bluuebunny/crossref_metadata_2025_split huggingface dataset:
Longitudinal change in proteinuria and kidney outcomes in C3 glomerulopathy
Authors: Caravaca-Fontán Fernando , Díaz-Encarnación Montserrat , Cabello Virginia , Ariceta Gema , Quintana Luis F , Marco Helena , Barros Xoana , Ramos Natalia , Rodríguez-Mendiola Nuria , Cruz Sonia , Fernández-Juárez Gema , Rodríguez Adela , Pérez de José Ana , Rabasco Cristina , Rodado Raquel , Fernández Loreto , Pérez Gómez Vanessa , Ávila Ana , Bravo Luis , Espinosa Natalia , Allende Natalia , Sanchez de la Nieta Maria Dolores , Rodríguez Eva , Olea Teresa , Melgosa Marta , Huerta Ana , Miquel Rosa , Mon Carmen , Fraga Gloria , de Lorenzo Alberto , Draibe Juliana , Cano-Megías Marta , González Fayna , Shabaka Amir , López-Rubio Maria Esperanza , Fenollosa María Ángeles , Martín-Penagos Luis , Da Silva Iara , Alonso Titos Juana , Rodríguez de Córdoba Santiago , Goicoechea de Jorge Elena , Praga Manuel 
Published: March 2021

AbstractIntroductionThe association between a change in proteinuria over time and its impact on kidney prognosis has not been analysed in complement component 3 (C3) glomerulopathy. This study aims to investigate the association between the longitudinal change in proteinuria and the risk of kidney failure.MethodsThis was a retrospective, multicentre observational cohort study in 35 nephrology departments belonging to the Spanish Group for the Study of Glomerular Diseases. Patients diagnosed with C3 glomerulopathy between 1995 and 2020 were enrolled. A joint modelling of linear mixed-effects models was applied to assess the underlying trajectory of a repeatedly measured proteinuria, and a Cox model to evaluate the association of this trajectory with the risk of kidney failure.ResultsThe study group consisted of 85 patients, 70 C3 glomerulonephritis and 15 dense deposit disease, with a median age of 26 years (range 13–41). During a median follow-up of 42 months, 25 patients reached kidney failure. The longitudinal change in proteinuria showed a strong association with the risk of this outcome, with a doubling of proteinuria levels resulting in a 2.5-fold increase of the risk. A second model showed that a ≥50% proteinuria reduction over time was significantly associated with a lower risk of kidney failure (hazard ratio 0.79; 95% confidence interval 0.56–0.97; P &lt; 0.001). This association was also found when the ≥50% proteinuria reduction was observed within the first 6 and 12 months of follow-up.ConclusionsThe longitudinal change in proteinuria is strongly associated with the risk of kidney failure. The change in proteinuria over time can provide clinicians a dynamic prediction of kidney outcomes.
BIMG-03. MOLECULAR IMAGING OF GLUCOSE METABOLISM FOR INTRAOPERATIVE FLUORESCENCE GUIDANCE DURING GLIOMA SURGERY
Authors: Belykh Evgenii , Jubran Jubran , George Laeth , Bardonova Liudmila , Healey Deborah , Georges Joseph , Quarles Chad , Eschbacher Jennifer , Mehta Shwetal , Scheck Adrienne , Nakaji Peter , Lawton Michael , Preul Mark 
Published: March 2021

Abstract

PURPOSE
This study evaluated the utility of using molecular imaging of fluorescent glucose analog 2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)Amino)-2-Deoxyglucose (2-NBDG) as a discriminatory marker for intraoperative tumor border identification in a mouse glioma model.

PROCEDURES
2-NBDG and were assessed in GL261 and U251 orthotopic tumor bearing mice. Intraoperative fluorescence of 2-NBDG administered topical and intravenous in normal and tumor regions was assessed with operating microscope, handheld confocal laser scanning endomicroscope (CLE) and benchtop confocal laser scanning microscope (LSM). Additionally, 2-NBDG fluorescence in tumors was compared to 5-aminolevulinic acid-induced protoporphyrin IX fluorescence.

