bluuebunny/crossref_metadata_2025 huggingface dataset:
The SWI/SNF nucleosome remodeler constrains enhancer activity during Drosophila wing development
Authors: Niederhuber Matthew J , Leatham-Jensen Mary , McKay Daniel J
Published: November 2023

Chromatin remodeling is central to the dynamic changes in gene expression that drive cell fate determination. During development, the sets of enhancers that are accessible for use change globally as cells transition between stages. While transcription factors and nucleosome remodelers are known to work together to control enhancer accessibility, it is unclear how the short stretches of DNA that they individually unmask yield the kilobase-sized accessible regions characteristic of active enhancers. Here, we performed a genetic screen to investigate the role of nucleosome remodelers in control of dynamic enhancer activity. We find that the Drosophila Switch/Sucrose Non-Fermenting complex, BAP, is required for repression of a temporally dynamic enhancer, brdisc. Contrary to expectations, we find that the BAP-specific subunit Osa is dispensable for mediating changes in chromatin accessibility between the early and late stages of wing development. Instead, we find that Osa is required to constrain the levels of brdisc activity when the enhancer is normally active. Genome-wide profiling reveals that Osa directly binds brdisc as well as thousands of other developmentally dynamic regulatory sites, including multiple genes encoding components and targets of the Notch signaling pathway. Transgenic reporter analyses demonstrate that Osa is required for activation and for constraint of different sets of target enhancers in the same cells. Moreover, Osa loss results in hyperactivation of the Notch ligand Delta and development of ectopic sensory structures patterned by Notch signaling early in development. Together, these findings indicate that proper constraint of enhancer activity is necessary for regulation of dose-dependent developmental events.
Lewis a−b− histo-blood group antigen phenotype is predictive of severe COVID-19 in the black South African population group
Authors: Magwira Cliff A , Nndwamato Ndivho P , Selabe Gloria , Seheri Mapaseka L
Published: November 2023

Several risk factors have been associated with SARS-CoV-2 infections and severity of COVID-19 disease it causes. This study investigated whether variations in histo-blood group antigen (HBGA) expression can predispose individuals to SARS-CoV-2 infections and severity of the disease. Nasopharyngeal swabs, randomly selected from SARS-CoV-2 positive and SARS-CoV-2 negative individuals, were tested for Lewis and H-type 1 HBGA phenotypes by ELISA using monoclonal antibodies specific to Lewis a, Lewis b and H type 1 antigens. The most common Lewis HBGA phenotype among all study participants was Lewis a−b+ (46%), followed by Lewis a−b− (24%), Lewis a+b− and Lewis a+b+ (15% each), while 55% of the study participants were H-type 1. Although SARS-CoV-2 negative individuals had a lower likelihood of having a Lewis a−b− phenotype compared to their SARS-CoV-2 positives counterparts (OR: 0.53, 95% C.I: 0.255–1.113), it did not reach statistical significance (P = 0.055). The frequency of Lewis a+b+, Lewis a+B−, Lewis a−b+, H type 1 positive and H type 1 negative were consistent between SARS-CoV-2 positive and SARS-CoV-2 negative individuals. When stratified according to severity of the disease, individuals with Lewis a+b− phenotype had a higher likelihood of developing mild COVID-19 symptoms (OR: 3.27, 95% CI; 0.9604–11.1), but was not statistically significant (P = 0.055), while Lewis a−b− phenotype was predictive of severe COVID-19 symptoms (OR: 4.3, 95% CI: 1.274–14.81), P = 0.016. In conclusion, individuals with Lewis a−b− phenotype were less likely to be infected by SARS-CoV-2, but when infected, they were at risk of severe COVID-19.
Exclusive Enteral Nutrition Mediates Beneficial Gut Microbiome Enrichment in Acute Severe Colitis
Authors: Bajaj Aditya , Markandey Manasvini , Singh Mukesh , Sahu Pabitra , Vuyyuru Sudheer K , Kante Bhaskar , Kumar Peeyush , Verma Mahak , Makharia Govind , Kedia Saurabh , Travis Simon P L , Ahuja Vineet
Published: November 2023

Background

Exclusive enteral nutrition (EEN) supplementation of the standard of care (SOC) augments steroid responsiveness in patients with acute severe ulcerative colitis (ASUC). EEN is known to alter gut microbial composition. The present study investigates EEN-driven gut microbial alterations in patients with ASUC and examines their correlations with clinical parameters.

Methods

Stool samples from patients with ASUC (n = 44) who received either EEN-supplemented SOC (EEN group; n = 20) or SOC alone (SOC group; n = 24) for 7 days were collected at baseline (day 0) and postintervention (day 7). Microbiome analysis was carried out using 16S ribosomal RNA gene sequencing followed by data processing using QIIME2 and R packages.

Results

Seven-day EEN-conjugated corticosteroid therapy in patients with ASUC enhanced the abundances of beneficial bacterial genera Faecalibacterium and Veillonella and reduced the abundance of Sphingomonas (generalized linear model fitted with Lasso regularization with robustness of 100%), while no such improvements in gut microbiota were observed in the SOC group. The EEN-associated taxa correlated with the patient’s clinical parameters (serum albumin and C-reactive protein levels). Unlike the SOC group, which retained its preintervention core microbiota, EEN contributed Faecalibacterium prausnitzii, a beneficial gut bacterial taxon, to the gut microbial core. EEN responders showed enhancement of Ligilactobacillus and Veillonella and reduction in Prevotella and Granulicatella. Analysis of baseline gut microbiota showed relative enhancement of certain microbial genera being associated with corticosteroid response and baseline clinical parameters and that this signature could conceivably be used as a predictive tool.

