bluuebunny/crossref_metadata_2025 huggingface dataset:
Co-benefits of deep carbon reduction on air quality and health improvement in Sichuan Province of China
Authors: Zhang Silu , Wu Yazhen , Liu Xiaorui , Qian Jun , Chen Junhui , Han Li , Dai Hancheng
Published: July 2021

Facing the dual challenges of air pollution and climate change, China has set ambitious goals and made decisive efforts to reduce its carbon emission and win the ‘Battle for Blue Sky’. However, how the low-carbon transition and air quality targets could be simultaneously achieved at the sub-national levels remains unclear. The questions arise whether province-level climate change mitigation strategies could help ease the air pollution and close the air quality gap, and how these co-benefits can be compared with the cost of the green transition. Here, using an integrated modeling framework, we combined with local air pollutant emission inventories and issued policy documents to quantitatively evaluated the current situation and targets of the air quality and health co-benefits of deep carbon mitigation in Sichuan, a fast-developing inland province in China. We found that by 2035, without system-wide energy transformation induced by carbon mitigation policies, the improvement in air quality in Sichuan Province might be limited, even under stringent end-of-pipe emission control measures. On the contrary, the co-benefits of low-carbon policies would be significant. On top of stringent end-of-pipe controls, the implementation of carbon mitigation policy in line with China’s enhanced climate target could further reduce the average PM2.5 concentration in Sichuan by as much as 2.8 µg m−3, or the population-weighted PM2.5 concentration by 5.9 µg m−3 in 2035. The monetized health co-benefits in Sichuan Province would amount to 23 billion USD under the stringent carbon mitigation scenario, exceeding 1.7 billion USD of the mitigation cost by 2035. The results indicate that significant air quality and health benefits could both be achieved from carbon mitigation at the provincial level. Both air-pollution or carbon-reduction oriented policies would be important for improving environmental quality and public health.
Development of Active PV Array Using Real-Time Scanning Method
Authors: Itako K , Xu C , Kudoh T , Koh K , Ge Q
Published: July 2021

This paper presents a novel control strategy for active photovoltaic (APV) array using real-time scanning method. This proposed technology reduces extreme power drops due to the partial shading conditions (PSCs). In this paper, PSIM software is used to simulate the conventional photovoltaic (PV) array and the newly proposed APV array. The comparative analysis results show that this newly proposed technology can effectively reduce the power loss caused by the PSCs to the PV generation system. Assuming a practical system, we will verify the practicality of the proposed system by conducting a demonstration experiment with a large array scale. We also built a monitor system to monitor the generated power of each unit.
Analysis of PV Generation in Honduras by a Mathematical Model in MATLAB / SIMULINK
Authors: Santos Ramirez J , Sánchez Villela G , Reyes Duke A , Villatoro Flores H
Published: July 2021

Today it is common to see how many countries are seeking to reduce their dependence on fossil fuels, so the incorporation of photovoltaic systems has become an alternative to such dependence. In Honduras, it is predicted that by the year 2038, 80% of the energy matrix will be renewable, and approximately 20% of the energy generated is through photovoltaic systems [1]. The objective of this document is to present a procedure for the mathematical modeling of PV modules with a significant volume of data from the different active weather stations distributed throughout the country as input parameters into Matlab/Simulink, and based on this, the electricity generation at the location of these stations is shown according to their solar hours. The model presented is based on equations obtained from an equivalent circuit of a diode that will be able to denote the I-V and P-V output characteristics of a typical 435 W solar module. These characteristics will be determined by the models developed under the meteorological conditions of temperature and solar irradiation that are present in the different departments of the Honduran territory where the weather stations are located. The design of the module is through easy-to-use icons, and a dialog box that the Simulink libraries provide.
Numerical Assessment of Total Nitrogen (Tn) Load Discharged from Rivers into Harima-Nada, the Seto Inland Sea, Using A Numerical Coupled Hydrological-Water Quality Model
Authors: Pintos Andreoli V , Mori M , Koga Y , Shimadera H , Suzuki M , Matsuo T , Kondo A
Published: July 2021

Harima-Nada region, located in the east of Seto Inland Sea, is a semi-enclosed sea-area next to Osaka Bay that has been suffering a sustained oligotrophication process during the past 25 years. A hydrogeological model, coupled with a water quality model, was applied to assess the numerical discharge of freshwater and total nitrogen (TN) load from rivers into the sea. The model was validated for the main rivers from the northern and southern regions (the Kako River and the Yoshino River, respectively). The obtained results showed that the main contribution of freshwater and TN load to the sea comes from Hyogo Prefecture Rivers. The type of activities developed on each watershed showed to be substantially more relevant on TN load contribution than the size itself of the considered watershed. For the eight years considered in this study (2009 - 2016), the annual average of TN discharged into Harima-Nada was almost constant, while the volume of discharged freshwater showed more variations. Additionally, the sustained decrement in nitrogen concentration in Harima-Nada seemed not to be directly bonded with riverine TN load, suggesting that nitrogen availability is closely related to sea nutrients mechanisms more than to TN inland contribution.
The Effect of the Number of Blades on the Efficiency of A Wind Turbine
Authors: Adeyeye Kehinde Adeseye , Ijumba Nelson , Colton Jonathan
Published: July 2021