RESULTS
Intravenously administered 2-NBDG was detectable in brain tumor and absent in contralateral normal brain parenchyma on wide field operating microscopy imaging. Intraoperative and benchtop CLE showed preferential 2-NBDG accumulation in the cytoplasm of glioma cells (tumor-background ratio of 2.76±0.43). Topically administered 2-NBDG did not create a sufficient tumor-background contrast for white field operating microscopy imaging, or under benchtop LSM (tumor-background ratio 1.42 ± 0.72). However, topical 2-NBDG did create sufficient contrast to evaluate cellular tissue architecture and differentiate tumor cells from normal brain parenchyma. PpIX imaging resulted in a more specific delineation of gross tumor margins than IV or topical 2-NBDG, and a significantly higher tumor-normal brain fluorescence intensity ratio.

CONCLUSION
After intravenous administration, 2-NBDG selectively accumulated in the experimental brain tumors and provided bright contrast under wide field fluorescence imaging with a clinical grade operating microscope. Topical 2-NBDG was able to create a sufficient contrast to differentiate tumor from normal brain cells based on visualization of cellular architecture with CLE. 5-ALA demonstrated superior specificity in outlining tumor margins and significantly higher tumor-background contrast. Given its non-toxicity, using 2-NBDG as a topical molecular marker for noninvasive in vivo intraoperative microscopy is encouraging, and warrants further clinical evaluation.
DDRE-08. NRF2/GLUTATHIONE METABOLISM AS A NOVEL THERAPEUTIC TARGET FOR IDH1-MUTATED GLIOMA
Authors: Liu Yang , Yu Di , Celiku Orieta , Li Aiguo , Larion Mioara , Yang Chunzhang 
Published: March 2021

Abstract

BACKGROUND
IDH1-mutated glioma is a recently defined disease entity with distinctive patterns of tumor cell biology, metabolism, and resistance to therapy. Although IDH1 mutations are highly prevalent in patients with WHO II/III glioma, curative molecular targeting approaches remain unavailable for this disease cluster.

METHODS
In the present study, we investigated the glutathione de novo synthesis pathway through the TCGA patient cohort and patient-derived cell lines with IDH1 mutation. The biologic function of nuclear factor erythroid 2-related factor 2 (NRF2) was analyzed by biochemistry and cell biology assays. Finally, NRF2 inhibitors were evaluated in IDH1-mutated cell lines and preclinical models as an experimental therapy.

RESULTS
IDH1 mutant neomorphic activity depletes the cellular pools of enzyme cofactors such as nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). The limitation of NAD(P) not only affects the anabolic reactions, but also results in oxidative stress and damages on DNA and protein. Further, we showed that the reprogrammed redox landscape results in constitutive activation of NRF2-governed cytoprotective pathways through the decoupling of NRF2 from its E3 ligase Kelch-like ECH-associated protein 1. NRF2 mediated the transcriptional activation of GCLC, GCLM, and SLC7A11, which not only strengthens the glutathione de novo synthesis, but also relieves the metabolic burden in IDH1-mutated cells. The importance of the glutathione synthesis is further confirmed through COX regression analysis on lower-grade glioma. Blockade of the NRF2/glutathione metabolic pathway synergizes with the elevated intrinsic oxidative stress, which results in overwhelming oxidative damage, as well as a substantial reduction in tumor cell proliferation and xenograft expansion.

CONCLUSION
We report that the NRF2-guided cytoprotective pathways play pivotal roles in the disease progression of IDH1-mutated glioma. Targeting NRF2 and glutathione metabolism could be novel targeting strategies for IDH1-mutated glioma.
DDRE-09. THERAPEUTIC TARGETING OF PURINE METABOLISM IN DIPG
Authors: Mersich Ian , Dasgupta Biplab 
Published: March 2021

