bluuebunny/crossref_metadata_2025 huggingface dataset:
Hierarchical deep learning for predicting GO annotations by integrating protein knowledge
Authors: Merino Gabriela A , Saidi Rabie , Milone Diego H , Stegmayer Georgina , Martin Maria J
Published: August 2022

Motivation

Experimental testing and manual curation are the most precise ways for assigning Gene Ontology (GO) terms describing protein functions. However, they are expensive, time-consuming and cannot cope with the exponential growth of data generated by high-throughput sequencing methods. Hence, researchers need reliable computational systems to help fill the gap with automatic function prediction. The results of the last Critical Assessment of Function Annotation challenge revealed that GO-terms prediction remains a very challenging task. Recent developments on deep learning are significantly breaking out the frontiers leading to new knowledge in protein research thanks to the integration of data from multiple sources. However, deep models hitherto developed for functional prediction are mainly focused on sequence data and have not achieved breakthrough performances yet.

Results

We propose DeeProtGO, a novel deep-learning model for predicting GO annotations by integrating protein knowledge. DeeProtGO was trained for solving 18 different prediction problems, defined by the three GO sub-ontologies, the type of proteins, and the taxonomic kingdom. Our experiments reported higher prediction quality when more protein knowledge is integrated. We also benchmarked DeeProtGO against state-of-the-art methods on public datasets, and showed it can effectively improve the prediction of GO annotations.

Availability and implementation

DeeProtGO and a case of use are available at https://github.com/gamerino/DeeProtGO.

Supplementary information

Supplementary data are available at Bioinformatics online.
MICER: a pre-trained encoder–decoder architecture for molecular image captioning
Authors: Yi Jiacai , Wu Chengkun , Zhang Xiaochen , Xiao Xinyi , Qiu Yanlong , Zhao Wentao , Hou Tingjun , Cao Dongsheng
Published: August 2022

Motivation

Automatic recognition of chemical structures from molecular images provides an important avenue for the rediscovery of chemicals. Traditional rule-based approaches that rely on expert knowledge and fail to consider all the stylistic variations of molecular images usually suffer from cumbersome recognition processes and low generalization ability. Deep learning-based methods that integrate different image styles and automatically learn valuable features are flexible, but currently under-researched and have limitations, and are therefore not fully exploited.

Results

MICER, an encoder–decoder-based, reconstructed architecture for molecular image captioning, combines transfer learning, attention mechanisms and several strategies to strengthen effectiveness and plasticity in different datasets. The effects of stereochemical information, molecular complexity, data volume and pre-trained encoders on MICER performance were evaluated. Experimental results show that the intrinsic features of the molecular images and the sub-model match have a significant impact on the performance of this task. These findings inspire us to design the training dataset and the encoder for the final validation model, and the experimental results suggest that the MICER model consistently outperforms the state-of-the-art methods on four datasets. MICER was more reliable and scalable due to its interpretability and transfer capacity and provides a practical framework for developing comprehensive and accurate automated molecular structure identification tools to explore unknown chemical space.

Availability and implementation

https://github.com/Jiacai-Yi/MICER.

Supplementary information

Supplementary data are available at Bioinformatics online.
‘It just fundamentally reflects the best of social work’: Social Worker’s Practice Understandings and Experience of the Best Interests Assessor role
Authors: Buckton Wayne
Published: August 2022

This article explores narratives of professional social workers tasked with undertaking the formal para-legal role of Best Interests Assessor under the Deprivation of Liberty Safeguards (DoLS) scheme. Wholesale reform of this practice has been debated in recent years and legislative changes have passed through Parliament—the Liberty Protection Safeguards (LPS). The process and debate preceding this change were, however, marked by a relative marginalisation of accounts and critical opinions of Best Interests Assessors (BIAs) themselves. Semi-structured interviews were conducted with a sample group of BIAs from a variety of social work teams within a single Local Authority. These accounts are explored using a thematic analysis underpinned by Ritzer’s McDonaldization theory and Sayer’s work on Contributive Justice. The work considers the professional identities of the BIAs within and beyond their employing organisation in association with social justice and human rights. Barriers and supports to practice are considered in relation to the organisational, technological and legal contexts of assessment work under the DoLS. The study holds relevance for social workers and organisations in contemplating the transition to LPS and workforce conversions to the Approved Mental Capacity Professional.
Transthyretin cardiac amyloidosis
Authors: Porcari Aldostefano , Fontana Marianna , Gillmore Julian D
Published: August 2022