Conclusions

Augmentation of clinical response by EEN-conjugated corticosteroid therapy is accompanied by beneficial gut microbial changes in patients with ASUC.
Comparing eDNA metabarcoding and conventional pelagic netting to inform biodiversity monitoring in deep ocean environments
Authors: Cote D , McClenaghan B , Desforges J , Fahner N A , Hajibabaei M , Chawarski J , Roul S , Singer G , Aubry C , Geoffroy M
Published: November 2023

The performance of environmental DNA (eDNA) metabarcoding has rarely been evaluated against conventional sampling methods in deep ocean mesopelagic environments. We assessed the biodiversity patterns generated with eDNA and two co-located conventional methods, oblique midwater trawls and vertical multinets, to compare regional and sample-level diversity. We then assessed the concordance of ecological patterns across water column habitats and evaluated how DNA markers and the level of sampling effort influenced the inferred community. We found eDNA metabarcoding characterized regional diversity well, detecting more taxa while identifying similar ecological patterns as conventional samples. Within sampling locations, eDNA metabarcoding rarely detected taxa across more than one replicate. While more taxa were found in eDNA than oblique midwater trawls within sample stations, fewer were found compared to vertical multinets. Our simulations show greater eDNA sampling effort would improve concordance with conventional methods. We also observed that using taxonomic data from multiple markers generated ecological patterns most similar to those observed with conventional methods. Patterns observed with Exact Sequence Variants were more stable across markers suggesting they are more powerful for detecting change. eDNA metabarcoding is a valuable tool for identifying and monitoring biological hotspots but some methodological adjustments are recommended for deep ocean environments.
Two-scale methods for the normalized infinity Laplacian: rates of convergence
Authors: Li Wenbo , Salgado Abner J
Published: November 2023

We propose a monotone and consistent numerical scheme for the approximation of the Dirichlet problem for the normalized infinity Laplacian, which could be related to the family of the so-called two-scale methods. We show that this method is convergent and prove rates of convergence. These rates depend not only on the regularity of the solution, but also on whether or not the right-hand side vanishes. Some extensions to this approach, like obstacle problems and symmetric Finsler norms, are also considered.
Weak error analysis for strong approximation schemes of SDEs with super-linear coefficients
Authors: Wang Xiaojie , Zhao Yuying , Zhang Zhongqiang
Published: November 2023

We present an error analysis of weak convergence of one-step numerical schemes for stochastic differential equations (SDEs) with super-linearly growing coefficients. Following Milstein’s weak error analysis on the one-step approximation of SDEs, we prove a general result on weak convergence of the one-step discretization of the SDEs mentioned above. As applications, we show the weak convergence rates for several numerical schemes of half-order strong convergence, such as tamed and balanced schemes. Numerical examples are presented to verify our theoretical analysis.
Strategies to reduce antimicrobials in livestock and aquaculture, and their impact under field conditions: a structured scoping literature review
Authors: Sucena Afonso João , El Tholth Mahmoud , Mcintyre K Marie , Carmo Luís Pedro , Coyne Lucy , Manriquez Diego , Raboisson Didier , Lhermie Guillaume , Rushton Jonathan
Published: November 2023

Antimicrobial resistance is a pandemic problem, causing substantial health and economic burdens. Antimicrobials are extensively used in livestock and aquaculture, exacerbating this global threat. Fostering the prudent use of antimicrobials will safeguard animal and human health. A lack of knowledge about alternatives to replace antimicrobials, and their effectiveness under field conditions, hampers changes in farming practices.

This work aimed to understand the impact of strategies to reduce antimicrobial usage (AMU) in livestock and aquaculture, under field conditions, using a structured scoping literature review. The Extension for Scoping Reviews of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines (PRISMA-ScR) were followed and the Patient, Intervention, Comparison, Outcome, Time and Setting (PICOTS) framework used. Articles were identified from CAB Abstracts, MEDLINE and Scopus. A total of 7505 unique research articles were identified, 926 of which were eligible for full-text assessment; 203 articles were included in data extraction. Given heterogeneity across articles in the way alternatives to antimicrobials or interventions against their usage were described, there was a need to standardize these by grouping them in categories.

There were differences in the impacts of the strategies between and within species; this highlights the absence of a ‘one-size-fits-all’ solution. Nevertheless, some options seem more promising than others, as their impacts were consistently equivalent or positive when compared with animal performance using antimicrobials. This was particularly the case for bioactive protein and peptides, and feed/water management. The outcomes of this work provide data to inform cost-effectiveness assessments of strategies to reduce AMU.
Free vibration analysis of Timoshenko pipes conveying fluid with gravity and different boundary conditions
Authors: Shui Bo , Li Yun-dong , Luo Yu-mei , Luo Fei
Published: November 2023

In this paper, the free vibration of Timoshenko pipes conveying fluid with gravity and different boundary conditions is analyzed by using the weak form quadrature element method. The dimensionless frequency and critical flow velocity have been calculated considering various parameters such as the mass ratio of pipe to fluid, slenderness ratio and gravity. The numerical results with different numbers of discrete points are tested, and the results show that the method has a fast convergence speed. Some numerical results are compared with the existing literature, which proves that the weak form quadrature element method has high accuracy and computational efficiency. This paper shows that the weak form quadrature element method is a preferred method for analyzing fluid-conveying pipes with various boundary conditions.
Development and feasibility of an educational module on medication reconciliation for hospital pharmacists in the United Arab Emirates: a pilot study
Authors: Farajallah Alaa , Zainal Hadzliana , Palaian Subish
Published: November 2023

Background

The practice of medication reconciliation by pharmacists is minimal in United Arab Emirates hospitals.

