bluuebunny/crossref_metadata_2025_split huggingface dataset:
RBIO-08. GTP SIGNALING LINKS ALTERED METABOLISM, DNA REPAIR AND TREATMENT RESISTANCE IN GLIOBLASTOMA
Authors: Zhou Weihua , Zhao Zitong , Lin Angelica , Yang John , Xu Jie , Wilder-Romans Kari , Yang Annabel , Li Jing , Solanki Sumeet , Speth Jennifer , Walker Natalie , Scott Andrew J , Kothari Ayesha , Yao Yangyang , Peterson Erik , Korimerla Navyateja , Werner Christian , Liang Jessica , Jacobson Janna , Palavalasa Sravya , Obrien Alexandra , Elaimy Ameer , Ferris Sean , Zhao Shuang , Sarkaria Jann , Győrffy Balázs , Zhang Shuqun , Al-Holou Wajd , Umemura Yoshie , Morgan Meredith , Lawrence Theodore , Lyssiotis Costas , Peters-Golden Marc , Shah Yatrik , Wahl Daniel 
Published: November 2023

Abstract

OBJECTIVE
We sought to define the mechanisms by which purines regulate DNA repair and therapy response.

METHODS
Phosphoproteomics was used to identify GTP-dependent (de)phosphorylation events after radiation (RT) and antibodies generated against novel sites. Animal models of glioblastoma (GBM) and normal tissues were used to assess DNA repair and treatment responses in vivo.

RESULTS
Pharmacogenomic inhibition of GTP (but not ATP) synthesis sensitized GBM cells to RT by inhibiting the activity of non-homologous end joining, but not homologous recombination. We found a GTP-dependent RT-induced dephosphorylation event on Abl interactor 1 (Abi-1) serine 323 (S323) using phosphoproteomics. We generated a new antibody for p-Abi-1 (S323), validated its specificity, and confirmed that RT causes a GTP-dependent dephosphorylation of Abi-1 (S323). Knockout of Abi-1 slowed RT-induced double-strand break (DSB) repair, and this was rescued by re-expression of dephosphomimetic Abi-1 (S323A) but not phosphomimetic Abi-1 (S323D). Abi-1 canonically binds to G protein Rac1. Expression of constitutively active Rac1 promoted but dominant negative Rac1 blocked the dephosphorylation of Abi-1 (S323) and DSB repair. Knock-down or inhibition of protein phosphatase 5 reversed the GTP- and Rac1-mediated dephosphorylation of Abi-1 and DSB repair. In GBM PDX samples, p-Abi-1 (S323) levels negatively correlated with Rac1 activity and predicted favorable efficacy of genotoxic treatments. In orthotopic GBM mouse models, inhibiting Rac1 enhanced RT responses and suppressed Abi-1 (S323) dephosphorylation. Abi-1 knockout enhanced efficacy of genotoxic treatments and could be rescued by Abi-1 S323A (but not Abi-1 S323D) re-expression. This regulation is generalizable beyond brain cancer, as GTP supplementation promoted DNA repair and p-Abi1 (S323) dephosphorylation in non-malignant cells and protected mice from RT-mediated gastrointestinal injury and bleomycin-induced pulmonary fibrosis.

CONCLUSION
The GTP-Rac1-PP5-Abi-1 signaling axis links metabolism and DNA repair. Disrupting this pathway can overcome GBM resistance to genotoxic therapy while augmenting it can mitigate genotoxic injury of normal tissues.
RBIO-09. HMGB2 INHIBITION RADIO-SENSITIZES GLIOBLASTOMA CELLS INDEPENDENTLY OF THEIR TP53-MUTATION STATUS
Authors: Becker Aline , Becker Valesio , Sebastian Ebin , Showalter Christian , McElroy Joseph , Jaharul Haque S , Chakravarti Arnab 
Published: November 2023