In this paper, we examine existing literature on the way that the number of blades of a wind turbine affects its efficiency and power generation. A wind turbine blade is an important component of a clean energy system because of its ability to capture energy from the wind. The power that a wind turbine extracts from the wind is directly proportional to the swept area of the blades; consequently, the blades have a direct effect on power generation. The number and configuration of the blades is very important because it affects the speed and efficiency of turbine. Unfortunately, as the number of blades increases, so does the slipstream effect. Too few a number of blades results in poor efficiency and thus inadequate performance. Too large a number of blades increases weight and production cost. The correct number of blades is important to fit the generator performance curve to optimize overall turbine performance and efficiency.
Effect of Pv Shadow on Cooling Load and Energy Consumption of Zone Toward Achieving NZEB
Authors: Ibrahim M , Shehata A , Elharidi A , Hanafy A
Published: July 2021

Development strategy offers us the resources required to investigate the connection between today’s environmental challenges and the possibility of their progress tomorrow. Currently, the world is facing the greatest surge of population expansion in modern history, which Forced governments to expand urbanization and establishing new cities to accommodate the massive population increase. As a result, the building sector’s CO2 emissions have proceeded to grow by almost 1% a year since 2010, So there is an urgent need to find untraditional solutions to overcome upcoming energy, emissions problems and facing the expected increase of electricity prices. Nearly zero-energy buildings (NZEB) is one of the emerging technologies in the building sector which depend on enhancing building’s energy performance and its extremely low energy demand is met with aid of renewable energy sources as PV solar panels. Via a study made on a conditioned zone located on the last floor of a university building belonging to Arab academy located in Alexandria, Egypt. The effect of the shadow caused by PV panels placed on the roof was studied. A 3D model of the zone was built, then a CFD analysis using the K-epsilon turbulence model was carried out to realize the essence of the shadow effect on this zone. For further clarity and using the DesignBuilder simulation tool the zone cooling load was calculated for both cases with and without PV on the roof, it was found that the zone cooling load reduced by 11.5% in case PV panels are installed on the roof.
Treatment of male breast cancer: meta-analysis of real-world evidence
Authors: Lin A. P. , Huang T.-W. , Tam K.-W.
Published: July 2021

Background

Breast cancer is rare in men and managed by extrapolating from breast cancer in women. The clinicopathological features of male breast cancer, however, differ from those of female breast cancer. Because clinical trials are rare, the synthesis of real-world data is one method of integrating sufficient evidence on the optimal treatment for this patient population.

Methods

PubMed, Embase, and Cochrane Library databases were searched. Clinical studies were included if they evaluated the treatments of interest in male breast cancer; these evaluations included breast-conserving surgery (BCS) versus mastectomy, postmastectomy radiation therapy versus no radiation, the accuracy of sentinel lymph node biopsy (SLNB), and a comparison of various endocrine therapies.

Results

Forty studies were retrieved. The pooled estimate of overall survival (OS) revealed no difference between BCS and mastectomy groups. Postmastectomy radiation to the chest wall significantly increased OS relative to no postmastectomy radiation (hazard ratio (HR) 0.67, 95 per cent confidence interval 0.54 to 0.84). The pooled estimates of identification and false-negative rates of SLNB were 97.4 and 7.4 per cent respectively. Tamoxifen treatment was associated with significantly increased OS compared with no tamoxifen intake (HR 0.62, 0.41 to 0.95).

Conclusion

Identification and false-negative rates for SLNB were comparable to those in female breast cancer. Breast-conserving surgery can be effective and safe; postmastectomy radiation to the chest wall and 5-year tamoxifen treatment improves survival.
Intracranial pressure spikes trigger spreading depolarizations
Authors: Oka Fumiaki , Sadeghian Homa , Yaseen Mohammad A , Fu Buyin , Kura Sreekanth , Qin Tao , Sakadžić Sava , Sugimoto Kazutaka , Inoue Takao , Ishihara Hideyuki , Nomura Sadahiro , Suzuki Michiyasu , Ayata Cenk
Published: July 2021

Spreading depolarizations are highly prevalent and spatiotemporally punctuated events worsening the outcome of brain injury. Trigger factors are poorly understood but may be linked to sudden worsening in supply–demand mismatch in compromised tissue. Sustained or transient elevations in intracranial pressure are also prevalent in the injured brain.

Here, using a mouse model of large hemispheric ischaemic stroke, we show that mild and brief intracranial pressure elevations (20 or 30 mmHg for just 3 min) potently trigger spreading depolarizations in ischaemic penumbra (4-fold increase in spreading depolarization occurrence). We also show that 30 mmHg intracranial pressure spikes as brief as 30 s are equally effective. In contrast, sustained intracranial pressure elevations to the same level for 30 min do not significantly increase the spreading depolarization rate, suggesting that an abrupt disturbance in the steady state equilibrium is required to trigger a spreading depolarization. Laser speckle flowmetry consistently showed a reduction in tissue perfusion, and two-photon pO2 microscopy revealed a drop in venous pO2 during the intracranial pressure spikes suggesting increased oxygen extraction fraction, and therefore, worsening supply–demand mismatch. These haemodynamic changes during intracranial pressure spikes were associated with highly reproducible increases in extracellular potassium levels in penumbra. Consistent with the experimental data, a higher rate of intracranial pressure spikes was associated with spreading depolarization clusters in a retrospective series of patients with aneurysmal subarachnoid haemorrhage with strong temporal correspondence.

