bluuebunny/crossref_metadata_2025 huggingface dataset:
BIMG-22. DEEP LEARNING SUPER-RESOLUTION MR SPECTROSCOPIC IMAGING TO MAP TUMOR METABOLISM IN MUTANT IDH GLIOMA PATIENTS
Authors: Li Xianqi , Andronesi Ovidiu , Strasser Bernhard , Jafari-Khouzani Kourosh , Cahill Daniel , Dietrich Jorg , Batchelor Tracy , Bendszus Martin , Neuberger Ulf , Vollmuth Philipp
Published: March 2021

Metabolic imaging can map spatially abnormal molecular pathways with higher specificity for cancer compared to anatomical imaging. However, acquiring high resolution metabolic maps similar to anatomical MRI is challenging due to low metabolite concentrations, and alternative approaches that increase resolution by post-acquisition image processing can mitigate this limitation. We developed deep learning super-resolution MR spectroscopic imaging (MRSI) to map tumor metabolism in patients with mutant IDH glioma. We used a generative adversarial network (GAN) architecture comprised of a UNet neural network as the generator network and a discriminator network for adversarial training. For training we simulated a large data set of 9600 images with realistic quality for acquired MRSI to effectively train the deep learning model to upsample by a factor of four. Two types of training were performed: 1) using only the MRSI data, and 2) using MRSI and prior information from anatomical MRI to further enhance structural details. The performance of super-resolution methods was evaluated by peak SNR (PSNR), structure similarity index (SSIM), and feature similarity index (FSIM). After training on simulations, GAN was evaluated on measured MRSI metabolic maps acquired with resolution 5.2×5.2 mm2 and upsampled to 1.3×1.3 mm2. The GAN trained only on MRSI achieved PSNR = 27.94, SSIM = 0.88, FSIM = 0.89. Using prior anatomical MRI improved GAN performance to PSNR = 30.75, SSIM = 0.90, FSIM = 0.92. In the patient measured data, GAN super-resolution metabolic images provided clearer tumor margins and made apparent the tumor metabolic heterogeneity. Compared to conventional image interpolation such as bicubic or total variation, deep learning methods provided sharper edges and less blurring of structural details. Our results indicate that the proposed deep learning method is effective in enhancing the spatial resolution of metabolite maps which may better guide treatment in mutant IDH glioma patients.
BIMG-23. SINGLE-VOXEL VERSUS MULTI-SLICE MRSI IN PATIENTS WITH GLIOMA ON A KETOGENIC DIET INTERVENTION
Authors: Munjapara Vasu , Kamson David , Berrington Adam , Strowd Roy , Schreck Karisa , Barker Peter
Published: March 2021

BACKGROUND

Ketogenic diet therapies (KDTs) may be beneficial by exploiting glioma metabolic vulnerabilities. The GLioma modified Atkins-based Diet study (GLAD; NCT02286167) evaluated systemic and cerebral (MR spectroscopy) biomarkers to determine the feasibility and biological effects of a KDT in glioma patients. While we observed metabolic changes in tumor and normal brain after KDT using single-voxel MRS (SV-MRS), optimal voxel placement was not always achieved. AIMS: We performed an exploratory analysis comparing cerebral metabolite changes using multi-slice MRSI (MS-MRSI) versus SV-MRS acquisition.

METHODS

We evaluated four patients from the GLAD study (mean age 39years; 2 female, 3 AA IDH-mutant, 1 GBM IDH-wildtype) who underwent MRS at baseline and following eight weeks of KDT. SV-MRS (sLASER, TR/TE 2.2s/34ms) was acquired from a 2x2x2cm voxel placed in the residual tumor and the contralateral homologous brain. MS-MRSI was acquired with a multi-slice spin echo sequence (TR/TE 3.6/144ms, 4 slices, nominal resolution 13x7x7mm, SENSE factor 3) and maps of total choline (tCho), total N-acetyl-aspartate (tNAA), and lactate (Lac) were reconstructed and normalized relative to creatine. Metabolite levels were measured on the MS-MRSI maps using a region of interest placed in the same areas studied with the SV-MRS.

RESULTS

Lesional tCho and tNAA levels showed strong correlation between SV-MRS and MS-MRSI both at baseline (Pearson’s r=0.92 and 0.97, respectively) and after 8 weeks of KDT (r=0.96 and 0.84, respectively). tCho and tNAA correlated less robustly between SV-MRS and MS-MRSI in the contralesional region (r=0.56–0.96). Lesional Lac was significantly lower after KDT (1.01±0.48 versus 0.59±0.24, paired t-test p=0.02).

CONCLUSIONS

While SV and MS-MRSI provided generally concordant lesional results, MS-MRSI offers added potential to map regional variations not captured by SV-MRS and thus may better define the control regions. MS-MRSI detected a decrease in tumoral lactate levels following study intervention, suggesting KDT-related changes in tumoral energy metabolism.
DDRE-06. REGULATION OF TUMOR MICROENVIRONMENT VIA ENDOTHELIAL-TO-MESENCHYMAL TRANSITION BLOCKADE IN GLIOBLASTOMA-ASSOCIATED BRAIN ENDOTHELIAL CELLS
Authors: Marin’ Ramos Nagore I , Jhaveri Niyati , Thein Thu Zan , Chen Thomas C
Published: March 2021

