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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

Enasidenib (ENA) is an inhibitor of isocitrate dehydrogenase 2 (IDH2) approved for the treatment of patients with IDH2-mutant relapsed/refractory acute myeloid leukemia (AML). In this phase 2/1b Beat AML substudy, we applied a risk-adapted approach to assess the efficacy of ENA monotherapy for patients aged ≥60 years with newly diagnosed IDH2-mutant AML in whom genomic profiling demonstrated that mutant IDH2 was in the dominant leukemic clone. Patients for whom ENA monotherapy did not induce a complete remission (CR) or CR with incomplete blood count recovery (CRi) enrolled in a phase 1b cohort with the addition of azacitidine. The phase 2 portion assessing the overall response to ENA alone demonstrated efficacy, with a composite complete response (cCR) rate (CR/CRi) of 46% in 60 evaluable patients. Seventeen patients subsequently transitioned to phase 1b combination therapy, with a cCR rate of 41% and 1 dose-limiting toxicity. Correlative studies highlight mechanisms of clonal elimination with differentiation therapy as well as therapeutic resistance. This study demonstrates both efficacy of ENA monotherapy in the upfront setting and feasibility and applicability of a risk-adapted approach to the upfront treatment of IDH2-mutant AML. This trial is registered at www.clinicaltrials.gov as #NCT03013998.

Regional citrate anticoagulation (RCA) is a preferred method for continuous renal replacement therapy (CRRT) due to its benefits of extended filter lifespan and reduced bleeding complications. However, RCA can cause metabolic side effects such as alkalosis, acidosis, hypotension, and electrolyte imbalances. Optimal anticoagulation requires careful adjustment of citrate infusion based on blood flow rate. Citrate accumulation can occur in certain conditions, leading to adverse effects. Strategies for adapting citrate anticoagulation include adjusting the dose based on the patient's condition. The Cori cycle has been proposed as an alternative pathway for citrate metabolism outside the liver mitochondria. Establishing thresholds for citrate initiation is important, and lactate levels can be used as an indicator of impaired citrate metabolism. The proposed hypothesis of an alternative inducible citrate metabolism pathway requires further research, including an animal model, to validate its effectiveness. Overall, RCA is a viable option for patients with liver failure, and further research is needed to optimize its application and improve anticoagulation strategies in various clinical contexts. [Extracted from the article]

To evaluate the performance of the multimodal model, termed variable Vision Transformer (vViT), in the task of predicting isocitrate dehydrogenase (IDH) status among adult patients with diffuse glioma. vViT was designed to predict IDH status using patient characteristics (sex and age), radiomic features, and contrast-enhanced T1-weighted images (CE-T1WI). Radiomic features were extracted from each enhancing tumor (ET), necrotic tumor core (NCR), and peritumoral edematous/infiltrated tissue (ED). CE-T1WI were split into four images and input to vViT. In the training, internal test, and external test, 271 patients with 1070 images (535 IDH wildtype, 535 IDH mutant), 35 patients with 194 images (97 IDH wildtype, 97 IDH mutant), and 291 patients with 872 images (436 IDH wildtype, 436 IDH mutant) were analyzed, respectively. Metrics including accuracy and AUC-ROC were calculated for the internal and external test datasets. Permutation importance analysis combined with the Mann–Whitney U test was performed to compare inputs. For the internal test dataset, vViT correctly predicted IDH status for all patients. For the external test dataset, an accuracy of 0.935 (95% confidence interval; 0.913–0.945) and AUC-ROC of 0.887 (0.798–0.956) were obtained. For both internal and external test datasets, CE-T1WI ET radiomic features and patient characteristics had higher importance than other inputs (p < 0.05). The vViT has the potential to be a competent model in predicting IDH status among adult patients with diffuse glioma. Our results indicate that age, sex, and CE-T1WI ET radiomic features have key information in estimating IDH status. • Multimodal analysis using demographics, radiomic features, and MRI was performed by vViT. • The accuracy vViT achieved for internal and external datasets was 1.00 and 0.935, respectively. • Our analyses revealed that the radiomic features of the contrast-enhanced part had key information for IDH prediction. [ABSTRACT FROM AUTHOR]

The 2021 World Health Organization (WHO) grading system of isocitrate dehydrogenase (IDH)‐mutant astrocytomas relies on histological features and the presence of homozygous deletion of the cyclin‐dependent kinase inhibitor 2A and 2B (CDKN2A/B). DNA methylation profiling has become highly relevant in the diagnosis of central nervous system (CNS) tumors including gliomas, and it has been incorporated into routine clinical diagnostics in some countries. In this study, we, therefore, examined the value of DNA methylation‐based classification for prognostication of patients with IDH‐mutant astrocytomas. We analyzed histopathological diagnoses, genome‐wide DNA methylation array data, and chromosomal copy number alteration profiles from a cohort of 385 adult‐type IDH‐mutant astrocytomas, including a local cohort of 127 cases and 258 cases from public repositories. Prognosis based on WHO 2021 CNS criteria (histological grade and CDKN2A/B homozygous deletion status), other relevant chromosomal/gene alterations in IDH‐mutant astrocytomas and DNA methylation‐based subclassification according to the molecular neuropathology classifier were assessed. We demonstrate that DNA methylation‐based classification of IDH‐mutant astrocytomas can be used to predict outcome of the patients equally well as WHO 2021 CNS criteria. In addition, methylation‐based subclassification enabled the identification of IDH‐mutant astrocytoma patients with poor survival among patients with grade 3 tumors and patients with grade 4 tumors with a more favorable outcome. In conclusion, DNA methylation‐based subclassification adds prognostic information for IDH‐mutant astrocytomas that can further refine the current WHO 2021 grading scheme for these patients. [ABSTRACT FROM AUTHOR]

Despite several therapeutic advancements, the proportion of patients with advanced biliary tract cancers (BTC) surviving 5 years from diagnosis remains dismal. The increasing recognition of targetable genetic alterations in BTCs has ushered in a new era in the treatment of these patients. Newer therapeutic agents targeting mutations such as isocitrate dehydrogenase (IDH), fibroblastic growth factor receptor (FGFR), human epidermal growth factor receptor (HER), and so on have established a new standard of care for treatment upon progression on frontline therapy in patients with disease harboring these mutations. The current review aims to concisely summarize progress with various targeted therapy options for BTC. We also briefly discuss future directions in clinical and translational research for the adoption of a personalized approach for the treatment of unresectable or advanced BTC. Several new agents continue to emerge as feasible treatment options for patients with advanced BTC harboring targetable mutations. There is a growing need to identify mechanisms to conquer primary and acquired resistance to these agents. The identification of potential biomarkers that predict response to targeted therapy may be helpful in adopting a more tailored approach. All patients receiving treatment for advanced BTC should undergo tissue genomic profiling at diagnosis. [ABSTRACT FROM AUTHOR]

Introduction: The tumor microenvironment and IRGs are highly correlated with tumor occurrence, progression, and prognosis. However, their roles in grade II and III gliomas, termed LGGs in this study, remain to be fully elucidated. Our research aims to develop immune-related features for risk stratification and prognosis prediction in LGG. Methods: Using the ssGSEA method, we assessed the immune characteristics of the LGG population. We conducted differential analysis using LGG samples from the TCGA database and normal samples from GTEx, identifying 412 differentially expressed immune-related genes (DEIRGs). Subsequently, we utilized univariate Cox, LASSO, and multivariate Cox regression analyses to establish both a gene predictive model and a nomogram predictive model. Results: Here, we found that the ESTIMATE score, immune score and stromal score of high-immunity, high-grade and isocitrate dehydrogenase (IDH) wild-type glioma were higher than those of the corresponding group, and the tumor purity was lower. Higher ESTIMATE scores, stromal scores and immune scores indicated a poor prognosis in patients with LGG. Our four-gene prognostic model demonstrated superior accuracy compared to other molecular features. Validation using the CGGA as a testing set and the combined TCGA and CGGA cohort confirmed its robust prognostic value. Additionally, a nomogram integrating the prognostic model and clinical variables showed enhanced predictive capability. Discussion: Our study highlights the prognostic significance of the identified four DEIRGs (KLRC3, MR1, PDIA2, and RFXAP) in LGG patients. The predictive model and nomogram developed herein offer valuable tools for personalized treatment strategies in LGG. Future research should focus on further validating these findings and exploring the functional roles of these DEIRGs within the LGG tumor microenvironment. [ABSTRACT FROM AUTHOR]

