bluuebunny/crossref_metadata_2025 huggingface dataset:
6. The widening mainstream
Authors: Gerber David A.
Published: March 2021

A persistent theme in responding to mass immigration has been fears about immigrants’ perceived unwillingness to become Americans. Much of this anxiety has been a consequence of misperceptions of the meanings for immigrants of their ethnic group life and identity. Such anxieties have led to Americanization programs, sometimes beneficial and well-meaning and sometimes coercive and nativist. It also is a consequence of not understanding how the dynamic historical growth and development of the United States have continually worked to expand its societal mainstream to accommodate constant economic and technological change as well as the growing diversity of the population. American social forms and processes, as the examples of both the labor movement and electoral politics suggest, have consistently demonstrated considerable absorptive capacities, and they continue to do so. While Americans have not always welcomed immigrants enthusiastically, these homogenizing processes work, though not necessarily rapidly or evenly, toward civil and cultural unity.
Mitigating the horrors of war
Authors: Mitchell Jolyon , Rey Joshua
Published: March 2021

‘Mitigating the horrors of war’ situations in which religion, rather than motivating or assisting war, has sought to be a force making warfare less barbarous and catastrophic. Many religions have a distinctive ethical code with regard to war. The Western Christian tradition has developed a concept of ‘just war’, and the Islamic notion of jihad also places limits on war. But perhaps the oldest body of ideas and teachings on this topic arose on the Indian sub-continent. This thought receives a subtle treatment in the Mahabharata epic. The Mahabharata presents an understanding of the ethics of warfare in which compromise is unavoidable.
Invoking peace
Authors: Mitchell Jolyon , Rey Joshua
Published: March 2021

‘Invoking peace’ describes religious pacifism, which is a spectrum. Some will take the religious imperative to peace as a simple prohibition on fighting, while some will take it as a command to active peace-building. Likewise, there are different ways in which religious pacifism is lived out and has an impact. Buddhist pacifism, Jainism, and Christian pacifism are worth considering, particularly the figures of Mahatma Gandhi and Bacha Khan. There are issues with contemporary Muslim peace-building and the limits of liberal peace-building and this can be seen through the example of an initiative to promote interfaith dialogue and understanding: the Interfaith Mediation Centre based in Kaduna, in Northern Nigeria.
4. Islamic and Confucian accounts of the virtues
Authors: Boyd Craig A. , Timpe Kevin
Published: March 2021

This chapter evaluates how two different cultural traditions understand virtue, specifically Islam and Confucianism. The work of Al-Ghazzali provides insight into the central role of virtue for Islam. In living out the five pillars of Islam—the shahadah, salat, zakat, sawm, and the hajj—one becomes a person properly related to Allah and to others. In this context, adab (the manner in which people acquire good character) provides an entrée into Islamic accounts of the virtues. Meanwhile, while there are important differences between the thinkers in the Confucian tradition, they all emphasized the dao (the ‘way’) as providing the highest human good and the proper cosmic ordering of the universe.
5. The theological virtues
Authors: Boyd Craig A. , Timpe Kevin
Published: March 2021

This chapter focuses on the theological virtues as initially presented in the Jewish tradition and then developed and augmented by later Christian thinkers. There is a hierarchical relationship among the theological virtues. Faith involves trust-based intellectual assent to revealed theological truths. Like faith, hope requires a trust in God and is the patient expectation—or habit—of waiting for the promised but ‘not-yet’ good that faith points to. But the fullness of the theological virtues is found in charity. In this virtue, a person is united with God and with others in a kind of ‘divine friendship’ that surpasses the boundaries of family, ethnicity, gender, and status.
Scedosporium and Lomentospora Infections Are Infrequent, Difficult to Diagnose by Histology, and Highly Virulent
Authors: DeSimone Mia S , Crothers Jessica W , Solomon Isaac H , Laga Alvaro C
Published: March 2021

Objective

To further characterize the histomorphology and clinicopathologic features of colonization and invasive disease by Scedosporium and Lomentospora.

Methods

We conducted a 20-year retrospective study. Patients with at least 1 histopathology specimen and concurrent culture were included. Clinical features, histopathology, microbiology, and outcomes were analyzed.

Results

Eighteen patients were identified, and all were immunocompromised. Eight patients had colonization, while 10 had invasive disease (pneumonia [n = 3], skin and soft-tissue infections [n = 3], disseminated disease [n = 4]). Scedosporium apiospermum was identified in 15 patients, Lomentospora prolificans in 2 patients, and Scedosporium ellipsoideum in 1 patient. Fungal elements were identified histologically in 11 patients. Granulomatous, suppurative, and necrotizing inflammation with irregular branching hyphae and characteristic microconidia were observed in 9 cases; conidiogenous cells were identified in 4 cases. Seven patients died of invasive disease despite therapy, and 3 recovered after treatment. No deaths were observed in patients with colonization.

Conclusions

Scedosporium and Lomentospora are rare, virulent opportunistic fungal pathogens. Fungal morphology may overlap with other hyaline molds, but identification of obovoid conidia should allow a diagnosis of non-Aspergillus hyalohyphomycosis and consideration of Scedosporium and Lomentospora. Histopathologic correlation with culture and polymerase chain reaction is critical for diagnosis and treatment.
News in Astronomy & Geophysics – April 2021
Authors: Bowler Sue , Gunn Alastair
Published: March 2021

A digest of some of the big stories from the past two months
European Hernia Society guidelines on management of rectus diastasis
Authors: Hernández-Granados P , Henriksen N A , Berrevoet F , Cuccurullo D , López-Cano M , Nienhuijs S , Ross D , Montgomery A
Published: March 2021

Background

The definition, classification and management of rectus diastasis (RD) are controversial in the literature and a variety of different surgical treatments have been described. This article reports on the European Hernia Society (EHS) Clinical Practice Guideline for RD.