Objectives

To design an educational module for pharmacists on medication reconciliation and assess its feasibility.

Methods

The study consisted of three parts: A pre-educational module survey using a validated knowledge, perception, practice, and barriers questionnaire (Cronbach’s α = 0.78), delivery of the educational module, and participants’ feedback. An educational module (general introduction to medication reconciliation, what is medication reconciliation, how to do medication reconciliation, and practicing medication reconciliation) was developed based on Miller’s pyramid and validated by three experts and pilot-tested. The knowledge and perceptions of pharmacists were evaluated by comparing pre-post educational module survey results.

Results

The module influenced the participants’ knowledge and perception of medication reconciliation. All of the participants gave ‘positive’ feedback on the intervention and the methodology applied, and they agreed on the need for training and workshops related to medication reconciliation. In addition, all ‘agreed’ that a lack of knowledge about medication reconciliation is the biggest barrier to medication reconciliation practices. The results further illustrated that all pharmacists had a ‘positive’ experience and ‘agreed strongly’ on understanding the majority of the content.

Conclusion

This study was successful in answering the research question by enrolling suitable participants, managing the timeline, and possessing resources for completing the study and hence considered feasible. This module can be utilized in continuous professional development programs to improve pharmacists’ knowledge, perceptions, and practice toward the medication reconciliation process aiming to reduce drug therapy-related problems in hospital settings.
Unraveling plant–microbe interactions: can integrated omics approaches offer concrete answers?
Authors: Kimotho Roy Njoroge , Maina Solomon
Published: November 2023

Advances in high throughput omics techniques provide avenues to decipher plant microbiomes. However, there is limited information on how integrated informatics can help provide deeper insights into plant–microbe interactions in a concerted way. Integrating multi-omics datasets can transform our understanding of the plant microbiome from unspecified genetic influences on interacting species to specific gene-by-gene interactions. Here, we highlight recent progress and emerging strategies in crop microbiome omics research and review key aspects of how the integration of host and microbial omics-based datasets can be used to provide a comprehensive outline of complex crop–microbe interactions. We describe how these technological advances have helped unravel crucial plant and microbial genes and pathways that control beneficial, pathogenic, and commensal plant–microbe interactions. We identify crucial knowledge gaps and synthesize current limitations in our understanding of crop microbiome omics approaches. We highlight recent studies in which multi-omics-based approaches have led to improved models of crop microbial community structure and function. Finally, we recommend holistic approaches in integrating host and microbial omics datasets to achieve precision and efficiency in data analysis, which is crucial for biotic and abiotic stress control and in understanding the contribution of the microbiota in shaping plant fitness.
ROS and RNS production, subcellular localization, and signaling triggered by immunogenic danger signals
Authors: Giulietti Sarah , Bigini Valentina , Savatin Daniel V
Published: November 2023

Plants continuously monitor the environment to detect changing conditions and to properly respond, avoiding deleterious effects on their fitness and survival. An enormous number of cell surface and intracellular immune receptors are deployed to perceive danger signals associated with microbial infections. Ligand binding by cognate receptors represents the first essential event in triggering plant immunity and determining the outcome of the tissue invasion attempt. Reactive oxygen and nitrogen species (ROS/RNS) are secondary messengers rapidly produced in different subcellular localizations upon the perception of immunogenic signals. Danger signal transduction inside the plant cells involves cytoskeletal rearrangements as well as several organelles and interactions between them to activate key immune signaling modules. Such immune processes depend on ROS and RNS accumulation, highlighting their role as key regulators in the execution of the immune cellular program. In fact, ROS and RNS are synergic and interdependent intracellular signals required for decoding danger signals and for the modulation of defense-related responses. Here we summarize current knowledge on ROS/RNS production, compartmentalization, and signaling in plant cells that have perceived immunogenic danger signals.
Accommodations of private and family life and non-traditional families: the limits of deference in cases of cross-border surrogacy before the European Court of Human Rights
Authors: Bracken Lydia
Published: November 2023

The European Court of Human Rights (ECtHR) case law on cross-border surrogacy establishes that a ‘general and absolute impossibility’ of obtaining recognition of the relationship, legally established in another country, between a surrogate-born child and their intended parents will violate the child’s right to respect for private life. This approach requires States to accommodate familial bonds created through cross-border surrogacy and limits the margin of appreciation available to States to determine their national response. In recent case law, the ECtHR has adopted an interventionist approach in respect of national decision-making and has gone further than might be expected under the principle of subsidiarity. Examination of the emerging body of jurisprudence on cross-border surrogacy, however, reveals a preference for ‘traditional’ family formations, with the ECtHR tending to adopt a less interventionist and more deferential approach to national decision-making where the family at the centre of the case deviates from the structure of the family reflected in the seminal cross-border surrogacy case of Mennesson v France App no 65192/11 (ECtHR, 26 June 2014). This approach leads to inconsistency in the cross-border surrogacy case law as it creates something of a moving target for the vindication of children’s rights in ‘less traditional’ family forms.
Quantification of Unsupported Thin-Film X-ray Spectra Using Bulk Standards
Authors: Ritchie Nicholas W M , Herzing Andrew , Oleshko Vladimir P
Published: November 2023