Based on our previous findings that salicylic acid and jasmonic acid increased Nostoc flagelliforme polysaccharide yield by regulating intracellular nitric oxide (NO) levels, the mechanism through which NO affects polysaccharide biosynthesis in Nostoc flagelliforme was explored from the perspective of S-nitrosylation (SNO). The addition of NO donor and scavenger showed that intracellular NO had a significant positive effect on the polysaccharide yield of N. flagelliforme. To explore the mechanism, we investigated the relationship between NO levels and the activity of several key enzymes involved in polysaccharide biosynthesis, including fructose 1,6-bisphosphate aldolase (FBA), glucokinase (GK), glucose 6-phosphate dehydrogenase (G6PDH), mitochondrial isocitrate dehydrogenase (ICDH), and UDP-glucose dehydrogenase (UGDH). The enzymatic activities of G6PDH, ICDH, and UGDH were shown to be significantly correlated with the shifts in intracellular NO levels. For further validation, G6PDH, ICDH, and UGDH were heterologously expressed in Escherichia coli and purified via Ni+-NAT affinity chromatography, and subjected to a biotin switch assay and western blot analysis, which revealed that UGDH and G6PDH were susceptible to SNO. Furthermore, mass spectrometry analysis of proteins treated with S-nitrosoglutathione (GSNO) identified the SNO modification sites for UGDH and G6PDH as cysteine 423 and cysteine 249, respectively. These findings suggest that NO modulates polysaccharide biosynthesis in N. flagelliforme through SNO of UGDH and G6PDH. This reveals a potential mechanism through which NO promotes polysaccharide synthesis in N. flagelliforme, while also providing a new strategy for improving the industrial production of polysaccharides. [ABSTRACT FROM AUTHOR]

Introduction: Peritumoral brain edema (PTBE) has been widely reported with many brain tumors, especially with glioma. Since the blood–brain barrier (BBB) is essential for maintaining minimal permeability, any alteration in the interaction of BBB components, specifically in astrocytes and tight junctions (TJ), can result in disrupting the homeostasis of the BBB and making it severely leaky, which subsequently generates edema. Objective: This study aimed to evaluate the functional gliovascular unit of the BBB by examining changes in the expression of claudin (CLDN) genes and the expression of transient receptor potential (TRP) membrane channels, additionally to define the correlation between their expressions. The evaluation was conducted using in vitro spheroid swelling models and tumor samples from glioma patients with PTBE. Results: The results of the spheroid model showed that the genes TRPC3, TRPC4, TRPC5, and TRPV1 were upregulated in glioma cells either wild‐type isocitrate dehydrogenase 1 (IDH1) or the IDH1 R132H mutant, with or without NaCl treatment. Furthermore, TRP genes appeared to adversely correlate with the up regulation of CLDN1, CLDN3, and CLDN5 genes. Besides, the upregulation of TRPC1 and TRPC4 in IDH1mt‐R132H glioma cells. On the other hand, the correlation analysis revealed different correlations between different proteins in PTBE. CLDN1 exhibits a slight positive correlation with CLDN3. Similarly, TRPV1 displays a slight positive correlation with TRPC1. In contrast, TRPC4 shows a slight negative correlation with TRPC5. On the other hand, TRPC3 demonstrates a slight positive correlation with TRPC5, while the non‐PTBE analysis highlights a moderate positive correlation between CLDN1 and TRPM4 while CLDN3 exhibits a moderate negative correlation with TRPC4. Additionally, CLDN5 demonstrates a slight negative correlation with TRPC4 but a moderate positive correlation with TRPC3. Furthermore, TRPC1 have a slight negative correlation with TRPV1, TRPC3 exhibiting a slight positive correlation with TRPC4, and TRPV1 showing a slight negative correlation with TRPC5. Conclusion: As a conclusion, the current study provided evidence of a slight negative correlation between TRPs and CLDN gene expression in PTBE patients and confirmatory results with some of the genes in cell model of edema. [ABSTRACT FROM AUTHOR]

Mutations of isocitrate dehydrogenase 1 (IDH1) are key biomarkers for glioma classification, but current methods for detection of mutated IDH1 (mIDH1) require invasive tissue sampling and cannot be used for longitudinal studies. Positron emission tomography (PET) imaging with mIDH1-selective radioligands is a promising alternative approach that could enable non-invasive assessment of the IDH status. In the present work, we developed efficient protocols for the preparation of four 18F-labeled derivatives of the mIDH1-selective inhibitor olutasidenib. All four probes were characterized by cellular uptake studies with U87 glioma cells harboring a heterozygous IDH1 mutation (U87-mIDH) and the corresponding wildtype cells (U87-WT). In addition, the most promising probe was evaluated by PET imaging in healthy mice and mice bearing subcutaneous U87-mIDH and U87-WT tumors. Although all four probes inhibited mIDH1 with variable potencies, only one of them ([18F]mIDH-138) showed significantly higher in vitro uptake into U87-mIDH compared to U87-WT cells. In addition, PET imaging with [18F]mIDH-138 in mice demonstrated good in vivo stability and low non-specific uptake of the probe, but also revealed significantly higher uptake into U87-WT compared to U87-mIDH tumors. Finally, application of a two-tissue compartment model (2TCM) to the PET data indicated that preferential tracer uptake into U87-WT tumors results from higher specific binding rather than from differences in tracer perfusion. In conclusion, these results corroborate recent findings that mIDH1-selective inhibition may not directly correlate with mIDH1-selective target engagement and indicate that in vivo engagement of wildtype and mutated IDH1 may be governed by factors that are not faithfully reproduced by in vitro assays, both of which could complicate development of PET probes. [ABSTRACT FROM AUTHOR]

Metabolic changes involving the tricarboxylic acid (TCA) cycle have been linked to different non-metabolic cell processes. Among them, apart from cancer and immunity, emerges the DNA damage response (DDR) and specifically DNA damage repair. The oncometabolites succinate, fumarate and 2-hydroxyglutarate (2HG) increase reactive oxygen species levels and create pseudohypoxia conditions that induce DNA damage and/or inhibit DNA repair. Additionally, by influencing DDR modulation, they establish direct relationships with DNA repair on at least four different pathways. The AlkB pathway deals with the removal of N-alkylation DNA and RNA damage that is inhibited by fumarate and 2HG. The MGMT pathway acts in the removal of O-alkylation DNA damage, and it is inhibited by the silencing of the MGMT gene promoter by 2HG and succinate. The other two pathways deal with the repair of double-strand breaks (DSBs) but with opposite effects: the FH pathway, which uses fumarate to help with the repair of this damage, and the chromatin remodeling pathway, in which oncometabolites inhibit its repair by impairing the homologous recombination repair (HRR) system. Since oncometabolites inhibit DNA repair, their removal from tumor cells will not always generate a positive response in cancer therapy. In fact, their presence contributes to longer survival and/or sensitization against tumor therapy in some cancer patients. [ABSTRACT FROM AUTHOR]

Chemical Exchange Saturation Transfer (CEST) is a technique that uses specific off-resonance saturation pulses to pre-saturate targeted substances. This process influences the signal intensity of free water, thereby indirectly providing information about the pre-saturated substance. Among the clinical applications of CEST, Amide Proton Transfer (APT) is currently the most wellestablished. APT can be utilized for the preoperative grading of gliomas. Tumors with higher APTw signals generally indicate a higher likelihood of malignancy. In predicting preoperative molecular typing, APTw values are typically lower in tumors with favorable molecular phenotypes, such as isocitrate dehydrogenase (IDH) mutations, compared to IDH wild-type tumors. For differential diagnosis, the average APTw values of meningiomas are significantly lower than those of high-grade gliomas. Various APTw measurement indices assist in distinguishing central nervous system lesions with similar imaging features, such as progressive multifocal leukoencephalopathy, central nervous system lymphoma, solitary brain metastases, and glioblastoma. Regarding prognosis, APT effectively differentiates between tumor recurrence and treatment effects, and also possesses predictive capabilities for overall survival (OS) and progression-free survival (PFS). [ABSTRACT FROM AUTHOR]

Objectives: To assess the diagnostic accuracy of machine learning (ML)-based radiomics for predicting isocitrate dehydrogenase (IDH) mutations in patients with glioma. Methods: A systematic search of PubMed, Web of Science, Embase, and the Cochrane Library from inception to 1 September 2023, was conducted to collect all articles investigating the diagnostic performance of ML for the prediction of IDH mutations in gliomas. Two reviewers independently screened all papers for eligibility. Methodological quality and risk of bias were assessed using the METhodological RadiomICs Score and Quality Assessment of Diagnostic Accuracy Studies-2, respectively. The pooled sensitivity, specificity, and 95% confidence intervals were calculated, and the area under the receiver operating characteristic curve (AUC) was obtained. Results: In total, 14 original articles assessing 1740 patients with gliomas were included. The AUC of ML for predicting IDH mutation was 0.90 (0.87-0.92). The pooled sensitivity, specificity, and diagnostic odds ratio were 0.83 (0.71-0.90), 0.84 (0.74-0.90), and 25 (12,50) respectively. In subgroup analyses, modeling methods, glioma grade, and the combination of magnetic resonance imaging and clinical features affected the diagnostic performance in predicting IDH mutations in gliomas. Conclusion: ML-based radiomics demonstrated excellent diagnostic performance in predicting IDH mutations in gliomas. Factors influencing the diagnosis included the modeling methods employed, glioma grade, and whether the model incorporated clinical features. [ABSTRACT FROM AUTHOR]