Abstract
Alterations in TP53 are major drivers of radiation resistance in gliomas. High Mobility Group Box 2 (HMGB2) has been implicated in resistance to temozolomide through p53-phosphorylation during DNA double-strand break repair and in silico analysis suggests its involvement in the p53-p21-RB signaling pathway. Nevertheless, the role of HMGB2 in radiation response has not been fully explored in gliomas. While HMGB2 is virtually not expressed in the normal adult brain, increasing expression with histopathological glioma grade correlates with poor patient survival. We confirmed increased HMGB2 expression in grade 3 compared to grade 2 gliomas using ClariomD and observed spatial heterogeneous HMGB2 expression in glioblastomas (GBMs) in histopathology-targeted supervised proteomic analysis employing liquid chromatography tandem mass spectroscopy (LC-MS-MS). Here, we aimed to study HMGB2 effects in cell proliferation and response to radiation in a set of molecularly distinct genetically engineered GBM cell lines (IDHwt). Using an established U87 GBM cell line and isogenic primary GBM cell lines GBM3359 TP53wt and CRISPR/Cas9-engineered mutant TP53 (R248W) generated in our laboratory, we successfully produced clones with either HMGB2 shRNA knockdown (KD – over 70% reduction) or HMGB2 lentiviral-mediated overexpression (OE – 3-76x higher expression). HMGB2-KD reduced cell proliferation (10% in U87; 20-25% in isogenic GBM3359 cell lines) and colony formation (more than 50% reduction), which was further rescued with HMGB2 OE in all cell lines. Half maximal inhibitory concentration (IC50) for radiation was determined by methylene blue cell proliferation and clonogenic assays, which showed that HMGB2-KD decreased the IC50 while rescued HMGB2 OE increased RT resistance of all clones. Taken together, our data suggest that HMGB2 inhibition may improve radiation response independently of TP53 status in gliomas. Further mechanistic studies to elucidate the relationship between HMGB2 and TP53 are underway to unfold the contribution of heightened HMGB2 expression to radiation resistance mechanisms in gliomas.
RTID-01. A RANDOMIZED STUDY OF LOW-INTENSITY FOCUSED ULTRASOUND FOR BLOOD-BRAIN BARRIER DISRUPTION FOR BRAIN METASTASIS FROM NON-SMALL CELL LUNG CANCER (LIMITLESS)
Authors: Ahluwalia Manmeet , McDermott Michael , Ozair Ahmad , Khosla Atulya , Sahgal Arjun , Mishra Mark V , Achrol Achal , Sahni K Singh , Sanai Nader , Lipsman Nir , Woodworth Graeme F 
Published: November 2023

Abstract

BACKGROUND
Blood-brain barrier disruption (BBBD) has been demonstrated, in preclinical models, to improve systemic drug delivery for BM. Low-intensity focused ultrasound (LIFU) with intravenously (IV) administered microbubble oscillators results in non-invasive BBBD, potentially permitting drug delivery. This randomized controlled trial (RCT) aims to determine the safety and efficacy of LIFU-mediated BBBD for NSCLC BM with immunotherapy.

METHODS
LIMITLESS is an ongoing prospective, multicenter, parallel-arm, open-label RCT that randomizes patients with NSCLC-BM on pembrolizumab monotherapy prescribed as per standard-of-care to LIFU plus pembrolizumab (arm 1) or pembrolizumab alone (arm 2) in 2:1 ratio. Included patients have age ≥18 years, normal organ function, KPS≥70, EGFR- and ALK-negative primary tumor, and ≤3 BM, with ≥1 BM meeting measurable disease RANO-BM criteria. Patients on both arms receive standard-of-care therapy, while those on arm 1 also undergo LIFU before each dose of pembrolizumab (200 mg IV every 3 weeks). These patients undergo pre-treatment MRI brain, followed by IV administration of oscillating microbubbles for enhanced sonication. MR-guided BBBD is then performed using 220 kHz LIFU device with real-time acoustic feedback. Pembrolizumab is infused immediately thereafter, and repeat MRI done confirming BBB closure each cycle. Primary study endpoint is overall objective response rate (ORR) at 6 months as per RANO-BM criteria. Using a Bayesian design, a superior ORR of 60% is assumed for the LIFU arm versus 30% in the control arm for N = 96, 64 subjects in LIFU and 32 in control arm, for 80% power, with alpha = 0.05. For upper-bound estimate ORR of 45% in LIFU arm and 30% in control arm, the study needs N = 369 subjects; 246 in the LIFU arm and 123 in the control arm. Secondary outcomes are the best overall response rate and median time-to-response. Exploratory outcomes are median PFS, OS, intracranial PFS, extracranial PFS, and quality of life. Clinical trial information: NCT05317858.
RTID-02. SILMET TRIAL: A RANDOMIZED, PLACEBO-CONTROLLED STUDY TO EVALUATE SILIBININ IN PREVENTING INTRACRANIAL RECURRENCE AFTER COMPLETE RESECTION OF A SINGLE BRAIN METASTASIS FROM NSCLC OR BREAST CANCER
Authors: Pellerino Alessia , Pace Andrea , Angileri Filippo Flavio , Caffo Maria , Gatti Marco , Olivi Alessandro , D'Alessandris Quintino Giorgio , Fabi Alessandra , Bertero Luca , Ricci Alessia Andrea , Mangherini Luca , Garbossa Diego , Priego Neibla , Bosch-Barrera Joaquim , Valiente Manuel , Soffietti Riccardo , Rudà Roberta 
Published: November 2023

