase (IDH)-mutant glioma preferentially accumulate iron. • IDH-mutant glioma exhibit iron-dependent growth. • Iron modulates IDH-mutant glioma membrane fluidity to promote tumor cell motility. [ABSTRACT FROM AUTHOR]

Background Purpose Methods Results Conclusion Quantitative blood oxygenation level–dependent (qBOLD) technique can be applied to detect tissue damage and changes in hemodynamic in gliomas. It is not known whether qBOLD‐based radiomics approaches can improve the prediction of isocitrate dehydrogenase‐1 (IDH‐1) mutation.To establish a qBOLD‐based clinical radiomics‐integrated model for predicting IDH‐1 mutation in gliomas.A total of 125 patients of grade II–IV glioma (IDH1 mutation: IDH1 wild‐type = 50:75) were divided into a training group (n = 87) and a validation group (n = 38). Contrast enhanced T1‐weighted (CE‐T1W), T2‐weighted (T2W), and 3D multi‐gradient‐recalled‐echo (MGRE) images were acquired. Radiomics features were extracted from the region of interests of each image. The feature selection and support vector machine radiomics models were established for each sequence. A clinical radiomics–integrated model was finally constructed combining the best radiomics model with age. The predictive effectiveness of the models was evaluated by area under the receiver operating characteristic curve (AUC). Brier score was used to assess overall predictive performance. Decision curve analysis and calibration curve were also conducted.The best radiomics model was CE‐T1W + T2W + qBOLD with AUCs of 0.823 (95% confidence interval [CI]: 0.743–0.831) in the training group and 0.751 (95% CI: 0.655–0.794) in the validation group, respectively. The clinical radiomics–integrated model, incorporating the best radiomics model with age, showed the best predictive effectiveness with AUCs of 0.851 (95% CI 0.759–0.918) in the training group and 0.786 (95% CI 0.622–0.902) in the validation group.A clinical radiomics‐integrated model that combined qBOLD parametric maps, CE‐T1W, and T2W images with age achieved promising performance for predicting IDH1 mutation in glioma patients. [ABSTRACT FROM AUTHOR]

Breast cancer, one of the most prevalent malignant tumors in women worldwide, is characterized by a poor prognosis and high susceptibility to recurrence and metastasis. Ferroptosis, a lipid peroxide–dependent programed cell death pathway, holds significant potential for breast cancer treatment. Therefore, investigating the regulatory targets and associated mechanisms of ferroptosis is crucial. In this study, we conducted proteomic screening and identified isocitrate dehydrogenase 2 (IDH2) as an important player in breast cancer progression. Our findings were further supported by CCK‐8 assays, transwell experiments, and scratch assays, which demonstrated that the elevated expression of IDH2 promotes breast cancer progression. Through both in vitro and in vivo experiments along with the erastin treatment, we discovered that increased expression of IDH2 confers resistance to ferroptosis in breast cancer cells. By employing Western blot analysis, Co‐IP techniques, and immunofluorescence staining methods, we elucidated the upstream molecular mechanism involving SENP1‐mediated SIRT3 de‐SUMOylatase, which enhances IDH2 enzyme activity through deacetylation, thereby regulating cell ferroptosis. In conclusion, our study highlights the role of the SENP1‐SIRT3 axis in modulating ferroptosis via IDH2 in breast cancer cells, providing valuable insights for developing targeted therapies aimed at enhancing ferroptosis for improved management of breast cancer. [ABSTRACT FROM AUTHOR]

Background: Giant cell (gc)-enriched glioblastoma (gcGB) represents a distinct histological variant of isocitrate dehydrogenase wild-type adult-type glioblastoma with notable enlarged mono- or multinuclear tumor cells. While some studies suggest a survival advantage for gcGB patients, the underlying causes remain elusive. GcGBs are associated with TP53 mutations, and gcs were shown to accumulate DNA double-strand breaks and show deficient mitosis, potentially triggering cellular senescence programs. Epigenetic clocks have emerged as valuable tools for assessing tumor-induced age acceleration (DNAMethAgeAcc), which has lately proved itself as prognostic biomarker in glioblastoma. Our study aimed to comprehensively analyze the methylome and key metabolic proteins of gcGBs, hypothesizing that they undergo cellular aging programs compared to non-gcGBs. Results: A total of 310 epigenetically classified GBs, including 26 gcGBs, and nine adults with malignant gliomas allocating to pediatric high-grade glioma molecular subclasses (summarized as "pediatric GB") were included. DNAMethAgeAcc was computed by subtraction of chronological patient ages from DNA methylome-derived age estimations and its increase was associated with better survival within gcGB and non-gcGB. GcGBs were significantly more often allocated to the subgroup with increased DNAMethAgeAcc and demonstrated the highest DNAMethAgeAcc. Hypothetical senescence/aging-induced changes of the tumor microenvironment were addressed by tumor deconvolution, which was able to identify a cluster enriched for tumors with increased DNAMethAgeAcc. Key metabolic protein expression did not differ between gcGB and non-gcGB and tumor with versus without increased DNAMethAgeAcc but for elevated levels of one single mitochondrial marker, anti-mitochondrial protein MT-C02, in gcGBs. Conclusions: With its sped-up epigenetic aging, gcGB presented as the epigenetic oldest GB variant in our cohort. Whereas the correlation between accelerated tumor-intrinsic epigenetic aging and cellular senescence in gcGB stays elusive, fostering epigenetic aging programs in GB might be of interest for future exploration of alternative treatment options in GB patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Glioblastoma is an aggressive and hard-to-treat brain cancer, with poor prognosis worldwide. The relationship between biological variation in different regions of each glioblastoma, including that of the residual infiltrative disease spared by standard treatment, is poorly understood. We summarize the current understanding of glioblastoma intra-tumour variation and consider antibiotic resistance as a helpful analogy for further insight. Isocitrate dehydrogenase wild-type glioblastoma, a Grade 4 malignant brain neoplasm, remains resistant to multimodal treatment, with a median survival of 16 months from diagnosis with no geographical bias. Despite increasing appreciation of intra-tumour genotypic variation and stem cell plasticity, such knowledge has yet to translate to efficacious molecular targeted therapies in this post-genomic era. Critically, the manifestation of molecular heterogeneity and stem cell biological process within clinically relevant infiltrative disease is little understood. Here, we review the interactions between neural plasticity, intra-tumour heterogeneity and residual infiltrative disease, and we draw upon antibiotic resistance as an insightful analogy to further explain tumour heterogeneity. [ABSTRACT FROM AUTHOR]

