bluuebunny/crossref_metadata_2025_split huggingface dataset:
SYST-28 FUNCTIONAL MAPPING REVEALS WIDESPREAD REMODELLING AND A NOVEL TARGETABLE PTP4A2-ROBO1 SIGNALING AXIS AT GLIOBLASTOMA RECURRENCE
Authors: Chokshi Chirayu , Shaikh Vaseem , Tieu David , Brakel Benjamin , Brown Kevin , chan Katherine , rossotti Martin , Maich William , Venugopal Chitra , Anand Alisha , Lazo John , Kislinger Thomas , Lu Jian , Provias John , Henry Kevin , Moffat Jason , Singh Sheila 
Published: August 2023

Abstract
Resistance to genotoxic therapies and tumor recurrence are hallmarks of glioblastoma (GBM), an aggressive brain tumor. Here, we explore the functional drivers of post-treatment recurrent GBM. By conducting genome-wide CRISPR-Cas9 screens in patient-derived GBM models, we uncover distinct genetic dependencies in recurrent tumor cells that were absent in their patient-matched primary predecessors, accompanied by increased mutational burden and differential transcript and protein expression. These analyses map a multilayered genetic response to drive tumor recurrence, identifying protein tyrosine phosphatase 4A2 (PTP4A2) as a novel modulator of self-renewal, proliferation and tumorigenicity at GBM recurrence. Mechanistically, genetic perturbation or small molecule inhibition of PTP4A2 represses axon guidance activity through a dephosphorylation axis with roundabout guidance receptor 1 (ROBO1), exploiting a functional dependency on ROBO signaling. Roundabout guidance receptor 1 (ROBO1) protein is involved in axonal guidance during neurodevelopment and aberrant ROBO1 signaling axis is associated with higher tumorigenicity in GBM. ROBO1 was highly expressed on the surface of malignant and treatment-refractory brain tumor initiating cells (BTICs) in rGBM, brain metastasis (BM) and medulloblastoma (MB). Importantly, engineered anti-ROBO1 single-domain antibodies also mimic the effects of PTP4A2 inhibition. We therefore developed and validated second-generation CAR-T cells against ROBO1, which demonstrated upregulation of activation markers, enhanced cytokine release, markedly increased proliferation, and induction of potent and specific tumor cell death compared to untransduced cells in all the three brain cancers. These findings were further validated in vivo in rGBM, MB and BM models, where ROBO1 CAR-T cells showed significant reduction in tumor burden and increase in survival of treated mice. We conclude that functional reprogramming drives tumorigenicity and dependence on a multi-targetable PTP4A2-ROBO1 signaling axis at GBM recurrence.
SYST-31 PROBIOTIC DELIVERY TO ORTHOTOPIC GLIOBLASTOMA MULTIFORME MODELS AS AN IMMUNOTHERAPY
Authors: Windemuth Sophia , Ali Alessandra , Molotkov Andrei , Hahn Jaeseung , Danino Tal , Leong Kam , Mintz Akiva 
Published: August 2023

Abstract
Therapeutic bacteria have been shown to be effective as an immunotherapy in several types of solid tumors because of their inherent immunogenicity and ability to target tumor tissue with systemic administration. Furthermore, advances in synthetic biology enable production and release of cancer therapeutics from bacteria. However, there is little work describing therapeutic probiotics in brain cancers such as glioblastoma multiforme (GBM). To bridge this gap, we tested different routes of administration for delivery of engineered strains of E. coli Nissle (EcN), and observed the colonization of orthotopic GBM tumors in immunocompetent mouse models. In these models, we successfully colonized tumors using both intratumoral and intravenous injection with little to no observable off-target colonization. This specificity in both delivery methods demonstrates that systemic delivery of wild-type EcN is sufficient to achieve targeted colonization of the tumor. After systemic delivery of bacteria was established in GBM, we sought to reduce edema reactions to the bacteria that occurred after colonization. To reduce the inflammatory response, we treated the edema with antibodies against vascular endothelial growth factor (VEGF), which are a clinical standard treatment for high intracranial pressure. Injecting anti-VEGF antibodies prior to bacteria administration substantially increased the survival rate compared to the mice not given anti-VEGF, suggesting that anti-VEGF significantly reduces the toxicity resulting from the bacteria that has been observed in our work and that of other works. This work therefore opens up the possibility of further work in optimizing the engineered strains for treating GBM.
TIPS-05 ADJUVANT TEMOZOLOMIDE CHEMOTHERAPY FOLLOWING RADIOTHERAPY IN NEWLY DIAGNOSED LOW-GRADE GLIOMA PATIENT WITH RESIDUE TUMORS: A MULTICENTER, OPEN LABEL, RANDOMIZED TRIAL
Authors: Chen Zhongping , Sai Ke , Yang Qunying , Guo Chengcheng , Wu Shaoxiong , Xia Yunfei , Xi Shaoyan , Liao Yixiang 
Published: August 2023