Glioblastoma multiforme (GBM) is a malignant brain tumor noted for its extensive vascularity, aggressiveness, and highly invasive nature. Glioma stem cells (GSC) are a subpopulation of cells resistant to treatments and considered responsible for tumor recurrence. GSC are found in the vascular niches of the tumors, where endothelial cells (EC) secrete factors that stimulate GSC self-renewal. There are several studies regarding the effects of the vasculature on CSC and tumorigenesis, but little is known about how GSC affects the vasculature. Resistance to therapies and tumor recurrence greatly rely on the pro-angiogenic nature and aberrant vasculature of GBM. The endothelial-to-mesenchymal transition (EndMT) supports the pro-angiogenic and invasive characteristics of GBM. Hence, blocking the EndMT would be a promising approach to inhibit tumor progression and recurrence. We have examined the dynamic cross-talk between GSC and EC during EndMT. We demonstrate that GSC induce EndMT in brain endothelial cells (BEC), through a collaboration between TGF-β and Notch pathways, nicotinamide N-methyltransferase upregulation and other key signaling routes. Elucidating the cells and molecular pathways responsible for this process represents a milestone in the understanding of the tumor microenvironment and will help develop novel treatments in glioma therapy. One promising treatment, developed by our research group, is the conjugate of temozolomide and perillyl alcohol (POH), NEO212. This drug blocks EndMT induction in BEC and reverts the mesenchymal phenotype of tumor-associated BEC (TuBEC), reducing the invasiveness and pro-angiogenic properties of GBM in vitro and in vivo. We are currently performing Investigational New Drug (IND)-enabling studies, and we foresee that NEO212 will be of great clinical value for the treatment of GBM.
DDRE-11. TARGETING FATTY ACID BIOSYNTHESIS IN GLIOBLASTOMA
Authors: Eyme Katharina M , Neustadt Rudolph , Badr Christian E
Published: March 2021

We recently provided evidence that endoplasmic reticulum (ER) stress promotes fatty acid (FA) biosynthesis in glioblastoma (GBM) cancer stem cells (GSCs). We determined that Stearoyl CoA Desaturase 1 (SCD), a key FA desaturase, is essential for regulating ER homeostasis in GSCs, and showed that these cells are highly susceptible to pharmacological perturbation of SCD activity. An impaired SCD activity leads to the toxic accumulation of saturated FA and activates cell death signaling mediated by the ER sensor Inositol-requiring enzyme 1 (IRE1). This in turn promotes an IRE1-mediated mRNA decay of key DNA damage repair genes and impairs the ability of GSCs to repair DNA damage caused by radiation or chemotherapy. Consequently, combining SCD inhibition with temozolomide (TMZ) leads to major cytotoxicity both in TMZ-sensitive, and TMZ-resistant patient-derived GBM cells. Pharmacological inhibition of SCD delivered through the nasal route in mice, had a remarkable therapeutic benefit in patient-derived orthotopic GSCs mouse models, yet the modest brain permeability of the currently available SCD inhibitors precludes their clinical translation. To overcome this challenge, we have recently acquired a first-in-class, clinically relevant SCD inhibitor. This compound has undergone extensive pharmacokinetic and pharmacodynamic studies which confirmed brain permeability, efficacy, and safety in small animals and non-human primates. We show that the combination of this SCD inhibitor with TMZ is effective both in cultured GSCs, and in preclinical GSCs orthotopic mouse models. Our results support the clinical investigation of this new class of SCD inhibitors, in combination with TMZ, in patients diagnosed with GBM.
DDRE-16. CYSTEINE IS AN ESSENTIAL AMINO ACID IN GLIOMAS
Authors: Ruiz-Rodado Victor , Dowdy Tyrone , Yung Jinkyu , Dios-Esponera Ana , Lita Adrian , Kramp Tamalee , Camphausen Kevin , Gilbert Mark , Larion Mioara
Published: March 2021

BACKGROUND

Cysteine is a non-essential amino acid, since it can be synthetized from methionine through the transsulfuration pathway; moreover, cysteine is also uptake from the diet as cystine. We have investigated the metabolism of cysteine in glioma cell lines, and how cysteine/cystine-deprivation alters their antioxidant response in addition to the effect of this nutrient restriction to viability and proliferation in vitro and in vivo.

METHODS

Cysteine metabolism was investigated through LCMS-based 13C-tracing experiments involving different probes such as 13C-methyl-Methionine, 13C-C3-Cysteine, 13C-C3,3’-Cystine, 13C-C3-Serine and 13C-U-Glutamine and the expression levels of key enzymes in the transsulfuration pathway were also explored. Finally, a mouse model of IDH1 mutant glioma was subjected to a cysteine/cystine-free diet and tumor metabolism was analyzed by LCMS.

RESULTS

We demonstrated that exogenous cysteine/cystine are crucial for glutathione synthesis, and impact growth and viability. We also found that methionine cycle is disconnected from the transsulfuration pathway based on 13C-tracing data and protein expression levels of cystathionine synthase and cystathioninase. Accordingly, cysteine-related metabolites such as GSH, involved in REDOX hemostasis, are downregulated, revealing a hypersensitive phenotype to ROS. Animal models upon a cysteine/cystine-free diet experienced an increase in survival and elevated levels of oxidative stress in tumor tissue.

