Isocitrate Dehydrogenase Research Articles

Oligoastrocytoma: The Vanishing Entity With True Dual Genotype, a Report, its Molecular Profiles and Review of Literature.

Isocitrate dehydrogenase (IDH) mutant gliomas are classified as astrocytoma or oligodendroglioma based on the recent application of ATRX mutation, TP53 mutation, and 1p/19q co-deletion. Astrocytomas classically show ATRX and TP53 mutations, whereas oligodendrogliomas are defined by 1p/19q co-deletion. However, there are reports of gliomas that harbor both astrocytoma and oligodendroglioma morphologically and molecularly. Here we present a patient of a 29-year-old woman who presented with a headache and underwent gross total excision. Magnetic resonance imaging showed a right frontal space-occupying lesion with T2 fluid-attenuated inversion recovery mismatch. Histology showed 2 distinct areas of morphology compatible with oligodendroglioma and astrocytoma. Immunohistochemistry showed both components being positive for IDH R132H. Alpha thalassemia/mental retardation syndrome X-linked (ATRX) showed loss of nuclear expression and p53 was strongly positive in the morphologic astrocytoma component, whereas ATRX was retained and p53 was negative in the morphologic oligodendroglioma component. Fluorescence in situ hybridization showed 1p/19q co-deletion in the oligodendroglioma component while co-deletion was absent in the astrocytoma component. TERT mutation was present in the oligodendroglioma component, whereas it was absent in the astrocytoma component. Although rare, gliomas harboring both oligodendroglioma and astrocytoma components in a single tumor exist and show genetically distinct areas.

Epigenetic Therapies.

Epigenetic therapies are emerging for pediatric cancers. Due to the relatively low mutational burden in pediatric tumors, epigenetic dysregulation and differentiation blockade is a hallmark of oncogenesis in some childhood cancers. By targeting epigenetic regulators that maintain tumor cells in a primitive developmental state, epigenetic therapies may induce differentiation. The most well-studied and clinically advanced epigenetic-targeted therapies include azacitidine and decitabine, which inhibit DNA methylation through competitive inhibition of the enzymatic activity of the DNA methyltransferase family enzymes. These DNA hypomethylating agents are Food and Drug Administration (FDA) approved for hematologic malignancies. The discovery that DNA hypermethylation occurs in patients with isocitrate dehydrogenase (IDH) mutations has led to the development and FDA approval of IDH inhibitors for hematologic and solid tumors. Epigenetic dysregulation in pediatric tumors is also driven by changes in the "histone code" that either promote oncogene expression or repress tumor suppressors. Cancers whose chromatin landscape is characterized by such aberrant histone posttranslational modifications may be amenable to targeted therapies that inhibit the chromatin-modifying enzymes that read, write, and erase these histone modifications. Small molecules that inhibit the enzymatic activity of histone deacetylases, acetyltransferases, and methyltransferases have been approved for the treatment of some adult cancers, and these agents are currently under investigation in various pediatric tumors. Chromatin regulatory complexes can be hijacked by oncogenic fusion proteins that are produced by chromosomal translocations, which are common drivers in pediatric cancer. Small molecules that disrupt oncogenic fusion protein activity and their associated chromatin complexes have demonstrated remarkable promise, and this approach has become the standard treatment for a subset of leukemias driven by the PML-RARA oncogenic fusion protein. A deeper understanding of the mechanisms that drive epigenetic dysregulation in pediatric cancer may hold the key to future success in this field, as the landscape of druggable epigenetic targets is also expanding.

SENP1 promotes deacetylation of isocitrate dehydrogenase 2 to inhibit ferroptosis of breast cancer via enhancing SIRT3 stability.

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.

Acute myeloid leukemia management and research in 2025.