Abstract
Low-grade glioma (LGG) with infiltrative nature and frequent growth in eloquent area in brain often makes total resection impossible. Although post-radiation adjuvant temozolomide (TMZ) is the standard of care for high-grade gliomas, and radiotherapy and/or TMZ are recommended for the treatment of residue low-grade gliomas, the efficacy of combined radiotherapy with adjuvant TMZ for residue LGG remains to be defined. We have initiated a randomized clinical trial in 2012 to test whether radiotherapy with subsequent TMZ chemotherapy will improve survival of patients with residue LGG compared to radiotherapy alone. This study was approved by the Ethics Committee of the Sun Yat-sen University Cancer Center, Guangzhou, China (approval No. 5010-2012-03) and was registered with ClinicalTrials.gov (NCT01649830). Inclusion Criteria: Patients age of 18 years to 60 years, with incompletely resected supratentorial WHO grade 2 astrocytoma, oligodendroglioma or oligodendroastrocytoma. Enrolled patients were randomized into: radiation therapy alone (RT) or radiotherapy with subsequent TMZ chemotherapy (RC) group. Start Date: July 2012, Estimated Primary Completion Date:August 2025. Radiation therapy will start within 8 weeks after neurosurgical procedures, with a total dose of 54.0 Gy in 27 - 30 fractions over 6 - 7 weeks. Four weeks after radiotherapy, patients in RC group will receive 6 cycle of TMZ dosed at 200 mg/m2 daily for 5 consecutive days, repeated every 28 days. We have completed enrollment on December 2018 with valid cases of 248 patients. Up to last follow-up date of Feb. 2023, 204 cases were analyzed (see table). There is no significant difference between RT group and RC group on both PFS and OS (5-year PFS 68.9% vs 75.2%, p=0.680; 5-year OS 92.0% vs 86.0%, p=0.400). Longer follow-up and molecular subgroup analysis are currently on the way, which could show benefit in special molecular subgroup.
TIPS-06 ADVANCING BEYOND THE HIPPOCAMPUS TO PRESERVE COGNITION FOR PATIENTS WITH BRAIN METASTASES: DOSIMETRIC RESULTS FROM A PHASE 2 TRIAL OF MEMORY-AVOIDANCE WHOLE BRAIN RADIOTHERAPY
Authors: Perlow Haley K , Nalin Ansel P , Ritter Alex R , Addington Mark , Ward Aubrie , Liu Michal , Nappi Collin , Blakaj Dukagjin M , Beyer Sasha J , Thomas Evan M , Grecula John C , Raval Raju R , Kotecha Rupesh , Boulter Daniel , Dawson Erica L , Zoller Wesley , Palmer Joshua D 
Published: August 2023