Method

The Guideline group consisted of eight surgeons. The Grading of Recommendation, Assessment, Development and Evaluation (GRADE) approach and the Appraisal of Guidelines for Research and Evaluation (AGREE) instrument were used. A systematic literature search was done in November 2018 and updated in November 2019 and October 2020. Nine Key Questions (KQs) were formulated.

Results

Literature reporting on the definition, classification, symptoms, outcomes and treatments was limited in quality, leading to weak recommendations for the majority of the KQs. The main recommendation is to define RD as a separation between rectus muscles wider than 2 cm. A new classification system is suggested based on the width of muscle separation, postpregnancy status and whether or not there is a concomitant hernia. Impaired body image and core instability appear to be the most relevant symptoms. Physiotherapy may be considered before surgical management. It is suggested to use linea alba plication in patients without concomitant hernia and a mesh-based repair of RD with concomitant midline hernias.

Conclusion

RD should be defined as a separation of rectus muscles wider than 2 cm and a new classification system is suggested.
Early neuroimaging and ultrastructural correlates of injury outcome after neonatal hypoxic-ischaemia
Authors: Kao Yu-Chieh Jill , Chen Seu-Hwa , Lu Chia-Feng , Hsieh Bao-Yu , Chen Cheng-Yu , Chang Ying-Chao , Huang Chao-Ching
Published: March 2021

Hypoxic ischaemia encephalopathy is the major cause of brain injury in new-borns. However, to date, useful biomarkers which may be used to early predict neurodevelopmental impairment for proper commencement of hypothermia therapy is still lacking. This study aimed to determine whether the early neuroimaging characteristics and ultrastructural correlates were associated with different injury progressions and brain damage severity outcomes after neonatal hypoxic ischaemia. Longitudinal 7 T MRI was performed within 6 h, 24 h and 7 days after hypoxic ischaemia in rat pups. The brain damage outcome at 7 days post-hypoxic ischaemia assessed using histopathology and MRI were classified as mild, moderate and severe. We found there was a spectrum of different brain damage severity outcomes after the same duration of hypoxic ischaemia. The severity of brain damage determined using MRI correlated well with that assessed by histopathology. Quantitative MRI characteristics denoting water diffusivity in the tissue showed significant differences in the apparent diffusion coefficient deficit volume and deficit ratios within 6 h, at 24 h and 7 days after hypoxic ischaemia among the 3 different outcome groups. The susceptible brain areas to hypoxic ischaemia were revealed by the temporal changes in regional apparent diffusion coefficient values among three outcome groups. Within 6 h post-hypoxic ischaemia, a larger apparent diffusion coefficient deficit volume and deficit ratios and lower apparent diffusion coefficient values were highly associated with adverse brain damage outcome. In the apparent diffusion coefficient deficit areas detected early after hypoxic ischaemia which were highly associated with severe damage outcome, transmission electron microscopy revealed fragmented nuclei; swollen rough endoplasmic reticulum and degenerating mitochondria in the cortex and prominent myelin loss and axon detraction in the white matter. Taken together, different apparent diffusion coefficient patterns obtained early after hypoxic ischaemia are highly associated with different injury progression leading to different brain damage severity outcomes, suggesting the apparent diffusion coefficient characteristics may be applicable to early identify the high-risk neonates for hypothermia therapy.
Long-term fate of moderate aortic regurgitation left untreated at the time of mitral valve surgery
Authors: Del Forno Benedetto , Ascione Guido , Bisogno Arturo , Carino Davide , Lapenna Elisabetta , Verzini Alessandro , Bargagna Marta , Ruggeri Stefania , Schiavi Davide , Meneghin Roberta , Agricola Eustachio , Monaco Fabrizio , Alfieri Ottavio , Castiglioni Alessandro , De Bonis Michele
Published: March 2021

OBJECTIVES

The appropriateness of moderate aortic regurgitation treatment during mitral valve (MV) surgery remains unclear. The goal of this study was to evaluate the immediate and long-term outcomes of patients with moderate aortic regurgitation at the time of MV surgery.

METHODS

We included 183 patients admitted to our institution for elective treatment of MV disease between 2004 and 2018, in whom moderate aortic regurgitation was diagnosed during preoperative evaluation. One hundred and twenty-two patients underwent isolated MV surgery (study group) whereas 61 patients underwent concomitant MV surgery and aortic valve replacement (control group).

RESULTS

One death (0.8%) occurred in the study group, and 3 deaths (4.8%) occurred in the control group (P = 0.52). The rate of the most common postoperative complication was similar between the 2 groups. At 12 years, the cumulative incidence function of cardiac death, with non-cardiac death as a competing risk, was 4.7 ± 2.8% in the study group; no cardiac deaths were observed in the control group (P = 0.078). At 6 and 12 years, in the study group, the cumulative incidence function of aortic valve reintervention, with death as a competing risk, was 2.5 ± 1.85% and 19 ± 7.1%, respectively.