The first 5 decades of research in acute myeloid leukemia (AML) were dominated by the cytarabine plus anthracyclines backbone, with advances in strategies including allogeneic hematopoietic stem cell transplantation, high-dose cytarabine, supportive care measures, and targeted therapies for the subset of patients with acute promyelocytic leukemia. Since 2017, a turning point in AML research, 12 agents have received regulatory approval for AML in the United States: venetoclax (BCL2 inhibitor); gemtuzumab ozogamicin (CD33 antibody-drug conjugate); midostaurin, gilteritinib, and quizartinib (fms-like tyrosine kinase 3 inhibitors); ivosidenib, olutasidenib, and enasidenib (isocitrate dehydrogenase 1 and 2 inhibitors); oral azacitidine (a partially absorbable formulation); CPX351 (liposomal encapsulation of cytarabine:daunorubicin at a molar ratio of 5:1); glasdegib (hedgehog inhibitor); and recently revumenib (menin inhibitor; approved November 2024). Oral decitabine-cedazuridine, which is approved as a bioequivalent alternative to parenteral hypomethylating agents in myelodysplastic syndrome, can be used for the same purpose in AML. Menin inhibitors, CD123 antibody-drug conjugates, and other antibodies targeting CD123, CD33, and other surface markers are showing promising results. Herein, the authors review the frontline and later line therapies in AML and discuss important research directions.

Advancing Systemic Therapy in Chondrosarcoma: New Horizons.

The systemic treatment landscape for advanced and metastatic chondrosarcoma, a malignancy with limited responsiveness to conventional therapies, has always been notoriously challenging. While standard chemotherapy offers minimal benefits, certain subtypes, such as mesenchymal and dedifferentiated chondrosarcomas, have shown some response to systemic therapies initially developed for other sarcomas. Investigational strategies are focusing on molecular targets, including mutations in the isocitrate dehydrogenase gene (IDH), signaling pathways, such as hedgehog and death receptor 5 (DR5) and immune modulation. IDH mutations, notably found in conventional and dedifferentiated chondrosarcomas, have prompted the evaluation of IDH inhibitors, which have demonstrated promising efficacy in preclinical and early clinical trials, despite limited data in chondrosarcoma. Additionally, the hedgehog pathway, implicated in chondrosarcoma progression, has been targeted with inhibitors, although clinical translation has shown mixed results. Immunotherapy, including programmed cell death 1 (PD-1) checkpoint inhibitors and chimeric antigen receptor-T (CAR-T) cells, is also being investigated but faces challenges due to the immunosuppressive tumour microenvironment. Among new approaches, DR5 agonists such as INBRX-109 have shown single-agent efficacy, with minimal toxicity, opening possibilities for use in combination therapies to improve outcomes. Given the heterogenous and treatment-resistant nature of chondrosarcoma, we highlight the need for multi-omics and genetic profiling to guide personalized, combination therapies that target multiple carcinogenic pathways. The integration of multi-targeted approaches could enhance efficacy, address tumour heterogeneity, and overcome resistance, presenting a hopeful direction for systemic therapy in this challenging cancer. The investigation of combination regimens with IDH inhibitors, immunotherapy and DR5 agonists hold promise for transforming the management of advanced chondrosarcoma.

Acute myeloid leukemia treatment outcomes with isocitrate dehydrogenase mutations: A systematic review and meta-analysis.

Isocitrate dehydrogenase (IDH) gene alterations and acute myeloid leukemia (AML) treatment results remain controversial. This study reviews the literature on IDH mutations in AML to determine the foundation of individualized therapy and improve effectiveness, survival time, and recurrence rate. Seven English and 2 Chinese databases were searched for literature on IDH mutations and AML outcomes. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. Twenty studies were included in this analysis. For the prognostic influence of IDH mutation on AML patients, the pooled HRs of overall survival in AML patients were 0.76 (95% CI, 0.63-0.93); the pooled HRs of event-free survival were 1.34 (95% CI, 1.15-1.57; heterogeneity: I2 = 52.2%, P = .027 < 0.05); the pooled HRs of recurrence free survival were 0.79 (95% CI, 0.61-1.02). The pooled HRs of overall survival in AML patients with mutant IDH1 were 1.62 (95% CI, 1.42-1.86) and of mutant IDH2 were 1.07 (95% CI, 0.89-1.29). The pooled HRs for event-free survival in AML patients with mutant IDH1 were 1.71 (95% CI, 1.40-2.08) and of mutant IDH2 were 0.93 (95% CI, 0.65-1.34). No evidence of publication bias was observed. Different subtypes of IDH mutations may lead to different AML prognoses, suggesting the feasibility of personalized treatment for AML patients.