Abstract
Recent advances to preserve neurocognitive function in patients treated for brain metastases include stereotactic radiosurgery (SRS), hippocampal avoidance whole brain radiation therapy (HA-WBRT), and memantine administration. The hippocampus, corpus callosum, fornix, and amygdala are key neurocognitive substructures with a low propensity for brain metastases. Herein, we report our preliminary experience using a “memory-avoidance” WBRT (MA-WBRT) approach that spares these substructures for patients with &gt;15 brain metastases. Ten consecutive patients treated with MA-WBRT on a phase 2 clinical trial were reviewed. In each patient, the hippocampi, amygdalae, corpus callosum, and fornix were contoured. Patients were not eligible for MA-WBRT if they had metastases in these substructures. A memory- avoidance region created using a 5mm volumetric expansion around these substructures. Hotspots were avoided in the hypothalamus and pituitary gland. Coverage of brain metastases was prioritized over memory avoidance dose constraints. Dose constraints for these avoidance structures included a D100% ≤ 9Gy and D0.03cc ≤ 16Gy (variation acceptable to 20Gy). LINAC-based volumetric modulated arc therapy (VMAT) plans were generated for a prescription dose of 30 Gy in 10 fractions. On average, the memory avoidance structure volume was 37.1 ccs (Range: 25.2-44.6 ccs), occupying 2.5% of the entire whole brain target volume. All treatment plans met the D100% dose constraint, and 8/10 plans met the D0.03cc constraint, with priority given to tumor coverage for the remaining 2 cases. Target coverage (D98% &gt;25Gy) and homogeneity (D2% ≤ 37.5Gy) were achieved for all plans. Modern VMAT techniques allow for sparing of the hippocampus, amygdala, corpus callosum, and fornix with good target coverage and homogeneity. After enrollment is completed, quality of life and cognitive data will be evaluated to assess the efficacy of MA-WBRT to mitigate declines in quality of life and cognition after whole brain radiation.
TIPS-16 A PROSPECTIVE COHORT STUDY ON THE IMPACT OF RADIOTHERAPY ON QUALITY OF LIFE AND DISEASE PROGRESSION IN PATIENTS WITH BRAIN METASTASES AND THEIR CAREGIVERS
Authors: Cialdella Fia , van Grinsven Eva , van der Boog Arthur , Nagtegaal Steven , Smid Ernst , Claes An , Kleynen Karin , Seravalli Enrica , Philippens Marielle , van Zandvoort Martine , Verhoeff Joost 
Published: August 2023

Abstract

INTRODUCTION
Brain metastases (BMs) are diagnosed in 10-30% of all cancer patients, and the incidence is expected to rise due to advancements in primary tumor management. Besides survival, the impact of treatment on quality of life (QoL) and course of disease is highly relevant for patients and their caregivers. The Cohort for patient-reported Outcomes, Imaging and trial inclusion in Metastatic BRAin disease (COIMBRA) study aims to gather data on natural disease progression, treatment response, tumor recurrence, complications, QoL (for both patient and caregiver), cognitive performance and survival of patients with BMs. Additionally, the study evaluates feasibility, performance and added value of new MRI techniques in patients with BMs, while providing an infrastructure for efficient and pragmatic randomized evaluation of new interventions.

DESIGN/METHODS
COIMBRA is an observational, prospective cohort for patients with brain metastases and their caregivers that are referred to a tertiary academic radiation oncology department. The study is designed according to the Trials within Cohorts (TwiCs) framework. ClinicalTrials.gov Identifier: NCT05267158.

PRELIMINARY RESULTS
Since April 2019, 419 patients have been included of which 51.2% were men and the majority of the patients had lung cancer (53.6%). Stereotactic radiosurgery (SRS) was administered in 92.4% and 68.1% received any systemic therapy. Median Overall Survival was 18.3 months. Questionnaires available at both baseline and 6 months after radiotherapy showed that 65.3% experienced stability or improvement in QoL measured via the EORTC QLQ-C30 questionnaire. Fewer patients reported anxiety or depression after SRS compared to before (28.4% vs 47.8%). Caregivers’ baseline responses indicated that 59% had to adjust their daily lives due to the patient’s diagnosis.