CONCLUSIONS

The appropriate management of moderate aortic regurgitation at the time of MV surgery deserves a careful evaluation by balancing the reintervention rate with the age, the operative risk and the life expectancy of the patient. Our findings suggest that a patient-tailored approach is the key to achieving the best clinical outcome for each individual patient.
DNA-SIP and repeated isolation corroborateVariovoraxas a key organism in maintaining the genetic memory for linuron biodegradation in an agricultural soil
Authors: Lerner Harry , Öztürk Başak , Dohrmann Anja B , Thomas Joice , Marchal Kathleen , De Mot René , Dehaen Wim , Tebbe Christoph C , Springael Dirk
Published: March 2021

The frequent exposure of agricultural soils to pesticides can lead to microbial adaptation, including the development of dedicated microbial populations that utilize the pesticide compound as a carbon and energy source. Soil from an agricultural field in Halen (Belgium) with a history of linuron exposure has been studied for its linuron-degrading bacterial populations at two time points over the past decade and Variovorax was appointed as a key linuron degrader. Like most studies on pesticide degradation, these studies relied on isolates that were retrieved through bias-prone enrichment procedures and therefore might not represent the in situ active pesticide-degrading populations. In this study, we revisited the Halen field and applied, in addition to enrichment-based isolation, DNA stable isotope probing (DNA-SIP), to identify in situ linuron-degrading bacteria in linuron-exposed soil microcosms. Linuron dissipation was unambiguously linked to Variovorax and its linuron catabolic genes and might involve the synergistic cooperation between two species. Additionally, two novel linuron-mineralizing Variovorax isolates were obtained with high 16S rRNA gene sequence similarity to strains isolated from the same field a decade earlier. The results confirm Variovorax as a prime in situ degrader of linuron in the studied agricultural field soil and corroborate the genus as key for maintaining the genetic memory of linuron degradation functionality in that field.
Relative contributions of egg-associated and substrate-associated microorganisms to black soldier fly larval performance and microbiota
Authors: J. J. Schreven Stijn , de Vries Hugo , D. A. Hermes Gerben , Smidt Hauke , Dicke Marcel , J. A. van Loon Joop
Published: March 2021

Larvae of the black soldier fly (BSF) can be used to convert organic waste into insect biomass for animal feed. In this process, they interact with microorganisms originating from the substrate, the insect and the environment. The substrate is the main determinant of the larval gut microbiota composition, but inoculation of the substrate with egg-associated bacteria can improve larval performance. We aimed to quantify the relative importance of substrate-associated and egg-associated microorganisms in BSF larval performance, bacterial abundance and bacterial community composition, when larvae were fed with chicken feed or chicken manure. For this, we inactivated substrate-associated microorganisms by autoclaving, or disinfected BSF eggs. Larval survival, weight and proportion of prepupae were determined on day 15. We collected substrate and larval samples on days 0 and 15 and performed 16S rRNA gene-targeted qPCR and amplicon sequencing. In both chicken feed and chicken manure, egg disinfection did not cause any difference in larval performance or overall microbiota composition. In contrast, in chicken manure, substrate-associated microorganisms increased larval biomass and sterilizing the substrate caused major shifts in microbiota. Thus, substrate-associated microorganisms impact not only larval microbiota but also larval performance, whereas egg-associated microorganisms have a minor role in the densities present.
The clinical path to deliver encapsulated phages and lysins
Authors: Pinto Ana Mafalda , Silva Maria Daniela , Pastrana Lorenzo M , Bañobre-López Manuel , Sillankorva Sanna
Published: March 2021

The global emergence of multidrug-resistant pathogens is shaping the current dogma regarding the use of antibiotherapy. Many bacteria have evolved to become resistant to conventional antibiotherapy, representing a health and economic burden for those afflicted. The search for alternative and complementary therapeutic approaches has intensified and revived phage therapy. In recent decades, the exogenous use of lysins, encoded in phage genomes, has shown encouraging effectiveness. These two antimicrobial agents reduce bacterial populations; however, many barriers challenge their prompt delivery at the infection site. Encapsulation in delivery vehicles provides targeted therapy with a controlled compound delivery, surpassing chemical, physical and immunological barriers that can inactivate and eliminate them. This review explores phages and lysins' current use to resolve bacterial infections in the respiratory, digestive and integumentary systems. We also highlight the different challenges they face in each of the three systems and discuss the advances towards a more expansive use of delivery vehicles.
Long-insert clone experimental evidence for assembly improvement and chimeric chromosomes detection in an allopentaploid beer yeast
Authors: Gómez-Muñoz Cintia , García-Ortega Luis Fernando , Montalvo-Arredondo Javier , Pérez-Ortega Esmeralda , Damas-Buenrostro Luis Cástulo , Riego-Ruiz Lina
Published: March 2021

Lager beer is made with the hybrid Saccharomyces pastorianus. Many publicly available S. pastorianus genome assemblies are highly fragmented due to the difficulties of assembling hybrid genomes, such as the presence of homeologous chromosomes from both parental types, and translocations between them. To improve the assembly of a previously sequenced lager yeast hybrid Saccharomyces sp. 790 and elucidate its genome structure, we proposed the use of alternative experimental evidence. We determined the phylogenetic position of Saccharomyces sp. 790 and established it as S. pastorianus 790. Then, we obtained from this yeast a bacterial artificial chromosome (BAC) genomic library with its BAC-end sequences (BESs). To analyze these data, we developed a pipeline (applicable to other assemblies) that classifies BES pairs alignments according to their orientation. For the case of S. pastorianus 790, paired-end BESs alignments validated parts of the assembly and unpaired-end ones suggested contig joins or misassemblies. Importantly, the BACs library was preserved and used for verification experiments. Unpaired-end alignments were used to upgrade the previous assembly and provided an improved detection of translocations. With this, we proposed a genome structure of S. pastorianus 790, which was similar to that of other lager yeasts; however, when we estimated chromosome copy number and experimentally measured its genome size, we discovered that one key difference is the outstanding S. pastorianus 790 ploidy level (allopentaploid). Altogether, our results show the value of combining bioinformatic analyses with experimental data such as long-insert clone information to improve a short-read assembly of a hybrid genome.
Transforming Zones of Exclusion to Zones of Inclusion? Local-Level UN Peacekeeping Deployments and Educational Attainment
Authors: Reeder Bryce W , Polizzi Marc S
Published: March 2021