Altogether, our data show that intracranial pressure spikes, even when mild and brief, are capable of triggering spreading depolarizations. Aggressive prevention of intracranial pressure spikes may help reduce spreading depolarization occurrence and improve outcomes after brain injury.
Community development and social work teaching and learning in a time of global interruption
Authors: Lynch Deborah , Lathouras Athena , Forde Catherine
Published: July 2021

In a rapidly changing and unpredictable global environment, there is new impetus to draw on community development approaches in the face of complex practice challenges that include the long-term impacts of the COVID-19 pandemic. As social work and community development educators in Ireland and Australia, the question becomes how can we respond in a time of major ‘disruption’ where there are both opportunities and constraints? This paper settles on this pause and uncertainty to seek new approaches to prepare social work students for changing conditions. Long-standing questions re-surface in relation to social, economic, political and environmental structures and conditions that are located in a neoliberal framework. The paper explores challenges and opportunities facing educators and social work students through a core set of principles—critical, relational and connected—that underpin our community development pedagogy. Within these themes, we explore teaching practices which seek to create a ‘Community of Learners’, generate a process of collaborative critical inquiry, engage students in reflective praxis enriched by contemporary theory and research, and foster a deep, connected and adaptive perspective on global and local issues. This stimulates creativity and meets the need for critical and adaptable practitioners capable of practical action through this period of disruption and crises of governance, climate and technologies of the future.
Optimal Interval Division
Authors: Tian Jianrong
Published: July 2021

This paper provides a simple unified analysis of optimal interval division problems. My primitive is a cell function that assigns a value to each subinterval (cell). Submodular cell functions conveniently imply the property of decreasing marginal returns. Also, for coarse decision problems, optimal cutoffs commonly increase as prior belief shifts upward. Its implications on language and efficient menus are discussed.
Factors Influencing the Oak Lace Bug (Hemiptera: Tingidae) Behavior on Oaks: Feeding Preference Does not Mean Better Performance?
Authors: Marković Čedomir , Dobrosavljević Jovan , Milanović Slobodan
Published: July 2021

Oak lace bug – Corythucha arcuata (Say, 1832) (Hemiptera: Tingidae) is a North American species that has been introduced to Europe and Asia, where it became a serious oak pest. As little is known about its behavior, we conducted a study in which we tested the preference and performance of the oak lace bug for different oak species and the influence of powdery mildew and CO2 on the behavior of the oak lace bug. Four of the most represented oak species in Serbia (Hungarian, pedunculate, sessile, and Turkey oak) were used for testing the preference and performance of the oak lace bug, and the influence of oak powdery mildew on the behavior of the oak lace bug. The influence of CO2 on the behavior of the oak lace bug was tested on pedunculate oak. The results of this study have shown that there are differences in preference and performance of the oak lace bug between the analyzed oak species; there are significant differences in the oak lace bug host preference in the laboratory and in field conditions; Hungarian oak is most threatened by the oak lace bug, as the oak lace bug performs best on this species and preferers this species in field conditions; the oak powdery mildew and oak lace bug are in an antagonistic relationship; and that the changes in the leaves caused by the expected increase in CO2 concentration in the future will probably not influence the feeding behavior of the oak lace bug adults.
Host-Feeding Patterns of the Mosquito Assemblage at Lomas Barbudal Biological Reserve, Guanacaste, Costa Rica
Authors: Gilkey Patrick L , Ortiz Diana L , Kowalo Tia , Troyo Adriana , Sirot Laura K
Published: July 2021

Mosquito-borne pathogens have spread throughout tropical regions of the Western Hemisphere causing increased burden of disease in the region. Outbreaks of dengue fever, yellow fever, chikungunya, West Nile, and Zika have occurred over the past several years. Mosquito blood-feeding patterns need to be assayed to assist in determining which vertebrates could act as hosts of these mosquito-borne pathogens and which mosquito species could act as vectors. We conducted bloodmeal analyses of mosquitoes collected at Lomas Barbudal Biological Reserve, a dry tropical forest reserve in Costa Rica. Mosquitoes were collected using backpack aspirators and light, gravid, and resting traps, and then identified morphologically. Blood-fed mosquitoes underwent DNA extraction, PCR amplification, and sequencing of the vertebrate cytochrome b and cytochrome c oxidase 1 genes to identify vertebrate bloodmeal hosts. Several mosquitoes known to vector pathogens were found including Culex (Melanoconion) erraticus Dyar & Knab (Diptera: Culicidae), Cx. (Mel.) pedroi Sirivanakarn & Belkin, Aedes (Stegomyia) albopictus Skuse, Ae. (Ochlerotatus) scapularis Rondani, Ae. (Och.) serratus Theobald, and Ae. (Och.) taeniorhynchus Wiedemann. The most common bloodmeal hosts were basilisk lizards (Basiliscus vittatus) Wiegmann (Squamata: Corytophanidae) in Culex (Linnaeus) species and white-tailed deer (Odocoileus virginianus) Zimmermann (Artiodactyla: Cervidae) in Aedes (Meigen) species. These results show the diversity of mosquito species in a tropical dry deciduous forest and identify associations between mosquito vectors and potential pathogen reservoir hosts. Our study highlights the importance of understanding interactions between vector species and their hosts that could serve as predictors for the potential emergence or resurgence of mosquito-borne pathogens in Costa Rica.
Biological Parameters of Three Populations of Triatoma dimidiata s. s. (Hemiptera: Reduviidae) From Western Mexico
Authors: Nogueda-Torres Benjamin , Montañez-Valdez Oziel D , Michel-Parra J G , Martínez-Grant Diana M , Martínez-Ibarra J Alejandro
Published: July 2021