Itaconic acid is an emerging platform chemical with extensive applications. Itaconic acid is currently produced by Aspergillus terreus through biological fermentation. However, A. terreus is a fungal pathogen that needs additional morphology controls, making itaconic acid production on industrial scale problematic. Here, we reprogrammed the Generally Recognized As Safe (GRAS) yeast Yarrowia lipolytica for competitive itaconic acid production. After preventing carbon sink into lipid accumulation, we evaluated itaconic acid production both inside and outside the mitochondria while fine-tuning its biosynthetic pathway. We then mimicked the regulation of nitrogen limitation in nitrogen-replete conditions by down-regulating NAD+-dependent isocitrate dehydrogenase through weak promoters, RNA interference, or CRISPR interference. Ultimately, we optimized fermentation parameters for fed-batch cultivations and produced itaconic acid titers of 130.1 grams per liter in 1-liter bioreactors and 94.8 grams per liter in a 50-liter bioreactor on semipilot scale. Our findings provide effective approaches to harness the GRAS microorganism Y. lipolytica for competitive industrial-scale production of itaconic acid. [ABSTRACT FROM AUTHOR]

Background: Due to increasing ecological concerns, microbial production of biochemicals from sustainable carbon sources like acetate is rapidly gaining importance. However, to successfully establish large-scale production scenarios, a solid understanding of metabolic driving forces is required to inform bioprocess design. To generate such knowledge, we constructed isopropanol-producing Escherichia coli W strains. Results: Based on strain screening and metabolic considerations, a 2-stage process was designed, incorporating a growth phase followed by a nitrogen-starvation phase. This process design yielded the highest isopropanol titers on acetate to date (13.3 g L−1). Additionally, we performed shotgun and acetylated proteomics, and identified several stress conditions in the bioreactor scenarios, such as acid stress and impaired sulfur uptake. Metabolic modeling allowed for an in-depth characterization of intracellular flux distributions, uncovering cellular demand for ATP and acetyl-CoA as limiting factors for routing carbon toward the isopropanol pathway. Moreover, we asserted the importance of a balance between fluxes of the NADPH-providing isocitrate dehydrogenase (ICDH) and the product pathway. Conclusions: Using the newly gained system-level understanding for isopropanol production from acetate, we assessed possible engineering approaches and propose process designs to maximize production. Collectively, our work contributes to the establishment and optimization of acetate-based bioproduction systems. [ABSTRACT FROM AUTHOR]

Background: Central nervous system tumors are the 10th most prevalent cause of mortality worldwide. The 2016 World Health Organization (WHO) classification of high grade gliomas (HGG) has identified Isocitrate dehydrogenase 1 (IDH 1) mutation as one of the primary molecular markers. Tumor protein 53 (p53) mutation is also closely associated with HGG. Aims and Objectives: The current study intended to ascertain the expression of IDH1 and P53 in patients with HGG and correlate that expression with clinical prognosis. Materials and Methods: The study included 34 patients with histopathological proven HGG. Relevant clinical information was recorded. The immunostaining results with anti-mouse monoclonal antibody for IDH 1 (R132H) and rabbit polyclonal antibody for p53 (RP 106-05) were statistically analyzed. Patients were followed up through telephone for a period of 1 year. Mortality within 1 year was regarded as a poor outcome. Results: About 85.29% (29/34) of the patients had Grade IV glioma, while only 14.71% (5/34) had Grade III glioma. Most patients with Grade III (3/5) (60.00%) and Grade IV (21/29) (72.41%) gliomas had p53 positivity. The majority of the patients with grade-III glioma (3/5) (60.00%) had IDH1 positivity, while most of the patients (23/29) (79.31%) with Grade IV gliomas had IDH1 negativity (P=0.0658). Age, gender, WHO grade, and adjuvant therapy did not show significant association with the outcome except for the p53 expression (P=0.0011*) and IDH1 expression (P=0.0025*). Correlation analysis showed a significant positive correlation between p53 makers with poor outcome (r=0.4781) and glioma grade (r=0.4028). Further, a negative yet insignificant correlation was recorded between IDH1 with age (r=-0.2285), p53 expression (r=-0.2568), and grade (r=-0.2988), although it showed a significant correlation with poor outcome (P=0.0001). Conclusion: p53-positive and IDH1-negative HGG had a significant correlation with the poor outcome. Thus, IDH1 and p53 are reliable markers for prognostication of HGG. [ABSTRACT FROM AUTHOR]

Introduction: Pediatric-type diffuse low-grade gliomas are a new entity that was introduced in the fifth edition of the World Health Organization Classification of Tumors of the Central Nervous System, which was published in 2021. Notably, the information regarding the radiophenotypes of this new entity is limited. Objective: T2-FLAIR mismatch sign has been mostly studied in adult-type diffuse gliomas so far. We aimed to present more pediatric cases for future research about T2-FLAIR mismatch signs in pediatric-type diffuse low-grade gliomas. Case presentation: The current study presents a case of a 2-year-old boy who has a subcortical tumor at the right precentral frontal region. This tumor exhibited a T2-fluid-attenuated inversion recovery (FLAIR) mismatch sign that was identified as specific for isocitrate dehydrogenase (IDH)-mutant 1p/19q non-co-deleted astrocytomas. The tumor was pathologically identified as pediatric-type diffuse low-grade gliomas, and it tested negative for IDH-1 immunohistochemistry. The whole-exome sequencing of tumor tissue revealed negative results for IDH mutation, 1p/19q co-deletion, MYB rearrangement, and all other potential pathogenic mutations. Conclusion: The T2-FLAIR mismatch sign may not be 100% specific for IDH-mutant gliomas, especially in children, and researchers must further investigate the pathophysiology of the T2-FLAIR mismatch sign in brain tumors and the radiophenotypes of entities of pediatric brain tumors. [ABSTRACT FROM AUTHOR]

Olutasidenib, a potent, selective, oral, mutant isocitrate dehydrogenase 1 (mIDH1) inhibitor, is FDA-approved for relapsed/refractory (R/R) acute myeloid leukemia (AML). Here we report efficacy and safety of olutasidenib in 18 patients with mIDH1 AML who were relapsed (10), refractory (6) or had complete remission with incomplete hematologic recovery (CRi; 2) to a venetoclax combination. Of the 16 patients who were R/R, 4 (25%) achieved complete remission (CR), one (6.3%) achieved CR with partial hematologic recovery (CRh), and 7 (43.8%) achieved a composite complete remission (CRc). Median time to CRc was 1.9 months (range 1–2.8). As of data cutoff (18 June 2021), median duration of CRc was not reached (range, 1.2-NR, ongoing at 30.4+ months). Both patients with CRi at study entry achieved a CR. Safety was consistent with the overall profile of olutasidenib. Olutasidenib offers a valuable treatment option for patients with mIDH1 AML previously treated with venetoclax. [ABSTRACT FROM AUTHOR]

Objective: High‐risk types of diffuse gliomas in adults include isocitrate dehydrogenase (IDH) wild‐type glioblastomas and grade 4 astrocytomas. Achieving noninvasive prediction of high‐risk molecular subtypes of gliomas is important for personalized and precise diagnosis and treatment. Methods: We retrospectively collected data from 116 patients diagnosed with adult diffuse gliomas. Multiple high‐risk molecular markers were tested, and various habitat models and whole‐tumor models were constructed based on preoperative routine and diffusion kurtosis imaging (DKI) sequences to predict high‐risk molecular subtypes of gliomas. Feature selection and model construction utilized Least absolute shrinkage and selection operator (LASSO) and support vector machine (SVM). Finally, the Wilcoxon rank‐sum test was employed to explore the correlation between habitat quantitative features (intra‐tumor heterogeneity score，ITH score) and heterogeneity, as well as high‐risk molecular subtypes. Results: The results showed that the habitat analysis model based on DKI performed remarkably well (with AUC values reaching 0.977 and 0.902 in the training and test sets, respectively). The model's performance was further enhanced when combined with clinical variables. (The AUC values were 0.994 and 0.920, respectively.) Additionally, we found a close correlation between ITH score and heterogeneity, with statistically significant differences observed between high‐risk and non‐high‐risk molecular subtypes. Interpretation: The habitat model based on DKI is an ideal means for preoperatively predicting high‐risk molecular subtypes of gliomas, holding significant value for noninvasively alerting malignant gliomas and those with malignant transformation potential. [ABSTRACT FROM AUTHOR]

