bluuebunny/crossref_metadata_2025 huggingface dataset:
An Analysis of Computational Resources of Event-Driven Streaming Data Flow for Internet of Things: A Case Study
Authors: Tenorio-Trigoso Alonso , Castillo-Cara Manuel , Mondragón-Ruiz Giovanny , Carrión Carmen , Caminero Blanca
Published: September 2021

Information and communication technologies backbone of a smart city is an Internet of Things (IoT) application that combines technologies such as low power IoT networks, device management, analytics or event stream processing. Hence, designing an efficient IoT architecture for real-time IoT applications brings technical challenges that include the integration of application network protocols and data processing. In this context, the system scalability of two architectures has been analysed: the first architecture, named as POST architecture, integrates the hyper text transfer protocol with an Extract-Transform-Load technique, and is used as baseline; the second architecture, named as MQTT-CEP, is based on a publish-subscribe protocol, i.e. message queue telemetry transport, and a complex event processor engine. In this analysis, SAVIA, a smart city citizen security application, has been deployed following both architectural approaches. Results show that the design of the network protocol and the data analytic layer impacts highly in the Quality of Service experimented by the final IoT users. The experiments show that the integrated MQTT-CEP architecture scales properly, keeps energy consumption limited and thereby, promotes the development of a distributed IoT architecture based on constraint resources. The drawback is an increase in latency, mainly caused by the loosely coupled communication pattern of MQTT, but within reasonable levels which stabilize with increasing workloads.
Analysis of Orientia tsutsugamushi promoter activity
Authors: Hunt Jason R , Carlyon Jason A
Published: September 2021

Orientia tsutsugamushi is an obligate intracellular bacterium that causes scrub typhus, a potentially fatal rickettsiosis, and for which no genetic tools exist. Critical to addressing this technical gap is to identify promoters for driving expression of antibiotic resistance and fluorescence reporter genes in O. tsutsugamushi. Such promoters would need to be highly conserved among strains, expressed throughout infection, and exhibit strong activity. We examined the untranslated regions upstream of O. tsutsugamushi genes encoding outer membrane protein A (ompA), 22-kDa type-specific antigen (tsa22) and tsa56. The bacterium transcribed all three during infection of monocytic, endothelial and epithelial cells. Examination of the upstream noncoding regions revealed putative ribosome binding sites, one set of predicted −10 and −35 sequences for ompA and two sets of −10 and −35 sequences for tsa22 and tsa56. Comparison of these regions among geographically diverse O. tsutsugamushi patient isolates revealed nucleotide identities ranging from 84.8 to 100.0%. Upon examination of the candidates for the ability to drive green fluorescence protein expression in Escherichia coli, varying activities were observed with one of the tsa22 promoters being the strongest. Identification and validation of O. tsutsugamushi promoters is an initial key step toward genetically manipulating this important pathogen.
The vitamin A transporter STRA6 adjusts the stoichiometry of chromophore and opsins in visual pigment synthesis and recycling
Authors: Ramkumar Srinivasagan , Parmar Vipul M , Samuels Ivy , Berger Nathan A , Jastrzebska Beata , von Lintig Johannes
Published: September 2021

The retinal pigment epithelium of the vertebrate eyes acquires vitamin A from circulating retinol binding protein for chromophore biosynthesis. The chromophore covalently links with an opsin protein in the adjacent photoreceptors of the retina to form the bipartite visual pigment complexes. We here analyzed visual pigment biosynthesis in mice deficient for the retinol-binding protein receptor STRA6. We observed that chromophore content was decreased throughout the life cycle of these animals, indicating that lipoprotein-dependent delivery pathways for the vitamin cannot substitute for STRA6. Changes in the expression of photoreceptor marker genes, including a downregulation of the genes encoding rod and cone opsins, paralleled the decrease in ocular retinoid concentration in STRA6-deficient mice. Despite this adaptation, cone photoreceptors displayed absent or mislocalized opsins at all ages examined. Rod photoreceptors entrapped the available chromophore but exhibited significant amounts of chromophore-free opsins in the dark-adapted stage. Treatment of mice with pharmacological doses of vitamin A ameliorated the rod phenotype but did not restore visual pigment synthesis in cone photoreceptors of STRA6-deficient mice. The imbalance between chromophore and opsin concentrations of rod and cone photoreceptors was associated with an unfavorable retinal physiology, including diminished electrical responses of photoreceptors to light, and retinal degeneration during aging. Together, our study demonstrates that STRA6 is critical to adjust the stoichiometry of chromophore and opsins in rod and cone photoreceptors and to prevent pathologies associated with ocular vitamin A deprivation.
Hyperbolicity for Log Smooth Families with Maximal Variation
Authors: Wei Chuanhao , Wu Lei
Published: September 2021

We prove that the base space of a log smooth family of log canonical pairs of log general type is of log general type as well as algebraically degenerate, when the family admits a relative good minimal model over a Zariski open subset of the base and the relative log canonical model is of maximal variation.
An approach to evaluate the sealing performance of sealing structures based on multiscale contact analyses
Authors: Wang Runliang , Liu Jianhua , Zhang Feikai , Ding Xiaoyu
Published: September 2021