Prevalence of SPOP and IDH Gene Mutations in Prostate Cancer in a Jordanian Population.

Speckle-type POZ (SPOP) is described as an essential tumor suppressor factor in gastric cancer, colorectal cancer, and prostate cancer (PCa). SPOP gene mutations were reported in primary human PCa. Isocitrate dehydrogenase-1 (IDH1) oncogene mutations were detected in gliomas, acute myeloid leukemia, some benign and malignant cartilaginous tumors, and only 1% of PCa. This study aimed to investigate the prevalence of mutations of SPOP and IDH1 genes in PCa in the Jordanian population. One hundred formalin-fixed paraffin-embedded tissue samples were collected from patients diagnosed with prostate adenocarcinoma. The obtained specimens were subjected to genomic DNA extraction, PCR amplification, and direct sequencing of exons 4, 5, 6, and 7 of the SPOP gene and exon 6 of the IDH1 gene. SPOP gene mutations were found in 17% of PCa cases, while no mutation was detected in the screened exon 6 of the IDH1 gene. Clinicopathological data demonstrated a strong correlation between prostate-specific antigen (PSA) levels and both Gleason score (GS) and the International Society of Urological Pathology (ISUP) grade group (GG). There was no significant correlation between PSA levels and age (p = 0.816) nor there were significant associations for SPOP mutational status with age (p = 0.659), PSA levels (p = 0.395), GS (p = 0.259), and ISUP GG (p = 0.424) in the tested population. The study found a strong correlation between PSA levels and both GS and ISUP GG. It also identified a high frequency (17%) of SPOP gene mutations in Jordanian Arab PCa patients, mainly in exon 7. No IDH1 mutations were detected in exon 6.

High-Throughput Drug Screening in Chondrosarcoma Cells Identifies Effective Antineoplastic Agents Independent of IDH Mutation

The term chondrosarcoma refers to a rare and heterogeneous group of malignant cartilaginous tumors that are typically resistant to chemotherapy and radiotherapy. Metastatic chondrosarcoma has a poor prognosis, and effective systemic therapies are lacking. Isocitrate dehydrogenase (IDH) mutations represent a potential therapeutic target, but IDH inhibitors alone have shown limited clinical efficacy to date. Although the role of conventional chemotherapy is still subject to debate, some evidence suggests it may provide therapeutic benefits in advanced cases. In this study, we aimed to identify effective compounds for combination therapy in chondrosarcoma. Using high-throughput screening, we evaluated a panel of anticancer agents in IDH1-mutant chondrosarcoma cell lines and their mutant IDH1 knockout derivatives. The top 20 most potent compounds were identified across all cell lines, irrespective of IDH mutation status. Representative drugs selected for further investigation included docetaxel, methotrexate, panobinostat, idarubicin, camptothecin, and pevonedistat. These drugs inhibited colony formation, induced apoptosis and cell cycle arrest, and exhibited synergistic antitumor activity in two-drug combinations. In conclusion, we identified several highly effective agents with potent anti-tumor activity in chondrosarcoma cells, independent of IDH mutation status. These agents represent promising candidates for chondrosarcoma therapy and warrant further preclinical investigation and potential inclusion in clinical trials.

Radiomics for predicting grades, isocitrate dehydrogenase mutation, and oxygen 6-methylguanine-DNA methyltransferase promoter methylation of adult diffuse gliomas: combination of structural MRI, apparent diffusion coefficient, and susceptibility-weighted imaging.