The T2-Fluid-Attenuated Inversion Recovery (T2-FLAIR) mismatch sign is a radiogenomic marker that is easily discernible on preoperative conventional MR imaging. Application of strict criteria (adult population, cerebral hemisphere location, and classic imaging morphology) permits the noninvasive preoperative diagnosis of isocitrate dehydrogenase (IDH)-mutant 1p/19q-non-codeleted diffuse astrocytoma with near-perfect specificity, albeit with variably low sensitivity. This leads to improved preoperative planning and patient counseling. More recent research has shown that the application of less strict criteria compromises the near-perfect specificity of the sign but remains adequate for ruling out IDH-wildtype (glioblastoma) phenotype, which bears a far grimmer prognosis compared to IDH-mutant diffuse astrocytic disease. In this review, we elaborate on the various definitions of the T2-FLAIR mismatch sign present in the literature, illustrate these with images obtained at a comprehensive cancer center, discuss the potential of the mismatch sign for application to certain pediatric-type brain tumors, namely dysembryoplastic neuroepithelial tumor and diffuse midline glioma, and elaborate upon the clinical, histologic, and molecular associations of the T2-FLAIR mismatch sign as recognized to date. Finally, the sign's correlates in diffusion- and perfusion-weighted imaging are presented, and opportunities to further maximize the diagnostic and prognostic applications of the sign in the context of the 2021 revision of the WHO Classification of Central Nervous System Tumors are discussed. [ABSTRACT FROM AUTHOR]

Background Patients with intrahepatic cholangiocarcinoma (ICC) are prone to recurrence and poor survival. Targeted therapy related to isocitrate dehydrogenase (IDH) is an extremely important treatment. IDH1 and IDH2 mutations are generally thought to have similar effects on the tumor landscape. However, it is doubtful whether these 2 mutations have exactly the same effects on tumor cells and the tumor microenvironment. Methods All collected tumor samples were subjected to simultaneous whole-exon sequencing and proteome sequencing. Results IDH1 mutations accounted for 12.2%, and IDH2 mutations accounted for 5.5%, all missense mutations. Tumors with IDH mutations had lower proportions of KRAS and TP53 mutations. Mutated genes were obviously enriched in the kinase pathway in the tumors with IDH2 mutations. The signaling pathways were mainly enriched in the activation of cellular metabolic activities and an increase of inhibitory immune cells in the tumors with IDH mutations. Moreover, tumors had unique enrichment in DNA repair in IDH1 mutants and secretion of biological molecules in IDH2 mutants. Inhibitory immune cells might be more prominent in IDH2 mutants, and the expression of immune checkpoints PVR and HLA-DQB1 was more prominent in IDH1 mutants. IDH mutants were more related to metabolism-related and inflammation-immune response clusters, and some belonged to the DNA replication and repair cluster. Conclusions These results revealed the differential IDH1 and IDH2 mutation-related landscapes, and we have provided an important reference database to guide ICC treatment. [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]

Background: Extraneural metastasis of central nervous system tumors is generally rare and most often reported in glioblastomas and medulloblastomas, whereas oligodendrogliomas seem to have the lowest risk of extracranial metastasis. Given its infrequent occurrence, both the diagnosis and therapy of metastatic oligodendroglioma is often challenging. Case presentation: This case study presents an oligodendroglioma, the isocitrate dehydrogenase 1 (IDH1) mutant, 1p/19q-codeleted tumor with bone marrow metastasis. The significance of this case lies in the comprehensive molecular analysis conducted for both the primary tumor and the metastasis. Chromosome 7 trisomy and chromosome 10 monosomy (+ 7/-10) were detected in the metastasis indicating molecular progression, which, to the best of our knowledge, has not been previously documented in metastatic oligodendroglioma. Conclusions: This case study serves additional information for better understanding of the metastatic capabilities of CNS tumors. [ABSTRACT FROM AUTHOR]

Background: Komagataella phaffii, a type of methanotrophic yeast, can use methanol, a favorable non-sugar substrate in eco-friendly bio-manufacturing. The dissimilation pathway in K. phaffii leads to the loss of carbon atoms in the form of CO2. However, the ΔFLD strain, engineered to lack formaldehyde dehydrogenase—an essential enzyme in the dissimilation pathway—displayed growth defects when exposed to a methanol-containing medium. Results: Inhibiting the dissimilation pathway triggers an excessive accumulation of formaldehyde and a decline in the intracellular NAD+/NADH ratio. Here, we designed dual-enzyme complex with the alcohol oxidase1/dihydroxyacetone synthase1 (Aox1/Das1), enhancing the regeneration of the formaldehyde receptor xylulose-5-phosphate (Xu5P). This strategy mitigated the harmful effects of formaldehyde accumulation and associated toxicity to cells. Concurrently, we elevated the NAD+/NADH ratio by overexpressing isocitrate dehydrogenase in the TCA cycle, promoting intracellular redox homeostasis. The OD600 of the optimized combination of the above strategies, strain DF02-1, was 4.28 times higher than that of the control strain DF00 (ΔFLD, HIS4+) under 1% methanol. Subsequently, the heterologous expression of methanol oxidase Mox from Hansenula polymorpha in strain DF02-1 resulted in the recombinant strain DF02-4, which displayed a growth at an OD600 4.08 times higher than that the control strain DF00 in medium containing 3% methanol. Conclusions: The reduction of formaldehyde accumulation, the increase of NAD+/NADH ratio, and the enhancement of methanol oxidation effectively improved the efficient utilization of a high methanol concentration by strain ΔFLD strain lacking formaldehyde dehydrogenase. The modification strategies implemented in this study collectively serve as a foundational framework for advancing the efficient utilization of methanol in K. phaffii. [ABSTRACT FROM AUTHOR]

Gliomas are the most common primary brain tumor and are uniformly lethal. Despite significant advancements in understanding the genetic landscape of gliomas, standard-of-care has remained largely unchanged. Subsets of gliomas are defined by gain-of-function mutations in the metabolic genes encoding isocitrate dehydrogenase (IDH). Efforts to exploit mutant IDH activity and/or directly inhibit it with mutant IDH inhibitors have been the focus of over a decade of research. The recently published INDIGO trial, demonstrating the benefit of the mutant IDH inhibitor vorasidenib in patients with low-grade IDH-mutant gliomas, introduces a new era of precision medicine in brain tumors that is poised to change standard-of-care. In this review, we highlight and contextualize the results of the INDIGO trial and introduce key questions whose answers will guide how mutant IDH inhibitors may be used in the clinic. We discuss possible combination therapies with mutant IDH inhibition and future directions for clinical and translational research. [ABSTRACT FROM AUTHOR]

Introduction: Patients with progressing intrahepatic cholangiocarcinoma (iCCA) harboring an isocitrate dehydrogenase 1 (IDH1) mutation who received ivosidenib showed a median progression-free survival (PFS) benefit of 1.3 months compared to placebo in the phase 3 ClarIDHy trial. Case Presentations: We describe 2 consecutive patients with previously treated unresectable and metastatic iCCA harboring an IDH1 R132 mutation who achieved durable clinical responses with ivosidenib 500 mg once daily for >12 months until disease progression. In one case with a mixed response, a single progressive liver metastasis was additionally treated locally with interstitial brachytherapy, while ivosidenib was continued until further progression. Ivosidenib therapy resulted in long-term disease control with PFS of 20 and 13 months and duration of treatment of 26 and 13 months, respectively, with no relevant side effects. Conclusion: Patients with unresectable or metastatic IDH1-mutated iCCA can achieve sustained clinical responses for >12 months with ivosidenib. No new safety signals were observed during long-term treatment with ivosidenib. [ABSTRACT FROM AUTHOR]

Despite the better understanding of the molecular mechanisms contributing to the pathogenesis of acute myeloid leukemia (AML) and improved patient survival in recent years, AML therapy still remains a clinical challenge. For this reason, it is important to search for new therapies that will enable the achievement of remission. Recently, the Food and Drug Administration approved three mutant IDH (mIDH) inhibitors for the treatment of AML. However, the use of mIDH inhibitors in monotherapy usually leads to the development of resistance and the subsequent recurrence of the cancer, despite the initial effectiveness of the therapy. A complete understanding of the mechanisms by which IDH mutations influence the development of leukemia, as well as the processes that enable resistance to mIDH inhibitors, may significantly improve the efficacy of this therapy through the use of an appropriate synergistic approach. The aim of this literature review is to present the role of IDH1/IDH2 mutations in the pathogenesis of AML and the results of clinical trials using mIDH1/IDH2 inhibitors in AML and to discuss the challenges related to the use of mIDH1/IDH2 inhibitors in practice and future prospects related to the potential methods of overcoming resistance to these agents. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is the most common malignant brain tumor in adults, which remains incurable and often recurs rapidly after initial therapy. While large efforts have been dedicated to uncover genomic/transcriptomic alternations associated with the recurrence of GBMs, the evolutionary trajectories of matched pairs of primary and recurrent (P-R) GBMs remain largely elusive. It remains challenging to identify genes associated with time to relapse (TTR) and construct a stable and effective prognostic model for predicting TTR of primary GBM patients. By integrating RNA-sequencing and genomic data from multiple datasets of patient-matched longitudinal GBMs of isocitrate dehydrogenase wild-type (IDH-wt), here we examined the associations of TTR with heterogeneities between paired P-R GBMs in gene expression profiles, tumor mutation burden (TMB), and microenvironment. Our results revealed a positive correlation between TTR and transcriptomic/genomic differences between paired P-R GBMs, higher percentages of non-mesenchymal-to-mesenchymal transition and mesenchymal subtype for patients with a short TTR than for those with a long TTR, a high correlation between paired P-R GBMs in gene expression profiles and TMB, and a negative correlation between the fitting level of such a paired P-R GBM correlation and TTR. According to these observations, we identified 55 TTR-associated genes and thereby constructed a seven-gene (ZSCAN10, SIGLEC14, GHRHR, TBX15, TAS2R1, CDKL1, and CD101) prognostic model for predicting TTR of primary IDH-wt GBM patients using univariate/multivariate Cox regression analyses. The risk scores estimated by the model were significantly negatively correlated with TTR in the training set and two independent testing sets. The model also segregated IDH-wt GBM patients into two groups with significantly divergent progression-free survival outcomes and showed promising performance for predicting 1-, 2-, and 3-year progression-free survival rates in all training and testing sets. Our findings provide new insights into the molecular understanding of GBM progression at recurrence and potential targets for therapeutic treatments. [ABSTRACT FROM AUTHOR]