Higher educational attainment levels are associated with better public health outcomes, lower levels of income inequality, more participation in democratic instructions, and safer communities. Promoting education in war-torn societies can have an immediate impact in mitigating violence and play a significant role in preventing conflict recurrence. This study investigates UN peacekeeping missions’ role in this process, positing that UN deployments to locations experiencing armed conflict lead to higher levels of educational attainment by increasing local stability, incentivizing individuals to return to school while also making renewed investment worthwhile. Testing this logic using new data on local-level educational attainment across Africa from 2000 to 2014, this study finds that conflict zones where the UN maintained peacekeeping deployments saw an increase in educational attainment when compared to those that did not, a finding corroborated by coarsened exact matching. Maintaining a modest number of UN forces is shown to increase female attainment by at least 4.89 percent and reduce gender disparity by 5.13 percent, revealing the critical role UN peacekeeping plays in restoring education in the shadow of political violence.
Common-Pool Hierarchy: Explaining the Emergence of Cooperative Hierarchies
Authors: Dillon Savage Jesse
Published: March 2021

Hierarchy in international relations has often been understood as an arrangement with a single dominant state controlling aspects of the subordinate actor's sovereignty. While such arrangements play an important role in structuring international politics, it does not exhaust the forms that hierarchy can take. Very often hierarchies have developed where multiple states jointly claim control of the same sovereign rights of the subordinate state. This paper introduces a new conceptualization of hierarchy where the sovereign rights of the subordinate state are understood as a resource that can be controlled by multiple dominant states. As with other resources, different types of property regimes can be developed to organize access and extraction of sovereignty, such as common property resources regimes. Finally, an explanation of common-pool hierarchy regimes is developed and explored using two case studies: European imperialism in the nineteenth-century China and the scramble for Africa.
A Survey on Applying Automated Recognition of Touchscreen Stroke Gestures to Children’s Input
Authors: Shaw Alex , Ruiz Jaime , Anthony Lisa
Published: March 2021

Gesture recognition algorithms help designers create intelligent user interfaces for a number of application areas. However, these recognition algorithms are usually designed to recognize the gestures of adults, not children, and as such they generally do not perform as well for children as adults. Recognition of younger children’s gestures is particularly poor when compared to recognition of older children’s and adults’ gestures. Researchers have begun to examine the aspects of children’s gesture articulation patterns that make recognition difficult. This paper extends the initial work examining child-specific recognition approaches by considering general-purpose approaches and how they might apply to the problem of recognizing children’s touchscreen gestures. This paper presents a survey of existing recognition and analysis techniques for gestures of both adults and children from a human-centered perspective, highlighting ways in which improved recognition can lead to a better experience for children using touchscreen gestures in a variety of contexts.
An LC-MS/MS Method for the Determination of Antibiotic Residues in Distillers Grains: Collaborative Study
Authors: De Alwis Hemakanthi G , Nochetto Cristina , Kijak Philip J
Published: March 2021

Background

Antibiotics are used in ethanol production to discourage the growth of bacteria that would lower the yield of the product. Any antibiotic residues remaining in distillers grain (DG) co-product could lead to antimicrobial resistance, which is a public health concern. The U.S. Food and Drug Administration (FDA) Center for Veterinary Medicine (CVM) previously developed an LC-MS/MS analytical method to detect residues of erythromycin A, penicillin G, virginiamycin M1, and virginiamycin S1 in DG to enable regulatory decision making.

Objective

The objective of this study was to ensure the method’s robustness by carrying out a multi-laboratory validation of the method.

Method

Test portions were extracted with a mixture of acetonitrile and buffer. The extract was cleaned by solid phase extraction. The concentrated eluant was reconstituted and analyzed by LC-MS/MS. Eight laboratories participated in the study.

Results

Average accuracies for the combined three matrixes for all four compounds at all fortification levels ranged from 83–>109% with repeatability relative standard deviation (RSDr; within laboratory) ≤17% and reproducibility relative standard deviation (RSDR; between laboratory) ≤21%. The Horwitz ration (HorRat) values ranged 0.4–1.0 indicating that method reproducibility is acceptable.

Conclusions

An interlaboratory study was successfully conducted to evaluate an LC-MS/MS method for the determination of the drugs of interest in DG. The results demonstrate that the method is fit for purpose to determine the drugs in DG and could serve as a regulatory method capable of being used for compliance actions for DG containing these antibiotic contaminants.

Highlights

The method was posted to the FDA/Foods Program Compendium of Analytical Laboratory Methods.
BIMG-02. IMAGING IMMORTALITY: TERT EXPRESSION ALTERS GLUCOSE METABOLISM IN LOW-GRADE GLIOMAS IN A MANNER THAT CAN BE LEVERAGED FOR NONINVASIVE METABOLIC IMAGING
Authors: Viswanath Pavithra , Batsios Georgios , Gillespie Anne Marie , Luchman Hema Artee , Costello Joseph , Pieper Russell , Ronen Sabrina
Published: March 2021