Chagas disease is a very important vector-borne disease in México, and Triatoma dimidiata sensu stricto (Latreille) is one of the most important vectors of Trypanosoma cruzi Chagas, mainly in southern and central states. In the Pacific Coast states with the highest prevalence of human T. cruzi infection, T. dimidiata s. s. is considered as a secondary vector. However, the vectorial capacity of those populations has not been studied. Therefore, the vector characteristics of three populations of T. dimidiata s. s. in western México were evaluated in this study. The populations were maintained in the laboratory at 27 ± 1°C and 75% ± 5% RH with a 12:12 h (light:dark) regime, fed on rabbits in a fortnight basis. The development times were short (172–238 d), and the number of bloodmeals to molt was low (11). Mortality was moderate (36–45%), the onset of feeding was relatively rapid (0.5–1.7 min), and feedings were extended (>15 min). More than 40% of individuals in most instars defecated in one of three categories: <1 min when feeding (5–37.9%), immediately after feeding (9–28.6%), or in <1 min post feeding (7–25.8%). The median number of laid eggs was high (over 2.5) in the three populations, as were the egg eclosion rates (>86%). Thus, the T. dimidiata s. s. in the three populations are potentially efficient vectors of T. cruzi and could contribute to the high prevalence of infection in human populations in western México.
Do Minimum Charity Care Provision Requirements Increase Nonprofit Hospital Performance? Examining Hospitals’ Responses to Regulatory Changes
Authors: Rothbart Michah W , Yoon Nara
Published: July 2021

Institutional form is believed to influence organizational behavior and performance in producing collective goods such as healthcare services. Recent efforts in the United States seek to increase healthcare services provided by hospitals, but it is unclear whether and how these organizations respond to the policy changes. In this study, we examine the extent to which nonprofit hospitals change their provision of charity care in response to a regulatory policy specifying a target benchmark aimed at expanding charitable obligations. Specifically, we focus on the minimum charity care provision (MCCP) requirements in Illinois. Importantly, unlike previous research, we differentiate between hospitals facing minimum charity care spending requirements (nonprofits) and those not (for-profit and public). We use panel data from Illinois’ Annual Hospital Questionnaire and county data from the American Community Survey, employing a differences-in-differences model. We find no evidence that nonprofit hospitals increase charity care in response to the MCCP requirements on average. Instead, we find that there is heterogeneity in responses; hospitals providing low levels of charity care prior to the policy increase charity care, while hospitals providing high levels of charity care prior to the policy do not respond or, if anything, decrease charity care. Thus, while regulations that set low-target benchmarks provide insufficient incentives for nonprofit hospitals to increase charity care on average, explicit policy mandates that reduce directive goal ambiguity may still narrow gaps in performance.
Post-colonoscopy appendicitis: a case report
Authors: Tepelenis Kostas , Stefanou Christos K , Stefanou Stefanos K , Tsoumanis Periklis , Ntalapa Konstantina M , Galani Vasiliki , Gogos-Pappas George , Vlachos Konstantinos
Published: July 2021

Appendicitis after colonoscopy is rare, with an estimated incidence of 3.8 cases per 10 000 colonoscopies. Herein, we report a 56-year-old female who visited the emergency department with a history of diffuse abdominal pain and nausea 8 h after a screening colonoscopy. Abdominal examination disclosed deep tenderness at Mc Burney point and positive Rovsign’s sign. Laboratory studies revealed elevated white blood cells and neutrophils (WBC 15.37 K/Ul and NEUT 86.5%) with normal C-reactive protein (5 mg/l). The initial diagnosis was acute appendicitis, which was confirmed by the ultrasonographic findings. The patient was admitted to the surgical department, and a laparoscopic appendectomy was performed. Post-colonoscopy appendicitis is increasingly recognized as a complication after colonoscopy in the last decade. Early recognition is vital in preventing morbidity and mortality. It may also be worthwhile to include appendicitis after colonoscopy as a possible complication during the consent before the procedure.
Kilohertz quasi-periodic oscillations in neutron-star X-ray binaries: flattening of the lag spectrum with increasing luminosity
Authors: Peirano Valentina , Méndez Mariano
Published: July 2021

We study the energy-dependent time lags and rms fractional amplitude of the kilohertz quasi-periodic oscillations (kHz QPOs) of a group of neutron-star low-mass X-ray binaries. We find that for the lower kHz QPO both the slope of the best-fitting linear model to the time-lag spectrum and the total rms amplitude integrated over the 2–25 keV energy band decrease exponentially with the luminosity of the source. For the upper kHz QPO, the slope of the time-lag spectrum is consistent with zero, while the total rms amplitude decreases exponentially with the luminosity of the source. We show that both the slope of the time-lag spectrum and the total rms amplitude of the lower kHz QPO are linearly correlated with a slope of ∼1. Finally, we discuss the mechanism that could be responsible for the radiative properties of the kHz QPOs, with the variability originating in a Comptonizing cloud or corona that is coupled to the innermost regions of the accretion disc, close to the neutron star.
A search for active galactic nuclei in low-mass compact galaxies
Authors: Ferré-Mateu A , Mezcua M , Barrows R S
Published: July 2021