CONCLUSION

This results presented herein reveal an alternative therapeutic approach combining cysteine/cysteine-deprivation diets and treatments involving ROS production by limiting the ability of glioma cells to quench oxidative stress through dietary interventions.
DDRE-19. PHASE 0/I TRIAL OF MYCOPHENOLATE MOFETIL COMBINED WITH RADIATION TO OVERCOME GLIOBLASTOMA TREATMENT RESISTANCE BY TARGETING DE-NOVO PURINE METABOLISM
Authors: Umemura Yoshie , Sun Yilun , Junck Larry , Leung Denise , Kim Michelle , Al-Holou Wajd , Sagher Oren , Heth Jason , Lyssiotis Costas , Marini Bernard , Lawrence Theodore , Wahl Daniel
Published: March 2021

BACKGROUND

Radiation resistance is one of the major limitations for effective control of glioblastoma. Guanosine triphosphate (GTP) supplementation promotes glioblastoma radioresistance. Conversely, GTP depletion overcomes glioblastoma radioresistance by slowing the repair of radiation-induced DNA damage. Mycophenolate mofetil (MMF) inhibits de novo GTP synthesis by inhibiting the key enzyme, inosine-5′-monophosphate dehydrogenase, and radiosensitizes glioblastoma in mice. These pre-clinical findings have led to Phase 0/I Dose Escalation Study of Mycophenolate Mofetil Combined with Radiation Therapy in Recurrent Glioblastoma (NCT04477200) to measure the concentration of active metabolite of MMF in glioblastoma, and to determine the safe dose of MMF when given in combination with radiation.

METHODS

Key eligibility criteria are age ≥18, patients with Karnofsky Performance Scale score ≥60, and recurrent glioblastoma or gliosarcoma with clinical indication for re-irradiation (phase I) or re-resection or biopsy (phase 0). Those with tumor involving ≥3 lobes or leptomeningeal space or bevacizumab use within 8 weeks are excluded. Eight participants will receive MMF 500–2000 mg PO BID for one week before surgery (phase 0). Approximately 30 subjects will receive MMF 250–2000 mg PO BID (starting: 1000mg) on TITE-CRM dose escalation model (phase I).

RESULTS

From 7/2020 to 11/2020, two phase 0 and three phase I subjects have completed MMF treatment without notable toxicity. Additionally, correlative measurements of the activity of de novo GTP synthesis are explored. The anticipated study duration is 48 months.

CONCLUSION

The results of this trial will aid in designing a randomized clinical trial to determine the efficacy of MMF combined with chemoradiation in glioblastoma, and to define potential biomarkers for effectiveness. MMF is widely available and inexpensive, so if positive efficacy result is observed, a brisk acceptance of MMF combined with the standard of care is anticipated.
DDRE-20. TARGETING SPHINGOLIPID PATHWAY REVEALS VULNERABILITY IN IDH1MUT GLIOMA
Authors: Dowdy Tyrone , Zhang Lumin , Celiku Orieta , Movva Sriya , Ruiz-Rodado Victor , Lita Adrian , Larion Mioara
Published: March 2021

BACKGROUND

While central carbon metabolism has been studied extensively in cancer, lipidomic research is sparse. Sphingolipids participate in cellular functions including secondary messengers, lymphocyte trafficking, inflammation, angiogenesis, migration, proliferation, necrosis and apoptosis, thus highlighting the importance of understanding their role to tumor phenotype. Our investigation into metabolic alterations involving sphingolipid pathway in patient-derived IDH1mut glioma cultures aimed to identify points of metabolic vulnerability.

METHODS

Dysregulation of sphingolipid metabolism was interrogated for brain tumor cultures via LCMS. Expression of enzymes within the pathway was assessed for IDHmut 1/2 and IDHWT glioblastoma patient cohorts via The Cancer Genome Atlas (TCGA) analysis and Western blot for tumor cultures. Biostatic drug response was examined via viability and cytotoxicity assays.

RESULTS

We probed the effect that decreasing D-2HG levels with IDH1mut inhibitor (AGI5198) treatments had on sphingolipid metabolism in tumor cultures. The probe revealed N,N-dimethylsphingosine (NDMS), and sphingosine were significantly elevated, while sphingosine-1-phosphate (S1P) was downregulated in IDH1mut cultures following treatment. Drug panel screening revealed that SPHK inhibitor (SPHKi), N,N-dimethylsphingosine in combination with sphingosine triggered lethal dose-dependent response in IDH1mut cultures; contrary to IDHWT. Westerns presented differential expression of SPHK1 and SPHK2 in IDHWT glioblastoma cells, while IDHmut exclusively expressed SPHK1.

CONCLUSION

This novel discovery showed how targeting sphingolipid metabolism in IDH1mut gliomas presents therapeutic implications. Elevated S1P was reported particularly for malignant glioblastomas in prior studies; whereas our research revealed relatively low S1P in the IDHmut compared with IDHWT cultures. In addition to reduced or silenced expression of SPHK2, we postulate that S1P levels in IDHmut gliomas might be closer to a critical threshold allowing treatment with SPHK1i to effectively suspend proliferation and anti-apoptotic defense mechanisms. Our findings revealed that the manipulation of pivotal, endogenous sphingolipids can ultimately trigger apoptosis in IDHmut gliomas. Future studies will probe these targets in preclinical models.
DDRE-29. DE NOVO PYRIMIDINE SYNTHESIS IS A TARGETABLE VULNERABILITY IN IDH-MUTANT GLIOMA
Authors: Shi Diana D , Wang Adam C , Levitt Michael M , Endress Jennifer E , Xu Min , Gao Wenhua , Khanal Januka , Bonal Dennis , Kornblum Harley I , Nguyen Quang-De , Gradl Stefan , Sutter Andreas , Jeffers Michael , Janzer Andreas , Cahill Daniel P , Ligon Keith L , Abdullah Kalil G , Harris Isaac S , Kaelin William G , McBrayer Samuel K
Published: March 2021