Telomerase reverse transcriptase (TERT) is essential for tumor immortality and uncontrolled proliferation, including in low-grade oligodendrogliomas (LGOGs). Since it is silenced in somatic cells, TERT is also a therapeutic target. Non-invasive imaging of TERT can differentiate tumor from normal brain or lesions such as gliosis and allow assessment of response to therapy. The goal of this study was to identify magnetic resonance spectroscopy (MRS)-detectable metabolic alterations associated with TERT that can be leveraged for noninvasive imaging in LGOGs. We examined patient-derived BT54 neurospheres in which TERT expression was silenced by RNA interference. 1H-MRS showed that steady-state levels of NAD(P)/H, glutathione, aspartate and AXP were elevated in BT54TERT+ neurospheres relative to BT54TERT-. Glucose flux through the pentose phosphate pathway (PPP) is essential for generating NADPH, which maintains glutathione homeostasis. 13C-MRS confirmed that [2-13C]-glucose flux through the PPP was elevated in BT54TERT+ neurospheres relative to BT54TERT-, an effect associated with higher activity of the PPP enzyme glucose-6-phosphate dehydrogenase (G6PDH). Hyperpolarized 13C-MRS is a method of increasing the signal to noise ratio of 13C-MRS such that it can monitor metabolic fluxes noninvasively in cells, animals and patients. Consistent with elevated PPP flux and G6PDH activity, hyperpolarized [U-13C]-glucose metabolism via the PPP to 6-phosphogluconate (6-PG) was elevated in BT54TERT+ neurospheres relative to BT54TERT-. Importantly, examination of an additional patient-derived LGOG model, the SF10417 model which readily forms orthotopic tumor xenografts in rats, showed that 6-PG production from hyperpolarized [U-13C]-glucose demarcated tumor from normal brain. Furthermore, LGOG patient biopsies had elevated NAD(P)/H, glutathione, aspartate, AXP and G6PDH activity relative to gliosis biopsies, confirming the clinical validity of our observations. Collectively, we have identified a metabolic signature of TERT expression that can be leveraged via hyperpolarized [U-13C]-glucose to improve diagnosis and treatment response monitoring for LGOG patients.
BIMG-08. DEUTERIUM MAGNETIC RESONANCE SPECTROSCOPY USING 2H-PYRUVATE ALLOWS NON-INVASIVE IN VIVO IMAGING OF TERT EXPRESSION IN BRAIN TUMORS
Authors: Batsios Georgios , Taglang Celine , Tran Meryssa , Gillespie Anne Marie , Costello Joseph , Ronen Sabrina , Viswanath Pavithra
Published: March 2021

Telomere shortening constitutes a natural barrier to uncontrolled proliferation and all tumors must find a mechanism of maintaining telomere length. Most human tumors, including high-grade primary glioblastomas (GBMs) and low-grade oligodendrogliomas (LGOGs) achieve telomere maintenance via reactivation of the expression of telomerase reverse transcriptase (TERT), which is silenced in normal somatic cells. TERT expression is, therefore, a driver of tumor proliferation and, due to this essential role, TERT is also a therapeutic target. However, non-invasive methods of imaging TERT are lacking. The goal of this study was to identify magnetic resonance spectroscopy (MRS)-detectable metabolic biomarkers of TERT expression that will enable non-invasive visualization of tumor burden in LGOGs and GBMs. First, we silenced TERT expression by RNA interference in patient-derived LGOG (SF10417, BT88) and GBM (GS2) models. Our results linked TERT silencing to significant reductions in steady-state levels of NADH in all models. NADH is essential for the conversion of pyruvate to lactate, suggesting that measuring pyruvate flux to lactate could be useful for imaging TERT status. Recently, deuterium (2H)-MRS has emerged as a novel, clinically translatable method of monitoring metabolic fluxes in vivo. However, to date, studies have solely examined 2H-glucose and the use of [U-2H]pyruvate for non-invasive 2H-MRS has not been tested. Following intravenous injection of a bolus of [U-2H]pyruvate, lactate production was higher in mice bearing orthotopic LGOG (BT88 and SF10417) and GBM (GS2) tumor xenografts relative to tumor-free mice, suggesting that [U-2H]pyruvate has the potential to monitor TERT expression in vivo. In summary, our study, for the first time, shows the feasibility and utility of [U-2H]pyruvate for in vivo imaging. Importantly, since 2H-MRS can be implemented on clinical scanners, our results provide a novel, non-invasive method of integrating information regarding a fundamental cancer hallmark, i.e. TERT, into glioma patient management.
BIMG-09. GLUTAMINE AND GLYCINE BY MR SPECTROSCOPY IDENTIFY AGGRESSIVE GLIOMAS
Authors: Choi Changho , Askari Pegah , Daoud Elena , Hatanpaa Kimmo , Raisanen Jack , Levy Michael , Pan Edward , Patel Toral , Mickey Bruce , Maher Elizabeth
Published: March 2021

Cancers reprogram their metabolism and the resulting alterations in metabolite abundance can be monitored in patients noninvasively using proton magnetic resonance spectroscopy (MRS). We evaluated glutamine, glycine and 2-hydroxyglutarate (2HG) in 27 adult subjects with gliomas (17 male and 10 female; age 22 - 69, median 39 years) using optimized MRS at 3T (PRESS TE 97ms) and examined their association with post-gadolinium enhancement, cell proliferation rate (MIB-1 labeling index), and overall survival of patients. The tumors included 9 glioblastomas (3 IDH mutated and 6 IDH wildtype), 10 astrocytomas (7 IDH mutated and 3 IDH wildtype), and 8 oligodendrogliomas (IDH mutated). The concentrations of glutamine and glycine were both significantly higher in enhancing tumors than in non-enhancing tumors (p=0.001 and 0.0001, respectively). The concentrations of glutamine and glycine were both positively correlated with MIB-1 (p=4E-5 and 1E-7, respectively). The sum of glutamine and glycine levels showed stronger association with MIB-1 (p=5E-10, r=0.89). In the Kaplan-Meier overall survival analysis, the survival was significantly shorter in patients with glutamine levels higher than 4.1 mM than those with concentrations less than 4.1 mM (p=0.02). For glycine, the patients with higher than 2.4 mM showed association with poor survival (p=0.03). The sum of glutamine and glycine levels showed stronger association with overall survival (p=0.008, cutoff 8.5mM). 2HG level greater than 0.5 mM was associated with long survival (p=0.01). We tested metabolic ratios to 2HG, in which 2HG estimates less than 1 mM were put as 1 mM (avoiding infinite ratios arising from null 2HG cases). The glutamine/2HG, glycine/2HG, and (glutamine+glycine)/2HG showed strong association with overall survival (p=2E-4, 2E-5 and 4.5E-7, respectively). Our data suggest that increased metabolism of glutamine and glycine is closely associated with rapid cell proliferation and poor survival, suggesting the metabolites are imaging biomarkers of glioma aggressiveness.
BIMG-10. IDH1 MUTATIONS INDUCE ORGANELLE DEFECTS VIA DYSREGULATED PHOSPHOLIPIDS
Authors: Yamasaki Tomohiro , Lita Adrian , Zhang Lumin , Rodado Victor Ruiz , Dowdy Tyrone , Gilbert Mark , Larion Mioara
Published: March 2021