Background: At present, heat stress (HS) has become a key factor that impairs broiler breeding industry, which causes growth restriction and poor meat quality of broilers. Selenium (Se) is an excellent antioxidant and plays a unique role in meat quality improvement. Recent years, nano-selenium (NanoSe) has received tremendous attention in livestock production, due to its characteristic and good antibacterial performance in vitro. Here, we developed the heat stressed-broiler model to investigate the protective effects of NanoSe on growth performance and meat quality of broilers and compare whether there are differences with that of other Se sources (Sodium selenite, SS; Selenoyeast, SeY; Selenomethionine, SeMet). Results: HS jeopardized the growth performance and caused poor meat quality of breast muscle in broilers, which were accompanied by lowered antioxidant capacity, increased glycolysis, increased anaerobic metabolism of pyruvate, mitochondrial stress and abnormal mitochondrial tricarboxylic acid (TCA) cycle. All Se sources supplementation exhibited protective effects, which increased the Se concentration and promoted the expression of selenoproteins, improved the mitochondrial homeostasis and the antioxidant capacity, and promoted the TCA cycle and the aerobic metabolism of pyruvate, thus improved the breast muscle meat quality of broilers exposed to HS. However, unlike the other three Se sources, the protective effect of NanoSe on meat quality of heat stressed-broilers was not ideal, which exhibited limited impact on the pH value, drip loss and cooking loss of the breast muscle. Compared with the other Se sources, broilers received NanoSe showed the lowest levels of slow MyHC, the highest levels of fast MyHC and glycogen, the highest mRNA levels of glycolysis-related genes (PFKM and PKM), the highest protein expression of HSP60 and CLPP, and the lowest enzyme activities of GSH-Px, citroyl synthetase (CS) and isocitrate dehydrogenase (ICD) in breast muscle. Consistent with the SS, the Se deposition in breast muscle of broilers received NanoSe was lower than that of broilers received SeY or SeMet. Besides, the regulatory efficiency of NanoSe on the expression of key selenoproteins (such as SELENOS) in breast muscle of heat stressed-broilers was also worse than that of other Se sources. Conclusion: Through comparing the meat quality, Se deposition, muscle fiber type conversion, glycolysis, mitochondrial homeostasis, and mitochondrial TCA cycle-related indicators of breast muscle in heat stressed broilers, we found that the protective effects of organic Se (SeY and SeMet) are better than that of inorganic Se (SS) and NanoSe. As a new Se source, though NanoSe showed some protective effect on breast muscle meat quality of heat stressed broilers, the protective effect of NanoSe is not ideal, compared with other Se sources. [ABSTRACT FROM AUTHOR]

Glycosphingolipids (GSLs) are essential components of cell membranes, particularly enriched in the nervous system. Altered molecular distributions of GSLs are increasingly associated with human diseases, emphasizing the significance of lipidomic profiling. Traditional GSL analysis methods are hampered by matrix effect from phospholipids and the difficulty in distinguishing structural isomers. Herein, we introduce a highly sensitive workflow that harnesses magnetic TiO2 nanoparticle-based selective enrichment, charge-tagging Paternò–Büchi reaction, and liquid chromatography-tandem mass spectrometry. This approach enables mapping over 300 distinct GSLs in brain tissues by defining sugar types, long chain bases, N-acyl chains, and the locations of desaturation and hydroxylation. Relative quantitation of GSLs across multiple structural levels provides evidence of dysregulated gene and protein expressions of FA2H and CerS2 in human glioma tissue. Based on the structural features of GSLs, our method accurately differentiates human glioma with/without isocitrate dehydrogenase genetic mutation, and normal brain tissue. The molecular profiling of glycosphingolipids (GSLs) is hindered by the coexistence of abundant phospholipids and diverse isomers. The authors introduce a highly sensitive workflow that maps out the structural atlas of neutral GSLs, previously deemed a "dark space" within the lipidome. [ABSTRACT FROM AUTHOR]

Summary: The treatment landscape of acute myeloid leukaemia (AML) is evolving rapidly. Venetoclax in combination with intensive chemotherapy or doublets or triplets with targeted or immune therapies is the focus of numerous ongoing trials. The development of mutation‐targeted therapies has greatly enhanced the treatment armamentarium, with FLT3 inhibitors and isocitrate dehydrogenase inhibitors improving outcomes in frontline and relapsed/refractory (RR) AML, and menin inhibitors showing efficacy in RR NPM1mut and KMT2A‐rearranged AML. With so many new drugs approved, the number of potential combinatorial approaches to leverage the maximal benefit of these agents has increased dramatically, while at the same time introducing clinical challenges, such as key preclinical and clinical data supporting the development of combinatorial therapy, how to optimally combine or sequence these novel agents, how to optimise dose and duration to maintain safety while enhancing efficacy, the optimal duration of therapy and the role of measurable residual disease in decision‐making in both intensive and low‐intensity therapy settings. In this review, we will outline the evidence leading to the approval of key agents in AML, their on‐label current approvals and how they may be optimally combined in a safe and deliverable fashion to further improve outcomes in AML. [ABSTRACT FROM AUTHOR]

AIM: To investigate the effects of the compound ANBP on wound healing in diabetic rats and explore its mechanism of action. METHODS: Ninety male SD rats were randomly divided into blank, model, compound ANBP, Beifuxin, and nicotinamide mononucleotide (NMN) groups, with 16 rats in each group. Wound healing in each group was observed and samples were taken on days 3, 7 and 14 to analyze the wound healing rate. Local histopathological changes were observed using HE and Masson staining. The expressions of pyruvate dehydrogenase E1 subunit alpha 1 (PDHAl), citrate synthase (CS), isocitrate dehydrogenase (IDH1) and oxoglutarate dehydrogenase (OGDH) were detected through immunofluorescence and Western blot. The number and morphology of mitochondria in the wound tissue were observed using transmission electron microscopy. RESULTS: Histomorphological changes revealed significant improvement in diabetic wound healing in the blank and compound ANBP groups compared to that of the model group. The wound healing rates of the blank, compound ANBP, Beifuxin, and NMN groups were significantly increased on days 3, 7, and 14 (P<0. 01). Compared to the model group, granulation tissue generation was higher in the other groups, covering the wound defect and producing abundant collagen fibers. At 3, 7, and 14 days after intervention, the blank, compound ANBP, Beifuxin, and NMN groups showed significantly enhanced fluorescence intensities of TCA cycling-related enzymes PDHA1, CS, IDH1, and OGDH indicating increased expression of these enzymes. The levels of the TCA cycling-related enzymes were significantly increased (P<0. 01) in the compound ANBP, Beifuxin and NMN groups but were significantly decreased (P<0. 01) in the model group. An increase in the number and density of mitochondria and a decrease in the cavitation rate of mitochondria with improved morphology (P<0. 05) was observed in the group treated with compound ANBP. CONCLUSION: Compound ANBP may increase the number of mitochondria, improve mitochondrial morphology and function, upregulate the expression levels of PDHA1, CS, IDH1, and OGDH proteins, and accelerate the regeneration of wound granulation tissue, thus promoting the healing of diabetic wounds in rats. [ABSTRACT FROM AUTHOR]