The 2021 World Health Organization (WHO) classification of the central nervous system (CNS) tumors has classified diffuse leptomeningeal glioneuronal tumor (DLGNT) as a mixed neuronal and glial tumor. Here, we report a DLGNT with two distinct morphological tumor components but identical molecular features. A four‐year‐old female child presented with progressive right upper extremity weakness. Magnetic resonance imaging (MRI) revealed the leptomeningeal enhancement over the brain stem and cervicothoracic spine. The histological examination of surgical specimens revealed two distinct tumor components: approximately half of the tumor is composed of oligodendroglioma‐like tumor intermingled with nodules of ganglioglioma‐like tumor. Immunohistochemistry confirmed the oligodendroglioma and ganglioglioma features. The molecular genetic studies demonstrated the features of DLGNT, including fusion of KIAA1549::BRAF, deletion of chromosome 1p, and absence of isocitrate dehydrogenase 1/2 (IDH1/2) mutation in both tumor components. Interestingly, the genetic studies also revealed the distinct chromosomal abnormalities of the loss of chromosome 4 only in oligodendroglioma‐like tumor and copy neutral loss of heterozygosity of 7Q34Q36.3 in the ganglioglioma‐like tumor component. This case highlights the critical role of molecular testing in the diagnosis of rare cases of DLGNT with diverse morphological components as well as in the identification of unique molecular alternations responsible for morphological phenotypes of the distinct tumors in DLGNT. [ABSTRACT FROM AUTHOR]

Introduction: Radiotherapy-related damage of normal tissue inevitably influences the treatment outcomes in the context of high-grade gliomas (HGGs) treatment. We reported the survival outcomes and toxicities of patients with HGG treated with helical tomotherapy (HT) and the prognostic factors were analyzed. Materials and methods: A total of 67 patients (29 had grade III and 38 had grade IV HGGs) who received HT between January 2016 and June 2020 were analyzed. Overall survival (OS) and progression-free survival (PFS) from the beginning of HT and OS from surgery were assessed, and toxicity and disease control were described briefly. Results: For patients with grade III HGGs, median OS (mOS) and median PFS (mPFS) from the beginning of HT were 68.933 and 62.967 months, respectively. For patients with grade IV HGGs, mOS and mPFS from the beginning of HT were 19.667 and 7.23 months, respectively. No grade ≥3 acute or late nonhematologic toxicities were observed. Multivariable Cox regression analysis showed that methylguanine methyltransferase (MGMT) methylated status, age, number of lesions, WHO grade, and monocyte count for PFS were significant. Age, monocyte count, and isocitrate dehydrogenase (IDH) status for OS. Conclusion: Treatment of HGGs with HT appears to be potentially effective and safe. HT is promising for glioblastomas (GBM), especially complex cases with infratentorial involvement or multiple lesions. This study highlighted the potential clinical significance of systemic inflammation indicators in predicting survival and disease progression. [ABSTRACT FROM AUTHOR]

Pembrolizumab leads to a durable response in ultra-hypermutated, high-grade, glioma. [ABSTRACT FROM AUTHOR]

Isocitrate dehydrogenase 1 (IDH1) is a metabolic enzyme that converts isocitrate to α-ketoglutarate in cells. However, research on IDH1 is more focused on the metabolite D-2-hydroxyglutarate than the cellular roles of the IDH1 protein. Metabolic enzymes can moonlight by participating in diverse cellular processes in cancer cells. This moonlighting function of the metabolic enzymes can contribute to changes in gene expression. It is unknown whether IDH1 associates with any transcription factor. We asked whether IDH1 coordinates with forkhead box protein M1 (FOXM1) in mitotic cells to regulate late genes expression. We found that depletion of IDH1 reduces canonical FOXM1-target expression in mitotic cells. Also, IDH1 binds to FOXM1 and a subset of MuvB proteins, Lin-9 and Lin-54, in mitotic cells. Based on these observations, we suggest that IDH1 coordinates with FOXM1 in mitotic cells to regulate late genes expression. [ABSTRACT FROM AUTHOR]

Since the overall glioma mass and its subcomponents—enhancing region (malignant part of the tumor), non‐enhancing (less aggressive tumor cells), necrotic core (dead cells), and edema (water deposition)—are complex and irregular structures, non‐Euclidean geometric measures such as fractal dimension (FD or "fractality") and lacunarity are needed to quantify their structural complexity. Fractality measures the extent of structural irregularity, while lacunarity measures the spatial distribution or gaps. The complex geometric patterns of the glioma subcomponents may be closely associated with the grade and molecular landscape. Therefore, we measured FD and lacunarity in the glioma subcomponents and developed machine learning models to discriminate between tumor grades and isocitrate dehydrogenase (IDH) gene status. 3D fractal dimension (FD3D) and lacunarity (Lac3D) were measured for the enhancing, non‐enhancing plus necrotic core, and edema‐subcomponents using preoperative structural‐MRI obtained from the The Cancer Genome Atlas (TCGA) and University of California San Francisco Preoperative Diffuse Glioma MRI (UCSF‐PDGM) glioma cohorts. The FD3D and Lac3D measures of the tumor‐subcomponents were then compared across glioma grades (HGGs: high‐grade gliomas vs. LGGs: low‐grade gliomas) and IDH status (mutant vs. wild type). Using these measures, machine learning platforms discriminative of glioma grade and IDH status were developed. Kaplan–Meier survival analysis was used to assess the prognostic significance of FD3D and Lac3D measurements. HGG exhibited significantly higher fractality and lower lacunarity in the enhancing subcomponent, along with lower fractality in the non‐enhancing subcomponent compared to LGG. This suggests that a highly irregular and complex geometry in the enhancing‐subcomponent is a characteristic feature of HGGs. A comparison of FD3D and Lac3D between IDH‐wild type and IDH‐mutant gliomas revealed that mutant gliomas had ~2.5‐fold lower FD3D in the enhancing‐subcomponent and higher FD3D with lower Lac3D in the non‐enhancing subcomponent, indicating a less complex and smooth enhancing subcomponent, and a more continuous non‐enhancing subcomponent as features of IDH‐mutant gliomas. Supervised ML models using FD3D from both the enhancing and non‐enhancing subcomponents together demonstrated high‐sensitivity in discriminating glioma grades (~97.9%) and IDH status (~94.4%). A combined fractal estimation of the enhancing and non‐enhancing subcomponents using MR images could serve as a non‐invasive, precise, and quantitative measure for discriminating glioma grade and IDH status. The combination of 2‐hydroxyglutarate‐magnetic resonance spectroscopy (2HG‐MRS) with FD3D and Lac3D quantification may be established as a robust imaging signature for glioma subtyping. [ABSTRACT FROM AUTHOR]

Research on the waterlogging tolerance mechanisms of Paeonia ostii helps us to further understand these mechanisms in the root system and enhance its root bark and oil yields in southern China. In this study, root morphological identification, the statistics of nine physiological and biochemical indicators, and a comparative transcriptome analysis were used to investigate the waterlogging tolerance mechanism in this plant. As flooding continued, the roots' vigor dramatically declined from 6 to 168 h of waterlogging, the root number was extremely reduced by up to 95%, and the number of roots was not restored after 96 h of recovery. Seven of the nine physiological indicators, including leaf transpiration and photosynthetic rate, stomatal conductance, root activity, and soluble protein and sugar, showed similar trends of gradually declining waterlogging stress and gradual waterlogging recovery, with little difference. However, the leaf conductivity and super oxide dismutase (SOD) activity gradually increased during flooding recovery and decreased in recovery. The tricarboxylic acid (TCA) cycle is essential for plants to grow and survive and plays a central role in the breakdown, or catabolism, of organic fuel molecules, also playing an important biological role in waterlogging stress. In total, 591 potential candidate genes were identified, and 13 particular genes (e.g., isocitrate dehydrogenase (IDH), malate dehydrogenase (MDH), ATP citrate lyase (ACLY), succinate dehydrogenase (SDH), and fumarase (FumA)) in the TCA cycle were also tested using qPCR. This study identifies potential candidate genes and provides theoretical support for the breeding, genetic improvement, and enhancement of the root bark yields of P. ostii, supporting an in-depth understanding of the plant's physiological and molecular response mechanisms to waterlogging stress, helping future research and practice improve plant waterlogging tolerance and promote plant growth and development. [ABSTRACT FROM AUTHOR]