CONCLUSION
Our study successfully collected clinical and QoL data from a large cohort of patients and their caregivers. The results suggest a modest improvement in anxiety and QoL after radiotherapy.
TIPS-18 TRIAL IN PROGRESS: A RANDOMIZED, MULTICENTER, DOUBLE-BLIND, PLACEBO-CONTROLLED, PHASE 2B STUDY TO ASSESS THE SAFETY AND EFFICACY OF IGV-001, AN AUTOLOGOUS CELL IMMUNOTHERAPY WITH ANTISENSE OLIGONUCLEOTIDE (IMV-001) TARGETING IGF-1R, IN NEWLY DIAGNOSED PATIENTS WITH GLIOBLASTOMA
Authors: Perez-Olle Raul , Diwanji Madhavi , Pennock Gregory , Scott Charles , Andrews David 
Published: August 2023

Abstract
Glioblastoma (GBM) is the most common primary brain malignancy in adults. Standard of care (SOC) for suspected GBM begins with maximal safe resection followed by adjuvant radiotherapy and temozolomide, and maintenance temozolomide. Imvax has developed the Goldspire™ platform to create IGV-001, an autologous biologic-device combination product for the treatment of newly diagnosed GBM (ndGBM). IGV-001 consists of autologous GBM tumor cells and an antisense oligonucleotide against IGF-1R mRNA (IMV-001), irradiated and administered via biodiffusion chambers implanted in the abdomen. Together, these components stimulate immunogenic cell death and antigen release. IGV-001 was well tolerated and multiple efficacy signals were observed in a Phase 1b study in patients with ndGBM, including significant improvements in progression-free survival (PFS), radiographic evidence of tumor response, and changes in immune response biomarkers. A Phase 2b randomized, multicenter, double-blind, placebo-controlled study has been initiated to assess the safety and efficacy of IGV-001 in patients with ndGBM (NCT04485949). After surgical resection, patients will be treated with IGV-001 or placebo followed by SOC. 25 US sites have been selected with a target enrollment of 93 patients (2:1 randomization) and the study is open to enrollment. Key inclusion criteria are 18 to 70 years of age, Karnofsky performance status score ≥ 70, diagnosis of GBM based on the treating neurosurgeon's best clinical judgement, confirmed measurable disease pre-operatively, tumor located in the supratentorial compartment, and adequate bone marrow and organ function. Key exclusioncriteria include bihemispheric disease, multicentric disease, or treatment with Tumor Treating Fields (Optune®) prior to documented progression. The primary outcome is PFS, defined as the time from randomization to first progression, as determined by blinded central radiology review, or death. Secondary outcomes include overall survival, defined as the time from randomization to death due to any cause, and safety.
TIPS-21 PHASE I/II STUDY OF STEREOTACTIC RADIOSURGERY WITH CONCURRENT OLAPARIB FOLLOWED BY ADJUVANT DURVALUMAB AND PHYSICIAN’S CHOICE SYSTEMIC THERAPY IN SUBJECTS WITH BREAST CANCER BRAIN METASTASES (SOLARA)
Authors: Shen Colette , Abdou Yara , Chen Linda , Tan Xianming , Gupta Gaorav , Lynce Filipa , Lobbous Mina , Stringer-Reasor Erica , Anders Carey 
Published: August 2023

Abstract

BACKGROUND
Despite progress in the treatment of brain metastasis (BrM) for HER2+ breast cancer (BC), outcomes for patients with HER2-negative BC BrM remain poor. Current standard of care consists of surgery and/or radiotherapy followed by systemic therapy. Preclinical studies show inhibitors of poly(ADP-ribose) polymerase (PARP) are effective together with radiotherapy as DNA damage response inhibitors. Triple-negative BC (TNBC) has higher rates of homologous recombination deficiency compared to other BC subtypes, and together with HER2-negative, BRCA-mutated BC would be particularly sensitive to PARP inhibition. PARP inhibition with immunotherapy has demonstrated promising efficacy in patients with germline BRCA-mutant and metastatic TNBC in clinical trials (MEDIOLA, TOPACIO). In addition, immunotherapy with stereotactic radiosurgery (SRS) is associated with favorable outcomes in patients with BrM. We hypothesize that this biologically-driven combination will enhance local control of SRS-treated BrM through synergy with PARP inhibition, while controlling micrometastatic disease in the brain and extracranial sites by potentiating the immune response.