Abstract
Diffuse intrinsic pontine glioma (DIPG) is an incurable brainstem malignancy in children with median survival less than 1 year and 5-year overall survival only 2 percent. Little progress has been made in treating this deadly disease due to its inoperable location and treatments aimed at targets defined in adult gliomas. Despite recent advances in genetic characterization of DIPGs there are still no targeted therapies that significantly improve overall survival. We recently generated a metabolic profile for patient-derived DIPG cell lines by integrating an untargeted metabolomics analysis with RNA-sequencing data from the same lines which demonstrated dysregulated purine metabolism in these cells. Furthermore, we have identified putative driver mutations common to DIPG patients as the direct cause for this metabolic alteration. Purine metabolism provides the basic components of nucleotides needed for tumor proliferation and thus considered a high-priority target in cancer treatment. De novo purine biosynthesis (DNPS) is a sequential ten step enzymatic process resulting in the production of inosine monophosphate. The DNPS enzymes co-localize into a metabolon known as the purinosome and our preliminary data demonstrates DIPG cell lines are selectively sensitive to pharmacological and genetic disruption of purinosome formation. Interestingly, antifolate compounds that inhibit DNPS, but do not disrupt purinosome assembly, are cytotoxic to both DIPG cells and normal cell types. Strikingly, cell viability could be rescued by purine supplementation when inhibiting this pathway with antifolates, however inhibition of DNPS by disruption of purinosome assembly could not be rescued. Metabolomics analysis showed DIPGs have a preference for generating GMP over AMP which is exacerbated when purinosome assembly is disrupted. This is likely due to the duel-role of the DNPS enzyme ADSL which is required for AMP production.
DDRE-21. THE FUNCTION OF MITOCHONDRIAL OSMR IN GLIOMA STEM CELL RESPIRATION AND GLIOBLASTOMA PATHOGENESIS
Authors: Jahani-Asl Arezu , Sharanek Ahmad 
Published: March 2021

Abstract
Glioblastoma contains a rare population of self-renewing brain tumor stem cells (BTSCs) which are endowed with properties to proliferate, spur the growth of new tumors, and at the same time, evade ionizing radiation (IR) and chemotherapy. However, the drivers of BTSC resistance to therapy remain unknown. The cytokine receptor for oncostatin M (OSMR) regulates BTSC proliferation and glioblastoma tumorigenesis. We have discovered that OSMR translocates to the mitochondria and regulates oxidative phosphorylation, independent of its role in cell proliferation. Mechanistically, OSMR is targeted to the mitochondrial matrix via the presequence translocase-associated motor complex components, mtHSP70 and TIM44. OSMR interacts with NADH ubiquinone oxidoreductase 1/2 (NDUFS1/2) of complex I and promotes mitochondrial respiration. Deletion of OSMR impairs spare respiratory capacity, increases reactive oxygen species, and sensitizes BTSCs to IR-induced cell death. Importantly, suppression of OSMR improves glioblastoma response to IR and prolongs lifespan.
DDRE-23. A COMPREHENSIVE CHARACTERIZATION OF THE GBM LIPIDOME REVEALS A MOLECULARLY-DEFINED SUB-GROUP WITH HEIGHTENED SENSITIVITY TO LIPID PEROXIDATION INDUCED CELL DEATH
Authors: Morrow Danielle , Minami Jenna , Bayley Nicholas , Williams Kevin , Bensinger Steven , Prins Robert , Liau Linda , Cloughesy Timothy , Nathanson David 
Published: March 2021