Ivosidenib is used for the treatment of acute myeloid leukemia (AML) with isocitrate dehydrogenase 1 (IDH1) mutations. However, increased blood concentrations of ivosidenib are associated with a risk of a prolonged QT interval in patients with AML. Therapeutic drug monitoring in patients with AML with IDH1 mutation offers the potential to improve treatment efficacy while minimizing toxicity. In this study, we developed an efficient high-performance liquid chromatography–ultraviolet (HPLC-UV) method for the quantification of ivosidenib in plasma. Human plasma samples (50 μL) were processed by protein precipitation using acetonitrile, followed by chromatographic separation on a reversed-phase column with an isocratic mobile phase of 0.5% KH₂PO₄ (pH 4.5) and acetonitrile (45:55, v/v) at a flow rate of 1.0 mL/min, with ultraviolet detection at 245 nm. Calibration curves were linear over the range of 0.25–20 μg/mL with a coefficient of determination (r 2) of 0.99999. Intra-day and inter-day precision were 1.20–8.04% and 0.69–4.20%, respectively. The assay accuracy was −2.00% to 1.93% and recovery was >91.2%. These findings support the effectiveness of the newly developed HPLC-UV method for the quantification of ivosidenib in human plasma. This simple and cost-effective method is expected to expand ivosidenib monitoring in laboratories lacking LC–MS/MS instruments. [ABSTRACT FROM AUTHOR]

Isocitrate dehydrogenase 1 (IDH1) is a necessary enzyme for cellular respiration in the tricarboxylic acid cycle. Mutant isocitrate dehydrogenase 1 (mIDH1) has been detected overexpressed in a variety of cancers. mIDH1 inhibitor ivosidenib (AG-120) was only approved by the Food and Drug Administration (FDA) for marketing, nevertheless, a range of resistance has been frequently reported. In this study, several mIDH1 inhibitors with the common backbone pyridin-2-one were explored using the three-dimensional structure–activity relationship (3D-QSAR), scaffold hopping, absorption, distribution, metabolism, excretion (ADME) prediction, and molecular dynamics (MD) simulations. Comparative molecular field analysis (CoMFA, R2 = 0.980, Q2 = 0.765) and comparative molecular similarity index analysis (CoMSIA, R2 = 0.997, Q2 = 0.770) were used to build 3D-QSAR models, which yielded notably decent predictive ability. A series of novel structures was designed through scaffold hopping. The predicted pIC50 values of C3, C6, and C9 were higher in the model of 3D-QSAR. Additionally, MD simulations culminated in the identification of potent mIDH1 inhibitors, exhibiting strong binding interactions, while the analyzed parameters were free energy landscape (FEL), radius of gyration (Rg), solvent accessible surface area (SASA), and polar surface area (PSA). Binding free energy demonstrated that C2 exhibited the highest binding free energy with IDH1, which was −93.25 ± 5.20 kcal/mol. This research offers theoretical guidance for the rational design of novel mIDH1 inhibitors. [ABSTRACT FROM AUTHOR]

The advent of comprehensive genomic profiling using next-generation sequencing (NGS) has unveiled an abundance of potentially actionable genetic aberrations that have shaped our understanding of the cancer biology landscape. Isocitrate dehydrogenase (IDH) is an enzyme present in the cytosol (IDH1) and mitochondria (IDH2 and IDH3). In the mitochondrion, it catalyzes the irreversible oxidative decarboxylation of isocitrate, yielding the production of α-ketoglutarate and nicotinamide adenine dinucleotide phosphate (NADPH) as well as carbon dioxide (CO2). In the cytosol, IDH catalyzes the decarboxylation of isocitrate to α-ketoglutarate as well as the reverse reductive carboxylation of α-ketoglutarate to isocitrate. These rate-limiting steps in the tricarboxylic acid cycle, as well as the cytoplasmic response to oxidative stress, play key roles in gene regulation, cell differentiation, and tissue homeostasis. Mutations in the genes encoding IDH1 and IDH2 and, less commonly, IDH3 have been found in a variety of cancers, most commonly glioma, acute myeloid leukemia (AML), chondrosarcoma, and intrahepatic cholangiocarcinoma. In this paper, we intend to elucidate the theorized pathophysiology behind IDH isomer mutation, its implication in cancer manifestation, and discuss some of the available clinical data regarding the use of novel IDH inhibitors and their role in therapy. [ABSTRACT FROM AUTHOR]

Background Purpose Methods Results Conclusion Measuring non‐parametric intravoxel mean diffusivity distributions (MDDs) using magnetic resonance imaging (MRI) is a sensitive method for detecting intracellular diffusivity changes during physiological alterations. Histological and molecular glioma classifications are essential for prognosis and treatment, with distinct water diffusion dynamics among subtypes.We developed a data‐driven approach using a fully connected network (FCN) to enhance the speed and stability of calculating MDDs across varying SNRs, enable tumor microstructural mapping, and test its reliability in identifying MIB‐1 labeling index (LI) levels and molecular status of gliomas.An FCN was trained to learn the mapping between the simulated diffusion decay curves and the ground truth MDDs. We performed 5 000 000 simulation curves with various diffusivity components and random SNR ∈[30,300]$ \in [ {30,\ 300} ]$. Eighty percent of simulation curves were used for the FCN training, 10% for validation, and the others were external tests for the FCN performance evaluation. In vivo data were collected to evaluate its clinical reliability. One hundred one patients (44 years ±$ \pm $ 14, 67 men) with gliomas and six healthy controls underwent a 3.0 T MRI examination with a spin echo–echo planar imaging (SE‐EPI) diffusion‐weighted imaging (DWI) sequence. The trained FCN was employed to calculate MDDs of each brain voxel by voxel. We used the Fuzzy C‐means algorithm to cluster the MDDs of tumor voxels, facilitating the characterization of distinct glioma tissues. Quantitative assessments were conducted through sectional integrals of the MDDs, demarcated by six bands to derive signal fractions (fn,n=1−6${{f}_n},\ n = 1 -6$) and diffusivities of the maximum peaks (Dpeak${{D}_{peak}}$). Cosine similarity scores (CSS) were used for MDD similarity. ANOVA and Mann–Whitney U test were used for difference analysis. Logistic regression and area under the receiver operator characteristic curve (AUC) were used for classification evaluation.The simulation results showed that the FCN‐based MDD approach (FCN‐MDD) achieved higher CSS than non‐negative least squares‐based MDD (NNLS‐MDD). For in vivo data, the spectra of ET and NET obtained by FCN‐MDD are more distinguishable than NNLS‐MDD. Fraction maps delineate the characteristics of different tumor tissues (enhancing and non‐enhancing tumor, edema, and necrosis). f3,f4,Dpeak${{f}_3},\ {{f}_4},{{D}_{peak}}$ showed a positive and negative correlation with MIB‐1 respectively (r=0.568,r=−0.521,r=−0.654$r = 0.568,\ r = - 0.521,\ r = - 0.654$, all p<0.001$p < 0.001$). The AUC of Dpeak${{D}_{peak}}$ for predicting MIB‐1 LI levels was 0.900 (95% CI, 0.826–0.974), versus 0.781 (0.677–0.886) of ADC. The highest AUC of isocitrate dehydrogenase (IDH) mutation status, assessed by a logistic regression model (f1+f3${{f}_1} + {{f}_3}$) was 0.873 (95% CI, 0.802–0.944).The proposed FCN‐MDD method was more robust to variations in SNR and less reliant on empirically set regularization values than the NNLS‐MDD method. FCN‐MDD also enabled qualitative and quantitative evaluation of the composition of gliomas. [ABSTRACT FROM AUTHOR]

Gliomas are the most common malignant primary brain tumours in adults and cannot usually be cured with standard cancer treatments. Gliomas show intratumoural and intertumoural heterogeneity at the histological and molecular levels, and they frequently contain mutations in the isocitrate dehydrogenase 1 (IDH1) or IDH2 gene. IDH-mutant adult-type diffuse gliomas are subdivided into grade 2, 3 or 4 IDH-mutant astrocytomas and grade 2 or 3 IDH-mutant, 1p19q-codeleted oligodendrogliomas. The product of the mutated IDH genes, d-2-hydroxyglutarate (D-2-HG), induces global DNA hypermethylation and interferes with immunity, leading to stimulation of tumour growth. Selective inhibitors of mutant IDH, such as ivosidenib and vorasidenib, have been shown to reduce D-2-HG levels and induce cellular differentiation in preclinical models and to induce MRI-detectable responses in early clinical trials. The phase III INDIGO trial has demonstrated superiority of vorasidenib, a brain-penetrant pan-mutant IDH inhibitor, over placebo in people with non-enhancing grade 2 IDH-mutant gliomas following surgery. In this Review, we describe the pathway of development of IDH inhibitors in IDH-mutant low-grade gliomas from preclinical models to clinical trials. We discuss the practice-changing implications of the INDIGO trial and consider new avenues of investigation in the field of IDH-mutant gliomas. Gliomas are the most common malignant primary brain tumours in adults, and they frequently contain mutations in the isocitrate dehydrogenase 1 (IDH1) or IDH2 gene. Small-molecule inhibitors of mutant IDH are emerging as a new therapeutic strategy for IDH-mutant cancers, and this Review charts their pathway of development for IDH-mutant gliomas. Key points: Gliomas are the most common malignant primary brain tumours in adults, and they frequently contain mutations in the isocitrate dehydrogenase 1 (IDH1) or IDH2 gene. Mutant IDH produces the oncometabolite d-2-hydroxyglutarate (D-2-HG), which induces DNA and histone hypermethylation and interferes with immunity, thereby stimulating tumour growth. In preclinical models, selective inhibitors of mutant IDH were shown to decrease the production of d-2-HG, slow tumour growth and promote cellular differentiation. In early clinical trials, ivosidenib, a mutant IDH1 inhibitor, and vorasidenib, a brain-penetrant pan-mutant IDH inhibitor, were found to reduce D-2-HG concentrations and induce high rates of MRI-detectable glioma stabilization or response. The phase III INDIGO trial has shown superiority of vorasidenib over placebo in residual or recurrent non-enhancing grade 2 gliomas after surgery, thereby raising the prospect of delaying of chemoradiotherapy. Future studies should evaluate vorasidenib in enhancing tumours of different grades of malignancy, investigate novel IDH inhibitors and combination of drugs, and develop advanced tools to monitor response and relapse. [ABSTRACT FROM AUTHOR]