BACKGROUND

Metabolic alterations of lipids have been identified as a hallmark of neoplasms, with the most prevalent being the balance between saturated fatty acid (SFA) and monosaturated fatty acid (MUFA). Stearoyl-CoA desaturase1 (SCD1), converting SFA to MUFA, is increased in many cancers, leading to worse prognosis. In glioma, the role of SCD1 remains unknown. Isocitrate dehydrogenase (IDH) mutations have been most commonly observed in glioma, but the involvement of mutant IDH in SCD1 expression also remains unknown.

METHODS

We conducted metabolic analysis to examine the alteration of SCD1 expression in genetically engineered glioma cell lines and normal human astrocyte (NHA). Lipid metabolic analysis was conducted by using LC-MS, Raman Imaging Microscopy and SCD1 expression was examined by Western-blotting and RT-PCR method. Electron microscopy was employed for organelle structure and genetic knock-down of SCD1 gene was performed.

RESULT

Herein, we uncovered increased MUFA and their phospholipids in Endoplasmic Reticulum (ER), generated by IDH1 mutation, that were responsible for Golgi and ER dilation. RNA seq data from The Cancer Genome Atlas, showed that SCD1 expression was significantly higher in IDH mutant gliomas compared with wild-type, and high SCD1 expression was associated with longer survival. Inhibition of IDH1 mutation or SCD1 silencing restored ER and Golgi morphology, while D-2HG and oleic acid induced morphological defects in these organelles. Moreover, addition of oleic acid, which tilts the balance towards elevated levels of MUFA, produced IDH1 mutant-specific cellular apoptosis.

CONCLUSION

Collectively, our results suggest that IDH1 mutant-induced SCD overexpression can rearrange the distribution of lipids in the organelles of glioma cells, providing a new insight on the link between lipids metabolism and organelle morphology in these cells, with potential and unique therapeutic implications. The results of the present study may also provide novel insights into the discovery of metabolic biomarkers for IDH mutant gliomas.
BIMG-12. [18F]FLUCICLOVINE PET TO DISTINGUISH PSEUDOPROGRESSION FROM TUMOR PROGRESSION IN POST-TREATMENT GLIOBLASTOMA
Authors: Nabavizadeh Ali , Doot Robert , Young Anthony , Nasrallah MacLean , Ware Jeffrey , Schubert Erin , Henderson Fraser , Pantel Austin , Desai Arati , Bagley Stephen , O’Rourke Donald , Brem Steven
Published: March 2021

PURPOSE

Differentiation of true tumor progression from pseudoprogression (PsP) is a major unmet need in patients with glioblastoma (GBM). [18F]Fluciclovine is a synthetic amino acid PET radiotracer that is FDA approved in the setting of biochemical recurrence in prostate cancer. The aim of this study was to assess the value of [18F]Fluciclovine PET in differentiation of true tumor progression and PsP in post-treatment of glioblastoma.

METHODS

15 patients with GBM with new contrast-enhancing lesions or lesions showing increased enhancement (>25% increase) on standard MRI after completion of radiation underwent 60-minutes dynamic [18F]Fluciclovine PET imaging. Patients subsequently (within 1 week) underwent resection of the enhancing lesion and the tumor percentage vs treatment-related changes were quantified on histopathology. Patients were considered true tumor progression if tumor represented ≥ 50% of the resected specimen and considered PsP if treatment-related changes represented ≥70% of the resected specimen. Summed 30- to 40-minute post-injection PET images were used to measure SUVpeak, SUVmax, and 50% threshold SUVmean.

RESULTS

10 patients with true tumor progression and 5 patients with PsP were included. Patients who demonstrated true tumor progression had significantly higher SUVpeak compared to patients with PsP (5.3±1.4 vs 3.1± 0.9, p=0.002, AUC=0.92, p<0.0001). SUVpeak cut-off of 3.5 provided 100% sensitivity, 80% specificity and 93% accuracy for differentiation of true tumor progression from PsP. There was a moderate to strong correlation between SUVpeak and tumor percentage on histopathology (Rho= 0.68, p=0.004). Alternative SUV measures had similar performance.