70–90% of lower-grade gliomas and secondary glioblastomas harbor gain-of-function mutations in isocitrate dehydrogenase 1 (IDH1), causing overproduction of the oncometabolite (R)-2-hydroxyglutarate [(R)-2HG]. Although inhibitors of mutant IDH enzymes are effective in other cancers, including leukemia, they have shown guarded efficacy in preclinical and clinical brain tumor studies, thus underscoring the need to identify additional therapeutic targets in IDH mutant glioma. We sought to identify tumor-specific metabolic vulnerabilities induced by IDH1 mutations that could be exploited therapeutically. To uncover such vulnerabilities, we conducted a chemical synthetic lethality screen using isogenic IDH1 mutant and IDH1 wild-type (WT) glioma cell lines and a novel metabolic inhibitor screening platform. We discovered that IDH1 mutant cells are hypersensitive to drugs targeting enzymes in the de novo pyrimidine nucleotide synthesis pathway, including dihydroorotate dehydrogenase (DHODH). This vulnerability is specific because inhibitors of purine nucleotide metabolism did not score in our screen. We validated that the cytotoxicity of pyrimidine synthesis inhibitors is on-target and showed that IDH1 mutant patient-derived glioma stem-like cell lines are also hyperdependent on de novo pyrimidine nucleotide synthesis compared to IDH1 WT lines. To test pyrimidine synthesis dependence of IDH1 mutant gliomas in vivo, we used a brain-penetrent DHODH inhibitor currently undergoing evaluation in leukemia patients, BAY 2402234. We found that BAY 2402234 displays monotherapy activity against gliomas in an orthotopic xenograft model of IDH1 mutant glioma, with an effect size that compared favorably with radiotherapy. We also developed novel genetically engineered and allograft mouse models of mutant IDH1-driven anaplastic astrocytoma and showed that BAY 2402234 blocked growth of orthotopic astrocytoma allografts. Our findings bolster rationale to target DHODH in glioma, highlight BAY 2402234 as a clinical-stage drug that can be used to inhibit DHODH in brain tumors, and establish IDH1 mutations as predictive biomarkers of DHODH inhibitor efficacy.
DDRE-30. THERAPEUTIC TARGETING OF DISRUPTED METABOLIC STATE IN DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Mbah Nneka , Myers Amy , Chung Chan , Thompson Joyce , Shan Mengrou , Hong Hanna , Koschmann Carl , Venneti Sriram , Lyssiotis Costas
Published: March 2021

BACKGROUND

Diffuse Intrinsic Pontine Glioma (DIPG) is a uniformly fatal pediatric brainstem tumor and the leading cause of brain-tumor related deaths in children. It is therefore imperative to identify novel treatment strategies for this aggressive and devastating disease. Metabolic reprogramming in tumors and in the tumor microenvironment contribute to evasion of therapy and tumor recurrence. The goal of this study was to identify and therapeutically target metabolic vulnerabilities in DIPG that mediate aggressiveness and treatment resistance.

METHODS

DIPG tumors are marked by cellular heterogeneity and are driven by a population of cells with stem cell properties. We took a comprehensive metabolomics and transcriptomic screening approach to determine the operative pathways in the tumor driving stem cell compartment. To demonstrate efficacy and potential therapeutic window of activity, we treated DIPG tumors with clinically available and brain-penetrant inhibitors of the identified dysregulated metabolic pathways.

RESULTS

Our multi-omics analyses revealed that tumorigenic patient-derived DIPG cells significantly upregulate metabolic programs including cholesterol biosynthesis and mitochondrial oxidative phosphorylation (OXPHOS) compared to DIPG cells that were induced to undergo differentiation (events associated with a loss of tumorigenic capabilities). The therapeutic targeting of DIPG tumors with clinically available and brain penetrant inhibitors of OXPHOS and cholesterol biosynthesis resulted in tumor cell killing and growth inhibition both in vitro and in vivo. Moreover, there was a therapeutic window of activity in tumorigenic DIPG cells compared with differentiated gliomas and non-malignant cells.

CONCLUSION

Our findings demonstrate that DIPG harbor perturbations in metabolic programs that can be exploited for therapeutic benefits. The results from this study defined the metabolic pathways operative in the tumor-driving population in DIPG and demonstrated efficacy of targeting these pathways.
ETMM-01. CANCER STEM CELL ENRICHMENT AND METABOLIC SUBSTRATE ADAPTABILITY ARE DRIVEN BY HYDROGEN SULFIDE SUPPRESSION IN GLIOBLASTOMA
Authors: Silver Daniel J , Roversi Gustavo A , Bithi Nazmin , Neumann Chase K A , Troike Katie M , Ahuja Grace K , Reizes Ofer , Brown J Mark , Hine Christopher , Lathia Justin D
Published: March 2021