A quantification model which uses standard X-ray spectra collected from bulk materials to determine the composition and mass thickness of single-layer and multilayer unsupported thin films is presented. The multivariate model can be iteratively solved for single layers in which each element produces at least one visible characteristic X-ray line. The model can be extended to multilayer thin films in which each element is associated with only one layer. The model may sometimes be solved when an element is present in multiple layers if additional information is added in the form of independent k-ratios or model assumptions. While the algorithm is suitable for any measured k-ratios, it is particularly well suited to energy-dispersive X-ray spectrometry where the bulk standard spectra can be used to deconvolve peak interferences in the thin-film spectra. The algorithm has been implemented and made available in the Open Source application National Institute of Standards and Technology DTSA-II. We present experimental data and Monte Carlo simulations supporting the quantification model.
Quasar feedback survey: molecular gas affected by central outflows and by ∼10-kpc radio lobes reveal dual feedback effects in ‘radio quiet’ quasars
Authors: Girdhar A , Harrison C M , Mainieri V , Fernández Aranda R , Alexander D M , Arrigoni Battaia F , Bianchin M , Calistro Rivera G , Circosta C , Costa T , Edge A C , Farina E P , Kakkad D , Kharb P , Molyneux S J , Mukherjee D , Njeri A , S. Silpa , Venturi G , Ward S R
Published: November 2023

We present a study of molecular gas, traced via CO (3–2) from Atacama Large Millimeter/submillimeter Array data, of four z < 0.2, ‘radio quiet’, type 2 quasars (Lbol ∼ 1045.3–1046.2 erg s−1; L$_{\mathrm{1.4\, GHz}}\sim 10^{23.7}\!-\!10^{24.3}$ W Hz−1). Targets were selected to have extended radio lobes (≥ 10 kpc), and compact, moderate-power jets (1–10 kpc; Pjet ∼ 1043.2–1043.7 erg s−1). All targets show evidence of central molecular outflows, or injected turbulence, within the gas discs (traced via high-velocity wing components in CO emission-line profiles). The inferred velocities (Vout = 250–440 km s−1) and spatial scales (0.6–1.6 kpc), are consistent with those of other samples of luminous low-redshift active galactic nuclei. In two targets, we observe extended molecular gas structures beyond the central discs, containing 9–53  per cent of the total molecular gas mass. These structures tend to be elongated, extending from the core, and wrap-around (or along) the radio lobes. Their properties are similar to the molecular gas filaments observed around radio lobes of, mostly ‘radio loud’, brightest cluster galaxies. They have the following: projected distances of 5–13 kpc; bulk velocities of 100–340 km s−1; velocity dispersion of 30–130 km s−1; inferred mass outflow rates of 4–20 M⊙ yr−1; and estimated kinetic powers of 1040.3–1041.7 erg s−1. Our observations are consistent with simulations that suggest moderate-power jets can have a direct (but modest) impact on molecular gas on small scales, through direct jet–cloud interactions. Then, on larger scales, jet-cocoons can push gas aside. Both processes could contribute to the long-term regulation of star formation.
Main belt asteroids taxonomical information from dark energy survey data
Authors: Carruba V , Camargo J I B , Aljbaae S , Ferreira F S , Lin E , Figueiredo-Peixoto V , Banda-Huarca M V , Pieres A , Boufleur R C , da Costa L N , Abbott T M C , Aguena M , Allam Sahar S , Alves O , Bernardinelli P H , Bertin E , Brooks D , Carnero Rosell A , Carretero J , Pereira M E S , Davis T M , De Vicente J , Desai S , Doel P , Ferrero I , Friedel D , Frieman J , García-Bellido J , Gatti M , Giannini G , Gruen D , Gruendl R A , Herner K , Hinton S R , Hollowood D L , James D J , Kent S , Kuehn K , Lahav O , Marshall J L , Mena-Fernández J , Miquel R , Palmese A , Plazas Malagón A A , Rodríguez-Monroy M , Sanchez E , Santiago B , Schubnell M , Smith M , Suchyta E , Swanson M E C , Tarle G , Walker A R , Weaverdyck N , Wiseman P ,   (DES Collaboration)
Published: November 2023

While proper orbital elements are currently available for more than 1 million asteroids, taxonomical information is still lagging behind. Surveys like SDSS-MOC4 provided preliminary information for more than 100 000 objects, but many asteroids still lack even a basic taxonomy. In this study, we use Dark Energy Survey (DES) data to provide new information on asteroid physical properties. By cross-correlating the new DES data base with other data bases, we investigate how asteroid taxonomy is reflected in DES data. While the resolution of DES data is not sufficient to distinguish between different asteroid taxonomies within the complexes, except for V-type objects, it can provide information on whether an asteroid belongs to the C- or S-complex. Here, machine learning methods optimized through the use of genetic algorithms were used to predict the labels of more than 68 000 asteroids with no prior taxonomic information. Using a high-quality, limited set of asteroids with data on gri slopes and i − z colours, we detected 409 new possible V-type asteroids. Their orbital distribution is highly consistent with that of other known V-type objects.
The translational oscillation in oocyte and early embryo development
Authors: Iyyappan Rajan , Aleshkina Daria , Ming Hao , Dvoran Michal , Kakavand Kianoush , Jansova Denisa , del Llano Edgar , Gahurova Lenka , Bruce Alexander W , Masek Tomas , Pospisek Martin , Horvat Filip , Kubelka Michal , Jiang Zongliang , Susor Andrej
Published: November 2023