The evaluation of sealing performance is important in the design stage and assembly process of sealing structures. To date, analyses of sealing structures have rarely quantitatively evaluated sealing performance: They tend to neglect microsurface topographic information or simplify rough surfaces. Herein, we propose a new and efficient simulation approach to analyse sealing performance based on a multiscale contact model. In this simulation approach, a new parameter, critical preload, is used as the index of sealing performance. The validity of the proposed index was verified using the case of a cone seal. The evolution of the contact characteristics during the assembly process, such as the real contact area, the distribution of contact pressure, and contact status, were studied in detail.
Effects of Different Legume Seeds on Individual Performance in the Bean Bug, Riptortus pedestris (Hemiptera: Alydidae)
Authors: Seong Jae Min , Lee Kwang Pum
Published: September 2021

The bean bug, Riptortus pedestris (Fabricius), is a serious pest of legume crops in East Asia. Here, we report how the consumption of different types of legume seeds affects various aspects of nymphal and adult traits related to fitness in R. pedestris. Two experiments were conducted. In the first experiment, we assessed how R. pedestris nymphs and adults performed on one of 10 different legume seeds: adzuki bean, chickpea, cowpea, two kidney bean varieties (red, white), mung bean, peanut, small black bean, and two soybean varieties (black, yellow). Riptortus pedestris fed on yellow soybean and chickpea performed well in terms of nymphal survivorship and fecundity. However, R. pedestris fed on two kidney bean varieties suffered 100% nymphal mortality and reduced fecundity. Small black bean and black soybean supported high fecundity, but were not suitable for nymphal development. Lipid content was 4- to 11-folds higher in R. pedestris raised on peanuts than those on the others. In the second experiment, we recorded the key parameters of adult performance from R. pedestris assigned to one of nine combinations of three nymphal and three adult diets (yellow soybean, adzuki bean, peanut). Riptortus pedestris raised on yellow soybean during development produced more eggs over their lifetime than those raised on the others. However, this beneficial effect of consuming yellow soybean during development occurred only when yellow soybean was consumed during adulthood. Our data have implications for predicting the occurrence and population dynamics of this pest.
Mapping Black London in World War II: A staged approach to digital spatial history
Authors: Whitworth William , Ayers Oliver
Published: September 2021

This article suggests ways scholars may be able to deploy digital techniques in contexts without readily available quantitative data. Using the Mapping Black London (MBL) project in World War II as a case study, the article proposes ways scholars can ‘reverse engineer’ qualitative information in order to generate the data needed to make meaningful digital maps. The MBL project conducted a staged approach to digitally map the black presence in London during World War II. In contrast to other phased approaches where work typically begins with a lengthy stage of database construction and data entry followed by ‘traditional’ analysis toward the end, MBL sought to minimize the lengthy and costly lead times common to many Historic Geographic Information Systems (HGIS) projects. Work progressed through three alternative stages where the MBL team ‘mapped the topic’, before mapping selected aspects of the secondary literature and primary evidence. This article discusses the benefits drawn from such an approach, as well as suggesting some circumstances where similar methods might be deployed by others seeking to ‘reverse engineer’ qualitative sources to create digital maps.
“Necessarily Hidden Truth(s)”: Documenting Queer Migrant Experience in Rigoberto González’s Crossing Vines
Authors: de la Garza Valenzuela José A
Published: September 2021

The interpretation of documents holds together the center of Rigoberto González’s Crossing Vines (2003). Presented as time-stamped vignettes detailing the life of laborers at a vineyard for an university assignment, the novel throws into question the distance between the experiences the characters have and those accessible to Leonardo, the ethnographer-in-training. In Crossing Vines, queer migrant characters such as Aníbal and Moreno develop a narrative agency over access to details that the government or ethnographer might solicit in these narrative gaps. Analyzing González’s use of character’s institutional and personal archives, such as Permanent Resident Cards/green cards, photographs, and Leonardo’s ethnography, I argue that despite offering competing narratives about migrant life, these documents methodologically limit how queer migrants are textually represented and interpreted. Crossing Vines critiques the institutional processes by which migrant stories are gathered, interpreted, and violently cross-examined to foreground the blurred lines between studying and surveilling migrant communities. Whereas Leonardo’s project and the inspection of green cards puts pressure on the migrants in the novel to disclose information to produce or cross-reference an institutional archive, González asks us to put the limitations of the documents under scrutiny. In representing what these archives cannot, Crossing Vines makes a case for the utility and centrality of fiction in attending to the often intentional oversights of institutional archives, including those in our own fields of study.
Turbulent transport of radiation in the solar convective zone
Authors: Rogachevskii I , Kleeorin N
Published: September 2021

A turbulent transport of radiation in the solar convective zone is investigated. The mean-field equation for the irradiation intensity is derived. It is shown that due to the turbulent effects, the effective penetration length of radiation can be increased several times in comparison with the mean penetration length of radiation (defined as an inverse mean absorption coefficient). Using the model of the solar convective zone based on mixing length theory, where the mean penetration length of radiation is usually much smaller than the turbulent correlation length, it is demonstrated that the ratio of the effective penetration length to the mean penetration length of radiation increases 2.5 times in the vicinity of the solar surface. The main reasons for this are the compressibility effects that become important in the vicinity of the solar surface where temperature and density fluctuations increase towards the solar surface, enhancing fluctuations of the radiation absorption coefficient and increasing the effective penetration length of radiation.
Uterine kisspeptin receptor critically regulates epithelial estrogen receptor α transcriptional activity at the time of embryo implantation in a mouse model
Authors: Schaefer Jennifer , Vilos Angelos G , Vilos George A , Bhattacharya Moshmi , Babwah Andy V
Published: September 2021