Glioblastoma (GBM) remains among the deadliest of human malignancies. The emergence of the cancer stem cell (CSC) phenotype represents a major challenge to disease management and durable treatment response. The extrinsic, environmental, and lifestyle factors that result in CSC enrichment are not well understood. The CSC state endows cells with a fluid metabolic profile, enabling the utilization of multiple nutrient sources. Therefore, to test the impact of diet on CSC enrichment, we evaluated disease progression in tumor-bearing mice fed an obesity-inducing high-fat diet (HFD) versus an energy-balanced, low-fat control diet. HFD consumption resulted in hyper-aggressive disease that was accompanied by CSC enrichment and shortened survival. HFD consumption also drove intracerebral accumulation of saturated fats, which in turn inhibited the production and signaling of the gasotransmitter hydrogen sulfide (H2S). H2S is an endogenously produced bio-active metabolite derived from sulfur amino acid catabolism. It functions principally through protein S-sulfhydration and regulates a variety of programs including mitochondrial bioenergetics and cellular metabolism. Inhibition of H2S synthesis resulted in increased proliferation and chemotherapy resistance, whereas treatment with H2S donors led to cytotoxicity and death of cultured GBM cells. Compared to non-cancerous controls, patient GBM specimens were reduced in overall protein S-sulfhydration, which was primarily lost from proteins regulating cellular metabolism. These findings support the hypothesis that diet-regulated H2S signaling serves to suppress GBM by restricting metabolic adaptability, while its loss triggers CSC enrichment and disease acceleration. Interventions augmenting H2S bioavailability concurrent with GBM standard of care may improve outcomes for GBM patients.
FSMP-17. GLOBAL METABOLOMIC PROFILING OF GLIOBLASTOMA MULTIFORME REVEALS METABOLIC VULNERABILITIES IN RESPONSE TO RADIATION THERAPY
Authors: Durairaj Aarooran , McReynolds Melanie , Wang Congcong , He Joy , Rabinowitz Joshua , Andreasson Katrin , Minhas Paras
Published: March 2021

Glioblastoma multiforme (GBM), the most aggressive primary brain tumor, originates in astrocytes and oligodendrocytes and yields a median survival time of less than 2 years and a 5-year survival of 2.5%. There has been little in the way of treatments and novel approaches are needed to combat the poor prognosis of GBM. Recent studies have established that GBM cells exhibit metabolic reprogramming to adapt to diverse metabolic gradients within heterogenous tumor microenvironments. Using an unbiased metabolomics approach, we investigated metabolic changes both pre- and post-ionizing radiation across several patient-derived GBM cell lines. Surprisingly, acute high dosage of ionizing radiation resulted in significant changes in the synthesis of aminolevulinic acid (ALA), a non-proteinogenic amino acid. Fractionation of radiation therapy resulted in dose-dependent changes in the heme synthesis pathway within these cells. Using an orthotopic xenograft mouse model of GBM, we identify several enzymatic vulnerabilities in vivo and discuss a novel combinatorial therapeutic approach of radiation and targeted pharmacological intervention. Our findings reveal the fundamental biosynthetic changes that GBMs adopt when exposed to ionizing irradiation as well as the benefits of a combinatorial approach.
TBMT-02. APOLLO: RAMAN-BASED PATHOLOGY OF MALIGNANT GLIOMA
Authors: Lita Adrian , Sjöberg Joel , Filipescu Stefan , Celiku Orieta , Petre Luigia , Gilbert Mark , Noushmehr Houtan , Petre Ion , Larion Mioara
Published: March 2021

BACKGROUND

DNA methylation is an essential component for integrative diagnosis of gliomas. Methylation subtype prediction of gliomas is currently done via sample extraction of high-quality DNA (~1ug), methylome profiling, followed by probe identification, curation and subsequent analysis via different random forest classifiers. However, the DNA methylation classification is not always available for all the samples. Examples include when the existing material is not suitable for methylation profiling or the sample is very limiting. Therefore, we hypothesized that Raman spectroscopy might be suitable to predict the glioma methylome, based upon its ability to create a molecular fingerprint of the tumor and would provide biological insights unknown before.

METHODS

Coherent Raman Spectroscopy was used for molecular fingerprinting of the regions of interest using 1mm2 FFPE tissue spots from 39 patient samples with LGm1 to LGm6 methylation subtypes. Spectral information was then used to train a convolutional neural network (CNN) and develop a prediction algorithm, capable of detecting the glioma methylation subtypes. 70 % of the dataset was used for model training while the remaining 30% for validation. Oversampling was used to obtain a subtype-balanced data distribution. In addition, supervised wrapper methods and random forests were used to identify the top 50 most discriminatory Raman frequencies out of 1738.

RESULTS

We demonstrate that Raman spectroscopy can accurately and rapidly classify gliomas according to their methylation subtype from achieved FFPE samples, which are routinely present in pathological laboratories as a complementary mean to obtain this important classification when other analyses are not available. The most discriminatory frequencies show differential spectral intensities depending upon the glioma subtypes across the larger areas of the tissue.

CONCLUSIONS

The non-destructive nature of this method and the ability to be applied on FFPE samples directly, allows the histopathologist to reuse of the same slide for subsequent staining and downstream analyses.
Age profile of NHS workers in occupational physician clinics
Authors: Telling W A
Published: March 2021

Background

The population in the UK is predicted to increase in size and age. The National Health Service (NHS) is the largest employer in the UK and demographic changes in the working population would be expected to be reflected in the NHS workforce. Such changes may present different challenges to an NHS occupational physician (OP).

Aims

To evaluate how the age profile of an NHS workforce is reflected in referral patterns, diagnoses and occupational outcomes for workers assessed by OPs.

Methods

NHS workers employed by a large acute Trust who were referred to an OP for assessment during 2011–12 were identified. Occupational health data relating to their assessment were analysed to investigate relationships with age.

Results

Seven hundred and two workers were identified; they were from all staff and age groups employed by the NHS Trust. The highest referral rate to an OP was in staff aged between 41 and 60 years. There was no evidence that workers with long-term conditions assessed by an OP were likely to be older. The occupational outcome of ill-health retirement was linked to age.