METHODS
We are conducting a multi-institution, Phase I/II trial of SRS plus olaparib, followed by durvalumab (with physician’s choice systemic therapy), for patients with TNBC (any BRCA status) or HER2-negative with BRCA-mutated (germline or somatic) BC BrM [NCT04711824]. The primary objectives are to evaluate safety and tolerability (Phase I) and intracranial disease control at 6 months (Phase II). Secondary objectives include assessing intracranial and global progression-free survival, overall survival, and intracranial/extracranial response rate. Exploratory objectives will assess potential biomarkers of treatment response, including changes in circulating tumor cells/DNA in blood and cerebrospinal fluid, germline and tumor mutations in DNA repair pathway genes, and PD-L1 expression, as well as quality of life and patient-reported outcomes. A surgical sub-study (n=5) will evaluate olaparib concentration/distribution in resected BrM. As of January 2023, cohort 1 of phase I has been completed without dose-limiting toxicity.
Three consecutive cytosolic glycolysis enzymes modulate autophagic flux
Authors: Lee Du-Hwa , Choi Ilyeong , Park Seung Jun , Kim Sumin , Choi Min-Soo , Lee Ho-Seok , Pai Hyun-Sook 
Published: August 2023

Abstract
Autophagy serves as an important recycling route for the growth and survival of eukaryotic organisms in nutrient-deficient conditions. Since starvation induces massive changes in the metabolic flux that are coordinated by key metabolic enzymes, specific processing steps of autophagy may be linked with metabolic flux-monitoring enzymes. We attempted to identify carbon metabolic genes that modulate autophagy using VIGS screening of 45 glycolysis- and Calvin–Benson cycle-related genes in Arabidopsis (Arabidopsis thaliana). Here, we report that three consecutive triose-phosphate-processing enzymes involved in cytosolic glycolysis, triose-phosphate-isomerase (TPI), glyceraldehyde-3-phosphate dehydrogenase (GAPC), and phosphoglycerate kinase (PGK), designated TGP, negatively regulate autophagy. Depletion of TGP enzymes causes spontaneous autophagy induction and increases AUTOPHAGY-RELATED 1 (ATG1) kinase activity. TGP enzymes interact with ATG101, a regulatory component of the ATG1 kinase complex. Spontaneous autophagy induction and abnormal growth under insufficient sugar in TGP mutants are suppressed by crossing with the atg101 mutant. Considering that triose-phosphates are photosynthates transported to the cytosol from active chloroplasts, the TGP enzymes would be strategically positioned to monitor the flow of photosynthetic sugars and modulate autophagy accordingly. Collectively, these results suggest that TGP enzymes negatively control autophagy acting upstream of the ATG1 complex, which is critical for seedling development.
Gestational Glucose Intolerance and Birth Weight–Related Complications
Authors: Maya Jacqueline , Selen Daryl J. , Thaweethai Tanayott , Hsu Sarah , Godbole Devika , Schulte Carolin C. M. , James Kaitlyn , Sen Sarbattama , Kaimal Anjali , Hivert Marie-France , Powe Camille E. 
Published: August 2023

OBJECTIVE:
To evaluate the risks of large-for-gestational-age birth weight (LGA) and birth weight–related complications in pregnant individuals with gestational glucose intolerance, an abnormal screening glucose loading test result without meeting gestational diabetes mellitus (GDM) criteria.