Embryo implantation failure is a major cause of infertility in women of reproductive age and a better understanding of uterine factors that regulate implantation is required for developing effective treatments for female infertility. This study investigated the role of the uterine kisspeptin receptor (KISS1R) in the molecular regulation of implantation in a mouse model. To conduct this study, a conditional uterine knockout (KO) of Kiss1r was created using the Pgr-Cre (progesterone receptor-CRE recombinase) driver. Reproductive profiling revealed that while KO females exhibited normal ovarian function and mated successfully to stud males, they exhibited significantly fewer implantation sites, reduced litter size and increased neonatal mortality demonstrating that uterine KISS1R is required for embryo implantation and a healthy pregnancy. Strikingly, in the uterus of Kiss1r KO mice on day 4 (D4) of pregnancy, the day of embryo implantation, KO females exhibited aberrantly elevated epithelial ERα (estrogen receptor α) transcriptional activity. This led to the temporal misexpression of several epithelial genes [Cftr (Cystic fibrosis transmembrane conductance regulator), Aqp5 (aquaporin 5), Aqp8 (aquaporin 8) and Cldn7 (claudin 7)] that mediate luminal fluid secretion and luminal opening. As a result, on D4 of pregnancy, the lumen remained open disrupting the final acquisition of endometrial receptivity and likely accounting for the reduction in implantation events. Our data clearly show that uterine KISS1R negatively regulates ERα signaling at the time of implantation, in part by inhibiting ERα overexpression and preventing detrimentally high ERα activity. To date, there are no reports on the regulation of ERα by KISS1R; therefore, this study has uncovered an important and powerful regulator of uterine ERα during early pregnancy.
TARG1 protects against toxic DNA ADP-ribosylation
Authors: Tromans-Coia Callum , Sanchi Andrea , Moeller Giuliana K , Timinszky Gyula , Lopes Massimo , Ahel Ivan
Published: September 2021

ADP-ribosylation is a modification that targets a variety of macromolecules and regulates a diverse array of important cellular processes. ADP-ribosylation is catalysed by ADP-ribosyltransferases and reversed by ADP-ribosylhydrolases. Recently, an ADP-ribosyltransferase toxin termed ‘DarT’ from bacteria, which is distantly related to human PARPs, was shown to modify thymidine in single-stranded DNA in a sequence specific manner. The antitoxin of DarT is the macrodomain containing ADP-ribosylhydrolase DarG, which shares striking structural homology with the human ADP-ribosylhydrolase TARG1. Here, we show that TARG1, like DarG, can reverse thymidine-linked DNA ADP-ribosylation. We find that TARG1-deficient human cells are extremely sensitive to DNA ADP-ribosylation. Furthermore, we also demonstrate the first detection of reversible ADP-ribosylation on genomic DNA in vivo from human cells. Collectively, our results elucidate the impact of DNA ADP-ribosylation in human cells and provides a molecular toolkit for future studies into this largely unknown facet of ADP-ribosylation.
ProNAB: database for binding affinities of protein–nucleic acid complexes and their mutants
Authors: Harini Kannan , Srivastava Ambuj , Kulandaisamy Arulsamy , Gromiha M Michael
Published: September 2021

Protein–nucleic acid interactions are involved in various biological processes such as gene expression, replication, transcription, translation and packaging. The binding affinities of protein–DNA and protein–RNA complexes are important for elucidating the mechanism of protein–nucleic acid recognition. Although experimental data on binding affinity are reported abundantly in the literature, no well-curated database is currently available for protein–nucleic acid binding affinity. We have developed a database, ProNAB, which contains more than 20 000 experimental data for the binding affinities of protein–DNA and protein–RNA complexes. Each entry provides comprehensive information on sequence and structural features of a protein, nucleic acid and its complex, experimental conditions, thermodynamic parameters such as dissociation constant (Kd), binding free energy (ΔG) and change in binding free energy upon mutation (ΔΔG), and literature information. ProNAB is cross-linked with GenBank, UniProt, PDB, ProThermDB, PROSITE, DisProt and Pubmed. It provides a user-friendly web interface with options for search, display, sorting, visualization, download and upload the data. ProNAB is freely available at https://web.iitm.ac.in/bioinfo2/pronab/ and it has potential applications such as understanding the factors influencing the affinity, development of prediction tools, binding affinity change upon mutation and design complexes with the desired affinity.
JS01.4.A The neurocognitive function changes with awake craniotomy for low-grade glioma in the left hemispheric eloquent regions
Authors: Wang Y , Ji P , Guo S , Liu J , Zhai Y , Wang N , Qu Y , Wang L
Published: September 2021

BACKGROUND

Cognitive deficit was frequently observed in glioma patients, especially for those on the eloquent area. Considering the increased life expectancy, brain mapping during awake craniotomy was preferentially applied to exacerbate neurocognitive deficits. The aim of the current study was to evaluate the neurocognitive changes during the perioperative period of resection of low-grade glioma (LGG) in the left side eloquent area with awake craniotomy in a major neurosurgical center in China for 5 years.