Metastatic cholangiocarcinoma (CCA) has poor prognosis. Chemotherapy in this indication demonstrated a limited benefit. Adding immunotherapy to standard chemotherapy is associated with an increase in median progressio.- free survival (mPFS) and increase in the response rate. An interesting therapeutic option for patients who have experienced progression during first line of treatment are targeted therapies. It is estimated that in over 50% of patients with CCA molecular tests based on next-generation sequencing (NGS) make it possible to identify genomic disorders, potentially enabling the use of targeted treatment. The most frequently reported disorders are fusions in the gene encoding fibroblast growth factor receptor 2 (FGFR2) and mutations in the IDH1 gene encoding isocitrate dehydrogenase (IDH). Ivosidenib is an oral reversible inhibitor of the abnormal form of IDH1 enzyme. The use of ivosidenib in patients with CCA and the IDH1 gene mutation after failure of previous therapy was evaluated in a phase III ClarIDHy study. The results of the trial confirmed its beneficial effect in terms of both PFS and overall survival (OS). [ABSTRACT FROM AUTHOR]

Gliomas are a common type of brain tumor that begins in the glial cells of the brain or spinal cord. IDH1 and IDH2 genes, encoding for the Isocitrate Dehydrogenase (IDH), are frequently mutated in gliomas, which leads to the conversion of aKetoglutarate (a-KG) to 2-Hydroxyglutarate (2-HG). This leads to several epigenetic changes in the genome, further leading to the activation of tumor cells in the brain. The mutation in the IDH1 gene also suppresses the immune system, offering new potential that can lead to the development of drugs and therapies that particularly target and strengthen the immune system. Due to the potential successes of new immunotherapy treatments, gliomas can be treated more effectively. Despite these successes in immunotherapy treatments for gliomas, further research needs to be conducted on the types of mechanisms by which drugs and immunotherapeutic treatments treat different gliomas. Through this paper, I hope to discuss the effects of IDH1 mutation in glioma cells and the potential therapies to treat gliomas. I further wish to discuss the potential benefits of combination therapeutics over monotherapy. [ABSTRACT FROM AUTHOR]

Mutations in isocitrate dehydrogenase (IDH) genes have important prognostic signifi cance for patients with glial neoplasms of the brain. Proton MR spectroscopy provides non-invasive determination of the metabolic properties of tumor tissue at the preoperative stage. The aim of the present work was to investigate the feasibility of determining isocitrate dehydrogenase (IDH) mutation status using magnetic resonance spectroscopy (MRS) to detect the presence of 2-hydroxyglutarate (2HG), the metabolic product of the enzyme IDH. We examined 33 patients with glial brain tumors with different degrees of malignancy (grades 2–4), with subsequent identifi cation of IDH mutations. IDH mutations found by proton MRS were confi rmed immunohistochemically in 20 cases. In 13 cases, the 2HG peak was not detected on the MR spectrum and analysis of IDH did not reveal mutations. The use of proton MRS has demonstrated that this method has high sensitivity in predicting the mutation status of glial brain tumors, which makes this method an important tool in preoperative diagnosis. [ABSTRACT FROM AUTHOR]

Abstract Background Glioma is the most common primary brain tumor with high mortality and disability rates. Recent studies have highlighted the significant prognostic consequences of subtyping molecular pathological markers using tumor samples, such as IDH, 1p/19q, and TERT. However, the relative importance of individual markers or marker combinations in affecting patient survival remains unclear. Moreover, the high cost and reliance on postoperative tumor samples hinder the widespread use of these molecular markers in clinical practice, particularly during the preoperative period. We aim to identify the most prominent molecular biomarker combination that affects patient survival and develop a preoperative MRI-based predictive model and clinical scoring system for this combination. Methods A cohort dataset of 2,879 patients was compiled for survival risk stratification. In a subset of 238 patients, recursive partitioning analysis (RPA) was applied to create a survival subgroup framework based on molecular markers. We then collected MRI data and applied Visually Accessible Rembrandt Images (VASARI) features to construct predictive models and clinical scoring systems. Results The RPA delineated four survival groups primarily defined by the status of IDH and TERT mutations. Predictive models incorporating VASARI features and clinical data achieved AUC values of 0.85 for IDH and 0.82 for TERT mutations. Nomogram-based scoring systems were also formulated to facilitate clinical application. Conclusions The combination of IDH-TERT mutation status alone can identify the most distinct survival differences in glioma patients. The predictive model based on preoperative MRI features, supported by clinical assessments, offers a reliable method for early molecular mutation prediction and constitutes a valuable scoring tool for clinicians in guiding treatment strategies.

PURPOSE: While the T2-FLAIR mismatch sign is highly specific for isocitrate dehydrogenase (IDH)-mutant, 1p/19q-noncodeleted astrocytomas among lower-grade gliomas, its utility in WHO grade 4 gliomas is not well-studied. We derived the partial T2-FLAIR mismatch sign as an imaging biomarker for IDH mutation in WHO grade 4 gliomas. METHODS: Preoperative MRI scans of adult WHO grade 4 glioma patients (n = 2165) from the multi-institutional ReSPOND (Radiomics Signatures for PrecisiON Diagnostics) consortium were analyzed. Diagnostic performance of the partial T2-FLAIR mismatch sign was evaluated. Subset analyses were performed to assess associations of imaging markers with overall survival (OS). RESULTS: One hundred twenty-one (5.6%) of 2165 grade 4 gliomas were IDH-mutant. Partial T2-FLAIR mismatch was present in 40 (1.8%) cases, 32 of which were IDH-mutant, yielding 26.4% sensitivity, 99.6% specificity, 80.0% positive predictive value, and 95.8% negative predictive value. Multivariate logistic regression demonstrated IDH mutation was significantly associated with partial T2-FLAIR mismatch (odds ratio [OR] 5.715, 95% CI [1.896, 17.221], p = 0.002), younger age (OR 0.911 [0.895, 0.927], p

Olutasidenib (FT-2102) is a potent, selective, oral, small-molecule inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1). Overall, 153 IDH1 inhibitor-naive patients with mIDH1R132 relapsed/refractory (R/R) acute myeloid leukemia (AML) received olutasidenib monotherapy 150 mg twice daily in the pivotal cohort of this study. The median age of participants was 71 years (range, 32-87 years) and the median number of prior regimens received by patients was 2 (1-7). The rate of complete remission (CR) plus CR with partial hematologic recovery (CRh) was 35%, and the overall response rate was 48%. Response rates were similar in patients who had, and who had not, received prior venetoclax. With 55% of patients censored at the time of data cut-off, the median duration of CR/CRh was 25.9 months. The median duration of overall response was 11.7 months, and the median overall survival was 11.6 months. Of 86 patients who were transfusion dependent at baseline, a 56-day transfusion independence was achieved in 29 (34%), which included patients in all response groups. Grade 3 or 4 treatment-emergent adverse events (≥10%) were febrile neutropenia and anemia (n = 31; 20% each), thrombocytopenia (n = 25; 16%), and neutropenia (n = 20; 13%). Differentiation syndrome adverse events of special interest occurred in 22 (14%) patients, with 14 (9%) grade ≥3 and 1 fatal case reported. Overall, olutasidenib induced durable remissions and transfusion independence with a well-characterized and manageable side effect profile. The observed efficacy represents a therapeutic advance in this molecularly defined, poor-prognostic population of patients with mIDH1 R/R AML. This trial was registered at www.clinicaltrials.gov as #NCT02719574.