Abstract
BACKGROUND: A subpopulation of reactive astrocytes (RAs) with activated signal transducer and activator of transcription 3 (STAT3) signalling in peritumoral tissue of brain metastases (BM) has been shown to favor a pro-metastatic microenvironment. High-pSTAT3 expression in RAs of BM has been correlated with a shorter intracranial progression-free survival (i-PFS) as compared with low-pSTAT3 BM. Pharmacological inhibition of the STAT3 pathway with silibinin has been suggested to be active in preliminary cohort of patients with BM. Patients and methods. A new “prevention” trial has been initiated in June 2023 to investigate the efficacy of silibinin in comparison to placebo (PCB) to prevent a secondary intracranial relapse in a multicentric cohort of patients with gross-total resected BM from NSCLC and breast cancer. Inclusion criteria are as follows: histologically confirmed BM from NSCLC or BC; single BM who underwent a complete resection; systemic disease not requiring a change of antineoplastic therapy; pSTAT3 presence in RAs of peritumoral tissue confirmed by central assessment; ≥ 18 – 70 years of age; KPS ≥ 70. The primary endpoint is to demonstrate a superiority of silibinin in prolonging time to local recurrence as compared to PCB. The secondary endpoints are time to distant recurrence of BM in the brain, i-PFS, overall PFS (intracranial and/or systemic), overall survival, tolerability, quality of life. Collection of blood and CSF samples for the analysis of STAT3 downstream pathways is an exploratory objective. The sample size (70 patients) was calculated by assuming a median time to local recurrence of BM of 7.5 months for PCB (control arm) according to Mahajan [1] and ≥15 months for silibinin arm. Clinical trial information: NCT05689619 [1] Mahajan A et al. Post-operative stereotactic radiosurgery versus observation for completely resected brain metastases: a single-centre, randomised, controlled, phase 3 trial. Lancet Oncol. 2017
RTID-04. GLUGLIO - A PHASE IB/II RANDOMIZED DRUG REPURPOSING TRIAL OF GLUTAMATE SIGNALING INHIBITORS IN COMBINATION WITH CHEMORADIOTHERAPY IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA (NCT05664464)
Authors: Wirsching Hans-Georg , Roth Patrick , Fischer Angela , Hottinger Andreas , Hundsberger Thomas , Migliorini Denis , Ochsenbein Adrian , Laeubli Heinz , Seystahl Katharina , Imbach Lukas , Hortobagyi Tibor , Held Leonhard , Bink Andrea , Weller Michael 
Published: November 2023

Abstract
Glioblastoma synthesizes and secretes large quantities of the excitatory neurotransmitter glutamate, driving epilepsy, neuronal death, tumor growth and invasion. Several brain-penetrating drugs that have obtained clinical approval in other pathologic conditions can inhibit glutamate synthesis, secretion and signalling, respectively, including (i) the anti-seizure drug gabapentin, which inhibits the glutamate synthesis enzyme, branched chain amino acid transaminase 1, (ii) the anti-inflammatory drug sulfasalazine, which inhibits glutamate secretion by blocking the cystine-glutamate exchanger system Xc, and (iii) the cognitive enhancer memantine, which can prevent glutamate-driven, calcium-induced neuronal death and tumor cell invasion by blocking N-methyl-D-aspartate (NMDA) type glutamate receptors. The multi-centre, open-label, parallel-group, two-arm, 1:1 randomized, phase Ib/II trial GLUGLIO explores the efficacy of a triple-combination of daily oral gabapentin, sulfasalazine and memantine in combination with standard chemoradiotherapy compared to chemoradiotherapy alone. Dosing of either drug will be sought up to the maximum approved dose and will be reevaluated in an interim safety analysis after 20 patients have been randomized into the experimental arm. The primary endpoint is progression-free survival at 6 months (PFS-6). The sample size of N = 120 patients was calculated to detect an increase in PFS-6 from 50% to 70% with a power of 80% performing exploratory hypothesis testing at a one-sided significance level of 10%. Secondary endpoints include progression-free, overall and seizure-free survival, response rate, quality of life of patients and caregivers, symptom burden, cognitive functioning, tumor glutamate levels by magnetic resonance spectroscopy as well as anti-convulsant and steroid use. Surgical tissues as well as peripheral blood and electroencephalography recordings will also be sampled longitudinally for translational analyses. Recruitment is ongoing and foreseen to be completed by mid 2026. The simultaneous targeting of glutamate synthesis, secretion and signalling will clarify whether glutamate should be further explored as a clinical target in glioblastoma patients.
RTID-05. SURGICAL WINDOW OF OPPORTUNITY TRIAL REVEALS MECHANISMS OF RESPONSE AND RESISTANCE TO NAVTEMADLIN (KRT-232) IN PATIENTS WITH RECURRENT GLIOBLASTOMA
Authors: Rendo Veronica , Lee Eudocia , Bossi Connor , Khuu Nicholas , Pal Sangita , Reynolds Abigail , Fassinou Auriole , Ligon Keith , Beroukhim Rameen , Wen Patrick , Rudek Michelle 
Published: November 2023