MATERIAL AND METHODS

We retrospectively analyzed patients with left-sided glioma in eloquent areas, who received awake craniotomy during 2016–2020. Montreal Cognitive Assessment Scale, BN-20, and EORTC-QLQ-C30 questionnaire were applied for neurological cognitive assessment. We performed a correlation analysis between changes in cognitive performance and tumor characteristics, including tumor location, pathological grade. Treatment-related factors were also analyzed, such as the extent of resection (EOR), preoperative and postoperative Karnofsky Performance Score (KPS), postoperative treatment strategy (chemo- and radiotherapy), progression-free survival (PFS), overall survival (OS).

RESULTS

68 patients were included in our current study. For the language domain, memory domain, and executive functions, 7.4% (5/68) patients presented mild postoperative cognitive performance deterioration compared to preoperative. Tumor location was the only factor that greatly influenced the postoperative cognitive performance, while other features (EOR, KPS, pathological grades) and treatment strategy were found no effect on cognitive change. The extent of tumor resection ranged from 81% to 100%.

CONCLUSION

Our study underlines the importance of the application of brain mapping during awake craniotomy, which helps to maximize extent of tumor resection while preserving cognitive function in individuals with LGG in eloquent regions.
OS03.4.A Irradiation of the subventricular and subgranular zone and overall survival in high-grade glioma patients
Authors: Bruil D , David S , Nagtegaal S , Verhoeff J
Published: September 2021

BACKGROUND

Previous research has shown that neural stem cells (NSCs) in the subventricular zone (SVZ) may support the growth of glioma by recruiting new cells to the tumor. NSCs are located in the SVZ as well as in the subgranular zone (SGZ) of the hippocampus, the two neurogenic niches of the brain. This might indicate that irradiation of the SVZ and SGZ, and thereby damaging NSCs, reduces tumor growth and improves overall survival (OS). However, irradiation may also inhibit the repair capacity of healthy brain tissue by these neurogenic niches. Therefore, we investigated the effects of SVZ and SGZ irradiation dose on OS, in a cohort of high-grade glioma patients.

MATERIAL AND METHODS

We have retrospectively selected 221 patients (2014–2020) with WHO grade III and IV gliomas that underwent radiotherapy. Next to clinical baseline characteristics, T1 weighted MRI- and CT-images were collected. The SVZ and SGZ regions on the individual T1 images were delineated via non-linear registration of brain atlases. SVZ labels were created in 0.5mm isotropic MNI T1 and T2 templates, while SGZ atlas labels were available via the Hippocampus and Subfields CoBrA atlas. Next, the mean dose from the acquired SVZ and SGZ labels were extracted. The relationship between SVZ doses, SGZ doses and OS were examined using the Cox proportional hazards model and the Kaplan-Meier method (using the Log Rank test for significance).

RESULTS

For the mean dose in the SVZ, the hazard ratio (HR) was 1.024 per Gy (P = 0.002, [95% confidence interval, 1.009–1.040]) and the mean SGZ dose had a HR of 1.021 per Gy (P< 0.001, [95% confidence interval, 1.012–1.031]). These results were then corrected for the following covariates: sex, age, total intracranial volume and extent of surgery. This resulted in a HR of 1.031 per Gy (P = 0,001, [95% confidence interval, 1.014–1.050]) for the mean SVZ dose, and a HR of 1.025 per Gy (P< 0.001, [95% confidence interval, 1.015–1.036]) for the mean SGZ dose. Patients whose SVZ received greater than the median SVZ dose (= 31.3 Gy) showed a significant decrease in OS compared to patients who received less than the median dose (10.7 months vs 13.5 months median OS, P = 0.001). Patients whose SGZ received greater than the median SGZ dose (= 31.9) showed a significant decrease in OS compared to patients who received less than the median dose (10.7 months vs 15.1 months median OS, P< 0.001).

CONCLUSION

Here, we present a large cohort of high-grade glioma patients, in which we show a statistically significant decrease in overall survival with increasing radiation dose on the SGZ and SVZ. This correlation suggests that both neurogenic niches might need to be spared during radiotherapy treatment to improve overall survival even in high-grade glioma patients. Modern radiotherapy planning and delivery options are available to implement this.
OS06.5A Fluorescence image-guided resection of intracranial meningioma: an experimental in vivo study on nude mice
Authors: Linsler S , Senger S , Müller S , Müller A , Oertel J
Published: September 2021

BACKGROUND

The use of photodynamic agents in malignant cranial tumor surgery is quite common. For example five-aminolevulinic acid (5-ALA)-induced porphyrins in malignant gliomas are potent photosensitizers. Until today there is no comparable selective fluorescent substance available for meningiomas. Nevertheless, there is a demand for intraoperative fluorescent identification of e.g. invasive skull base meningiomas to increase radicality. This study was established to investigate fluorescent image-guided resection with somatostatin receptor labelled fluorescence dye for intracranial meningioma in the nude mice.

MATERIAL AND METHODS

Primary meningioma cell culture samples were stereotactically implanted subdural into 20 nude mice. 90 days after inoculation of the cells, a cranial MRI with contrast agent revealed tumor growth. After detection of tumor mass in MRI, FAM-TOC5,6-Carboxyfluoresceine-Tyr3-Octreotide was injected intravenously and tumor mass was hereafter resected under visualization via fluorescence microscope and endoscope. After attempted total resection, animal were sacrificed brain slices were obtained and histologically analysed to verify the resection extent.