Low-mass compact galaxies (ultracompact dwarfs, UCDs, and compact ellipticals, cEs) populate the stellar size–mass plane between globular clusters and early-type galaxies. Known to be formed either in situ with an intrinsically low mass or resulting from the stripping of a more massive galaxy, the presence of a supermassive or an intermediate-mass black hole (BH) could help discriminate between these possible scenarios. With this aim, we have performed a multiwavelength search of active BH activity, i.e. active galactic nuclei (AGN), in a sample of 937 low-mass compact galaxies (580 UCDs and 357 cEs). This constitutes the largest study of AGN activity in these types of galaxies. Based on their X-ray luminosity, radio luminosity, and morphology, and/or optical emission line diagnostic diagrams, we find a total of 11 cEs that host an AGN. We also study for the first time the location of both low-mass compact galaxies (UCDs and cEs) and dwarf galaxies hosting AGN on the BH–galaxy scaling relations, finding that low-mass compact galaxies tend to be overmassive in the BH mass–stellar mass plane but not as much in the BH mass–stellar velocity dispersion correlation. This, together with available BH mass measurements for some of the low-mass compact galaxies, supports a stripping origin for the majority of these objects that would contribute to the scatter seen at the low-mass end of the BH–galaxy scaling relations. However, the differences are too large to be explained solely by this scatter, and thus our results suggest that a flattening at such low masses is also plausible, happening at a velocity dispersion of ∼20–40 km s−1.
The Star Formation Reference Survey – V. The effect of extinction, stellar mass, metallicity, and nuclear activity on star-formation rates based on H α emission
Authors: Kouroumpatzakis K , Zezas A , Maragkoudakis A , Willner S P , Bonfini P , Ashby M L N , Sell P H , Jarrett T H
Published: July 2021

We present new H α photometry for the Star Formation Reference Survey (SFRS), a representative sample of star-forming galaxies in the local Universe. Combining these data with the panchromatic coverage of the SFRS, we provide calibrations of H α-based star-formation rates (SFRs) with and without correction for the contribution of [N ii] emission. We consider the effect of extinction corrections based on the Balmer decrement, infrared excess, and spectral energy distribution (SED) fits. We compare the SFR estimates derived from SED fits, polycyclic aromatic hydrocarbons, hybrid indicators such as 24 µm + H α, 8 µm + H α, FIR + FUV, and H α emission for a sample of purely star-forming galaxies. We provide a new calibration for 1.4 GHz-based SFRs by comparing to the H α emission, and we measure a dependence of the radio-to-H α emission ratio based on galaxy stellar mass. Active galactic nuclei introduce biases in the calibrations of different SFR indicators but have only a minimal effect on the inferred SFR densities from galaxy surveys. Finally, we quantify the correlation between galaxy metallicity and extinction.
Withdrawn as duplicate: Commentary: "Zooming in" on Glioblastoma: Understanding Tumor Heterogeneity and its Clinical Implications in the Era of Single-Cell Ribonucleic Acid Sequencing
Authors: Lucas Alfredo , Eberwine James H , Bagley Stephen J , Fan Yi , Nasrallah MacLean , Brem Steven
Published: July 2021

This article has been withdrawn due to an error that caused the article to be duplicated. The definitive version of this article is published under DOI 10.1093/neuros/nyab288.
CSAO-1. Interrogative Biology: Unraveling insights into causal disease drivers by use of a dynamic systems biology and Bayesian AI to identify the intersect of disease and healthy signatures
Authors: Narain Niven , Kiebish Michael , Vishnudas Vivek , Tolstikov Vladimir , Miller Gregory , Gesta Stephane , Granger Elder , Sarangarajan Rangaprasad
Published: July 2021

The past decade has been witness to an explosive proliferation of data analytics modalities, all seeking to unravel insight into large-scale data sets. Machine learning and AI methodologies now occupy a central role in analyses of data sets that range in nature from genomics, “omics”, clinical, real-world evidence, and demographic data. Despite advances in data analytics/machine learning, access to complex population level clinical and related datasets, translating information into actionable guidance in human health and disease remains a challenge. Interrogative Biology, a systems biology/AI platform generates an unbiased, data-informed network for identifying targets (disease drivers) and biomarkers for disease interception at the point of transition to dysregulation, preceding clinical phenotype. The data topology is enabled by a systematic acquisition and interrogation of longitudinal bio-samples of clinically annotated human matrices (e.g. blood, urine, saliva, tissues) subjected to comprehensive multi-omic (genomic, proteomics, lipidomics and metabolomics) profiling over time. The molecular profiles are integrated with clinical health information using Bayesian artificial intelligence analytics, bAIcis, to generate causal network maps of overall health. Differentials between “health” and “disease” network maps identifies drivers (targets and biomarkers) of disease and are rapidly validated in orthogonal wet-lab disease specific perturbed model systems. Target information imputed into the bAIcis framework can define therapeutic strategies including identification of existing drugs and bio-actives for corrective response. Using a combination of clinic based sampling and dried blood spot analysis for longitudinal dynamic monitoring of markers of health-disease status provides opportunity for proactive clinical management and intervention for corrective response in advance of major deterioration of health status. Taken together, the approach herein allows for health surveillance based on in-depth biological profiling of alterations in the patient narrative to guide treatment modalities and strategies in a longitudinal and dynamic manner to identify, track, intercept, and arrest human disease.
ECOA-3. MLL4, UTX, and EZH2 regulate the expression of transcription factors associated with the epithelial-to-mesenchymal transition of lung cancer during metastasis to the brain at posttranscriptional steps
Authors: Kim Young Zoon
Published: July 2021