Abstract
Over half of glioblastoma multiforme (GBM) patients retain wild-type p53, resulting in potential susceptibility to MDM2 inhibitors. These molecules disrupt the interaction between p53 and its negative regulator MDM2, resulting in downstream pathway signaling and cell fate decisions such as growth inhibition and death from cellular stress. We have analyzed clinical samples from 21 patients with recurrent GBM treated with the MDM2 inhibitor KRT-232, all of which relapsed despite the biological promise of this small molecule. By analyzing on-treatment biopsy samples, we detected upregulation of p53 transcriptional targets, suggesting blood-brain barrier penetrance and drug pharmacodynamics. However, in patient-derived cell lines, treatment with KRT-232 at the clinically achieved concentration was only sufficient to stall but not reduce tumor growth. Cell death via apoptosis was achieved in these cell line models when MDM2 inhibition was combined with the chemotherapeutic agent temozolomide. These drugs have non-overlapping mechanisms of action and exhibit synergy in our cell line models. Normal human bone marrow cells underwent a reversible growth inhibition phenotype when treated with KRT-232 and TMZ, supporting the idea that a therapeutic window exists with this combination. We additionally observed that tumor progression occurred in the absence of p53 inactivating mutations, suggesting that other mechanisms of resistance to KRT-232 may modulate drug response and resistance in GBM. Indeed, drug treatment induced an adaptive response in human tumors, characterized by the upregulation of genes involved in glial cell differentiation processes. Ongoing work is focused on understanding how tumor heterogeneity and cell state modulate response and resistance of GBMs to MDM2 inhibition and other therapeutic strategies that reactivate p53 signaling. Our study highlights the utility of tissue sampling during clinical trials and represents the first clinical effort to detect adaptive changes in human tumor tissue associated with p53 reactivation.
SURG-01. DIFFERENTIATION OF GLIOBLASTOMA AND MALIGNANT MENINGIOMA FROM NORMAL BRAIN BY TISSUE STIFFNESS UTILIZING MICROSURGICAL FORCEPS EQUIPPED WITH HAPTICS TECHNOLOGY
Authors: Ezaki Taketo , Kisima Kohki , Shibao Shunsuke , Matsunaga Takuya , Pareira Eriel Sandika , Kitamura Yohei , Takahara Kento , Iwama Takashi , Sampetrean Oltea , Ohnishi Kouhei , Shimono Tomoyuki , Sasaki Hikaru 
Published: November 2023

Abstract
Stiffness of human cancers strongly correlate with their pathology, and it is reported that stiffness can be used as a biomarker. Furthermore, comprehensive analysis has suggested the usefulness of cancer stiffness in diagnosis and malignancy prediction and its association with molecular expression, as well as its potential for predicting and diagnosing postoperative complications. Neurosurgeons perform tumor resection relying on the sensations that they feel with their own fingertips (tactile sensation), but it takes years of surgical experience to accurately distinguish brain tumor from the surrounding normal brain tissue.
Haptics is a new technology regarding touching sensation. Especially, our technology, real haptics, can communicate, record, and reproduce the real sensation. It is also possible to measure and analyze the physical property such as stiffness of the touching object from the obtained haptic data.
We developed a surgical forceps equipped with haptics technology to distinguish brain tumor tissue from surrounding normal brain tissue. three glioblastoma cell lines (SF126, U87, U251) and a malignant meningioma cell line (IOMM-Lee) were each transplanted intracranially into 5 nude mice. Tumor size was periodically monitored and mice were euthanized at appropriate time points. The stiffness of the tumor and normal brain tissue was measured using a master-slave integrated surgical forceps prototype. The results statistically showed that all four types of brain tumor tissues were stiffer than normal brain tissues. (p = 0.001) In addition, malignant meningioma was statistically stiffer than glioblastomas. (p = 0.025) This result is consistent with actual surgical sensations.
We have shown that our surgical forceps has the ability to distinguish pathology of brain tumors as well as to distinguish brain tumor from normal brain tissue. The forceps is also helpful for the neurosurgeons to sense minute change in tissue stiffness.
SURG-05. HYPER SMART CYBER OPERATING THEATER TO PERFORM FUTURE PREDICTIVE SURGERY
Authors: Muragaki Yoshihiro , Masamune Ken , Sasayama Takashi , Kawamata Takakazu 
Published: November 2023