There has been no research investigating susceptibility-weighted imaging (SWI) radiomics features in evaluating molecular makers in gliomas. The aim of this study was to assess the predictive value of radiomics features extracted from structural magnetic resonance imaging (MRI), apparent diffusion coefficient (ADC), and SWI in determining World Health Organization (WHO) Grade, isocitrate dehydrogenase (IDH) mutation, and oxygen 6-methylguanine-DNA methyltransferase (MGMT) promoter methylation in patients with diffuse gliomas. Retrospective MRI data of 539 patients from University of California San Francisco and Nanjing Drum Tower Hospital between January 2010 and December 2022 were analyzed in this study. The training, internal validation, and external test cohorts included 426 (median age 60 years, 168 female), 67 (median age 56 years, 31 female), and 46 (median age 55 years, 22 female) patients, respectively. A total of 7,896 radiomics features were extracted from structural MRI, ADC, and SWI within two regions of interest (ROIs). Feature selection was conducted using analysis of variance (ANOVA) F-test, and random forest was employed to establish predictive models. Chi-square test and Mann-Whitney U test were used for assessing the statistical differences in patients' clinical characteristics. Delong test was performed to compare the areas under the curve (AUCs) of different radiomics models. For WHO Grade task, the combined model of structural MRI, ADC, and SWI achieved the highest AUC of 0.951 [95% confidence interval (CI): 0.886-1.000] on the external test cohort. For IDH mutation task, the structural MRI model achieved the highest AUC of 0.917 (95% CI: 0.801-1.000) on the external test cohort. For MGMT task, the combined model of structural MRI and ADC achieved the highest AUC of 0.650 (95% CI: 0.485-0.814) on the internal validation cohort. The combined structural MRI, ADC, and SWI models achieved promising performance in assessing WHO Grade and IDH mutation status but showed no efficacy in predicting MGMT methylation status. Adding SWI and ADC features cannot provide extra information to structural MRI in predicting WHO grade and IDH mutation.

Morphological, physiological, and biochemical responses of rice (Oryza sativa L.) varieties to drought stress via regulating respiration and ROS metabolism during germination

Germination marks a pivotal and sensitive phase in the life cycle of crops, with drought stress, precipitated by water scarcity, posing a significant impediment to the germination process in rice. Despite this, the regulation mechanism of respiratory and reactive oxygen species (ROS) metabolism during rice germination under drought stress remains to be fully elucidated. This manuscript presents an integrative analysis encompassing morphological, physiological, biochemical, and molecular attributes of germinated seeds from a cultivated drought-sensitive rice variety (JN10) and a drought-resistant rice variety (NG36). Our findings revealed that drought stress adversely affected the germination of both rice varieties, with NG36 exhibiting a more rapid germination rate compared to JN10 under such stress conditions. This differential response was attributed to the heightened activity of key enzymes, elevated levels of metabolic intermediates, and upregulated expression of genes encoding enzymes involved in ROS and respiratory metabolic pathways in NG36. To further dissect the interplay between these metabolic pathways, we selected specific enzyme activities for detailed examination. Notably, a robust positive linear correlation was established among phosphofructokinase (PFK), α-ketoglutarate dehydrogenase (KGDH), citrate synthase (CS), and isocitrate dehydrogenase (ICDH) in NG36. This correlation underscores the pivotal role of glycolytic pathways, particularly the tricarboxylic acid (TCA) cycle, in conferring drought resistance to NG36 during the germination phase under drought stress. To encapsulate our findings, the results of this investigation suggest that the rice cultivar NG36 manifests a heightened degree of drought tolerance relative to JN10. This is primarily achieved through the adept modulation of its respiratory metabolic pathways and the stringent preservation of ROS homeostasis during the germination phase under conditions of water deficit. These revelations provide unprecedented insights into the intricate regulatory mechanisms that subserve rice's drought resistance, potentially paving the way for the development of novel strategies in the breeding of rice cultivars with improved drought resilience.

Intraoperative label-free tissue diagnostics using a stimulated Raman histology imaging system with artificial intelligence: An initial experience.