Background and objectives: Isocitrate dehydrogenase (IDH) inhibitor drugs (Enasidenib, Ivosidenib) restore normal metabolism and epigenetic regulation in cells, offering a precision-targeted therapeutic option for acute myeloid leukemia (AML) patients with IDH mutations by specifically inhibiting mutated IDH enzymes. This research evaluates the relationship between adverse drug reactions (ADR) and the use of two isocitrate dehydrogenase inhibitors by using the database from the World Health Organization (WHO) VigiAccess and compares the characteristics of ADRs of the two drugs. Methods: This study design used the retrospective descriptive analysis. We calculated the ratio of ADRs recorded in reports to compare the same points and different points in ADRs between two medications. Proportional reporting ratio (PRR) and reported odds ratio were used to evaluate the relationship between these two isocitrate dehydrogenase inhibitor medications and adverse events. Results: Overall, during the search, 4,072 adverse events related to two types of isocitrate dehydrogenase inhibitors were reported in VigiAccess. The results revealed that the top 10 most common AEs were off label use, death, fatigue, nausea, diarrhea, acute myeloid leukemia, drug ineffective, differentiation syndrome, platelet count decreased and decreased appetite. Compared two drugs, enasidinib had the highest adverse reaction reporting rate in general disorders and administration site conditions while ivosidenib had the highest adverse drug reactions reporting rate in injury, poisoning and procedural complications. Conclusion: Based on the current comparative observational studies, the ADR reports received by the World Health Organization, Food and Drug Administration for these drugs list common and specific adverse drug reactions. Clinical doctors should develop individualized treatment plans based on the adverse reactions of different drugs and the specific conditions of patients to promote the rational use of these expensive medications. [ABSTRACT FROM AUTHOR]

Objective Methods Results Interpretation To differentiate glioma grading and determine isocitrate dehydrogenase (IDH) mutation status, which are crucial for prognosis assessment and treatment planning in glioma patients.This retrospective study included patients diagnosed with adult diffuse glioma from 1 January, 2018 to 31 July, 2023 in two independent institutions. It documented and analysed clinical and radiographic features. A nomogram model was constructed using stepwise regression to predict lower‐grade gliomas and IDH mutation status.A total of 383 adult patients with diffuse glioma were included in the study, with Cohort A (297 patients) serving as the training set and Cohort B (86 patients) serving as the validation cohort. Consistent with previous reports, the Hyper fluid‐attenuated inversion recovery (FLAIR) rim sign exhibited higher sensitivity in lower‐grade gliomas for IDH mutant gliomas compared with the T2‐FLAIR mismatch sign. However, the Hyper FLAIR rim sign was also present in Grade 4 gliomas, and thus, the T2‐FLAIR mismatch sign exhibited better clinical efficacy in predicting glioma grade and IDH mutation compared with the Hyper FLAIR rim sign in clinical applications. Meanwhile, preoperative magnetic resonance spectroscopy (MRS) indicators, particularly the Cho/Cr ratio, have shown excellent performance in predicting glioma grade and IDH mutation status. The nomogram developed through stepwise regression demonstrated excellent predictive capabilities in distinguishing glioma grade and IDH mutation status.Combining imaging and molecular features, the predictive model established in this study offers a reliable non‐invasive tool for predicting glioma grading and IDH mutation status, aiding the clinical decision‐making process and improving patient management. [ABSTRACT FROM AUTHOR]

Isocitrate dehydrogenase 2 (IDH2) and glutamate dehydrogenase 1 (GLUD1) are key enzymes involved in the production of α-ketoglutarate (α-KG), a metabolite central to the tricarboxylic acid cycle and glutamine metabolism. In this study, we investigated the impact of IDH2 and GLUD1 on early porcine embryonic development following IDH2 and GLUD1 knockdown (KD) via double-stranded RNA (dsRNA) microinjection. Results showed that KD reduced α-KG levels, leading to delayed embryonic development, decreased blastocyst formation, increased apoptosis, reduced blastomere proliferation, and pluripotency. Additionally, IDH2 and GLUD1 KD induced abnormally high levels of trimethylation of lysine 20 of histone H4 (H4K20me3) at the 4-cell stage, likely resulting in transcriptional repression of embryonic genome activation (EGA)-related genes. Notably, KD of lysine methyltransferase 5C (KMT5C) and supplementation with exogenous α-KG reduced H4K20me3 expression and partially rescued these defects, suggesting a critical role of IDH2 and GLUD1 in the epigenetic regulation and proper development of porcine embryos. Overall, this study highlights the significance of IDH2 and GLUD1 in maintaining normal embryonic development through their influence on α-KG production and subsequent epigenetic modifications. [ABSTRACT FROM AUTHOR]

Isocitrate dehydrogenase (IDH) and O6-methylguanine-DNA methyltransferase (MGMT) genes are critical molecular markers in determining treatment options and predicting the prognosis of adult-type diffuse gliomas. Objectives: this study aimed to investigate whether multimodal MRI enables the differentiation of genotypes in adult-type diffuse gliomas. Methods: a total of 116 adult-type diffuse glioma patients (61 males, 51.5 (37, 62) years old) who underwent multimodal MRI before surgery were retrospectively analysed. Multimodal MRI included conventional MRI, proton magnetic resonance spectroscopy (1H-MRS), and diffusion tensor imaging (DTI). Conventional visual features, N-acetyl-aspartate (NAA)/Creatine (Cr), Choline (Cho)/Cr, Cho/NAA, fractional anisotropy (FA), mean diffusivity (MD), and diffusion histogram parameters were extracted on the whole tumour. Multimodal MRI parameters of IDH-mutant and IDH-wildtype gliomas were compared using the Mann–Whitney U test, Student's t-test, or Pearson chi-square tests. Logistic regression was used to select the MRI parameters to predict IDH-mutant gliomas. Furthermore, multimodal MRI parameters were selected to establish models for predicting MGMT methylation in the IDH-wildtype gliomas. The performance of models was evaluated by the receiver operating characteristics curve. Results: a total of 56 patients with IDH-mutant gliomas and 60 patients with IDH-wildtype glioblastomas (GBM) (37 with methylated MGMT and 17 with unmethylated MGMT) were diagnosed by 2021 WHO classification criteria. The enhancement degree (OR = 4.298, p < 0.001), necrosis/cyst (OR = 5.381, p = 0.011), NAA/Cr (OR = 0.497, p = 0.037), FA-Skewness (OR = 0.497, p = 0.033), MD-Skewness (OR = 1.849, p = 0.035), FAmean (OR = 1.924, p = 0.049) were independent factors for the multimodal combined prediction model in predicting IDH-mutant gliomas. The combined modal based on conventional MRI, 1H-MRS, DTI parameters, and histogram performed best in predicting IDH-wildtype status (AUC = 0.890). However, only NAA/Cr (OR = 0.17, p = 0.043) and FA (OR = 0.38, p = 0.015) were associated with MGMT methylated in IDH-wildtype GBM. The combination of NAA/Cr and FA-Median is more accurate for predicting MGMT methylation levels than using these elements alone (AUC, 0.847 vs. 0.695/0.684). Conclusions: multimodal MRI based on conventional MRI, 1H-MRS, and DTI can provide compound imaging markers for stratified individual diagnosis of IDH mutant and MGMT promoter methylation in adult-type diffuse gliomas. [ABSTRACT FROM AUTHOR]