Translation is critical for development as transcription in the oocyte and early embryo is silenced. To illustrate the translational changes during meiosis and consecutive two mitoses of the oocyte and early embryo, we performed a genome-wide translatome analysis. Acquired data showed significant and uniform activation of key translational initiation and elongation axes specific to M-phases. Although global protein synthesis decreases in M-phases, translation initiation and elongation activity increases in a uniformly fluctuating manner, leading to qualitative changes in translation regulation via the mTOR1/4F/eEF2 axis. Overall, we have uncovered a highly dynamic and oscillatory pattern of translational reprogramming that contributes to the translational regulation of specific mRNAs with different modes of polysomal occupancy/translation that are important for oocyte and embryo developmental competence. Our results provide new insights into the regulation of gene expression during oocyte meiosis as well as the first two embryonic mitoses and show how temporal translation can be optimized. This study is the first step towards a comprehensive analysis of the molecular mechanisms that not only control translation during early development, but also regulate translation-related networks employed in the oocyte-to-embryo transition and embryonic genome activation.
ANGI-05. CDKN2A/B HOMOZYGOUS DELETION IN IDH-MUTANT ASTROCYTOMA ALTERS TUMOR CELL INVASION AND VASCULAR FORMATION
Authors: Grief Dustin , D'Angelo Fulvio , Caruso Francesca , Sereduk Christopher , Ceccarelli Michele , Hu Leland , Loftus Joseph , Tran Nhan , Ensign Shannon Fortin
Published: November 2023

High-grade gliomas represent the most common type of primary adult malignant brain tumor historically diagnosed and graded from histologic criteria alone. Gliomas harboring isocitrate dehydrogenase (IDH) 1 or 2 mutations are associated with lower grade tumors and portend a favorable prognosis relative to IDH-wildtype glioma. However, molecular profiling has identified additional alterations in lower grade gliomas that confer an aggressive high-grade phenotype and a worse clinical prognosis. Of these, the loss of CDKN2A/B in IDH-mutant astrocytoma is the strongest implicated alteration and is sufficient to define a grade 4 tumor regardless of histologic grade. However, there remain no effective therapies targeted at molecular subgroups in aggressive gliomas to date. Here, we sought to elucidate the biologic pathways and functional outcomes associated with the acquisition of high-grade behavior under loss of CDKN2A/B in IDH-mutant astrocytoma to inform future therapeutic strategies. We analyzed a cohort of patient IDH-mutant astrocytomas with whole exome and RNA sequencing data and found several candidate genes/pathways regulated concurrent with CDKN2A/B loss, including regulators of embryonic development, extracellular matrix organization and regulation of vascular processes. Moreover, we identified 1 tumor that displayed intratumoral heterogeneity of CDKN2A/B expression across biopsies. Using grade 4 IDH-mutant astrocytoma patient-derived (PDX) and established cell-lines harboring CDKN2A/B homozygous deletion, we then stably re-expressed cell cycle regulators p14, p15, and p16 using a Tet-inducible lentiviral system and confirmed their decreased proliferation as compared to parental lines. IDH-mutant cell lines with re-expression of p14, p15 or p16 were characterized by differential transcription factor activation and distinct vascular formation patterns as compared to parental lines. These lines also displayed an increased cell migration and invasive potential and were associated with enhanced integrin signaling through integrin beta-3. Together, our work supports a hypothesis of regional tumor evolution with distinct biologic phenotypes across IDH-mutant gliomas.
ANGI-11. MOLECULAR MECHANISM OF TARGETING EPITHELIAL MEMBRANE PROTEIN-2 IN MALIGNANT MENINGIOMAS
Authors: Yang Isaac , Mekonnen Mahlet , Chandla Anubhav , Aguirre Brian , Wadehra Madhuri
Published: November 2023

BACKGROUND

Meningiomas comprise approximately one-third of all primary central nervous system neoplasms. While many meningiomas remain benign, as many as 35% of meningiomas are graded as atypical or anaplastic/malignant with a 5-y survival rate as low as 35%. Targeting the tetraspan protein epithelial membrane protein-2 (EMP2)-HIF1α pathway through EMP2 knockdown may inhibit tumor growth, invasion, and neoangiogenesis in malignant meningioma.

METHODS

In collaboration with the UCLA Brain Tumor SPORE, we gathered a panel of malignant meningiomas (IOMM-LEE, CH157). To determine the function of EMP2, we created EMP2 vector control and knockdown models in both cell lines and analyzed the cells by RNA sequencing, transcriptomic functional analysis, and migration assay.

RESULTS

Gene functional analysis enriched for biological processes showed that knockdown of EMP2 inhibited multiple malignant pathways in these meningioma cells including the response to hypoxia, cell proliferation, invasion, and stem cell maintenance. Further analyses of EMP2 expression with other differentially expressed genes of interest revealed that VEGFA expression significantly decreased when EMP2 is knocked down (p< 0.001). Moreover, cellular migration and invasion regulated by EMP2 were tested in control and EMP2 knockdown malignant cells using a scratch assay, where knockdown of EMP2 reduced the rate of cell invasion by 50% (p = 0.0003). Additionally, anti-EMP2 mAb treatment in the control malignant cell line significantly reduced EMP2-mediated signal transduction (p = 0.0031).

CONCLUSIONS

Our study is the first to demonstrate the modulation of EMP2 and its implications in malignant meningioma pathogenesis, VEGFA-HIF1α pathway, and stem cell regulation. Targeting EMP2 may result in therapeutic benefits for malignant meningioma.
BIOM-02. CSF LIQUID-BASED DIAGNOSIS OF LEPTOMENINGEAL DISEASE (LMD) FROM NON-SMALL CELL LUNG CANCER (NSCLC) USING DDPCR AGAINST EGFR MUTATIONS
Authors: Li Kay Ka-Wai , Fung Jackie Mei-Wah , Woo Peter Yat-Ming , Liu Anthony Pak-Yin , Chow Chit , Ng Ho-Keung
Published: November 2023