Abstract
Cancers, including the universally lethal glioblastoma (GBM), have reprogrammed lipid metabolism to fuel tumor growth and promote survival. However, the full extent to which lipid content is altered across molecularly heterogeneous patient tumors has yet to be fully elucidated. Additionally, the molecular alterations responsible for aberrant lipid metabolism, and the potential for identifying new therapeutic opportunities are not fully understood. To systematically investigate the GBM lipidome, we performed integrated transcriptomic, genomic and shotgun lipidomic analysis of an extensive library of molecularly diverse patient-derived GBM tumors across tumor microenvironments both in vivo (n=23) and in vitro (n=30). Using this comprehensive approach, we discovered two GBM sub-groups defined by their combined molecular and lipidomic profile. Triacylglycerides (TAGs) enriched in polyunsaturated fatty acids (PUFAs) were among the most significantly altered lipids between the two groups of GBM tumors. TAGs are the main components of lipid droplets, which have been shown to sequester PUFAs away from membrane phospholipids where their sensitivity to peroxidation leads to cell death. The GBM subgroup with a depletion of PUFA TAGs showed heightened sensitivity to lipid peroxidation both under basal conditions and in response to pro-oxidant compounds in vitro. Our findings suggest a novel association between specific molecular signatures of GBM, lipid metabolism and lipid peroxidation-induced cell death. This relationship may present a new therapeutic opportunity to target reprogrammed lipid metabolism in a molecularly-defined subset of GBMs.
DDRE-31. FEASIBILITY AND BIOLOGIC ACTIVITY OF A KETOGENIC / INTERMITTENT FASTING DIET IN GLIOMA PATIENTS
Authors: Schreck Karisa , Hsu Fang-Chi , Berrington Adam , Henry-Barron Bobbie , Vizthum Diane , Blair Lindsay , Kossoff Eric , Easter Linda , Whitlow Christopher , Cervenka Mackenzie , Barker Peter , Blakeley Jaishri , Strowd Roy 
Published: March 2021

Abstract

BACKGROUND
There has been increasing interest in exploring ketogenic diet therapies (KDT) in patients with glioma given the poor prognosis. The purpose of this single-arm, open label phase 2 study was to rigorously examine the feasibility, safety, systemic biological activity, and cerebral activity of a KDT in patients with glioma.

METHODS
25 patients with biopsy-confirmed WHO Grade 2–4 astrocytoma with stable disease following adjuvant chemotherapy were enrolled in an 8-week GLioma Atkins-based Diet (GLAD). GLAD consisted of 2 fasting days (calories&lt;20% calculated estimated needs) interleaved between 5 modified Atkins diet days (net carbohydrates≤20 gm/day) each week. The primary outcome was dietary adherence by food records. Markers of systemic and cerebral activity included weekly urine ketones, serum insulin, glucose, hemoglobin A1c, IGF-1, and MR spectroscopy at baseline and week 8.

RESULTS
21 patients completed the study. 80% of patients reached ≥40 mg/dL urine acetoacetate during the study. 48% of patients were adherent by food record. The diet was well-tolerated with two grade 3 adverse events (neutropenia, seizure). Measures of systemic activity including hemoglobin A1c, insulin, and fat body mass decreased significantly, while lean body mass increased. MR spectroscopy demonstrated increased ketone concentrations (β-hydroxybutyrate (bHB) and acetone (Ace)) in both lesional and contralateral brain, compared to baseline. Higher total choline (tCho) and glutamine (Gln) levels were observed in lesional as compared to contralateral brain at baseline, and both decreased following intervention. Average ketonuria correlated with cerebral ketones in lesional (tumor) and contralateral brain (bHB Rs0.52, p=0.05). There were no differences in cerebral metabolites in IDH-mutant glioma after controlling for ketonuria.

CONCLUSIONS
The GLAD dietary intervention, while demanding, produced meaningful ketonuria, and significant systemic and cerebral metabolic changes in participants. Participant ketonuria correlated with cerebral ketone concentration and appears to be a better indicator of systemic activity than patient-reported food records.
ETMM-04. AURKA INHIBITION REPROGRAMS METABOLISM AND IS SYNTHETICALLY LETHAL WITH FATTY ACID OXIDATION INHIBITION IN GLIOBLASTOMA MODEL SYSTEMS
Authors: Nguyen Trang , Shu Chang , Shang Enyuan , Mela Angeliki , Humala Nelson , Mahajan Aayushi , Akman Hasan , Quinzii Catarina , Zhang Guoan , Westhof Mike-Andrew , Karpel-Massler Georg , Bruce Jeffrey , Canoll Peter , Siegelin Markus 
Published: March 2021