Purpose

The objective of this study was to investigate the epigenetic role of histone lysine methylation/demethylation on the expression of epithelial-to-mesenchymal transition (EMT) associated transcriptional factors (TFs) during the metastasis of lung adenocarcinoma to the brain.

Methods

Paired samples of lung adenocarcinoma and brain metastasis (BM) were analyzed in 46 individual patients. Both samples were obtained by surgical resection or biopsy of the lung and brain. The paraffin-fixed formalin-embedded samples were obtained from the pathology archives in our institute. In samples of lung adenocarcinoma and BM, immunohistochemical staining was performed for epithelial markers, mesenchymal markers, EMT-TFs, histone lysine methyltransferase and demethylase. And the verification of the present result was performed by qRT-PCR.

Results

The immunoreactivity of EMT-TFs such as Slug (15.6% vs. 42.6%, p = 0.005), Twist (23.6% vs. 45.9%, p = 0.010) and ZEB1 (15.0% vs. 55.9%, p = 0.002) was increased in BM compared with that in lung adenocarcinoma. Epigenetic inducers such as H3K4 methyltransferase (MLL4, p = 0.018) and H3K36me3 demethylase (UTX, p = 0.003) were statistically increased, and epigenetic repressors such as EZH2 (H3K27 methyltransferase, p = 0.046) were significantly decreased in BM compared with those in lung adenocarcinoma. The expression of UTX-ZEB1 (R2 linear = 1.204) and MLL4-Slug (R2 linear = 0.987) was increased in direct proportion, and EZH2-Twist (R2 linear = - 2.723) decreased in reverse proportion. The qRT-PCR showed the same results.

Conclusion

The results suggest that certain histone lysine methyltransferase/demethylase, such as MLL4, UTX, and EZH2, regulate the expression of EMT-TFs such as Slug, ZEB1, and Twist epigenetically, which may thereby influence cancer metastasis from the lung to the brain.
ECOA-6. Genomic and transcriptomic analyses reveal diverse mechanisms responsible for deregulation of epigenetic enzyme/modifier expression in glioblastoma
Authors: Maleszewska Marta , Wojtas Bartosz , Gielniewski Bartlomiej , Mondal Shamba , Mieczkowski Jakub , Dabrowski Michal , Siedlecki Janusz , Bujko Mateusz , Naumann Pawel , Grajkowska Wieslawa , Kotulska Katarzyna , Kaminska Bozena
Published: July 2021

Malignant gliomas represent over 70% of primary brain tumors and the most deadly is glioblastoma (GBM, WHO grade IV), due to frequent dysfunctions of tumor suppressors or/and oncogenes. Recent whole genome studies of gliomas demonstrated that besides genetic alterations, epigenetic dysfunctions contribute to tumor development and progression. Alterations in genes encoding epigenetic enzyme/protein or aberrations in epigenetic modification pattern have been found in gliomas of lower grade, yet no epigenetic driver was identified in GBM. We sought to identify different mechanisms driving aberrant expression of epigenetic genes in GBM.

We analyzed gene expression and coding/non-coding regions of 96 major epigenetic enzymes and chromatin modifiers in 28 GBMs, 23 benign gliomas (juvenile pilocytic astrocytomas, JPAs, WHO grade I) and 7 normal brain samples. We found a profound and global down-regulation of expression of most tested epigenetic enzymes and modifiers in GBMs when compared to normal brains and JPAs. For some genes changes in mRNA level correlated with newly identified single nucleotide variants within non-coding regulatory regions. To find a common denominator responsible for the coordinated down-regulation of expression of epigenetic enzymes/modifiers, we employed PWMEnrich tool for DNA motif scanning and enrichment analysis. Among others, we discovered the presence of high affinity motifs for the E2F1/E2F4 transcription factors, within the promoters of the epigenetic enzyme/modifier encoding genes. Knockdown of the E2F1/E2F4 expression affected the expression of a set of epigenetic enzymes/modifiers. Altogether, our results reveal a novel epigenetic-related pathway by which E2F1/E2F4 factors contribute to glioma pathogenesis and indicate novel targets for glioma therapy.