This study presents the first molecular phylogenetic analysis of the Clinocerinae, challenging the traditionally accepted monophyly of this subfamily. DNA was extracted from fresh and museum specimens representing all biogeographical regions. Maximum likelihood (ML) and Bayesian inference (BI) phylogenetic analyses were performed based on sequences from two mitochondrial genes, cytochrome c oxidase subunit I (COI) and cytochrome β, and three nuclear genes, carbomoylphosphate synthase domain of rudimentary, elongation factor‐1α and isocitrate dehydrogenase. Through molecular data and morphological examination, our results reveal a division within Clinocerinae, distinguishing 'typical' or Clinocerinae (s.s.) from several genera, specifically Afroclinocera Sinclair, Asymphyloptera Collin and Proagomyia Collin, possibly lending support for a reclassification of these genera outside Clinocerinae. Bergenstammia Mik is proposed as a junior synonym of Phaeobalia Mik, syn. n., and the following new combinations are recognized: Phaeobalia albanica (Wagner) comb. n., Phaeobalia aurinae (Pusch & Wagner) comb. n., Phaeobalia carniolica (Horvat) comb. n., Phaeobalia frigida (Vaillant) comb. n., Phaeobalia glacialis (Palaczyk & Słowińska) comb. n., Phaeobalia multiseta (Strobl) comb. n., Phaeobalia nudimana (Vaillant) comb. n., Phaeobalia nudipes (Loew) comb. n., Phaeobalia pulla (Vaillant & Wagner) comb. n., Phaeobalia pyrenaica (Vaillant & Vinçon) comb. n., Phaeobalia slovaca (Wagner) comb. n. and Phaeobalia thomasi (Vaillant & Vinçon) comb. n. Re‐evaluation of the genus Roederiodes resulted in the following new combinations: Clinocerella macedonicus (Wagner & Horvat) comb. n. and Clinocerella montenegrinus (Wagner & Horvat) comb. n. The origins of Clinocerinae (s.s.) are traced back to the Holarctic region, Laurasian origin, with a likely complex history of dispersal events into the Southern Hemisphere. Based on current knowledge, the greatest generic and species richness is confined to the Palaearctic Region. These findings provide valuable insights into the evolutionary relationships and distribution patterns of Clinocerinae (s.s.), challenging existing taxonomic classifications and shedding light on their historical biogeography. [ABSTRACT FROM AUTHOR]

Abstract Background This study aimed to evaluate the T2W hypointense ring and T2-FLAIR mismatch signs in gliomas and use these signs to construct prediction models for glioma grading and isocitrate dehydrogenase (IDH) mutation status. Methods Two independent radiologists retrospectively evaluated 207 glioma patients to assess the presence of T2W hypointense ring and T2-FLAIR mismatch signs. The inter-rater reliability was calculated using the Cohen’s kappa statistic. Two logistic regression models were constructed to differentiate glioma grade and predict IDH genotype noninvasively, respectively. Receiver operating characteristic (ROC) analysis was used to evaluate the developed models. Results Of the 207 patients enrolled (119 males and 88 females, mean age 51.6 ± 14.8 years), 45 cases were low-grade gliomas (LGGs), 162 were high-grade gliomas (HGGs), 55 patients had IDH mutations, and 116 were IDH wild-type. The number of T2W hypointense ring signs was higher in HGGs compared to LGGs (p

Abstract Background Acute respiratory distress syndrome (ARDS) is a severe and fatal disease. Although mesenchymal stem cell (MSC)-based therapy has shown remarkable efficacy in treating ARDS in animal experiments, clinical outcomes have been unsatisfactory, which may be attributed to the influence of the lung microenvironment during MSC administration. Extracellular vesicles (EVs) derived from endothelial cells (EC-EVs) are important components of the lung microenvironment and play a crucial role in ARDS. However, the effect of EC-EVs on MSC therapy is still unclear. In this study, we established lipopolysaccharide (LPS) - induced acute lung injury model to evaluate the impact of EC-EVs on the reparative effects of bone marrow-derived MSC (BM-MSC) transplantation on lung injury and to unravel the underlying mechanisms. Methods EVs were isolated from bronchoalveolar lavage fluid of mice with LPS - induced acute lung injury and patients with ARDS using ultracentrifugation. and the changes of EC-EVs were analysed using nanoflow cytometry analysis. In vitro assays were performed to establish the impact of EC-EVs on MSC functions, including cell viability and migration, while in vivo studies were performed to validate the therapeutic effect of EC-EVs on MSCs. RNA-Seq analysis, small interfering RNA (siRNA), and a recombinant lentivirus were used to investigate the underlying mechanisms. Results Compared with that in non-ARDS patients, the quantity of EC-EVs in the lung microenvironment was significantly greater in patients with ARDS. EVs derived from lipopolysaccharide-stimulated endothelial cells (LPS-EVs) significantly decreased the viability and migration of BM-MSCs. Furthermore, engrafting BM-MSCs pretreated with LPS-EVs promoted the release of inflammatory cytokines and increased pulmonary microvascular permeability, aggravating lung injury. Mechanistically, LPS-EVs reduced the expression level of isocitrate dehydrogenase 2 (IDH2), which catalyses the formation of α-ketoglutarate (α-KG), an intermediate product of the tricarboxylic acid (TCA) cycle, in BM-MSCs. α-KG is a cofactor for ten-eleven translocation (TET) enzymes, which catalyse DNA hydroxymethylation in BM-MSCs. Conclusions This study revealed that EC-EVs in the lung microenvironment during ARDS can affect the therapeutic efficacy of BM-MSCs through the IDH2/TET pathway, providing potential strategies for improving the therapeutic efficacy of MSC-based therapy in the clinic.

Isocitrate dehydrogenase (IDH) is the more mutation-prone human metabolic gene. In the presence of nicotinamide adenine dinucleotide phosphate (NADPH), mutant IDH can bind to α-ketoglutaric acid (α-KG) and reduce it to 2-hydroxyglutaric acid (2-HG), participating in various biological processes of tumorigenesis. IDH has been widely studied in glioma and acute myeloid leukemia, and rarely in chondrosarcoma. Chondrosarcoma is prone to recurrence and metastasis due to the presence of high-frequency mutations in the IDH gene, and treatment options are limited after recurrence or metastasis, resulting in a poor prognosis for patients and an urgent clinical need to find new treatment options. This article reviews the role of IDH mutations in the development, prognosis, differential diagnosis and treatment of chondrosarcoma, further elaborates the biological role of IDH gene mutation in the occurrence and development of chondrosarcoma, and provides an outlook on the development of powerful IDH inhibitors and anti-cancer drugs, in order to provide a reference for the establishment of therapeutic regimen and prognostic evaluation.

Enzymes of the central metabolism tend to assemble into transient supramolecular complexes. However, the functional significance of the interactions, particularly between enzymes catalyzing non-consecutive reactions, remains unclear. Here, by co-localizing two non-consecutive enzymes of the TCA cycle from Bacillus subtilis, malate dehydrogenase (MDH) and isocitrate dehydrogenase (ICD), in phase separated droplets we show that MDH-ICD interaction leads to enzyme agglomeration with a concomitant enhancement of ICD catalytic rate and an apparent sequestration of its reaction product, 2-oxoglutarate. Theory demonstrates that MDH-mediated clustering of ICD molecules explains the observed phenomena. In vivo analyses reveal that MDH overexpression leads to accumulation of 2-oxoglutarate and reduction of fluxes flowing through both the catabolic and anabolic branches of the carbon-nitrogen intersection occupied by 2-oxoglutarate, resulting in impeded ammonium assimilation and reduced biomass production. Our findings suggest that the MDH-ICD interaction is an important coordinator of carbon-nitrogen metabolism. Enzymes of central metabolism tend to assemble into transient supramolecular complexes. Here, the authors stoichiometrically perturbed the supramolecular complex of TCA cycle enzymes in B. subtilis and propose that MDH-ICD clustering causes 2-oxoglutartae sequestration by reducing its diffusion rate, a mechanism that has evolved to regulate flux through the carbon-nitrogen metabolic branch-point. [ABSTRACT FROM AUTHOR]

Mutations affecting codon 172 of the isocitrate dehydrogenase 2 (IDH2) gene define a subgroup of sinonasal undifferentiated carcinomas (SNUCs) with a relatively favorable prognosis and a globally hypermethylated phenotype. They are also recurrent (along with IDH1 mutations) in gliomas, acute myeloid leukemia, and intrahepatic cholangiocarcinoma. Commonly reported mutations, all associated with aberrant IDH2 enzymatic activity, include R172K, R172S, R172T, R172G, and R172M. We present a case of SNUC with a never-before-described IDH2 mutation, R172A. Our report compares the methylation pattern of our sample to other cases from the Gene Expression Omnibus database. Hierarchical clustering suggests a strong association between our sample and other IDH-mutant SNUCs and a clear distinction between sinonasal normal tissues and tumors. Principal component analysis (PCA), using 100 principal components explaining 94.5% of the variance, showed the position of our sample to be within 1.02 standard deviation of the other IDH-mutant SNUCs. A molecular modeling analysis of the IDH2 R172A versus other R172 variants provides a structural explanation to how they affect the protein active site. Our findings thus suggest that the R172A mutation in IDH2 confers a gain of function similar to other R172 mutations in IDH2, resulting in a similar hypermethylated profile. [ABSTRACT FROM AUTHOR]