A new aromatic polyketide, alternaphenol B2 (1), and four known compounds (2–5) were isolated from the coral-derived fungus Parengyodontium album SCSIO SX7W11. Their structures were elucidated by high-resolution mass spectrometry, 1D and 2D NMR spectroscopy and comparison with reported literatures. Compounds 1 and 2 exhibited selective inhibitory activity against isocitrate dehydrogenase mutant R132H (IDH1m), with IC50 values of 41.9 and 27.7 μM, respectively. Our findings thus provide a fresh incentive for investigation on IDH1m inhibitors as lead compounds for cancer treatment. [ABSTRACT FROM AUTHOR]

Aerobic respiration is the key driver of Vibrio cholerae proliferation and infection. Our previous transcriptome results suggested that degS knockout downregulates a few genes involved in NADH and ATP synthesis in the aerobic respiratory pathway. In this study, non-targeted metabolomics results showed that the differential metabolites affected by degS knockout were associated with aerobic respiration. Further results suggested that the key products of aerobic respiration, NADH and ATP, were reduced upon degS deletion and were not dependent on the classical σE pathway. The two-component system response factor aerobic respiration control A (ArcA) is involved in regulating NADH and ATP levels. qRT-PCR demonstrated that DegS negatively regulates the transcription of the arcA gene, which negatively regulates the expression of isocitrate dehydrogenase (ICDH), a key rate-limiting enzyme of the tricarboxylic acid cycle. NADH and ATP levels were partially restored with the knockout of the arcA gene in the ΔdegS strain, while levels were partially restored with overexpression of ICDH in the ΔdegS strain. In a growth experiment, compared to the ΔdegS strain, the growth rates of ΔdegSΔarcA and ΔdegS -overexpressed icdh strains (ΔdegS+icdh) were partially restored during the logarithmic growth period. Colonization of the intestines of suckling mice showed a significant reduction in the colonizing ability of the ΔdegS strain, similar colonizing ability of the ΔdegS::degS strain and the wild-type strain, and a partial recovery of the colonizing ability of the ΔdegS + icdh strain. Overall, these findings suggest that the DegS protease regulates the expression of ICDH through ArcA, thereby affecting the NADH and ATP levels of V. cholerae and its growth and intestinal colonization ability. [ABSTRACT FROM AUTHOR]

Introduction: Diffuse high-grade gliomas are the most common malignant adult neuroepithelial tumors in humans and a leading cause of cancer-related death worldwide. The advancement of high throughput transcriptome sequencing technology enables rapid and comprehensive acquisition of transcriptome data from target cells or tissues. This technology aids researchers in understanding and identifying critical therapeutic targets for the prognosis and treatment of diffuse high-grade glioma. Methods: Spatial transcriptomics was conducted on two cases of isocitrate dehydrogenase (IDH) wild-type diffuse high-grade glioma (Glio-IDH-wt) and two cases of IDH-mutant diffuse high-grade glioma (Glio-IDH-mut). Gene set enrichment analysis and clustering analysis were employed to pinpoint differentially expressed genes (DEGs) involved in the progression of diffuse high-grade gliomas. The spatial distribution of DEGs in the spatially defined regions of human glioma tissues was overlaid in the t-distributed stochastic neighbor embedding (t-SNE) plots. Results: We identified a total of 10,693 DEGs, with 5,677 upregulated and 5,016 downregulated, in spatially defined regions of diffuse high-grade gliomas. Specifically, SPP1 , IGFBP2 , CALD1 , and TMSB4X exhibited high expression in carcinoma regions of both Glio-IDH-wt and Glio-IDH-mut, and 3 upregulated DEGs (SMOC1 , APOE , and HIPK2) and 4 upregulated DEGs (PPP1CB , UBA52 , S100A6 , and CTSB) were only identified in tumor regions of Glio-IDH-wt and Glio-IDH-mut, respectively. Moreover, Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene ontology (GO) enrichment analyses revealed that upregulated DEGs were closely related to PI3K/Akt signaling pathway, virus infection, and cytokine-cytokine receptor interaction. Importantly, the expression of these DEGs was validated using GEPIA databases. Furthermore, the study identified spatial expression patterns of key regulatory genes, including those involved in protein post-translational modification and RNA binding protein-encoding genes, with spatially defined regions of diffuse high-grade glioma. Discussion: Spatial transcriptome analysis is one of the breakthroughs in the field of medical biotechnology as this can map the analytes such as RNA information in their physical location in tissue sections. Our findings illuminate previously unexplored spatial expression profiles of key biomarkers in diffuse high-grade glioma, offering novel insight for the development of therapeutic strategies in glioma. [ABSTRACT FROM AUTHOR]

Background: Odontotermes formosanus (Shiraki) is a highly damaging agroforestry pest. Serratia marcescens is a broad-spectrum insecticidal pathogen and is highly lethal to O. formosanus. However, little is known about the mechanism between them. To improve the biological control of pests, a more in-depth analysis of the interactions between the pests and the pathogens is essential. Results: We used RNA-seq, enzyme activity assays and real-time fluorescent quantitative PCR (qPCR) to explore the defense responses of O. formosanus against SM1. RNA-seq results showed that 1,160, 2,531 and 4,536 genes were differentially expressed at 3, 6 and 12 h after SM1 infection, and Kyoto Encyclopedia of Genes and Genomes (KEGG) results indicated that immune response and energy metabolism were involved in the defense of O. formosanus against SM1. Reactive oxygen species (ROS) levels and ROS synthesis genes were significantly elevated, and the antioxidant system were induced in O. formosanus after SM1 infection. In addition, the cellular immune genes were affected, and the Toll, immune deficiency (Imd), Janus kinase/signal transducer and activator of transcription (JAK/STAT), c-Jun N-terminal Kinase (JNK) and melanization pathways were activated. In vitro, Oftermicin, an antimicrobial peptide, had a significantly inhibitory effect on SM1. Furthermore, the expression levels and enzyme activities of phosphofructokinase (PFK), lactate dehydrogenase (LDH), succinate dehydrogenase (SDH) and isocitrate dehydrogenase (IDH) in glycolysis and tricarboxylic acid (TCA) cycles were increased. Conclusions: Our results clearly demonstrated that O. formosanus defended against SM1 by activating the antioxidant system, innate immunity and energy metabolism. This study would provide useful information for the development of biological controls of O. formosanus. [ABSTRACT FROM AUTHOR]