RESULTS

In 18 mice tumor growth was detected in MRI after 90 days of inoculation. The tumor mass could be clearly identified with fluorescence microscope and endoscope after injecting FAM-TOC5,6-Carboxyfluoresceine-Tyr3-Octreotide. The tumor margins could be better visualized. After fluorescence-guided resection no remaining tumor could be identified in histological analysis.

CONCLUSION

This study describes for the first time the use of FAM-TOC5,6-Carboxyfluoresceine-Tyr3-Octreotide and demonstrates its value of fluorescent identification of meningioma cells in vivo. Furthermore, the authors established a new experimental animal model for fluorescence meningioma surgery.
P11.01 Symptom networks in glioma: a novel approach to study multidimensional symptomatology in glioma patients
Authors: Varkevisser T M C K , Röttgering J G , de Witt Hamer P , Kouwenhoven M C M , Reijneveld J C , Belgers V , van Lingen M , Klein M , Douw L
Published: September 2021

BACKGROUND

Glioma patients experience a high symptom burden contributing to poorer quality of life. Symptoms include depression, cognitive impairment, and fatigue and vary throughout the disease. These symptoms are rarely studied from a comprehensive perspective, while their interdependence may be relevant for their development, perpetuation, and ultimately successful treatment. The emerging field of symptom network analysis uncovers the multidimensional symptom space. Nodes are the symptoms, and edges are operationalized as the full conditional association, or partial correlation, between two symptom severity scores across patients. Highly connected nodes are considered central and may be particularly relevant targets for treatment as disruption of these central nodes impact the entire network. We visualized the overall glioma symptom network, compared multidimensional results to known literature, and statistically compared networks between relevant patient subgroups.

MATERIAL AND METHODS

A dataset comprised of 355 observations of 180 glioma patients at different disease phases was analysed. Cognitive testing and questionnaires regarding health-related and glioma-specific quality of life, fatigue, depression, and cognition resulted in the definition of 30 symptom nodes. Symptom clusters were visually explored in the resulting networks, as were node strength, betweenness, and closeness centrality measures for each node. Networks were statistically compared between preoperative patients and patients during stable disease, as well as patients with low versus high-grade gliomas. Networks of patients with normal versus severe levels of fatigue were also compared as cancer-/glioma-related fatigue has a strong impact on quality of life and can correlate with other common symptoms such as pain, depression, and/or sleep disturbance.

RESULTS

Symptom clusters existed between: 1) bodily pain, headache and physical functioning; 2) concentration and motivation; and 3) fatigue and drowsiness. Fatigue and mental health were the most central nodes in the networks. Furthermore, the overall connectivity between symptoms was significantly higher in the severely fatigued patients than in patients with normal fatigue. No network differences were found between low versus high-grade, and preoperative versus stable disease networks.

CONCLUSION

Fatigue is a central node in glioma patients’ burden of disease, and symptoms are more tightly intercorrelated in patients experiencing severe fatigue. From our data, we hypothesize that fatigue co-exists with or perpetuates other symptoms. Thus, although these results are preliminary, the network approach may innovate hypothesis generation in symptom management.
P11.04 Autonomy duration as analyzed by KPS≥70 cumulative time in patients with biopsy-only glioblastoma (BO-GBM). A sub-analysis of the Timone cohort
Authors: Harlay V , Loundou A , Boucard C , Petrirena G , Barrie M , Campello C , Autran D , Padovani L , Figarella D , Boissonneau S , Dufour H , Baumstarck K , Tabouret E , Chinot O
Published: September 2021

BACKGROUND

Improvement or maintenance of autonomy is a crucial and understudied issue for glioblastoma (GBM) patients whose outcome is poor. Biopsy-only GBM (BO-GBM) is a situation where survival is short and independence is of particular importance. Our objective was to explore functional outcome in biopsy-only patients.

MATERIAL AND METHODS

A regional glioma SIRIC cohort was conducted at CHU Timone in 2014–2017 and we retrospectively reviewed the BO-GBM subgroup. We prospectively collected age, corticosteroid dose, tumoral surface, treatment allocated and completed, and survival outcome. Functional independence was analyzed as a cumulative time of Karnofsky performance status (KPS) ≥70 from the date of diagnosis until death. We analyzed potential factors associated to time with KPS ≥70.

RESULTS

Among 535 patients enrolled in the cohort, surgery was restricted to biopsy in 139 patients (BO-GBM). Mean tumoral surface measured on gadolinium-enhanced T1-weighted MRI was 1198mm2 (min: 65; max: 4515mm2). Mean steroid dose at diagnosis was 50mg prednisolone per day. Corticosteroid dose was ≥50mg prednisolone per day for 77 patients and <50mg per day for 56 patients. Fifty-four patients (39%) were referred to radiotherapy-temozolomide (RT-TMZ), 68 (49%) considered unfitted for RT received chemotherapy upfront only (CT-UF), and 17 patients (12%) were referred to palliative care only. Median overall survival (OS) was 7.5 months (95%CI: 6.0–9.2), 14.0 months (95%CI: 9.7–18.7) and 6.0 months (95%CI: 4.6–7.7) for BO-GBM, RT-TMZ and CT-UF respectively. At diagnosis, 81 (58.3%) patients presented with self-care capacity (KPS ≥ 70%). For these patients, median time of autonomy preservation was 7.6 months (95%CI: 6.1–9.0). Median time of autonomy preservation differed according to treatment modalities: it was 8.6 months (95%CI: 5.9–11.3) versus 6.3 months (95%CI: 2.9–9.7) for RT-TMZ versus CT-UF group respectively (p<0.001). In univariate analysis, time with KPS ≥ 70% was correlated with age (p=0.001), initial KPS (p<0.001), tumoral surface measured on gadolinium-enhanced T1-weighted MRI (p=0.03) and corticosteroid dose (p=0.001). In multivariate analysis, time with KPS≥70 was correlated with age (p=0.001) and KPS at diagnosis (p<0.001).