Abstract
Gliomas are invasive tumors in which the extent of tumor resection is believed to correlate with prognosis. However, aggressive extraction risks deterioration due to functional tissue damage. One strategy for resolving this conflict is the technology of new modalities. The basis of this technology is digital transformation (DX), converting analog information called tacit knowledge on experiences into digital information for explicit knowledge. In the future, we will develop an AI system, generated by DX data, and support intraoperative decision-making with highly accurate future predictions. In order to realize this future-prediction surgery, we have developed a smart cyber operating theater (SCOT) with intraoperative MRI. More than 20 medical devices are connected by middleware (OPeLiNK®), and navigation spatial records and time-synchronized data are displayed on the strategy desk. A hyper version of SCOT has currently performed 277 surgeries, including 262 gliomas, 51 awake craniotomies, and 88 photodynamic therapies. For WHO grade 4 glioblastomas, we try to remove contrast-enhanced areas, and for grade 2/3 gliomas, to formulate an extraction strategy for each 3 genotypes, we perform preoperative AI prediction and intraoperative genetic diagnosis for genotype. Intraoperative flow cytometry is useful to predict the genotype (oligodendroglioma) and determine the extent of resection in some cases. Time-synchronized data showed points of surgical maneuvers causing speech arrest in awake surgery and decreases in MEP, and provided feedback during and after surgery. AI technology is also used for preoperative surgical simulation (GRID®), artifact reduction in iMRI, and brain shift prediction. The hyper SCOT supports the optimal removal of gliomas through intraoperative future prognosis prediction through device data and AI analysis. Furthermore, we are developing an AI robot (AIREC) that performs surgery through deep predictive learning, with the aim of commercialization after 2040. This work was partially supported by JST [Moonshot R&D] [Grant Number JPMJMS2031].
SURG-06. DEVELOPING A LASER INTERSTITIAL THERMAL THERAPY (LITT) PLATFORM FOR THE TREATMENT OF INTRACRANIAL LESIONS IN CANINES
Authors: Wachsmuth Lucas , Ruterbories Laura , Tsvankin Vadim , Bramall Alexa , Tyc Richard , Mariani Christopher , Fecci Peter 
Published: November 2023

Abstract
Malignant gliomas are devastating intracranial tumors with dismal prognoses that impose unique therapeutic challenges. Treatment options include surgical resection, radiation, and chemotherapy, but efficacy is limited and carries associated morbidity. Promise persists for newer modalities, such as immune-based platforms, but obstacles include limited therapeutic access due to the blood-brain barrier (BBB) and the highly immunosuppressive tumor microenvironment. Laser interstitial thermal therapy (LITT) is a minimally invasive surgical intervention permitting thermal ablation of intracranial tumors. During LITT, a laser probe is stereotactically placed in the lesion through a skull burr hole. Real-time MRI is used to calculate thermal dosage zones to monitor ablation progress. LITT is not only cytoreductive but also opens the BBB and induces a powerful hyperthermia-driven anti-tumor immune response; it thus may synergize with other emerging therapies. Spontaneous canine glioma offers a matchless, optimally recapitulative appropriately sized tumor model, providing a unique opportunity to investigate and optimize the LITT platform. We adapted a commercially available LITT system (Monteris Medical) for application in canines with intracranial lesions. Initially, canine cadavers were used to optimize LITT procedures; we then performed LITT in live dogs. Our approach consists of 1. obtaining volumetric MRI studies for trajectory planning, 2. fixing canine patients to the surgical bed, 3. registering anatomic landmarks (Brainlab) to a volume rendered image, 4. using an integrated instrument holder (Varioguide, Brainlab) to guide drilling of 4.5 mm skull burr holes for placement of self-tapping titanium “mini-bolts” (Monteris Medical), and 5. introducing the laser through the mini-bolts for ablation in the MRI suite. This method allows for rigid stereotaxy, successful neuronavigation, and a minimally invasive approach. We have successfully performed LITT on four canine patients with intracranial gliomas. Future studies will explore immunologic mechanisms underlying the post-LITT anti-tumor response as well as combination therapeutic platforms, including nanoparticles and stereotactic radiotherapy.