Accurate intraoperative tissue diagnostics could impact on decision making regarding the extent of resection (EOR) during brain tumor surgery. Stimulated Raman histology (SRH) is a label-free optical imaging method that uses different biochemical properties of tissue to generate a hematoxylin-eosin-like image and, in combination with an artificial intelligence-based image classifier, offers the opportunity to obtain rapid intraoperative tissue diagnoses. The goal of this study was to report on our initial experience with SRH to evaluate its accuracy in comparison to final tissue diagnosis. We evaluated 70 consecutive adult cases with brain tumors. We compared results of the three different SRH classifier (diagnostic, molecular and tumor/non-tumor) to the respective final histopathological result. Similarly, we evaluated the isocitrate dehydrogenase (IDH) mutations in 18 patients using SRH. Lastly, we compared SRH results of samples taken from the tumor margins with early postoperative MRI. Prediction accuracy was evaluated by logistic regression and Receiver Operator Curve (ROC) analysis. We included 19 gliomas, 9 metastases, 22 meningiomas and 14 other tumor entities. Regarding accuracy of intraoperative SRH predictions, regression analysis showed an Area Under the Curve (AUC) of 0.77 (95 % C.I. 0.64-0.89, p = 0.0008), suggesting agreement of predictions with final diagnosis. For specific tumor entities, variable accuracies were observed: The highest accuracy was obtained for meningiomas followed by high-grade glioma. IDH mutations were predicted with an AUC of 0.93 (95 % C.I. 0.88-0.98; p < 0.0001). The SRH examination of tissue samples from tumor margins corresponded with postoperative MRI in 4 out of 5 cases. Our initial experience with SRH shows that this novel imaging technique is a promising approach to obtain rapid intraoperative tissue diagnosis to guide surgical decision making based on histology and cell-density. With further refinement of AI-based automated image classification and a better integration into the surgical workflow, prediction accuracy and reliability could be improved.

SLC12A9 is an immunological and prognostic biomarker for glioma

BackgroundGlioma is one of the most common malignant brain tumors. It has a high rate of progression and a poor prognosis, and effective biomarkers still need to be identified. The solute carrier family 12 (SLC12) family has been reported to be involved in various physiological and pathological processes, but their functional roles in glioma remain unclear. MethodsUsing public datasets, we studied the mutation and expression level of SLC12 family genes in glioma and identified the significantly differentially expressed member solute carrier family 12 member 9 (SLC12A9). We further predicted the prognostic role of SLC12A9 in glioma by using the Kaplan–Meier method and Cox regression analysis. Then, we performed biological functional enrichment analysis. We focused on the relationships between SLC12A9 expression and immune infiltration in glioma. Meanwhile, we conducted in vitro experiments to evaluate the effect of SLC12A9 expression on glioma cells. ResultsAmong the members of the SLC12 family, SLC12A9 had the highest mutation rate in glioma, with gene amplification as the major mutation type, and its expression was significantly upregulated in glioma. Higher SLC12A9 expression was significantly associated with older age, higher grade, wild-type isocitrate dehydrogenase (IDH), and a worse prognosis. The functional enrichment analysis indicated that SLC12A9 is mainly related to ion channel annotation. Gene set enrichment analysis (GSEA) revealed that SLC12A9 was mainly related to the DNA replication pathway. Furthermore, we found that SLC12A9 correlated with tumor-infiltrating immune cells and immune checkpoints. Thus, SLC12A9 may be involved in regulating the immune response of glioma. Finally, our in vitro experiments revealed that silencing SLC12A9 dramatically inhibited glioma cell growth and migration. ConclusionsWe showed that SLC12A9 may be a new predictive biomarker for glioma diagnosis, prognosis, and immunotherapy response, offering helpful guidelines to advance glioma treatment.

Treatment Options for IDH-Mutant Malignant Gliomas.