Conclusions

This study suggested that older workers, aged between 41 and 60 years, may be more likely to be referred for assessment by an OP than younger workers. The only occupational outcome linked to age was ill-health retirement, which was more likely for workers over 50 years of age.
Techniques of Onyx Embolization of Arteriovenous Malformation: 2-Dimensional Operative Video
Authors: Wagner Kathryn M , Srinivasan Visish M , Kan Peter
Published: March 2021

Advances in endovascular techniques and tools have allowed for treatment of complex arteriovenous malformations (AVMs), which historically may have posed unacceptable risk for open surgical resection. Endovascular treatment may be employed as an adjunct to surgical resection or as definitive therapy. Improvements in embolization materials have made endovascular AVM treatment safer for patients and useful across a variety of lesions. While many techniques are employed for transarterial AVM embolization, the essential tenets apply to all procedures: (1) great care should be taken to cannulate only vessels directly supplying the lesion, and not en passage vessels, prior to injecting embolisate; (2) embolisate should travel into the nidus, but not into the draining veins; (3) embolistate reflux proximal to the microcatheter should be avoided. There are several techniques that accomplish these goals, including the plug and push method, or using a balloon to prevent embolisate reflux. We use controlled injection of liquid Onyx (Medtronic), with increasing pressure over multiple injections pushing the embolisate forward into the AVM. This is repeated in multiple feeding vessels to decrease or eliminate supply to the AVM. Here, we present a 36-yr-old female with a right parietal AVM discovered on workup of headaches. After informed consent was obtained, she underwent preoperative embolization using this technique prior to uncomplicated surgical resection. The video shows the endovascular Onyx embolization of multiple feeding vessels over staged treatment.
Judicial Review
Authors: Schillig Michael
Published: March 2021

The exercise of extensive powers by authorities during the recovery and resolution process may interfere with constitutionally protected fundamental rights of stakeholder in a multitude of ways. Particularly relevant are the right to conduct a business and the right to property under the EU Charter of fundamental rights, as well as the takings clause under the US constitution. A balance needs to be struck between the aims and objectives of bank resolution and the rights of investors and the requirements of due process. This is normally achieved through expedited and limited judicial review. This chapter assesses whether and to what extent the respective procedures are in line with constitutional and fundamental rights requirements.
Resolution Funding
Authors: Schillig Michael
Published: March 2021

The chapter traces the hierarchy of resolution funding from the most readily available sources to the ultima ratio of government bailouts and the possibility of a supranational bailout as a last resort. Resolution-funding arrangements and deposit guarantee schemes interact in a multitude of ways. The discussion of this interaction is followed by an analysis of deposit guarantee schemes and resolution financing arrangements in the EU and the US, including the Single Bank Resolution Fund and the Orderly Liquidation Fund. The chapter further considers the available government financial stabilization tools in the form of direct recapitalization of an institution and temporary public ownership. It also provides a brief assessment of direct bank recapitalization through the European Stability Mechanism (ESM).
Resolution and Corporate Insolvency Law
Authors: Schillig Michael
Published: March 2021

The chapter seeks to delineate the interaction of corporate insolvency law and resolution proceedings. In Europe, the legal framework provided by the Bank Recovery and Resolution Directive and even the Single Resolution Mechanisms remain incomplete, with national corporate insolvency law filling the gaps. This is perhaps most relevant for the ranking of creditors under national law. The chapter provides an overview of the corporate insolvency procedures that are available in the jurisdictions under consideration. These may function as either a self-standing resolution mechanism or as supplementary devices within the framework of resolution. Given the relevance for all insolvency procedures under consideration as well as for resolution, not least through the ‘no-creditor-worse-off’ principle, the chapter discusses the ranking of different classes of creditors as determined by the Directive and national law, as well as the privileged treatment of certain financial creditors.
Winding-Up and Liquidation
Authors: Schillig Michael
Published: March 2021

Liquidation procedures may be relevant for unprofitable or defunct subsidiaries, even though other parts of a financial group may be successfully restructured. For certain types of financial companies, liquidation may be the only available process. The chapter provides an overview of the liquidation proceedings available for financial institutions in England, Germany and the US. It focuses on the English compulsory winding-up procedure and bank insolvency, the German general insolvency procedure with an enhanced role for BaFin as the competent authority, and the liquidation of broker-dealers in the US through a Chapter 7 stockbroker liquidation and under the Securities Investor Protection Act of 1970 (SIPA liquidation).
Proof of loss and loss of a chance
Authors: Burrows Andrew
Published: March 2021

A word is merited about the terminology of damages for loss of a chance. While it may be possible to distinguish conceptually between damages for loss of a chance and damages for the chance of a loss, this chapter draws no such distinction. Rather it uses the terminology of loss of a chance in a wide sense which covers both the lost chance of acquiring a benefit and the lost chance of avoiding a detriment. Increasing the chance of a loss equates to the lost chance of avoiding a detriment and this explains why a case like Barker v Corus (UK) Plc—where, as we have seen in the previous chapter, the courts awarded damages proportionately to the ‘material increase in risk’ of a disease—is equally well viewed as a loss of a chance case.
Aims and Interpretation of the EU-wide Legislation
Authors: Stone David
Published: March 2021