Leptomeningeal disease (LMD) due to spreading of solid cancers to the leptomeninges has a very poor prognosis and is poorly diagnosed. MR imaging may be negative and CSF cytology, the gold standard, is not sensitive enough, due to small number of cells inherent in CSF, small volume and inter-observer variability in microscopy. We tested the hypothesis that cfDNA from CSF could be a unique source of DNA from LMD which can be used for diagnosis as well as research. We collected 39 CSF samples from patients suspected of LMD from NSCLCs. CfDNA was extracted by cobas® cfDNA Sample Preparation Kit. Hotspot EGFR mutations (G719X, S768I, T790M, C797S, L858R, L861Q, and 19 del) were tested by multiplexed droplet-digital PCR (ddPCR). EGFR mutation status of the original primary NSCLCs were previously tested for by real-time PCR using formalin-fixed paraffin-embedded tissues. Six samples did not yield sufficient DNA. For the remaining 33 cases, EGFR mutations were detected in 16 samples. For fifteen of these positive cases, identical mutations were found in the matched tissue samples. EGFR status of one primary tumor was unknown. Cytology was negative in 10 cases, atypical in five and only positive in one case. For the 17 negative samples, in 11 cases, the corresponding tumor tissues lacked EGFR mutations. Five patients from the negative group were eventually found not to have LMD. Only in one case was the lung tissue found to have EGFR mutation but mutation was not found in CSF cfDNA. In a few selected cases, we studied the genomics of the cfDNA together with the primary tumor tissues with low-pass WGS and similar CNVs were found in both. CSF cfDNA is a unique source of DNA from LMD and can be used as a useful tool in clinical diagnosis and research.
BIOM-04. IMPROVEMENT OF LEPTOMENINGEAL DISEASE (LMD) WITH MEK AND BRAF INHIBITORS, CRANIOSPINAL IRRADIATION (CSI), AND INTRATHECAL (IT) CHEMOTHERAPY IN ANAPLASTIC PLEOMORPHIC XANTHOASTROCYTOMA (PXA)
Authors: Nahm Joshua , Vu Mia , Schumann Eva Highberg , Bhattacharjee Meenakshi , Blanco Angel , Tandon Nitin , Zhu Jay-Jiguang
Published: November 2023

Anaplastic pleomorphic xanthoastrocytomas (aPXA) are rare gliomas with a five-year survival of 57%. Standard treatment involves maximal safe resection followed by radiotherapy. BRAF mutation is frequently seen in these patients and is a promising target with concurrent BRAF and MEK inhibitors. However, there is no standard treatment for patients with aPXA and leptomeningeal disease (LMD). Literature review identified four cases with overall survivals (OS) of 3, 4, 18, and 66 months, respectively. We report a 23-year-old female who presented with headache, nausea, vomiting, and aphasia with MRI evidence of a left temporal lobe enhancing mass. Her tumor was initially diagnosed as epithelioid glioblastoma, WHO grade IV after craniotomy. She received concurrent radiation and temozolomide with subsequent 12 cycles of TMZ. After identification of BRAF V600E mutation by next generation sequencing, we revisited her diagnosis, and it was changed to aPXA. Three years later, she presented to the ER with aphasia, headache, weakness, nausea, and vomiting with MRI evidence of hydrocephalus and LMD by brain and spine MRI as well as cerebrospinal fluid analysis. Her treatment regimen consisted of the MEK inhibitor cobimetinib, the BRAF inhibitor vemurafenib, partial craniospinal irradiation (CSI), and intrathecal (IT) chemotherapy with methotrexate, topotecan, cytarabine, and thiotepa sequentially. She is currently doing well with mild bilateral leg weakness. She continues on therapy with BRAF and MEK inhibitors. Her OS is 56 months. Adverse events (AE) were tabulated according to the Common Terminology Criteria for Adverse Events Version 5.0 and included grade IV neutropenia, grade III anemia, grade II rash acneiform, and grade II nausea/vomiting. All AEs were manageable and reversible. Despite the limitations of a case report and retrospective review, our findings suggest that MEK and BRAF inhibitors, CSI, and IT chemotherapy may be effective treatment options for patients with aPXA and LMD.
BIOM-11. THE ROLE OF INSULIN-LIKE GROWTH FACTOR 2 BINDING PROTEIN 3 (IGF2BP3) AS A DRIVER OF TUMORIGENESIS IN GLIOBLASTOMA
Authors: Chow Jocelyn , Chen Alexander , Oh Se-yeong , Young Elizabeth , Boyd Nathaniel , Read Renee
Published: November 2023

Glioblastoma (GBM) is the most aggressive primary brain tumor with a poor median survival of fifteen months after diagnosis. GBM accounts for half of malignant and fifteen percent of all primary brain tumors diagnosed in adults. To promote targeted therapy, there are ongoing efforts to understand GBM at a molecular level. This involves characterization of these tumors via their transcriptional and mutational profile. Recent studies indicate aberrations in receptor tyrosine kinase (RTKs), including EGFR and PDGFRA, and the Pi-3 kinase (PI3K) signaling pathways are major drivers of tumorigenesis in GBM. Using a proteomics approach to locate downstream targets of these pathways, we identified IGF2 Binding Protein 3 (IGF2BP3), which is an RNA binding protein, as a downstream effector of aberrant RTK-PI3K signaling in gliomagenesis. Our subsequent follow-up studies indicate that IGF2BP3, which is overexpressed in RTK mutant human GBMs, drives survival and proliferation of RTK-PI3K-dependent human GBM cells. To understand how IGF2BP3 functions to promote RTK-PI3K driven tumorigenesis, we used cultured human GBM cells and in GBM xenograft models to test the effects of loss of IGF2BP3 function in tumorous glia as well as normal glia. Our results indicate that IGF2BP3 activity is essential for self-renewal and maintenance of neural stem-cell like features of GBM tumor cells, but dispensable for the growth of normal glia. Currently, we are using genetic approaches to identify and validate RNA targets of IGF2BP3 function in tumor cells and to understand how these targets are specifically regulated by RTK-PI3K-dependent signaling in glioma. Overall, our data suggests that IGF2BP3 may play a role in promoting GBM tumorigenesis and our future directions aim to reveal an important tumor-specific RNA target signaling pathway for consideration in potential therapeutics.
BIOM-15. CIRCULATING EXOSOMES CORRELATE WITH RADIOGRAPHIC PROGRESSION IN GLIOBLASTOMA PATIENTS AFTER ULTRASOUND-BASED OPENING OF THE BLOOD-BRAIN BARRIER
Authors: Youngblood Mark W , Kumari Abha , Gould Andrew , Kang Yoon-Tae , Chen Li , Habashy Karl , Amidei Christina , Ward Rachel , Gomez Cristal , Bouchoux Guillaume , Canney Michael , Stupp Roger , Nagrath Sunitha , Sonabend Adam
Published: November 2023