CONCLUSION

Patients with inoperable GBM referred to radiotherapy-temozolomide present a valuable duration of functional independence, although shorter in patients not referred to RT. Duration of functional independence could be considered in addition to PFS and OS for treatment evaluation in patients with GBM.
P13.15 Pre-clinical trial of T601 oncolytic virus for high grade glima via intra-tumoral injection
Authors: He Z , Meng Z , Liang P , Xing L , Zheng X , Wang G
Published: September 2021

BACKGROUND

An effective therapeutic method still hasn’t been devised for lethal high grade glioma. Thus, a method with high anti-tumoral efficiency, tumoral targeting, and acceptable side effect needs to be designed. Oncolytic virotherapy which can specifically lyse tumor cells via mass replication and deleting nucleotide metabolism related gene, like TK, required in viral replication and overexpressed in tumor cells, provides hope for patients. However, the virus only contained TK deletion is unable to show sufficient specificity of anti-tumoral response in tumor cells. Here, the adapted strain of vaccinia virus with high tumoral specificity due to TK and RR deletion and FUC1 insertion, named T601, is chosen in this project. In clinical application, intra-tumoral injection showed improved anti-tumoral efficiency and acceptable side effect. However, intra-tumoral viral injection in orthotropic glioma model is rare. In this project, various biosafety and antitumoral efficiency parameter would be tested for confirming the biosafety and reliability of intra-tumoral T601 viral injection for future clinical trials.

MATERIAL AND METHODS

For measuring the IC50 of T601, 10 different amounts of virus was tested in vitro via calculating cell viability with CCK-8(cell counting kit-8). For measuring the further antitumoral response of FCU1, different concentration of the 5-FC was added into the medium with IC50 viral amount. To ensure the biosafety of T601, MTD (maximum tolerance dose) was measured. Based on the MTD result, for evaluating the anti-tumoral efficiency, 106 pfu,105 pfu,104 pfu of virus was intra-tumoral injected in orthotopic GBM bearing mice. Tumor size was measured once a week through in vivo bioimaging system.

RESULTS

0.022 MOI, the IC50 of T601, showed high cytotoxicity of T601. Moreover, the significantly decreased cell viability under the combined treatment of 5-FC and 0.22MOI T601 showed intact anti-tumoral function. In MTD assay, except for 107 group, no significant weight loss was found. However, in 107 pfu group, mean body weight decreased around 10% and animal fatality happened on day 9. According to the MTD result, certain amount of virus was intra-tumorally injected. In all treatment group, the tumor size was significantly shrined. At the same time, the survival rate of mice under viral treatment was significantly extended.

CONCLUSION

In summary, T601 exhibited efficient anti-tumoral function and acceptable side effect. T601 treatment prolonged the survival period of GBM mice with acceptable neurotoxicity, demonstrating that T601 contains necessary criterial for intra-tumoral injection. Ultimately, this project provided basic reference information of dose for future clinical trial.
P13.18 Inhibition of epidermal growth factor receptor and platelet-derived growth factor receptor-alpha exerts synergistic efficacy in glioblastoma
Authors: Noch E , Alnahhas I , Palma L , Cantley L
Published: September 2021

BACKGROUND

Despite our understanding of the genetic changes that precipitate gliomagenesis, targeted therapy has failed in glioblastoma (GBM) with median survival not significantly improved over the past two decades. Epidermal growth factor receptor (EGFR) alterations, including amplification and activating mutations, are among the most common genetic changes in GBM, occurring in more than half of cases. EGFR is located on Chr. 7, and Chr. 7 gain is one of the earliest events precipitating gliomagenesis. Various EGFR inhibitors, including tyrosine kinase inhibitors, monoclonal antibodies, vaccines, and CAR-T cells have failed in GBM due to intrinsic heterogeneity and receptor tyrosine kinase bypass pathways that mediate therapeutic resistance. New targeted therapeutic approaches to leverage synergistic combinations are desperately needed to improve GBM prognosis. Using the TCGA and other GBM databases, we have previously demonstrated that the presence of PDGFRAamplification in patients with EGFR-amplified GBM carries significantly worse survival. EGFR and PDGFRA co-expression occur in more than one-third of GBM patients. The PDGFRA ligand PDGFA is also located on Chr. 7, and its expression is significantly increased with Chr. 7 gain and EGFR copy number increase. Therefore, Chr. 7 gain inherently leads to co-activation of both EGFR and PDGFRA signaling pathways.

MATERIALS AND METHODS

We used models of patient-derived glioblastoma cells to test combined inhibition of epidermal growth factor receptor and platelet-derived growth factor receptor-alpha in vitro.