As the peak incidence of isocitrate dehydrogenase (IDH)-mutant gliomas is amongst young adults, there is a need to balance tumor control with long term side effects of therapy. Following initial clinical presentation and acquisition of contrasted diagnostic imaging, tissue diagnosis is essential in suspected diffuse glioma. Depending on the location and extent of disease, maximal surgical resection is preferred both for histologic diagnosis and initial therapy. Partial resection or biopsy alone is considered when the tumor cannot be completely resected or if there are clinical reservations regarding a more significant operation. The classification of diffuse glioma has evolved over time, with histopathology and molecular marker status guiding discussions of prognosis and postoperative management. In patients with IDH-mutant grade 2 glioma and low-risk features, observation with active surveillance is generally recommended following a gross total resection. For those with high-risk features, which historically included age > 40years or subtotal resection, adjuvant chemotherapy and radiation therapy are generally recommended, however decisions for adjuvant therapy pose challenges as many of the landmark historical trials guiding adjuvant therapy were performed prior to the molecularly defined era. This is an area where multiple clinical trials are ongoing and hold promise to inform treatment paradigms, including recent data on the use of IDH-mutant inhibitors in grade 2 tumors with recurrent or residual disease. For IDH-mutant grade 3 and 4 glioma, adjuvant chemotherapy and radiation are recommended for all patients after initial resection.

Tubular MYDGF Slows Progression of Chronic Kidney Disease by Maintaining Mitochondrial Homeostasis.

Mitochondrial dysfunction is a key event driving the maladaptive repair of tubular epithelial cells during the transition from acute kidney injury to chronic kidney disease (CKD). Therefore, identifying potential targets involved in mitochondrial dysfunction in tubular epithelial cells is clinically important. Myeloid-derived growth factor (MYDGF), a novel secreted protein, plays important roles in multiple cardiovascular diseases, but the function of MYDGF in tubular epithelial cells remains unknown. In the present study, it is found that MYDGF expression is significantly reduced in the cortex of the kidney, especially in the proximal tubules, from mice with CKD. Notably, lower expression of MYDGF is observed in tubules from patients with CKD and the level of MYDGF correlated with key factors related to kidney fibrosis and estimated glomerular filtration rate (eGFR) in patients with CKD. Tubule-specific deletion of Mydgf exacerbates kidney injury in mice with CKD; however, Mydgf overexpression attenuates kidney fibrosis by remodeling mitochondrial homeostasis in tubular epithelial cells. Mechanistically, renal tubular MYDGF positively regulates the expression of isocitrate dehydrogenase 2 (IDH2), restores mitochondrial homeostasis, and slows CKD progression. Thus, this study indicates that MYDGF derived from tubules may be an effective therapeutic strategy for patients with CKD.

Patient-derived glioma organoids real time identification of IDH mutation, 1p/19q-codeletion and CDKN2A/B homozygous deletion with differential ion mobility spectrometry.

Extent of brain tumor resection continues to be one of the central decisions taken during standard of care in glioma patients. Here, we aimed to evaluate the most essential molecular factors, such as IDH (isocitrate dehydrogenase) mutation in gliomas classification with patient-derived glioma organoids (PGOs) using differential mobility spectrometry (DMS). we prospectively recruited 12 glioma patients, 6 IDH-mutated and 6 IDH wild-type tumors, from which PGOs were generated ex-vivo. Altogether, 320 PGOs DMS spectra were analyzed with a classifier algorithm based on linear discriminant analysis (LDA). LDA model classification accuracy (CA) obtained between IDH-mutant and IDH wild-type PGOs was 90% (91% sensitivity and 89% specificity). Furthermore, 1p/19q codeletion classification within IDH mutant PGOs reached 98% CA (93% sensitivity and 99% specificity), while CDKN2A/B homozygous loss status had 86% CA (63% sensitivity 93% specificity). DMS suitability to differentiate IDH-mutated PGOs was thus validated in ex vivo cultured samples, PGOs. Preliminary results regarding 1p/19q codeleted PGOs and CDKN2A/B loss PGOs identification endorse testing in a prospective intraoperative glioma patient cohort. Our results reveal a sample classification set-up that is compatible with real-time intraoperative surgery guidance.