Non-invasive methods to detect progression of glioblastoma (GBM) are needed to optimize patient management. Circulating blood-based biomarkers for GBM progression are limited by the blood-brain barrier, which restricts leakage of tumor-related elements into circulation. To address this, we investigated circulating GBM-associated exosomes using samples obtained as part of a clinical trial where the blood-brain barrier was temporarily opened with a skull-implantable ultrasound system (NCT04528680). Samples were collected after an intra-operative sonication procedure at multiple time points, as well as longitudinally before and after subsequent outpatient sonication cycles. Plasma exosomes were isolated using a newExoChip microfluidic device, and enrichment of tumor-derived exosomes was based on expression of Phosphatidylserine (which binds to Annexin V on the device). Tumoral origin of the exosomes was validated with GBM cell lines as positive controls, using Western blots and variant-specific ddPCR to confirm tumor contents. We observed a 2.1-fold increase in exosome concentration in plasma samples obtained intraoperatively between 2 and 45 minutes after sonication, relative to pre-operative baseline (n = 4 patients; 19 plasma samples; one-tailed t-test p = 0.02). In a longitudinal analysis of eight patients, volumetric MRI analysis of enhancement was compared with changes in exosome concentration after sonication. Among patients with short progression-free survival (PFS) (n = 4; PFS < 90 days), multi-subject analysis yielded a repeated-measures correlation of -0.59 (p = 0.06), compared to 0.01 among long PFS patients (p = 0.96). In both cohorts, use of raw pre-sonication exosome concentrations had less association with MRI enhancement (p = 0.67 and 0.98 respectively). Considering each sample independently, we found the average Pearson correlation among short PFS patients was 0.73 (avg. p = 0.39), while no correlation was seen among long PFS patients (avg. r value = 0.10; avg. p-value = 0.54). Circulating exosomes hold promise as a non-invasive method to track GBM progression upon opening of the blood-brain barrier. Further refinement and validation in larger cohorts is warranted.
BIOM-18. MOLECULAR FEATURES RELATED TO LONG-TERM SURVIVAL IN GLIOBLASTOMA
Authors: Nisnboym Michal , Raphael Itay , Drappatz Jan
Published: November 2023

Glioblastoma Multiforme (GBM) remains the most common malignant primary brain tumor with a dismal prognosis that rarely exceeds beyond 2years of survival despite multimodal treatment. Strikingly, small fractions of GBM patients seem to display extended survival. However, the underlying mechanisms for this peculiarity remain largely unknown. Long-term survival (LTS) is often defined as a survival time of more than 3-5years from diagnosis. Several clinical variables have been associated with patients' survival, with age, Karnofsky performance score (KPS), and extent of resection being the most consistent. With advances in multi-omics technologies and their integration with disease diagnostics, numerous prognostic molecular markers have been proposed. So far, only O6-methylguanine-DNA-methyltransferase (MGMT) gene promotor hypermethylation is a well-established biomarker that is linked to outcome and therapy response. The objective of this study is to revisit patients diagnosed with GBM according to the 2021 WHO classification and investigate molecular characteristics associated with LTS. We analyzed records of IDH-wildtype GBM patients, > 18 years old, operated and treated at our institution between 2013 and 2020. From a patient perspective, we defined long-term survivorship as patients surviving more than 5 years. We compared LTSs to an equal number of matched controls (by clinical features and MGMT status) with STS, surviving less than 18 months. The analysis of their molecular features was performed by using the well-established and commonly used next-generation sequencing (NGS) assay, Glioseq. RESULTS: will be presented. With this retrospective work, we hope to shed a broader light on the still unknown molecular features as possible mechanisms behind the LTS of GBM patients. This is to pave the way for a consolidated conclusion on this important topic.
BIOM-19. PLASMA EXTRACELLULAR VESICLE SAMPLING FROM HIGH GRADE GLIOMA PATIENTS DEMONSTRATES A SMALL RNA SIGNATURE INDICATIVE OF DISEASE AND IDENTIFIES LNCRNA RPPH1 AS A HIGH GRADE GLIOMA BIOMARKER
Authors: Han Jae Ho , Wajnberg Gabriel , Attwood Kathleen , Hannay Brandon , Cormier Robert , Chacko Simi , Croul Syndey , Wilms Maya , Schmidt Matthias , Hebb Andrea , MacNeil Mary , Roy Jeremy , Weeks Adrienne
Published: November 2023