Supported by a National Science Centre grant 2013/09/B/NZ3/01402 (MM).
OMRT-12. Nanoparticle-based CRISPR-Cas9 delivery for anti-glioblastoma immunotherapy
Authors: Aguilar Rocio , Fierro Javier , Perez Joshua , Dou Huanyu
Published: July 2021

Anti-glioblastoma GBM) immunotherapy poses a great challenge due to immunosuppressive brain tumor environments and the blood brain barrier (BBB). Programmed death ligand 1 (PD-L1) is an immune checkpoint that mediated the immune resistance. Inhibition of PD-L1 by antibodies was widely studied to treat many type of cancers. However, the inefficient therapeutic immune response became a significant barrier for treatment of GBM. CRISPR/Cas9 gene editing can be used to knockout both membrane and cytoplasmic PD-L1, leading to an enhanced immunotherapeutic strategy. It is extremely difficulty to deliver CRISPR/Cas9 containing plasmid for translational and clinic applications. We have been developed a core-shell nanoparticle (NP) to carry CRISPR/Cas9 plasmid for PD-L1 knockout. The different NP formulations were made and optimized to deliver CRISPR/Cas9 plasmid. NPs were prepared by modifying the water temperature, sonication power and time and formulation time. The obtained NPs had a size of 115-160nm and a charge of 40-50mV. The size and charge were significantly altered after CRISPR/Cas9 plasmids were loaded into NPs (Cas9-NPs). Agarose gel electrophoresis showed that CRISPR/Cas9 plasmids were fully encapsulated by NPs with 1 and 2 ug. The positive DNA bands occurred with 4ng, indicating the overloaded CRISPR/Cas9 plasmid. Fluorescence microscopy determined Cas9-NPs uptake by U87 cells under a time-dependent manner. GFP tagged Cas9-NPs were treated to U87 cells for transfection evaluation. The obtained different NPs delivery of CRISPR/Cas9 exhibited various transfection efficiencies in U87 cells. Visualization of intracellular Cas9-NPs showed increases in uptake by U87 cells from 0.5, 1, 2, and 4 hours. The greater nuclear accumulation of Cas9-NPs was seen at 24 hours. A western blot assay determined the success of PD-L1 deletion by Cas9-NPs in human GBM U87 cells. NPs-based CRISPR/Cas9 gene-editing system has great potential as an immunotherapeutic platform to treat GBM.
OTEH-3. Targeted Gene-Expression analysis during malignant transformation in primary and secondary malignant meningioma
Authors: Maier Andrea Daniela , Meddis Alessandra , Haslund-Vinding Jeppe , Mirian Christian , Areskeviciute Ausrine , Nguyen Phuong , Westergaard Casper , Melchior Linea Cecilia , Munch Tina Nørgaard , Skjøth-Rasmussen Jane , Poulsgaard Lars , Ziebell Morten , Bartek Jiri , Broholm Helle , Poulsen Frantz Rom , Gerds Thomas Alexander , Scheie David , Mathiesen Tiit Illimar
Published: July 2021

Background

Malignant meningiomas comprise 2–5% of all meningiomas. The process of malignant transformation when benign meningiomas (WHO grade I-II) become malignant (WHO grade III) has not previously been investigated in sequential tumour surgeries. Upregulation of FOXM1 expression and DREAM-complex repression have shown phenotypical subgroups correlating with WHO grade and aggressiveness. We investigated the RNA expression of 30 genes central to meningioma biology and 770 genes involved in neuroinflammatory pathways in primary and secondary malignant meningioma patients who underwent one to several operations.

Methods

We identified a cohort of consecutive malignant meningioma patients treated at Rigshospitalet, Copenhagen from 2000–2020 (n=51) and gathered their malignant tumours and previous WHO grade I/II tumours. The malignant cohort (MC) was counter matched with a benign cohort (BC) where patients had no recurrences during follow-up. RNA expression signatures from 140 samples from the MC and 51 samples from the BC were analysed with the Nanostring Neuroinflammation panel customized with 30 genes known to be relevant in meningioma phenotypes.

Results

49% of MC patients had a previous grade I/II meningioma making them secondary malignant meningioma patients. Progression-free survival calculated from first malignant surgery to first recurrence or death showed no significant difference in the primary vs. secondary patients. Preliminary results of single-gene analysis of MC tumours showed FOXM1, MYBL2, TOP2A, BIRC5 expression was higher in WHO grade III samples. Gene-expression signatures in the individual patients and gene ontology enrichment analyses are in process.

Conclusions

FOXM1, MYBL2, TOP2A, BIRC5 RNA expression levels seem to rise during malignant progression across patients. Gene-expression analysis using the Nanostring technology is feasible and a potentially powerful tool to distinguish meningiomas prone to malignant transformation from truly benign meningiomas.
OTEH-12. Assessing Adaptive Responses to Loss of Extrachromosomal DNA Amplification
Authors: Berezovsky Artem , Datta Indrani , She Ruicong , Hasselbach Laura , Poisson Laila , deCarvalho Ana C
Published: July 2021

Background

Oncogene activation through somatic gene amplification happens frequently in GBM, with over 70% of these tumors presenting amplification of at least one putative driver gene, oftentimes in small extrachromosomal circular DNA segments composed of chromatin (ecDNA). A molecularly diverse and representative panel of GBM patient-derived cancer stem-like cells (CSC) and orthotopic mouse xenografts (PDX), which retain the original genomic abnormalities and ecDNA amplifications, was employed to assess adaptive response to the absence of ecDNA amplification.

Methods

We have isolated ecDNA negative cell populations from two patient-derived models. HF3035 harbors a MET amplification and HF3253 harbors a PDGFRA constitutively active genomic rearrangement and extrachromosomal amplification. We conducted paired, whole RNA-sequencing on 20 HF3253 populations (ecDNA+/-: 6 clones from 3 biological replicate PDXs and 4 clones from 4 in vitro technical replicates) and 12 HF3035 population (ecDNA+/-: 6 clones from 3 biological replicate PDXs).