Abstract
Aurora kinase A (AURKA) has emerged as a viable drug target for glioblastoma (GBM), the most common malignant primary brain tumor in adults with a life expectancy of 12–15 months. However, resistance to therapy remains a critical issue, which partially may be driven by reprogramming of metabolism. By integration of transcriptome, chromatin immunoprecipitation with sequencing (CHIP-seq.), assay for transposase-accessible chromatin with sequencing (ATAC-seq.), proteomic and metabolite screening followed by carbon tracing (U-13C-Glucose, U-13C-Glutamine and U-13C-Palmitic acid) and extracellular flux analysis we provided evidence that genetic (shRNA and CRISPR/Cas9) and pharmacological (Alisertib) AURKA inhibition elicited substantial metabolic reprogramming supported in part by inhibition of MYC targets and concomitant activation of PPARA signaling. While glycolysis was suppressed by AURKA inhibition, we noted a compensatory increase in oxygen consumption rate fueled by enhanced fatty acid oxidation (FAO). Whereas interference with AURKA elicited a suppression of c-Myc, we detected an upregulation of PGC1A, a master regulator of oxidative metabolism. Silencing of PGC1A reversed AURKAi mediated metabolic reprogramming and sensitized GBM cells to AURKAi driven reduction of cellular viability. Chromatin immunoprecipitation experiments showed binding of c-Myc to the promoter region of PGC1A, which is abrogated by AURKA inhibition and in turn unleashed PGC1A expression. Consistently, ATAC-seq. confirmed higher accessibility of a MYC binding region within the PGC1A promoter, suggesting that MYC acts as a repressor of PGC1A. Combining alisertib with inhibitors of FAO or the electron transport chain exerted substantial synergistic growth inhibition in PDX lines in vitro and extension of overall survival in orthotopic GBM PDX models without induction of toxicity in normal tissue. In summary, these findings support that simultaneous targeting of oxidative energy metabolism and AURKAi might be a potential novel therapy against GBM.
FSMP-07. CYSTATHIONINE-Γ-LYASE DRIVES ANTIOXIDANT DEFENSE IN CYSTEINE-RESTRICTED IDH1 MUTANT ASTROCYTOMAS
Authors: Cano-Galiano Andrés , Oudin Anais , Fack Fred , Allega Maria-Francesca , Sumpton David , Martinez-Garcia Elena , Dittmar Gunnar , Hau Ann-Christin , Herold-Mende Christel , Bjerkvig Rolf , Meiser Johannes , Tardito Saverio , Niclou Simone P 
Published: March 2021

Abstract
Mutations in isocitrate dehydrogenase 1 or 2 (IDH1/2) define glioma subtypes and are considered primary events in gliomagenesis, impacting tumor epigenetics and metabolism. IDH enzymes are crucial for the generation of reducing potential, yet the impact of the mutation on the cellular antioxidant system is not understood. Here, we investigate how glutathione (GSH) levels are maintained in IDH1 mutant gliomas, despite an altered NADPH/NADP balance. We find that IDH1 mutant astrocytomas specifically upregulate cystathionine γ-lyase (CSE), the enzyme responsible for cysteine production upstream of GSH biosynthesis. Genetic and chemical interference with CSE in patient-derived glioma cells carrying the endogenous IDH1 mutation, sensitized tumor cells to cysteine depletion, an effect not observed in IDH1 wild-type gliomas. This correlated with reduced GSH synthesis as shown by in vitro and in vivo serine tracing and led to delayed tumor growth in mice. Thus we show that IDH1 mutant astrocytic gliomas critically rely on NADPH-independent de novo GSH synthesis to maintain the antioxidant defense, which uncovers a novel metabolic vulnerability in this dismal disease.
FSMP-09. FORMATE PROMOTES CANCER CELL INVASION AND METASTASIS VIA CALCIUM SIGNALING
Authors: Delbrouck Catherine , Pozdeev Vitaly I , Oudin Anais , Grzyb Kamil , Neises Laura , Kiweler Nicole , Skupin Alexander , Letellier Elisabeth , Niclou Simone P , Meiser Johannes 
Published: March 2021