The long and bumpy road to EU-wide legislation is littered with drafts, papers, and opinions: deducing from them an agreed collective aim is difficult. However, given the purposive interpretation methodology favoured by the Court of Justice, it is important to attempt to distil the aims of the legislation.
Right to the Community Design
Authors: Stone David
Published: March 2021

The Regulation needed to provide for who would own the newly created Community designs. Many of the provisions of the Regulation relating to ownership are directly derived from the corresponding provisions of the CTM Regulation. These provisions largely use the law of the member state in which the owner is domiciled to determine issues of ownership.
Novelty
Authors: Stone David
Published: March 2021

Registered and unregistered Community designs and national and Benelux registered designs are protected to the extent that they are new and have individual character. This chapter considers novelty.
RCDs
Authors: Stone David
Published: March 2021

Article 12 of the Regulation provides for the registration of RCDs. Upon registration by the Office, a design which meets the requirements under Section 1 of Title II of the Regulation is protected as an RCD for a period of five years as from the date of the filing of the application. The RCD may be renewed in periods of five years each, up to a total term of 25 years from the date of filing.
Safe Harbours
Authors: Riordan Jaani
Published: March 2021

European law recognises various limits on the primary and secondary liability which may be imposed upon internet intermediaries for the acts of third parties. These limits fall into four categories: first, ‘safe harbours’ which insulate passive and neutral information society service providers from monetary liability for transmitting, caching, and storing third parties’ information; second, protection from general duties to monitor third parties’ information and activity; third, limits necessary to protect the fundamental rights of intermediaries and their users; and fourth, miscellaneous general limits on injunctive relief.
Website Blocking in Europe
Authors: Riordan Jaani
Published: March 2021

This chapter considers website blocking practices in European nations besides the United Kingdom. Most member states have enacted legislation to permit courts or administrative authorities to issue website blocking injunctions in some form. The majority of these statutory remedies are restricted to the enforcement of copyright and related rights, but some target other rights or pursue public policies such as the regulation of online gaming or the prohibition of images depicting child abuse. In some jurisdictions, blocking orders are available without any specific legislative basis, pursuant to ordinary rules governing injunctive relief.
Data Retention and Interception
Authors: Riordan Jaani
Published: March 2021

This chapter considers statutory duties that are owed by internet intermediaries to retain communications metadata for periods beyond their ordinary lifespan, and to disclose those data (and in narrower circumstances, the contents of the communications) for use in criminal investigations. These duties serve a range of public purposes—principally the preservation of national security, law enforcement, and public order. Their justification is said to be a rise in the criminal exploitation of internet and communications technologies, in particular to perpetrate cybercrime and to plan and carry out terrorist activities.
The Interaction with Other Areas of the Law
Authors: Mühlendahl Alexander , Botis Dimitris , Maniatis Spyros , Wiseman Imogen
Published: March 2021

Competition law and the free movement of goods principles have guided the development of trade mark law in Europe. This chapter will examine other relationships. The first part considers the use of trade marks in comparative advertisements. We have seen in Chapter 7 how comparative advertising has delineated the limits of trade mark law. Here the other side of the relationship is examined. Chapter 5 considered whether a geographical name can function and be protected as a trade mark and the limits of such protection. The second part of this chapter gives a flavour of the system of protecting product designations as geographical indications of origin. The third part looks at the clash between trade marks and domain names and the catalysing role of the concept of bad faith. The fourth part is a good example of how one dispute between distinguishing signs can become the common theme of distinct plots performed before different European audiences;
Conclusion
Authors: Mühlendahl Alexander , Botis Dimitris , Maniatis Spyros , Wiseman Imogen
Published: March 2021

The Court of Justice has considered within a relatively short period of time a large number of trade mark cases from two perspectives: as an interpretive court for the purposes of both the Directive and the Regulation and as a supreme court of appeal under the Regulation and its implementing rules. In both contexts it has interpreted and applied provisions that were essentially identical. However, under the Regulation the Court also had to be supportive of the new Union-wide trade mark right and the bodies administering it. For example, by strengthening the role of the Boards of Appeal and streamlining their decision-making trends, the Court could achieve a number of things: make the registration process more efficient, raise the level of dependency on the decision-making instances of OHIM, make the appeal route to the courts in Luxembourg more difficult, and lessen the burden imposed on the General Court (previously the Court of First Instance) and the Court of Justice.
Void or Voidable?
Authors: Ashdown Michael
Published: March 2021

For almost as long as the existence of the Re Hastings-Bass rule has been acknowledged, there has been uncertainty as to the consequences of the rule being successfully invoked in respect of the exercise of a power or discretion. Three principal possibilities have been put forward: first, that the trustee or fiduciary exercising the power may incur personal liability, but the exercise is nevertheless valid and effective; secondly, that the exercise of the power is voidable, and so is effective until set aside; and thirdly, that the purported exercise is wholly void and ineffective. The first of these has attracted no judicial support, and in any case Pitt v Holt puts beyond doubt that the validity of trustees’ decision can be called into question by the Re Hastings-Bass rule, with Lord Walker in the Supreme Court giving a clear endorsement of Lloyd LJ’s judgment to this effect in the Court of Appeal. As between the second and third options, though, the question of ‘void’ versus ‘voidable’ has been hard-fought.
Argentina
Authors: Araya Tomás M
Published: March 2021

The author would like to express his gratitude to M & M Bomchil associate Pedro de Elizalde for his valuable help in reviewing the cases mentioned in this chapter. The material contained herein is intended as a general guide only and is not intended to be a memorandum of law study, nor to provide legal advice, and should not be treated as a substitute for legal advice concerning particular situations. Legal advice should always be sought before taking any action based on the information provided. The publishers, editors, and author bear no responsibility for any errors or omissions contained therein.
Canada
Authors: Weinczok Mike , Le Kathy
Published: March 2021