DISCUSSION

Our preliminary results indicated that [18F]Fluciclovine PET imaging can accurately differentiate true tumor progression from PsP. Further studies are required to confirm these promising early results and determine the optimal criteria for interpreting [18F]Fluciclovine PET to distinguish PsP from true tumor progression.
BIMG-14. IDENTIFICATION OF IDH MUTATION STATUS USING PROTON MR SPECTROSCOPY AND MASS SPECTROMETRY: A STUDY OF 178 GLIOMAS
Authors: Sacli-Bilmez Banu , Akin-Levi Cansu , Danyeli Ayça Ersen , Yakicier Cengiz , Pamir M Necmettin , Özduman Koray , Dincer Alp , Can Ozge , Ozturk-Isik Esin
Published: March 2021

IDH mutation, a key factor in predicting glioma prognosis, alters the levels of some metabolites in brain, including 2-hydroxyglutarate (2HG), glutamine (Gln), and glutathione (GSH). While proton MR spectroscopy (1H-MRS) enables in-vivo detection of these metabolites, liquid chromatography-mass spectrometry (LC-MS/MS) is a sensitive in-vitro method to measure absolute metabolite concentrations. This study aims to examine the correlation of metabolic concentrations measured using 1H-MRS and LC-MS/MS in gliomas, and to detect IDH mutation with machine learning based on 1H-MRS and LC-MS/MS metabolic intensities. The patient cohort included 178 glioma patients (111M/67F, mean age:44.09±13.95 years, 100 IDH-mut, 78 IDH-wt). The patients were scanned pre-surgery by a 3T MR scanner with a 32-channel head coil. 1H-MRS was obtained from a manually placed region of interest with no necrosis, edema, and hemorrhage, using a Point Resolved Spectroscopy (PRESS) sequence (TR/TE=2000/30ms). LCModel software was used for quantification of eighteen metabolites of 1H-MRS data. Metabolite concentrations including creatine (Cr), choline (Cho), Gln, glutamate (Glu), gamma-aminobutyric acid (GABA), N-acetyl aspartate (NAA), myo-inositol (mIns), 2HG, and lactate (Lac) were also determined with LC-MS/MS for surgical specimen of the same patients. Spearman correlation coefficients were calculated between the metabolite concentrations measured with 1H-MRS and LC-MS/MS. Additionally, machine-learning algorithms were used to detect IDH mutation in gliomas based on metabolite concentrations obtained with 1H-MRS and LC-MS/MS. Consequently, there were statistically significant correlations between 1H-MRS and LC-MS/MS results for 2HG (p=0.036), Cr (p=0.009), mIns (p<0.001), Lac (p=0.007) and NAA (p=0.004). IDH mutation was detected with an accuracy of 92.42% (sensitivity=91.70%, specificity=93.46) and 82.94% (sensitivity=84.04, specificity=81.43) based on LC-MS/MS and 1H-MRS metabolic intensities, respectively. In conclusion, 1H-MRS and LC-MS/MS metabolic intensities were highly correlated and these techniques were successful in identifying IDH mutation in gliomas. This study has been supported by TUBITAK 1003 grant 216S432.
BIMG-17. EFFECTS OF THE TUMOUR MICROENVIRONMENT ON PROTOPORPHYRIN IX ACCUMULATION IN GLIOBLASTOMA
Authors: Walker Paul , Finch Alina , Wykes Victoria , Watts Colin , Tennant Dan
Published: March 2021

Glioblastoma is the most common primary brain tumour and has a poor prognosis. The median survival is less than two years despite clinical intervention that usually involves the resection of the tumour volume, chemotherapy and radiotherapy. Achieving gross-total resection is challenging due to poorly defined boundaries as a result of tumour infiltration. Fluorescence-guided surgery (FGS) utilises an apparently selective accumulation of protoporphyrin IX (PPIX) that occurs in areas of glioblastoma after administration of the metabolite, 5-aminolevulinic acid (5-ALA). 5-ALA and the fluorescent metabolite, PPIX, sit within the endogenous heme biosynthetic pathway, which suggests that FGS is not only an important clinical tool, but also highlights differing metabolic phenotypes naturally present throughout the tumour. Genetic and mechanistic studies into this phenomenon have shown that differential expression of metabolite transporters, altered activity of the heme pathway enzymes and variable nutrient availability are all factors in the accumulation of PPIX. However, little is known about the cellular driving force for the uptake of 5-ALA and subsequent conversion into PPIX. Our data suggest that different microenvironments within the tumour alter the activity of the heme biosynthetic pathway, resulting in differential fluorescence in glioblastoma. It paves the way for work to alter the glioblastoma microenvironment in order to further improve the use of FGS in guiding surgery across these devastating tumours.
DDRE-01. METABOLIC PLASTICITY AND HETEROGENEITY IN IDH1MUT CELL LINES PRODUCES RESISTANCE TO GLUTAMINASE INHIBITION BY CB839
Authors: Larion Mioara , Ruiz-Rodado Victor
Published: March 2021

BACKGROUND

Mutant IDH1 (IDH1mut) gliomas have characteristic genetic and metabolic profiles and exhibit phenotype that is distinct from their wild-type counterparts. The glutamine/glutamate pathway has been hypothesized as a selective therapeutic target in IDH1mut gliomas. However, little information exists on the contribution of this pathway to the formation of D-2-hydroxyglutarate (D-2HG), a hallmark of IDHmut cells, and the metabolic consequences of inhibiting this pathway.

METHODS

We employed an untargeted metabolic profiling approach in order to detect metabolic changes arising from glutaminase (GLS) inhibition treatment. Subsequently, 13C metabolic tracing analysis through a combined Nuclear Magnetic Resonance and Liquid Chromatography-Mass Spectrometry approach, we explored the fate of glutamine and glucose under treatment with CB839 a glutaminase-GLS-inhibitor and their respective contributions to D-2HG formation.