Sulfur redirects carbon metabolism to optimize nitrogen utilization and promote andrographolide biosynthesis in Andrographis paniculata seedlings

Sulfur (S) is an important mineral nutrient element that improves plant growth and secondary metabolism. S affects the biosynthesis of andrographolide in medicinal plant Androgaphis paniculata by regulating nitrogen (N) metabolism. However, its specific role in N utilization and the connection with andrographolide biosynthesis have not yet been thoroughly understood. Here, a soilless cultivation experiment with low S (LS, 0.1 mM) and high S (HS, 2.4 mM) was conducted to investigate how S influences carbon (C) metabolism and N utilization to promote andographolide biosynthesis in Andrographis paniculata. The results showed that HS significantly increased plant biomass and N use efficiency (NUE), accompanying with remarkable enhanced andrographolide content. HS promoted the expression of photosynthetic genes, and redirected C metabolism towards to sugars accumulation by enhancing the activities of NAD-dependent glutamate dehydrogenase (NAD-GDH), malic enzyme (ME) and phosphoenolpyruvate carboxykinase (PEPCK) (P < 0.05). On the other hand, HS reduced N and S assimilation, and stimulated a greater N allocation in photosynthesis. Accordingly, NUE was increased and andrographolided biosynthesis could profit from the shift of C resource reallocation. Additionally, the significantly increased activities of ME, glucose 6-phosphate dehydrogenase (G6PDH) and isocitrate dehydrogenase (ICDH) provided reductants for secondary metabolism. HS also considerably upregulated the expression of genes in andrographolide biosynthetic pathway, including ApDXS, ApDXR, ApHDS and ApHDR in the MEP pathway, and ApGGPS. Transcription factors in the families of MYB, WRKY, ERF and bHLH, and plant hormones ABA and JA were in response to HS. Our results revealed that S synergistically promotes NUE and andrographolide biosynthesis via remodeling of C metabolism in A. paniculata.

Activity of NAD(P)-Dependent Dehydrogenases of Ovarian Vein Lymphocytes in Women with Pelvic Varicose Veins.

The activities of NAD- and NADP-dependent isocitrate dehydrogenases (NAD-ICDH and NADP-ICDH), NAD- and NADP-dependent glutamate dehydrogenases (NAD-GDH and NADP-GDH), and NAD- and NADP-dependent malate dehydrogenases (NAD-MDH and NADP-MDH) in ovarian veins lymphocytes in 183 women of reproductive age with pelvic varicose veins (PVV) and 30 women in the control group were determined. The indicators of intracellular enzymatic activity showed multidirectional changes with increasing severity of the disease. Compared to the control group, women with stage II of PVV had higher median values for lactate dehydrogenase (16.69), NAD-GDH (39.48), NADP-GDH (7.48), NADP-MDH (9.06) and lower values of NAD-ICDH (65.41). Women with stage III of PVV had lower median values for succinate dehydrogenase (9.27), NAD-MDH (26.19), and higher values for glucose-6-phosphate dehydrogenase (8.62), lactate dehydrogenase (24.67), NAD-GDH (63.81), NADP-MDH (21.05) compared to the control group. Studying the activity of NAD(P)-dependent dehydrogenases in lymphocytes at the local level during PVV allows us to evaluate the intensity and dynamics of local varicose veins progression, as well as to optimize its correction.

Evolving cell states and oncogenic drivers during the progression of IDH-mutant gliomas.