RESULTS

Using patient-derived GBM models with Chr. 7 gain, we found that combined inhibition of both EGFR and PDGFRA using a variety of FDA-approved EGFR-targeted agents (Erlotinib, Gefitinib, Dacomitinib, Neratinib, and Osimertinib) and Crenolanib, respectively, leads to synergistic cytotoxicity in vitro. We found that inhibition of either EGFR or PDGFRA alone led to receptor cross-activation, and EGF and PDGF-AA-induced receptor tyrosine kinase activation was blocked by Neratinib and Crenolanib. Immunoprecipitation experiments and proximity ligation assays demonstrated that combined inhibition prevents EGFR and PDGFRA heterodimerization and pathways of therapeutic resistance. This combined inhibition led to decreased activation of downstream signaling pathways, including phosphatidylinositol 3-kinase and mitogen-activated protein kinase.

CONCLUSIONS

We show that combined inhibition of EGFR and PDGFRA exerts synergistic cytotoxicity in GBM and prevents resistance pathways that emerge during single-agent targeted therapy against these receptor tyrosine kinases. These pathways are targetable with FDA-approved agents that could be used in patients with GBM with Chr. 7 gain.
P14.02 The Natural History of a Residual Intracranial Meningioma- Volumetric Growth and Predictors of Progression
Authors: Gillespie C S , Richardson G E , Mustafa M A , Islim A I , Keshwara S M , Taweel B A , Bakhsh A , Kumar S , Millward C P , Mehta S , Rathi N , Chavredakis E , Brodbelt A R , Mills S J , Jenkinson M D
Published: September 2021

BACKGROUND

Resection of meningioma leaves residual solid tumour in ~25% of patients. Selection for further treatment and follow-up strategy may benefit from knowledge of volumetric growth and associated prognostic factors.

MATERIAL AND METHODS

Growth rates were assessed using a linear mixed effects model, in a retrospective adult cohort that underwent subtotal resection of meningioma (2004–2018). Endpoints were re-treatment, end of follow-up or death. Cox regression analysis was used to identify prognostic factors for progression, defined using the Response Assessment in Neuro-Oncology (RANO) volumetric criteria.

RESULTS

236 patients were included. Mean age at surgery was 56.3 years (SD=13.7) and 73.7% were female. WHO grades were 1 (n=195, 82.6%), 2 (n=40, 16.9%) and 3 (n=1, 0.5%). Adjuvant fractionated radiotherapy (fRT) was administered to 34 patients (14.4%), with no propensity towards higher WHO grade or residual volume. Median pre-operative meningioma and post-operative residual volumes were 34.0cm3 (IQR 16.0–63.0) and 2.0cm3 (IQR 0.8–5.2), respectively. Median follow-up was 64 months (IQR 42–104). Median absolute growth rate (AGR) and relative growth rate (RGR) were 0.1cm3/year and 4.3%/year, respectively. According to RANO criteria, 132 (55.9%) patients progressed, of which 13 (9.8%) developed symptoms. Median progression-free survival was 56 months (95% CI 43.1–69.0). Multivariable analysis identified adjuvant fRT (HR 1.7, [95% CI 1.0–2.8], P=0.046), skull base location (HR 1.5, [95% CI 1.0–2.4], P=0.047) and Ki-67 index (HR 3.7 [95% CI 1.3–10.8], P=0.017) as prognostic factors for volumetric progression. WHO grade was not significant (HR 1.0, [95% CI 0.5–1.7], P=0.905). Forty-nine patients who progressed (37.1%) underwent further treatment: fRT (n=19), re-operation (n=15), Stereotactic radiosurgery (SRS) (n=10) and surgery+adjuvant fRT (n=5). Of those, 8 (16.3%) progressed further (after re-operation [n=6] and SRS [n=2]). Seven were treated with a 2nd re-operation (n=3), fRT (n=3), and SRS (n=1). One patient progressed after a 2nd reoperation and was treated with SRS, after which they remained stable. Median survival was not reached. 5- and 10-year overall survival (OS) was 96% and 86% respectively.

CONCLUSION

Growth rates of a residual meningioma vary with a dichotomy observed in progression rates. Half of patients with a residual meningioma showed radiological progression requiring multiple treatment to control the tumour. The other half demonstrate a more indolent course. Skull base location and higher Ki67 are important prognostic factors for progression and therefore, should be considered to stratify patients for adjuvant radiotherapy.
P14.33 Preoperative Lactate Dehydrogenase levels as a predictor of venous thromboembolism development in glioblastoma patients
Authors: Jacquerie A , Huijs S , Moers-Hornikx V M P , van der Heijden-Montfroy A M H G , van Goor M P J , Pasmans R C O S , Anten M H M E , Verduin M , Broen M P G
Published: September 2021

BACKGROUND

Venous thromboembolism (VTE) is a common complication in patients with glioblastoma. Despite high incidence of up to 30% per year, concerns about bleeding complications have limited the use of primary anticoagulant prophylaxis. Finding a suitable biomarker to assess the risk of occurrence is therefore of utmost clinical interest. We performed an exploratory study of preoperative routinely used haematological markers as predictor for the development of VTE in glioblastoma patients.

MATERIAL AND METHODS

Data was retrospectively collected from an existing database of 307 patients diagnosed with glioblastoma by the Oncology Network South-East Netherlands (OnzoZON) between 2006 and 2020. Collected preoperative haematological markers included: haemoglobin, platelets, lactate dehydrogenase, neutrophils, lymphocytes, albumin and derived ratios. In addition, type and date of VTE were retrieved from medical records. Receiver operating curve was used to identify the optimal cut-off values of the preoperative haematological markers. Univariate and multivariate logistic regression analyses were performed to predict VTE for each haematologic marker independently. Variables included in the multivariate analyses were age, gender, type of surgery, Karnofsky performance score, MGMT status, weight, height and BMI, already available from the primary database.