The correction notice for the article "Revisiting gliomatosis cerebri in adult-type diffuse gliomas" addresses errors in author affiliation details and figure misalignments. The correction includes the renumbering of affiliations and improvements in the resolution of figures. The corrected figures depict patient characteristics, imaging cases, and Kaplan-Meier curves related to adult diffuse gliomas. The correction ensures accuracy and clarity in the original article. [Extracted from the article]

Objectives: To investigate the clinical value of hemodynamic parameters derived from dynamic contrast-enhanced MRI (DCE-MRI) in predicting glioma genotypes including isocitrate dehydrogenase (IDH) mutation, 1p/19q codeletion status and the tumor proliferation index (Ki-67) noninvasively. And to compare the diagnostic performance of parameters of distributed parameter (DP)model and extended Tofts (Ex-Tofts) model. Materials and methods: Dynamic contrast-enhanced MRI (DCE-MRI) data of patients with glioma were prospectively enrolled from April 2021 to May 2023. The imaging data were analyzed using DP and Ex-Tofts model for evaluating the perfusion and permeability characteristics of glioma. Comparisons were performed according to IDH genotype in all glioma patients and 1p/19q codeletion in IDH mutation glioma patients. Receiver operating characteristic (ROC) curves were generated for DCE-MRI parameters. The Spearman rank correlation coefficients were calculated between DCE MRI parameters and Ki-67 index. Results: In IDH -mutation gliomas, a higher blood flow (F) was found in 1p/19q codeletion gliomas than in 1p/19q intact gliomas. No parameter derived from Ex-Tofts model showed significant differences in predicting 1p/19q status. Fractional volume of interstitial space (V e) derived from both the DP and Ex-Tofts models exhibited optimal performance in predicting IDH genotype (AUC = 0.818, 0.828, respectively). V e also showed the highest correlations with Ki-67 LI within their respective models in all gliomas (ρ = 0.62, 0.61), indicating comparable moderate positive associations. Ki-67 Conclusion: DP model showed a clear advantage in predicting 1p/19q status compared to Ex-Tofts model. The DP and Ex-Tofts models performed similarly in predicting IDH mutation and Ki-67 index. [ABSTRACT FROM AUTHOR]

The isocitrate dehydrogenase (IDH) mutation status is one of the most important markers according to the 2021 WHO classification of CNS tumors. Preoperatively, this information is usually obtained based on invasive biopsies, contrast-enhanced MR images or PET images generated using radioactive tracers. However, the completely non-invasive determination of IDH mutation status using routinely acquired preoperative native CT images has hardly been investigated to date. In our study, we show that radiomics-based machine learning allows to determine IDH mutation status based on preoperative native CT images both with very high accuracy and completely non-invasively. Based on independent test data, we are able to correctly identify 91.1% of cases with an IDH mutation. Our final model, containing only six features, exhibits a high area under the curve of 0.847 and an excellent area under the precision-recall curve of 0.945. In the future, such models may be used for a completely non-invasive prediction of important genetic markers, potentially allowing treating physicians to reduce the number of biopsies and speed up further treatment planning. [ABSTRACT FROM AUTHOR]

Objective: To study clinical efficacy of isocitrate dehydrogenase 1 (IDH1) mutation on temozolomide chemotherapy for glioma patients and its impact on immune cytokines and prognosis. Methods; A total of 134 patients with glioma who underwent surgical resection and were confirmed by pathology in Dushu Lake Hospital Affiliated to Sooehow University from October 2021 to October 2022 were selected as research subjects. 1DH1 mutation status was measured by direct sequencing method, and 1DH1 expression rate in glioma tissue was determined by immunohistochemistry. All patients with brain glioma were treated with temozolomide chemotherapy. Effects of 1DH1 mutation on clinical efficacy, immune cytokines (IFN-γ, IL-2, 1L-4, IL-10) and prognosis of glioma were analyzed. Results; Seventy-nine cases out of 134 cases of glioma tissue had IDH1 mutations, mostly at R132, with a mutation rate of 58.96%, significantly higher than normal brain tissue (χ²=48.066, P<0.05). Immunohistochemistry showed strong positive expression of 1DH1 in 56 out of 134 glioma tissues. Proportion of WHO grade IV in IDH1 mutant group was lower than 1DH1 wild type group [11.39% (9/79) vs 63.64% (35/55),Z=41.020, P<0.05], Proportion of low differentiation in IDH1 mutant group was higher than IDH1 wild type group [50.63%(40/79) vs 20.00%(11/55),/=12.907,P<0.05], Total effective rate in IDH1 mutant group was higher than IDH1 wild type group [91.14%(72/79) ps 76.36%(42/55),χ²=5.575,P<0.05], IFN-γ and IL-2 levels were higher than IDH1 wild type group [ (28.98±3.25) pg/ml vs (20.15±2.54) pg/ml, (33.42±4.25) pg/ml ts (25.23±3.52) pg/ml, 1=16.870, 11.750, P< 0.05], IL-4 and 1L-10 levels were lower than 1DH1 wild type group [ (7.90±1.02) pg/ml t;s (12.38+1.66) pg/ml, (8.79+1.00) pg/ml vs (15.26+1.23) pg/ml,f=19.330,33.500,P<0.05], 1DH1 mutation was positively correlated with IFN-γ and IL-2 levels after temozolo- mide chemotherapy (r=0.845, 0.772, P<0.05), and negatively correlated with IL-4 and IL-10 levels after temozolomide chemotherapy (r=-0.786,-0.685, P<0.05). Survival rate after chemotherapy in IDH1 mutant group was higher than 1DH1 wild type group [89.87% (71/79) vs 72.70%(40/55), Log Rank test χ²=5.208,P<0.05], Cox regression analysis found that WHO grade III (RR= 1.342), poorly differentiated (RR=1.783), IFN-γ III (RR= 1.808), IL-2 (RR=2.112), IL-4 (RR=2.342), IL-10 (RR=1.342) as risk factors, temozolomide chemotherapy efficacy (RR=0.653), IDH1 mutation (RR=0.895) as protective factors affect prognosis of temozolomide chemotherapy in glioma patients (P<0.05). Conclusion; IDH1 mutation is related to disease grade and differentiation degree of glioma patients, and can affect efficacy of temozolomide chemotherapy and expressions of immune cytokines, which is a protective factor for prognosis and survival after temozolomide chemotherapy. [ABSTRACT FROM AUTHOR]