RESULTS AND CONCLUSIONS

The effects of CB839 on cellular proliferation differed among the cell lines tested, leading to designations of GLS-inhibition super-sensitive, -sensitive or -resistant. Our data indicates a decrease in the production of downstream metabolites of glutamate, including those involved in the TCA cycle, when treating the sensitive cells with CB839 (glutaminase -GLS- inhibitor). Notably, CB839-sensitive IDH1mutcells respond to GLS inhibition by upregulating glycolysis and lactate production. In contrast, CB839-resistantIDH1mut cell lines do not rely only on glutamine for the sustenance of TCA cycle. In these cells, glucose contribution to TCA is enough to compensate the downregulation of glutamine-derived TCA metabolites. This investigation reveals that the glutamine/glutamate pathway contributes differentially to D-2HG in a cell-line dependent fashion on a panel of IDHmut cell lines. Further, these results demonstrate that there is a heterogeneous landscape of IDH1mut metabolic phenotypes. This underscores the importance of detailed metabolic profiling of IDH1mut patients prior to the decision to target glutamine/glutamate pathway clinically.
DDRE-05. STEAROYL COA DESATURASE IS ESSENTIAL FOR REGULATION OF ENDOPLASMIC RETICULUM HOMEOSTASIS AND TUMOR GROWTH IN GLIOBLASTOMA CANCER STEM CELLS
Authors: Park David , Badr Christian
Published: March 2021

INTRODUCTION

Emerging evidence suggest that, in addition to glucose, fatty acids can also drive glioma growth. Increased lipid synthesis is one of the metabolic hallmarks of cancer, and indeed, unsaturated fatty acids (UFA) are particularly abundant in glioblastoma. However, the exact role of fatty acids in GBM tumors remains unclear. Blocking fatty acids synthesis can present a new therapy for GBM.

METHODS

Through targeted inhibitors screening on glioma stem cells (GSCs), we found that they are highly susceptible to Stearoyl CoA Desaturase 1 (SCD1) inhibitors. SCD1 is a key enzyme responsible for the conversion of saturated fatty acids (SFA) to UFA. 1) Through cell-based assays and immunoblot analyses, we tried to understand the role of UFA, SFA and SCD1 in GSCs differentiation and proliferation. We investigated the mechanism between fatty acids and tumor growth through ER stress modulation linked with SCD1 expression. 2) As we found that GSCs are highly susceptible to SCD1 inhibition, we tested CAY, SCD1 inhibitor, in GSCs orthotopic mouse models and assess its effect on tumor growth and overall survival.

RESULTS

We found that GSCs with extensive self-renewal capacity have an increased dependence on SCD1 activity. Through immunoblot analyses, we demonstrated that SCD1 inhibition exacerbates ER stress through accumulation of SFA and SCD1-mediated UFA synthesis mitigates ER stress. Survival analyses between SCD1 inhibitor-treated group and control group showed significant survival benefit in SCD1-inhibitor-treated group, in both mesenchymal (p=0.008, 35 days vs 18) and proneural (p=0.0002) type glioma cells (n=8/groups).

CONCLUSIONS

We demonstrate that SCD1, the fatty acid desaturase, is essential for the maintenance of glioblastoma cancer stem cells. SCD1 is activated by ER stress and exerts a cytoprotective function by regulating ER homeostasis, thus favoring survival and tumor growth. Pharmacological targeting of SCD1 exhibits potent therapeutic efficacy in brain tumor mouse models.
DDRE-12. HETEROGENOUS RESPONSE OF IDH-MUTANT AND IDH-WT GLIOMA TO NAMPT INHIBITION
Authors: Rahman Masum , Hirte Renee , Olson Ian , Mansour Moustafa , Ikram Samar , MunozCasabella Amanda , Sutiwisesak Rujapope , Carlstrom Lucas , Warrington Arthur , Rajani Karishma , Sarkaria Jann , Burns Terry
Published: March 2021

BACKGROUND

NAD+ is required for cell metabolism and DNA repair. It is generated from nicotinic acid (NA) by NAPRT and from Nicotinamide (NAM) by NAMPT. D2HG in IDH-mutant tumors methylates and inactivates NAPRT, increasing dependence on NAMPT. Toxic side effects of NAMPT inhibition can be prevented by NA supplementation in healthy cells without NAPRT methylation. A1326133 is a recently described CNS-penetrant NAMPT inhibitor hypothesized to selectively eliminate IDH-mutant NAPRT-methylated gliomas, likely in combination with other therapies. Our group is looking for biomarkers of drug efficacy to augment individualized therapies. To that end, we sought to identify GBM cell lines with varying sensitivity to NAMPT inhibition.

METHODS

Human non-immortalized astrocytes and human GBM cell lines were utilized from the Mayo Clinic Glioma patient-derived xenograft resource, including IDH-R132Hmutant lines (GBM164, 196) and IDH-WT lines (GBM6, 12, 76). Cell viability was analyzed after 4days incubation with the NAMPT inhibitor, A1326133 +/- Temozolomide (TMZ) or NA. IC50 for A1326133 was estimated based on intracellular ATP using Cell-Titer-Glo.

RESULTS

Marked heterogeneity between lines was observed in response to A1326133 +/- NA or TMZ. Sensitive and resistant lines were identified among both IDH-mutant and IDH-WT cell lines. IC50s: GBM164, 12, 6, 196 and 76 were 5.6, 9.3, 39.2, 910, and 9455nM, respectively. NA partially rescued GBM164 by NA (IC50 increased to 20.8nM) but not GBM6 nor 12. IC50 for Human astrocytes was 221.7nM, but >10,000nM with NA. Addition of TMZ did not improve A1326133 efficacy.

CONCLUSION

Our data illustrate the potential utility of NAMPT inhibition to kill a subset of IDH-WT and IDH mutant lines, but conflict with previously reported TMZ synergy and correlation with mutant IDH. NA may increase safety but could decrease efficacy in certain lines. Ongoing studies seek metabolic biomarkers of therapeutic efficacy to guide individualized therapy with NAMPT inhibitors.