Isocitrate dehydrogenase (IDH) mutants define a class of gliomas that are initially slow-growing but inevitably progress to fatal disease. To characterize their malignant cell hierarchy, we profiled chromatin accessibility and gene expression across single cells from low-grade and high-grade IDH-mutant gliomas and ascertained their developmental states through a comparison to normal brain cells. We provide evidence that these tumors are initially fueled by slow-cycling oligodendrocyte progenitor cell-like cells. During progression, a more proliferative neural progenitor cell-like population expands, potentially through partial reprogramming of 'permissive' chromatin in progenitors. This transition is accompanied by a switch from methylation-based drivers to genetic ones. In low-grade IDH-mutant tumors or organoids, DNA hypermethylation appears to suppress interferon (IFN) signaling, which is induced by IDH or DNA methyltransferase 1 inhibitors. High-grade tumors frequently lose this hypermethylation and instead acquire genetic alterations that disrupt IFN and other tumor-suppressive programs. Our findings explain how these slow-growing tumors may progress to lethal malignancies and have implications for therapies that target their epigenetic underpinnings.

Decoding Glioblastoma Heterogeneity: Neuroimaging Meets Machine Learning.

Recent advancements in neuroimaging and machine learning have significantly improved our ability to diagnose and categorize isocitrate dehydrogenase (IDH)-wildtype glioblastoma, a disease characterized by notable tumoral heterogeneity, which is crucial for effective treatment. Neuroimaging techniques, such as diffusion tensor imaging and magnetic resonance radiomics, provide noninvasive insights into tumor infiltration patterns and metabolic profiles, aiding in accurate diagnosis and prognostication. Machine learning algorithms further enhance glioblastoma characterization by identifying distinct imaging patterns and features, facilitating precise diagnoses and treatment planning. Integration of these technologies allows for the development of image-based biomarkers, potentially reducing the need for invasive biopsy procedures and enabling personalized therapy targeting specific pro-tumoral signaling pathways and resistance mechanisms. Although significant progress has been made, ongoing innovation is essential to address remaining challenges and further improve these methodologies. Future directions should focus on refining machine learning models, integrating emerging imaging techniques, and elucidating the complex interplay between imaging features and underlying molecular processes. This review highlights the pivotal role of neuroimaging and machine learning in glioblastoma research, offering invaluable noninvasive tools for diagnosis, prognosis prediction, and treatment planning, ultimately improving patient outcomes. These advances in the field promise to usher in a new era in the understanding and classification of IDH-wildtype glioblastoma.

Molecular Analysis of Genes CEBPA, NPM1, IDH1, and RUNX1 Polymorphisms as Biomarker Potential in Leukemia Patients.

Leukemia is found in approximately 2.3 million people worldwide and causes many deaths all over the world. This research study was conducted to figure out the link of single nucleotide polymorphisms of genes CEBPA (rs34529039), NPM1 (rs753788683), IDH1 (of rs11554137) and RUNX1 (rs13051066) polymorphisms as biomarker potential in leukemia patients. A total of 600 subjects were included in the study which included 300 patients and 300 healthy controls with age and gender matched. After DNA extraction, PCR was carried out to analyze polymorphisms of selected genes. A significant association with increased risk of leukemia by almost twofolds is observed in homozygous mutant (AA) of rs34529039 SNP of gene CEBPA (odds ratio [OR] = 1.71; 95% confidence interval [CI] = 1.04-2.82; p = 0.03) while highly significant association but with decrease risk of leukemia is observed in heterozygote genotype (CA) of same SNP (OR = 0.36; 95% CI = 0.22-0.59; p = 0.0001). A highly significant association with increased risk of leukemia up to twofolds is observed in heterozygote genotype (AG) of rs753788683 of gene NPM1 (OR 2.10: 95% CI 1.32-3.36 p = 0.0017) while increasing risk by two-fold and show significant association in homozygous mutant (AA) (OR = 1.75; 95% Cl = 1.09-2.79; p = 0.01). Leukemia risk increases by twofold and shows significant association in the homozygous mutant (AA) of rs11554137 (OR = 1.75; 95%Cl = 1.09-2.79; p = 0.01). Leukemia risk increases by twofold and shows significant association in the homozygous mutant (AA) of rs13051066 of gene RUNX1 (OR = 0.63; 95%Cl = 0.39-1.63; p = 0.06).