Results

Nonparametric differentially expressed gene (DEG) analysis using NOISeqBio (R/Bioconductor), identified 564 differentially expressed genes (482 upregulated in ecDNA(-)) employing a stringent false discovery rate of 0.05. Genes significantly associated with PDGF stimulation, central carbon metabolism, and H3K27me3 were downregulated in ecDNA(-), while genes significantly associated with astrocytic processes, neuronal differentiation, and EGFR signaling were upregulated in ecDNA(-) (EnrichR). We employed an additive linear model with PDX serving as a blocking factor to compare ecDNA+ and ecDNA- populations in both models (R/edgeR). 2071 genes were upregulated in ecDNA+ PDX specimens and 2365 genes were downregulated. Specifically, E2F targets were highly enriched in ecDNA+ populations, in addition to mRNA pre-processing. ecDNA loss primarily targeted glycogen metabolism, NTRK signaling, and inositol phosphate catabolism.

Conclusions

We have identified PDX-specific and non-specific features to an adaptive response to the loss of ecDNA amplification. Notably, a signature adaptation is an upregulation of seemingly redundant receptor tyrosine kinases.
OTME-2. Regulation of chromatin accessibility in the hypoxic tumor microenvironment of glioblastoma
Authors: Dzwigonska Monika , Mieczkowski Jakub , Pilanc Paulina , Cyranowski Salwador , Kominek Agata , Piwocka Katarzyna , Kaminska Bozena , Leszczynska Katarzyna B
Published: July 2021

Chromatin structure is often dysregulated in cancers, including glioblastoma (GBM), the most common primary brain tumor in adults. GBM has the poorest prognosis and no efficient cure to date due to diffusive growth into the surrounding brain, preventing complete surgical resection and leading to inevitable tumor relapse. Tumor microenvironment (TME) of GBM contains brain-residing microglia and bone-marrow derived macrophages (collectively known as glioma-associated microglia/macrophages, GAMs) that constitute up to 30% of the tumor mass and promote tumor invasion. Hypoxia (a shortage of oxygen) is a key factor in tumor progression of GBM as it can globally and rapidly alter the gene expression, induce cancer cell invasiveness, stemness and lead to therapy resistance. Hypoxia can enhance the pro-tumorigenic function of GAMs, e.g. by inducing expression of cytokines and cell surface receptors both in GAMs and glioma cells, but little is known about chromatin alterations of GBM under hypoxia. Since regulation of expression of such molecules could depend on the epigenetic alterations, we hypothesize that hypoxia may potently alter the chromatin accessibility and functions of GAMs and glioma cells.

We determine the genome-wide changes in chromatin accessibility in GAMs and glioma cells in response to hypoxic stress using single-cell Pi-ATAC-seq (Protein-indexed Assay of Transposase Accessible Chromatin with sequencing), which allows simultaneous genome-wide assessment of chromatin accessibility and expression of intracellular protein markers in single cells, allowing faithful selection of hypoxic and non-hypoxic cells. Secondly, we are employing an oxygen-dependent co-culture model in vitro to study the mechanisms of chromatin alterations in GAMs and glioma cells under controlled hypoxic conditions and test how these changes depend on the glioma - GAMs cross-communication. In summary, we characterize the interactions between innate immune cells and glioma cells by looking at their chromatin alterations under hypoxia.

Supported by the National Science Center grant (Poland) 2019/33/B/NZ1/01556 (KBL).
OTME-4. IDH mutated gliomas promote epileptogenesis via D-2-hydroxyglutarate dependent mTOR hyperactivation
Authors: Mortazavi Armin , Fayed Islam , Bachani Muzna , Maric Dragan , Dowdy Tyrone , Larion Mioara , Ksendzovsky Alexander , Zaghloul Kareem
Published: July 2021

Epilepsy in the context of brain tumors provides a great burden in these patients, yet mechanisms underlying this process are poorly understood. It has been demonstrated that isocitrate dehydrogenase (IDH) mutations are an independent factor in epileptogenesis in patients with low grade gliomas. Here, using electrographically sorted human cortical tissue from patients with IDH mutated tumor related epilepsy and in vitro cortical cultures, we explore a metabolic paradigm and its impact on increased neuronal excitability. We hypothesize the IDH mutation promotes epileptogenesis through its neomorphic activity of D-2-hydroxyglutarate (D-2-HG) production in turn interrupts surrounding normal neuronal circuitry potentially through metabolic perturbations. We demonstrate D-2-HG increases neuronal spiking activity, promotes distinct metabolic profiles independent of neuronal spiking activity, as well as increases neuronal mTOR signaling, which is reflected in human peritumoral epileptic cortex. Increased mTOR signaling is sufficient to upregulate neuronal spiking activity and, reciprocally, inhibition of mTOR corrects neuronal activity as well as partially corrects metabolic reprogramming. Our results suggest D-2-HG can lead to mTOR activation within the peritumoral neurons, thereby suggesting an additional possible mechanism of epileptogenesis in patients with IDH mutated low grade gliomas. Ultimately, our results raise the possibility of mTOR inhibition may be a promising treatment of seizures in patients with these tumors.