[Objectives] This article aimed to explore the effects of chitosan and ozone on the preservation of postharvest grape fruits. [Methods] ‘Shine Muscat' grapes were used as the test material, and the grape fruits were soaked in 10 g·L-1 chitosan for 60 seconds and treated with ozone at a concentration of 4.288 mg·L-1 for 1 h, respectively. The grapes without any treatment were used as the control, the physiological indicators and volatile aroma components of the fruit at different time were measured, as well as the expression levels of genes related to carotenoid, acid metabolism, and aroma metabolism. [Results] Chitosan and ozone treatment could maintain the hardness of the fruit, inhibit the increase of soluble solids, affect fruit coloring, and improve appearance quality. In the short term (0-20 days), chitosan and ozone treatment slowed down the decrease in sugar and acid content of ‘Shine Muscat', increased the content of lutein and maintained the contents of aldehydes, alcohols, and terpenes in fruits. The gene expression analysis results showed that chitosan and ozone treatment could up-regulate carotenoid related genes expression to varying degrees, such as zeta-carotene desaturase gene (ZDS), 1-deoxyxylulose-5-phosphate reductive isomerase gene (DXR) and 4-diphosphocytidine-2-C-methylerythritol kinase gene (CMK); aroma metabolism related genes 3-hydroxy-3-methylglutaryl-CoA reductase gene (HMGR1, HMGR2, HMGR3), 1-hydroxy-2-methyl-2- (E) -butenyl-4-diphosphate reductase gene (HDR); soluble sugar related genes such as acid invertase gene (AI), neutral invertase gene (NI), invertase gene (INV); as well as organic acid metabolism related genes such as malate dehydrogenase gene (MDH), isocitrate dehydrogenase gene (IDH) and phosphoenolpyruvate carboxylase gene (PEPC) . [Conclusions] Chitosan and ozone treatment significantly increased the soluble sugar and organic acid content of grape fruits, while the chitosan maintained the postharvest aroma contents of ‘Shine Muscat', especially aldehydes, alcohols, and terpenes. [ABSTRACT FROM AUTHOR]

In this study, we first thoroughly assayed the response of the key enzymes of energy metabolism and the antioxidant system in Yarrowia lipolytica yeast at extreme pH. The activity of the tricarboxylic acid cycle enzymes, namely NAD-dependent isocitrate dehydrogenase, aconitate hydratase, NAD-dependent malate dehydrogenase, and fumarate hydratase, NADPH-producing enzymes of glucose-6-P dehydrogenase and NADP-dependent isocitrate dehydrogenase, and the enzymes of the glutathione system was assessed. All the enzymes that were tested showed a significant induction contrary to some decrease in the aconitate hydratase activity with acidic and alkaline stress. It is probable that a change in the enzyme activity in the mitochondria matrix is involved in the regulation of the cellular metabolism of Y. lipolytica, which allows the species to prosper at an extreme ambient pH. It distinguishes it from any other type of ascomycete. A close relationship between the induction of the Krebs cycle enzymes and the key enzymes of the glutathione system accompanied by an increased level of reduced glutathione was shown. The assumption that the increased activity of the Krebs cycle dehydrogenases and promotion of the pentose phosphate pathway at pH stress launches a set of events determining the adaptive response of Y. lipolytica yeast. [ABSTRACT FROM AUTHOR]

Simple Summary: In this review, we discuss the role of isocitrate dehydrogenase in a normal biological context and its subsequent role in oncogenesis when certain mutations are acquired. In particular, we focus on the many downstream effects of the oncometabolite D-2-Hydroxyglutarate, the byproduct of mutant isocitrate dehydrogenase. D-2-Hydroxyglutarate interferes with essential biological pathways that result in significant alterations to epigenetics, metabolism, RNA transcript stability, and DNA damage repair. Additionally, we review the diagnostic methods available for detecting isocitrate dehydrogenase mutations and/or D-2-Hydroxyglutarate. The clinical implications, including the classification of isocitrate dehydrogenase mutants in glioma and pharmaceutical inhibitors, are also discussed. In 2021, the World Health Organization classified isocitrate dehydrogenase (IDH) mutant gliomas as a distinct subgroup of tumors with genetic changes sufficient to enable a complete diagnosis. Patients with an IDH mutant glioma have improved survival which has been further enhanced by the advent of targeted therapies. IDH enzymes contribute to cellular metabolism, and mutations to specific catalytic residues result in the neomorphic production of D-2-Hydroxyglutarate (D-2-HG). The accumulation of D-2-HG results in epigenetic alterations, oncogenesis and impacts the tumor microenvironment via immunological modulations. Here, we summarize the molecular, cellular, and clinical implications of IDH mutations in gliomas as well as current diagnostic techniques. [ABSTRACT FROM AUTHOR]

Klebsiella pneumoniae and Legionella pneumophila are common Gram-negative bacteria that can cause lung infections. The multidrug resistance of K. pneumoniae presents a significant challenge for treatment. This study focuses on isocitrate dehydrogenase (IDH), a key enzyme in the oxidative metabolic pathway of these two bacteria. KpIDH and LpIDH were successfully overexpressed and purified, and their biochemical characteristics were thoroughly investigated. The study revealed that KpIDH and LpIDH are homodimeric enzymes with molecular weights of approximately 70 kDa. They are completely dependent on the coenzyme NADP+ and are inactive towards NAD+. KpIDH exhibits the highest catalytic activity at pH 8.0 in the presence of Mn2+ and at pH 7.8 in the presence of Mg2+. Its optimal catalytic performance is achieved with both ions at 55 °C. LpIDH exhibited its highest activity at pH 7.8 in the presence of Mn2+ and Mg2+, respectively, and exhibits optimal catalytic performance at 45 °C. Heat inactivation studies showed that KpIDH and LpIDH retained over 80% of their activity after being exposed to 45 °C for 20 min. Furthermore, we successfully altered the coenzyme specificity of KpIDH and LpIDH from NADP+ to NAD+ by replacing four key amino acid residues. This study provides a comprehensive biochemical characterization of two multidrug-resistant bacterial IDHs commonly found in hospital environments. It enhances our understanding of the characteristics of pathogenic bacteria and serves as a reference for developing new therapeutic strategies. [ABSTRACT FROM AUTHOR]

Reactive oxygen species (ROS) play a vital role in cellular functions but can lead to oxidative stress and contribute to degenerative diseases when produced in excess. Maintaining redox balance is essential and can be achieved through innate defense mechanisms or external antioxidants. Superoxide dismutase (SOD) is a key enzyme that mitigates intracellular oxidative stress by converting harmful free radicals into hydrogen peroxide, which is subsequently neutralized by catalase and glutathione peroxidase. Previous studies have demonstrated the antioxidant capabilities of SOD derived from Bacillus amyloquefaciens GF424 (BA-SOD) in murine models exposed to either irradiation or SOD1 gene deletion. In this study, a randomized clinical trial was conducted to evaluate the antioxidative benefits of BA-SOD in healthy individuals undergoing acute aerobic exercise (AAE). Eighty participants were randomly assigned to receive either BA-SOD or a placebo for 8 weeks. Antioxidant enzyme activities and glutathione levels were measured before, immediately after, and 30 min post-exercise. A single dose of BA-SOD significantly reduced ROS levels induced by AAE, primarily by enhancing SOD activity in erythrocytes and activating glutathione peroxidase. Continuous BA-SOD administration was associated with a sustained increase in catalase activity and elevated levels of reduced glutathione (GSH). Transcriptomic and metabolomic analyses revealed that a single BA-SOD dose facilitated GSH oxidation, as evidenced by decreased levels of serine, glutamine, and glycine, and increased pyroglutamate levels. Additionally, repeated dosing led to increased expression of genes encoding isocitrate dehydrogenase and malic enzyme, which are involved in NADPH synthesis, as well as nicotinamide phosphoribosyl transferase and NAD kinase, which are essential for NADP availability–critical for converting oxidized glutathione (GSSG) back to GSH. These molecular insights align with clinical observations, suggesting that both acute and long-term BA-SOD supplementation may effectively enhance antioxidant defenses and maintain redox balance under oxidative stress conditions. [Display omitted] • Acute aerobic exercise assessed antioxidative response to oxidative stress in healthy adults. • BA-SOD supplementation enhances endogenous antioxidant defense. • Single BA-SOD dose boosts SOD activity, increasing glutathione oxidation and countering H2O2. • Repeated BA-SOD administration increases catalase activity and preserves GSH/GSSG balance. [ABSTRACT FROM AUTHOR]