High grade gliomas (HGGs) and cells of the tumour microenvironment (TME) secrete extracellular vesicles (EVs) into the plasma that contain genetic and protein cargo which function in paracrine signaling. Isolation of these EVs and their cargo from plasma could lead to a simplistic tool that can inform on diagnosis and disease course of HGG. In the present study, plasma extracellular vesicles (EVs) were captured utilizing a peptide affinity method (Vn96 peptide) from high grade glioma (HGG) patients and normal controls followed by next generation sequencing (NovaSeq6000) to define a small RNA (sRNA) signature unique to HGG. Over 750 differentially expressed sRNA (miRNA, snoRNA, lncRNA, tRNA, mRNA fragments and non-annotated regions) were identified between HGG and controls. MiEAA 2.0 pathway analysis of the miRNA in the sRNA signature revealed miRNA highly enriched in both EV and HGG pathways demonstrating the validity of results in capturing a signal from the TME. Also revealed were several novel HGG plasma EV sRNA biomarkers including lncRNA RPPH1 (Ribonuclease P Component H1), RNY4 (Ro60-Associated Y4) and RNY5 (Ro60-Associated Y5). Furthermore, in paired longitudinal patient plasma sampling, RPPH1 informed on surgical resection (decreased on resection) and importantly RPPH1 increased again on clinically defined progression. The present study supports the role of plasma EV sRNA sampling (and particularly RPPH1) as part of a multi-pronged approach to HGG disease course surveillance.
BIOM-21. LIQUID BIOPSY IN SERA OF HIGH-GRADE GLIOMA PATIENTS: PROTOPORPHYRIN IX AS A BIOMARKER
Authors: Walke Anna , Krone Christopher , Stummer Walter , König Simone , Molina Eric Suero
Published: November 2023

High-grade gliomas (HGG) carry a dismal prognosis. Diagnosis comprises magnetic resonance imaging (MRI) followed by histopathological evaluation of tumor tissue after biopsy collection; no blood biomarker is currently available. Patients are subjected to repeated surgery and MRI for relapse monitoring. Protoporphyrin IX (PpIX) is already in routine use for selectively visualizing HGG tissue during fluorescence-guided resection (FGR). We investigated if it can also serve as serum HGG marker. Patients (HGG: n = 23 primary, pHGG; n = 5 recurrent, rHGG) undergoing FGR received 5-aminolevulinic acid (5-ALA) following standard clinical procedure. The control group of eight healthy volunteers (HCTR) also received 5-ALA. Serum was collected before and repeatedly up to 72 h after drug administration. PpIX was analyzed following liquid-liquid and solid-phase extraction using liquid chromatography coupled to ion trap mass spectrometry. The serum PpIX level before 5-ALA administration was similar in patient and control groups. Significant PpIX accumulation in HGG was observed after 5-ALA administration (ANOVA: p = 0.005, post-hoc: HCTR vs. pHGG p = 0.029, HCTR vs. rHGG p = 0.006). Separation of HCTR from pHGG was possible within CI95% of tMax (AUC: 0.943, CI95% 0.884 - 1.000, p < 0.001); the optimal cut-off for diagnosis was 1275 pmol PpIX/ml serum, reaching 87.0 % accuracy, 90.5 % positive predictive value and 84.0 % negative predictive value. Distinguishing pHGG patients from healthy controls based on serum PpIX is possible. The prodrug 5-ALA is required for PpIX induction, which is safe for the standard clinical dosage. Thus, PpIX is a new target for liquid biopsy in glioma, but larger clinical studies are required to characterize its full potential.
BIOM-23. IDENTIFICATION OF NOVEL BIOMARKERS FOR BRAIN TUMOR USING PRECISION MEDICINE APPROACHES: ORC6 PLAYS A CRITICAL ROLE IN GLIOBLASTOMA THERAPEUTICS
Authors: Chang Pei-Chi , Huang Jin-Hong , Li Yao-Feng
Published: November 2023

INTRODUCTION

Brain tumors remain challenging to treat despite diagnostic advancements. Current approaches involving surgery, radiotherapy, and chemotherapy tend to fail due to drug resistance. Our team identified potential biomarkers associated with aggressive brain tumors, including ORC6 and GPC4. ORC6, implicated in DNA replication and overexpressed in many cancers, presents a promising therapeutic target. In this study, we leverage advanced bioinformatics and experimental validation to further elucidate ORC6's potential for cancer treatment. Material and methods: This study uses R programming and packages to identify biomarkers from genomic databases like TCGA, CGGA, and GLASS. Protein expression is also assessed via tissue microarray and immunohistochemistry. Changes in the ORC6 gene are studied using GO, KEGG, and gene set enrichment analysis techniques. The tumor microenvironment is predicted using CIBERSORT.

RESULTS

are presented with 3D CLARITY images, and a deep learning algorithm is introduced for potential clinical application optimization.

RESULTS

Utilizing bioinformatics analyses, we identified ORC6 and GPC4 as potential biomarkers impacting tumor growth. This study focuses on ORC6, which demonstrated significantly increased expression in IDH-wildtype astrocytoma versus normal brain tissue. This heightened ORC6 expression correlated with tumor grading, poor prognosis, and increased KI67 expression in all glioma subgroups. ATAC sequencing and gene set enrichment analysis revealed E2F factors as potential ORC6 regulators and showed that increased ORC6 expression affected cell proliferation signaling pathways. Single-cell sequencing data further indicated ORC6 expression correlation with tumor cells, proliferative stem cells, and M0, M1, and M2 macrophages. Additionally, high ORC6 expression was observed in several brain tumor cell lines (U87MG, U118MG, LN229, GBM8401) that could be down-regulated using siRNA, paving the way for more complex gene editing and functional modeling experiments.

CONCLUSION

This study employs sophisticated bioinformatics and experimental validation techniques to explore the potential of targeting ORC6 for cancer therapy. Keywords: ORC6, Glioblastoma, TCGA, CGGA, GLASS, biomarker