We thank Lisa S Corne, a Partner in the Bankruptcy and Insolvency Group of Dickinson Wright LLP for her revisions to and comments on the chapter. The material contained herein is intended as a general guide only and is not intended to be a memorandum of law study, nor to provide legal advice, and should not be treated as a substitute for legal advice concerning particular situations. Legal advice should always be sought before taking any action based on the information provided. The publishers, editors, and authors bear no responsibility for any errors or omissions contained therein.
Czech Republic
Authors: Hájek Daniel
Published: March 2021

The material contained herein is intended as a general guide only and is not intended to be a memorandum of law study, nor to provide legal advice, and should not be treated as a substitute for legal advice concerning particular situations. Legal advice should always be sought before taking any action based on the information provided. The publishers, editors, and author bear no responsibility for any errors or omissions contained therein.
Greece
Authors: Klissouras Constantinos
Published: March 2021

The material contained herein is intended as a general guide only and is not intended to be a memorandum of law study, nor to provide legal advice, and should not be treated as a substitute for legal advice concerning particular situations. Legal advice should always be sought before taking any action based on the information provided. The publishers, editors, and author bear no responsibility for any errors or omissions contained therein.
Thailand
Authors: Pereira Santhapat , Duncan David
Published: March 2021

The material contained herein is intended as a general guide only and is not intended to be a memorandum of law study, nor to provide legal advice, and should not be treated as a substitute for legal advice concerning particular situations. Legal advice should always be sought before taking any action based on the information provided. The publishers, editors, and authors bear no responsibility for any errors or omissions contained therein.
Corporate Group Restructuring Finance Global Law Reform
Authors: Baer Gregor
Published: March 2021

The material contained herein is intended as a general guide only and is not intended to be a memorandum of law study, nor to provide legal advice, and should not be treated as a substitute for legal advice concerning particular situations. Legal advice should always be sought before taking any action based on the information provided. The publishers, editors, and author bear no responsibility for any errors or omissions contained therein. Provisions of UNCITRAL and World Bank texts quoted or summarized in this chapter are provided courtesy of the United Nations Commission on International Trade Law and the World Bank, the respective copyright owners.
Disclosure of Information to the Beneficiaries and Letters of Wishes
Authors: Panico Paolo
Published: March 2021

This chapter deals with the trustees’ duty to disclose information to the beneficiaries, which is an essential mechanism of enforcement of a proper administration of the trust.
Members’ Unfair Prejudice Claims and Winding-Up Petitions
Authors: Adam Al-Attar
Published: March 2021

The 2006 Act, Part 30, ss 994–9 contains the provisions protecting members from unfair prejudice arising from the conduct of the affairs of the company. These provisions came into force on 1 October 2007 and replaced provisions in the 1985 Act, ss 459–61 without change, except for the introduction of the 2006 Act, s 999, which contains new supplementary provisions where the company’s constitution is altered. With effect from 6 April 2008 a new s 994(1A) was inserted which provides that the removal from office of the company’s auditor should in certain circumstances be treated as unfairly prejudicial to the interests of some part of the members.
Members’ Unfair Prejudice Claims and Winding-Up Petitions
Authors: Robins Stephen
Published: March 2021

The primary purpose of this chapter is to describe the functions, responsibilities, and liabilities of company directors in relation to accounting records, the requirements for disclosure of annual accounts and reports, and audit (the 2006 Act, Parts 15 and 16). This broad subject area breaks down into several parts.
Directors’ liabilities in Insolvency Proceedings
Authors: Cooke Charlotte
Published: March 2021

This chapter discusses the liabilities of directors in consequence of a company entering insolvency proceedings. Sections B and C(1) concern claims which were available to the company when it entered insolvency proceedings and can be brought in its own name or by a liquidator using the summary procedure in the Insolvency Act, s 212. Sections C(2) and (3) and D consider a director’s personal liability under the Insolvency Act for wrongful trading, fraudulent trading, or contravention of the restriction on reuse of a company name, which may result from the company entering insolvency proceedings. Section E discusses the impact on directors of the provisions in the Insolvency Act for adjusting prior transactions.
Tax Issues in Restructuring
Authors: Mallon Christopher , Waisman Shai Y , Schrock Ray C
Published: March 2021

A company engaged in the modification or restructuring of its debt, or simply the buying back of its debt, should carefully consider the tax implications. In some cases, even what seems like an innocuous action (as in the case of the US tax rules relating to modifications of debt) may have significant tax implications. In other cases, advance planning may yield more efficient structures, or otherwise ensure that taxes are properly factored into the decision-making process. Depending on the situation, the tax cost can take the form of current or deferred tax payments, the reduction or elimination of the company’s valuable tax benefits (such as net operating losses or tax basis), or other limitations on the company’s use of such tax benefits.
Pension Scheme Trustees and Regulators
Authors: Mallon Christopher , Waisman Shai Y , Schrock Ray C
Published: March 2021

Superficially, the UK and the US pensions regime when companies are restructuring look similar. Both countries have a significant number of defined benefit pension plans, both have a regulatory safety net for those plans and both have active regulatory bodies to patrol that safety net that can play a substantial role in the restructuring of the sponsoring employer. Under both regimes, substantial debts can be triggered on the employers.