Background: Sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) enhances tumor immune escape and leads to tumor growth. Purpose: To investigate the expression of Siglec-15 in diffuse gliomas and its correlation with tumor magnetic resonance imaging (MRI) features. Material and Methods: This study included 57 patients with gliomas. Morphological MRI features, including the largest tumor diameter, enhancement category, location, calcification, cysts, and hemorrhage, were visually rated. Apparent diffusion coefficient (ADC) values were calculated in tumor region. MRI morphologic features and ADC were compared between patients with positive and negative Siglec-15 expression. Receiver operating characteristic (ROC) curves were further constructed to assess the diagnostic performance. Results: Siglec-15 was expressed in immunocytes, such as macrophages in the peritumoral area. Siglec-15 expression was positive in 20/57 (35.09%) patients, with higher expression in patients with IDH-mutant gliomas and lower grade gliomas. The tumor diameter was significantly smaller in patients with positive Siglec-15 expression than in those with negative expression for all patients (P = 0.017) and for patients with IDH-mutant gliomas (P = 0.020). Moreover, ADC values of the tumor were significantly higher in patients with positive Siglec-15 expression than in those with negative expression for all patients (P = 0.027). The areas under the ROC curve (AUCs) of the diameter and ADC were 0.702 and 0.686, respectively. A combination of these two parameters generated an improved AUC of 0.762. Conclusion: Siglec-15 was expressed in immunocytes such as macrophages in the peritumoral area, with a positive rate of 35.09%. Positive Siglec-15 expression in diffuse gliomas was correlated with smaller tumor size and higher ADC values. [ABSTRACT FROM AUTHOR]

Despite the fact that environmental pollution has been implicated in the global rise of diabetes, the research on the impact of emerging pollutants such as novel flame retardants remains limited. In line with the shift towards the use of non-animal approaches in toxicological testing, this study aimed to investigate the effects of two novel flame retardants tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) and triphenyl phosphate (TPhP) in rat (INS1E) and human (NES2Y) pancreatic beta-cell lines. One-week exposure to 1 μM and 10 μM TDCIPP and TPhP altered intracellular insulin and proinsulin levels, but not the levels of secreted insulin (despite the presence of a statistically insignificant trend). The exposures also altered the protein expression of several factors involved in beta-cell metabolic pathways and signaling, including ATP citrate lyase, isocitrate dehydrogenase 1, perilipins, glucose transporters, ER stress-related factors, and antioxidant enzymes. This study has brought new and valuable insights into the toxicity of TDCIPP and TPhP on beta-cell function and revealed alterations that might impact insulin secretion after more extended exposure. It also adds to the scarce studies using in vitro pancreatic beta-cells models in toxicological testing, thereby promoting the development of non-animal testing strategy for identifying pro-diabetic effects of chemical pollutants. [ABSTRACT FROM AUTHOR]

Purpose: To assess the diagnostic utility of clinical magnetic resonance spectroscopy (MRS) and diffusion-weighted imaging (DWI) in distinguishing between histological grading and isocitrate dehydrogenase (IDH) classification in adult diffuse gliomas. Methods: A retrospective analysis was conducted on 247 patients diagnosed with adult diffuse glioma. Experienced radiologists evaluated DWI and MRS images. The Kruskal-Wallis test examined differences in DWI and MRS-related parameters across histological grades, while the Mann–Whitney U test assessed molecular classification. Receiver Operating Characteristic (ROC) curves evaluated parameter effectiveness. Survival curves, stratified by histological grade and IDH classification, were constructed using the Kaplan–Meier test. Results: The cohort comprised 141 males and 106 females, with ages ranging from 19 to 85 years. The Kruskal-Wallis test revealed significant differences in ADC mean, Cho/NAA, and Cho/Cr concerning glioma histological grade (P <.01). Subsequent application of Dunn's test showed significant differences in ADC mean among each histological grade (P <.01). Notably, Cho/NAA exhibited a marked distinction between grade 2 and grade 3/4 gliomas (P <.01). The Mann–Whitney U test indicated that only ADC mean showed statistical significance for IDH molecular classification (P <.01). ROC curves were constructed to demonstrate the effectiveness of the specified parameters. Survival curves were also delineated to portray survival outcomes categorized by histological grade and IDH classification. Conclusions: Clinical MRS demonstrates efficacy in glioma histological grading but faces challenges in IDH classification. Clinical DWI's ADC mean parameter shows significant distinctions in both histological grade and IDH classification. [ABSTRACT FROM AUTHOR]

We present the final analyses of tumor dynamics and their prognostic significance during a 6-week course of concurrent chemoradiotherapy for glioblastoma in the Glioblastoma Longitudinal Imaging Observational study. This is a prospective serial magnetic resonance imaging study in 129 patients with glioblastoma who had magnetic resonance imaging obtained at radiation therapy (RT) planning (F0), fraction 10 (F10), fraction 20 (F20), and 1-month post-RT. Tumor dynamics assessed included gross tumor volume relative to F0 (V rel) and tumor migration distance (d migration). Covariables evaluated included: corpus callosum involvement, extent of surgery, O6-methylguanine-DNA-methyltransferase methylation, and isocitrate dehydrogenase mutation status. The median V rel were 0.85 (range, 0.25-2.29) at F10, 0.79 (range, 0.09-2.22) at F20, and 0.78 (range, 0.13-4.27) at 1 month after completion of RT. The median d migration were 4.7 mm (range, 1.1-20.4 mm) at F10, 4.7 mm (range, 0.8-20.7 mm) at F20, and 6.1 mm (range, 0.0-45.5 mm) at 1 month after completion of RT. Compared with patients who had corpus callosum involvement (n = 26), those without corpus callosum involvement (n = 103) had significant V rel reduction at F20 (P =.03) and smaller d migration at F20 (P =.007). Compared with patients who had biopsy alone (n = 19) and subtotal resection (n = 71), those who had gross total resection (n = 38) had significant V rel reduction at F10 (P =.001) and F20 (P =.001) and a smaller d migration at F10 (P =.03) and F20 (P =.002). O6-Methylguanine-DNA-methyltransferase methylation and isocitrate dehydrogenase mutation status were not significantly associated with tumor dynamics. The median progression-free survival and overall survival (OS) were 8.5 months (95% CI, 6.9-9.9) and 20.4 months (95% CI, 17.6-25.2). In multivariable analyses, patients with V rel ≥ 1.33 at F10 had worse OS (hazard ratio [HR], 4.6; 95% CI, 1.8-11.4; P =.001), and patients with d migration ≥ 5 mm at 1-month post-RT had worse progression-free survival (HR, 1.76; 95% CI, 1.08-2.87) and OS (HR, 2.2; 95% CI, 1.2-4.0; P =.007). Corpus callosum involvement and extent of surgery are independent predictors of tumor dynamics during RT and can enable patient selection for adaptive RT strategies. Significant tumor enlargement at F10 and tumor migration 1-month post-RT were associated with poorer OS. [ABSTRACT FROM AUTHOR]