METHODS:
In a retrospective cohort study of 46,989 individuals with singleton pregnancies who delivered after 28 weeks of gestation, those with glucose loading test results less than 140 mg/dL were classified as having normal glucose tolerance. Those with glucose loading test results of 140 mg/dL or higher and fewer than two abnormal values on a 3-hour 100-g oral glucose tolerance test (OGTT) were classified as having gestational glucose intolerance. Those with two or more abnormal OGTT values were classified as having GDM. We hypothesized that gestational glucose intolerance would be associated with higher odds of LGA (birth weight greater than the 90th percentile for gestational age and sex). We used generalized estimating equations to examine the odds of LGA in pregnant individuals with gestational glucose intolerance compared with those with normal glucose tolerance, after adjustment for age, body mass index, parity, health insurance, race and ethnicity, and marital status. In addition, we investigated differences in birth weight–related adverse pregnancy outcomes.

RESULTS:
Large for gestational age was present in 7.8% of 39,685 pregnant individuals with normal glucose tolerance, 9.5% of 4,155 pregnant individuals with gestational glucose intolerance and normal OGTT, 14.5% of 1,438 pregnant individuals with gestational glucose intolerance and one abnormal OGTT value, and 16.0% of 1,711 pregnant individuals with GDM. The adjusted odds of LGA were higher in pregnant individuals with gestational glucose intolerance than in those with normal glucose tolerance overall (adjusted odds ratio [aOR] 1.35, 95% CI 1.23–1.49, P<.001). When compared separately with pregnant individuals with normal glucose tolerance, those with either gestational glucose intolerance subtype had higher adjusted LGA odds (gestational glucose intolerance with normal OGTT aOR 1.21, 95% CI 1.08–1.35, P<.001; gestational glucose intolerance with one abnormal OGTT value aOR 1.77, 95% CI 1.52–2.08, P<.001). The odds of birth weight–related adverse outcomes (including cesarean delivery, severe perineal lacerations, and shoulder dystocia or clavicular fracture) were higher in pregnant individuals with gestational glucose intolerance with one abnormal OGTT value than in those with normal glucose tolerance.

CONCLUSION:
Gestational glucose intolerance in pregnancy is associated with birth weight–related adverse pregnancy outcomes. Glucose lowering should be investigated as a strategy for lowering the risk of these outcomes in this group.
Repurposing Antihypertensive and Statin Medications for Spinal Pain
Authors: Suri Pradeep , Elgaeva Elizaveta E. , Williams Frances M.K. , Freidin Maxim B. , Verzun Dmitrii A. , Tsepilov Yakov A. 
Published: August 2023

Study Design.
Mendelian randomization (MR) study.

Objective.
To examine whether antihypertensive medications (beta-blockers, calcium channel blockers, and angiotensin-converting enzyme inhibitors) and statins can be repurposed to prevent or treat spinal pain (back or neck pain).

Summary of Background Data.
Observational studies and a recent MR study have found associations between elevated blood pressure and a greater risk of back pain. Observational studies have found associations between hyperlipidemia and statin use and greater risk of back pain. No prior MR studies have examined the effects of antihypertensives or statins on spinal pain.

Materials and Methods.
This was a two-sample MR study using publicly available summary statistics from large-scale genome-wide association studies (GWAS). Sample sizes in exposure GWASs were n=757,601 (systolic blood pressure) and n=173,082 (low-density lipoprotein cholesterol), and n=1,028,947 for the outcome GWAS of spinal pain defined as health care seeking for any spinal pain-related diagnosis. Genes and cis-acting variants were identified as proxies for the drug targets of interest. MR analyses used inverse-variance weighted meta-analysis. The threshold for statistical significance after correction for multiple testing was P<0.0125.

Results.
No statistically significant associations of these medications with spinal pain were found. However, findings were suggestive of a protective effect of beta-blockers on spinal pain risk (odds ratio [OR] 0.84, 95% confidence interval [CI] 0.72–0.98; P=0.03), and calcium channel blockers on greater spinal pain risk (OR 1.12, 95% CI 1.02–1.24; P=0.02).

Conclusions.
A protective effect of beta-blockers on spinal pain was suggested in the current study, consistent with findings from observational studies of various other pain phenotypes. The detrimental effect of calcium channel blockers on spinal pain suggested in the current study must be interpreted in the context of conflicting directions of effect on nonspinal pain phenotypes in other observational studies.