Abstract
Serine catabolism via the folate cycle provides formate that is essential for nucleotide synthesis in proliferating cells. In addition to this canonical function to support biomass production in anabolic cells, we have recently demonstrated in vitro and in vivo that formate production in cancer cells is often in excess of the anabolic demand. This excess formate production is characterized by formate overflow and thus, net formate excretion into the tumor microenvironment. Interestingly, we observe increased rates of formate overflow upon different chemical perturbations that induce growth arrest. Thus, stressed cancer cells that encounter growth restriction such as upon chemotherapy, are often characterized by increased formate release rates. We demonstrated that such high formate levels in the extracellular space promote invasion of glioblastoma cells. Using ex vivo brain slice cultures and an orthotopic brain tumor model, we demonstrate that silencing MTHFD1L, the essential enzyme to enable formate overflow, results in decreased invasiveness of the tumor. Embarking from this observation, we investigated the underlying mechanism and now provide evidence that the formate-dependent increase of cell motility is mediated by an activation of Ca2+ signaling. Activation of Ca2+ signaling triggers integrin and matrix metallopeptidase (MMP) responses enabling the invasion process. Targeting either the Ca2+ response or MMP release can suppress the formate dependent increase in invasion. Finally, we tested the effect of formate also in context of breast cancer where we were able to recapitulate our observation of increased invasiveness and, in this case, formate also promoted the metastatic potential. We conclude that excreted formate might serve as a cellular stress signal that represents a promotive trigger to support tumor escape mechanisms.
TBMT-01. HYPERPOLARIZED δ-[1-13C]GLUCONOLACTONE MONITORS TERT-INDUCED ELEVATION IN PENTOSE PHOSPHATE PATHWAY FLUX IN BRAIN TUMORS IN VIVO
Authors: Batsios Georgios , Viswanath Pavithra , Taglang Celine , Flavell Robert , Costello Joseph , Pieper Russell O , Larson Peder , Ronen Sabrina 
Published: March 2021

Abstract
Telomerase reverse transcriptase (TERT) expression is essential for tumor proliferation and is an attractive therapeutic target for gliomas. TERT expression has previously been shown to enhance glucose flux via the pentose phosphate pathway (PPP) in low grade gliomas expressing TERT. Hyperpolarized δ-[1-13C]gluconolactone has been used to detect flux via the PPP by monitoring its conversion to 6-phospho-[1-13C]gluconate (6PG) in isolated perfused liver. The goal of our study was to evaluate whether hyperpolarized δ-[1-13C]gluconolactone can be used to monitor elevated PPP flux induced by TERT expression in low grade gliomas, thereby providing a non-invasive method of assessing TERT expression in vivo. Immortalized normal human astrocytes without (NHApre) and with TERT expression (NHApost) were used in cell bioreactor experiments. In vivo experiment with rats bearing orthotopic NHApost or patient-derived low-grade oligodendroglioma (SF10417) tumors were contacted. Dynamic 13C MR spectra were acquired at 14T (cells) or 3T (rats) following injection of hyperpolarized δ-[1-13C]gluconolactone. NHApost cells showed significantly higher flux through the PPP compared to NHApre. This finding was in agreement with previous results indicating that TERT expression elevates PPP flux. In all rats δ-[1-13C]gluconolactone and 6PG were observed indicating that δ-[1-13C]gluconolactone crosses the blood-brain barrier and is rapidly metabolized. Furthermore, both models presented homogeneous distribution of δ-[1-13C]gluconolactone in the brain and higher ratio of 6PG-to-δ-[1-13C]gluconolactone in the tumor area. In summary we show in vivo that hyperpolarized δ-[1-13C]gluconolactone metabolism to 6-phospho-[1-13C]gluconate is significantly higher in tumor compared to contralateral normal brain in TERT-expressing genetically-engineered and patient-derived low-grade oligodendrogliomas. Due to its fundamental role in tumor proliferation, TERT is both a tumor biomarker and a therapeutic target. Monitoring HP δ-[1-13C]gluconolactone metabolism, therefore, has the potential to inform on tumor burden and response to therapy in the clinic.