RESULTS

In the total dataset, 45 patients (15%) suffered from a VTE, most common pulmonary embolism (51%) followed by deep vein thrombosis (31%). Mean time from diagnosis until VTE was 4.3 months (SD = 5.5). Preoperative haemoglobin value was available for analyses in 265 patients, platelets value in 226, lactate dehydrogenase in 98, neutrophils in 133, lymphocytes in 133 and albumin in 56 patients. A preoperative lactate dehydrogenase value > 243 U/L was found to increase the risk of VTE in both univariate and multivariate analysis (P <0.05). Seventeen out of 98 patients of whom lactate dehydrogenase level was available suffered from a VTE, most common pulmonary embolism (59%), followed by deep vein thrombosis (29%) and cerebral venous sinus thrombosis (12%). An elevated lactate dehydrogenase in serum increased the odds for getting a VTE by 3.2 (1.1–9.4). None of the other investigated haematological markers or ratios were found to be significantly correlated with the occurrence of VTE in our study.

CONCLUSION

Glioblastoma initiates locally haemostatic abnormalities, that propagate systemically though circulating mediators. Our exploratory analysis shows for the first time that preoperative lactate dehydrogenase levels might aid clinicians in identifying patients at risk for a venous thromboembolism. Ultimately this could lead to preventive measures and patient education, but larger and prospective validation of these findings is warranted.
P14.41 Cost-effectiveness of FET PET for early treatment response assessment in glioma patients following adjuvant temozolomide chemotherapy
Authors: Rosen J , Ceccon G , Bauer E K , Werner J M , Kabbasch C , Fink G R , Langen K J , Galldiks N
Published: September 2021

BACKGROUND

In light of increasing healthcare costs, higher medical expenses should be justified socio-economically. Therefore, we calculated the effectiveness and cost-effectiveness of PET using the radiolabeled amino acid O-(2-[18F]-fluoroethyl)-L-tyrosine (FET) compared to conventional MRI for early identification of responders to adjuvant temozolomide chemotherapy. A recent study in IDH-wildtype glioma patients suggested that after two cycles, FET-PET parameter changes predicted a significantly longer survival while MRI changes were not significant.

MATERIALS AND METHODS

To determine the effectiveness and cost-effectiveness of serial FET-PET imaging, we analyzed published clinical data and calculated the associated costs in the context of the German healthcare system.Based on a decision-tree model, FET-PET and MRI’s effectiveness was calculated, i.e., the probability to correctly identify a responder as defined by an overall survival ≥15 months. To determine the cost-effectiveness, the incremental cost-effectiveness ratio (ICER) was calculated, i.e., the cost for each additionally identified responder by FET-PET who would have remained undetected by MRI. The robustness of the results was tested by deterministic and probabilistic (Monte Carlo simulation) sensitivity analyses.

RESULTS

Compared to MRI, FET-PET increases the rate of correctly identified responders to chemotherapy by 26%; thus, four patients need to be examined by FET-PET to identify one additional responder. Considering the respective cost for serial FET-PET and MRI, the ICER resulted in €4,396.83 for each additional correctly identified responder by FET-PET. The sensitivity analyses confirmed the robustness of the results.

CONCLUSION

In contrast to conventional MRI, the model suggests that FET PET is cost-effective in terms of ICER values. Concerning the high cost of temozolomide, the integration of FET-PET has the potential to avoid premature chemotherapy discontinuation at a reasonable cost.
P14.53 Immunotherapy in the complex treatment of HGG
Authors: Rynda A , Olyushin V , Rostovtsev D
Published: September 2021

BACKGROUND

To improve the long-term results of complex treatment of patients with malignant gliomas

MATERIAL AND METHODS

The long-term results of treatment of 220 patients with malignant gliomas of supratentorial localization (anaplastic astrocytomas, glioblastomas, giant cell glioblastomas, gliosarcomas) were evaluated. Of these patients, in addition to standard treatment methods (surgery, radiation therapy and chemotherapy), 110 patients underwent specific antitumor immunotherapy. In 110 patients, only standard methods were used in the complex treatment structure. Follow-up results were considered follow-up data, and a relapse-free period was also evaluated.

RESULTS

The implementation of specific antitumor immunotherapy in patients with malignant gliomas was safe and did not lead to an increase in the number of complications compared with the control group. It was revealed that the use of immunotherapy based on autologous dendritic cells, in addition to standard methods of treating patients, increases the average life expectancy (in patients with anaplastic astrocytomas up to 40.5 months (p = 0.001), in patients with glioblastomas up to 21.8 months (p = 0.002)) and the value of the relapse-free period (in patients with anaplastic astrocytomas up to 17.4 months (p = 0.002), in patients with glioblastomas up to 14.3 months (p = 0.003)), provided that three or more courses are carried out. Conducting 1 or 2 courses of immunotherapy does not significantly affect the average life expectancy and median survival of patients.

CONCLUSION

The development and use in clinical practice of specific antitumor immunotherapy based on autologous dendritic cells seems to be a very promising direction for further research, the development of which will improve the long-term results of treatment of patients.