Mutation of isocitrate dehydrogenase 2 (IDH2) is a key factor in promoting cytarabine (Ara‐C) resistance in acute myeloid leukemia (AML), however the underly mechanism remains unclear. Acute myeloid leukemia cells, were cultured with either IDH2 knockdown (KD‐IDH2) or overexpression (OE‐IDH2) to elucidate the role of IDH2 in these leukemic cell lines. Additionally, mutant cell lines were engineered to replicate clinically relevant IDH2 mutations. To investigate cellular responses, the glycolytic inhibitor 2‐deoxy‐D‐glucose (2‐DG) was administered to the cells. Cell proliferation was quantified using a Cell Counting Kit‐8 (CCK‐8), while apoptosis was evaluated through propidium iodide staining followed by flow cytometry. Glycolytic metabolism levels were measured using a specific reagent kit, and Western blotting was employed to determine the expression levels of glycolysis‐related proteins. Transcriptome sequencing was conducted to elucidate the mechanisms by which IDH2 mutations influence glycolysis. Furthermore, both in vitro cell experiments and in vivo subcutaneous transplantation tumor models in nude mice were utilized to validate these mechanisms. OE‐IDH2 in AML cells, enhances resistance to the Ara‐C, promotes cell proliferation and glycolysis, and inhibits apoptosis. KD‐IDH2 exhibits opposite effects. Both IDH2 mutations and OE‐IDH2 produce similar effects on these cellular processes. The increase in glycolysis levels following IDH2 mutation may contribute to the reduced efficacy of Enasidenib in inhibiting the proliferation of IDH‐mutant AML cells. Transcriptome sequencing results indicate an enrichment of the PI3K/Akt signaling pathway in IDH2‐mutant AML cells. BEZ235 significantly inhibits the expression of phosphorylated PI3K (p‐PI3K), phosphorylated Akt (p‐Akt), mTOR, glycolytic metabolism, and Ara‐C resistance both in vitro and in vivo. Overexpression and mutation of IDH2 coordinate with the Warburg effect through the PI3K/Akt/mTOR pathway to promote Ara‐C resistance in AML. [ABSTRACT FROM AUTHOR]

Mutations in isocitrate dehydrogenase (IDH) are important markers of glioma prognosis. However, few studies have examined the gene expression regulatory network (GRN) in IDH‐mutant and wild‐type gliomas. In this study, single‐cell RNA sequencing and spatial transcriptome sequencing were used to analyze the GRN of cell subsets in patients with IDH‐mutant and wild‐type gliomas. Through gene transcriptional regulation analysis, we identified the M4 module, whose transcription factor activity is highly expressed in IDH wild‐type gliomas compared to IDH‐mutants. Enrichment analysis revealed that these genes were predominantly expressed in microglia and macrophages, with significant enrichment in interferon‐related signaling pathways. Interferon regulatory factor 7 (IRF7), a transcription factor within this pathway, showed the highest percentage of enrichment and was primarily localized in the core region of wild‐type IDH tumors. A machine‐learning prognostic model identified novel subgroups within the wild‐type IDH population. Additionally, IRF7 was shown to promote the proliferation and migration of T98G and U251 cells in vitro, and its knockdown affected glioma cell proliferation in vivo. This study systematically established the regulatory mechanism of IDH transcriptional activity in gliomas at the single‐cell level and drew a corresponding cell map. The study presents a transcriptional regulatory activity map for IDH wild‐type gliomas, involving single‐cell RNA sequencing and spatial transcriptomics to identify gene regulatory networks, machine learning models for IDH subtyping, and experimental validation, highlighting the role of IRF7 in glioma progression. [ABSTRACT FROM AUTHOR]

Opinion Statement: Mutations in isocitrate dehydrogenase-1 (IDH1) are recurrent in several malignancies and prevalent in acute myeloid leukemia (AML). Olutasidenib and ivosidenib are inhibitors that target mutant IDH1 (mIDH1) and are FDA approved for the treatment of patients with mIDH1 AML. Olutasidenib and ivosidenib were identified through unique molecular screens and thus are structurally very different molecules. A difference in clinical outcomes has been observed with olutasidenib, which has a longer duration of response than ivosidenib, despite similar rates of response being achieved with the two drugs, such as complete remission (CR) or CR with partial hematologic recovery (CR/CRh). In the absence of a head-to-head trial, this review examines both the extent of differences in clinical outcomes with the two drugs and provides the first comparison of the unique molecular and mechanistic features of each drug, such as molecular structure and binding kinetics, that may contribute to the observed clinical difference in outcomes. Olutasidenib is structurally smaller with a lower molecular weight than ivosidenib (FW 355 vs FW 583) and thus occupies less space in the binding pocket of IDH1 dimers, making it resistant to displacement by IDH1 second-site mutations. In biochemical studies, olutasidenib selectively inhibits mutant but not wild-type IDH1, whereas ivosidenib appears to potently block both mutant and wild-type IDH1. Although they have the same target, olutasidenib and ivosidenib have unique molecular features, which may translate to selectivity differences in their inhibitory activity against IDH1. [ABSTRACT FROM AUTHOR]

Introduction: Myelodysplastic syndromes/neoplasms (MDS) are a heterogeneous group of hematologic malignancies that are stratified into high-risk (HR-MDS) and low-risk (LR-MDS) categories. Until recently, LR-MDS has been typically managed by supportive measures and erythropoiesis-stimulating agents (ESAs); whereas management of HR-MDS typically included hypomethylating agents and allogeneic hematopoietic stem cell transplant. However, the limited rates and durations of response observed with these interventions prompted the search for targeted therapies to improve the outcomes among patients with MDS. Areas covered: Here, we review the current landscape of targeted therapies in MDS. These include pyruvate kinase and hypoxia-inducible factor (HIF) activators; TGF-beta, telomerase, BCL2 and isocitrate dehydrogenase (IDH) inhibitors; as well as novel approaches targeting inflammation, pyroptosis, immune evasion, and RNA splicing machinery. Expert opinion: This review highlights the progress and challenges in MDS treatment. Despite some promising results, many therapies remain in early development or have faced setbacks, emphasizing the need for a more comprehensive understanding of the disease's pathobiology. Continued research into targeted therapies, homogenous clinical trial designs, as well as increased incorporation of molecular prognostic tools and artificial intelligence into trial design are essential for developing effective treatments for MDS and improving patient outcomes. [ABSTRACT FROM AUTHOR]