Transthyretin cardiac amyloidosis (ATTR-CA) is an increasingly recognized cause of heart failure (HF) and mortality worldwide. Advances in non-invasive diagnosis, coupled with the development of effective treatments, have shifted ATTR-CA from a rare and untreatable disease to a relatively prevalent condition that clinicians should consider on a daily basis. Amyloid fibril formation results from age-related failure of homoeostatic mechanisms in wild-type ATTR (ATTRwt) amyloidosis (non-hereditary form) or destabilizing mutations in variant ATTR (ATTRv) amyloidosis (hereditary form). Longitudinal large-scale studies in the United States suggest an incidence of cardiac amyloidosis in the contemporary era of 17 per 100 000, which has increased from a previous estimate of 0.5 per 100 000, which was almost certainly due to misdiagnosis and underestimated. The presence and degree of cardiac involvement is the leading cause of mortality both in ATTRwt and ATTRv amyloidosis, and can be identified in up to 15% of patients hospitalized for HF with preserved ejection fraction. Associated features, such as carpal tunnel syndrome, can preceed by several years the development of symptomatic HF and may serve as early disease markers. Echocardiography and cardiac magnetic resonance raise suspicion of disease and might offer markers of treatment response at a myocardial level, such as extracellular volume quantification. Radionuclide scintigraphy with ‘bone’ tracers coupled with biochemical tests may differentiate ATTR from light chain amyloidosis. Therapies able to slow or halt ATTR-CA progression and increase survival are now available. In this evolving scenario, early disease recognition is paramount to derive the greatest benefit from treatment.
Worsening cardiac tamponade after pericardiocentesis in a patient with anterior mediastinum mass: a case report
Authors: Adi Osman , Fong Chan Pei , Ahmad Azma Haryaty , Panebianco Nova
Published: August 2022

Background

Mediastinal mass is an entity with variable pathology and clinical spectrum. Anterior mediastinal mass can result in severe symptoms due to involvement of surrounding vital structures such as the great vessels, trachea-bronchial tree, and heart. We highlight a case of cardiac tamponade in a patient with an anterior mediastinal mass that was paradoxically worsened after decompressive pericardiocentesis.

Case summary

A 21-year-old male presented to the emergency department (ED) with breathlessness and hypotension. Bedside focused cardiac ultrasound revealed cardiac tamponade which was made worse with an anterior mediastinal mass compressing the right heart chambers. The patient was intubated for respiratory failure, following which an ultrasound-guided pericardiocentesis was performed. Unexpectedly, his hemodynamic status worsened after aspiration of 1000 mL of pericardial fluid. A repeat focused cardiac ultrasound showed reduced pericardial effusion, but worsening of right heart chambers compression by the mediastinal mass. Re-expansion of the pericardium space with 600 mL of normal saline improved the patient’s vital signs, and reduced the right heart compression. Computed tomography was deferred due to the patient’s hemodynamic instability. Despite resuscitation with fluids and initiation of vasopressor, the patient’s condition deteriorated. He succumbed to his illness due to obstructive shock causing multi-organ failure. The autopsy showed a large anterior mediastinal mass, and histopathological examination confirmed the diagnosis of lymphoma.

Discussion

This case demonstrated the therapeutic challenges of managing a shock patient with anterior mediastinal mass, and massive pericardial effusion causing cardiac tamponade.
Cardiac remodelling in the highest city in the world: effects of altitude and chronic mountain sickness
Authors: Doutreleau Stéphane , Ulliel-Roche Mathilde , Hancco Ivan , Bailly Sébastien , Oberholzer Laura , Robach Paul , Brugniaux Julien V , Pichon Aurélien , Stauffer Emeric , Perger Elisa , Parati Gianfranco , Verges Samuel
Published: August 2022

Aims

A unique Andean population lives in the highest city of the world (La Rinconada, 5100 m, Peru) and frequently develops a maladaptive syndrome, termed chronic mountain sickness (CMS). Both extreme altitude and CMS are a challenge for the cardiovascular system. This study aims to evaluate cardiac remodelling and pulmonary circulation at rest and during exercise in healthy and CMS highlanders.

Methods and results

Highlanders living permanently at 3800 m (n = 23) and 5100 m (n = 55) with (n = 38) or without CMS (n = 17) were compared with 18 healthy lowlanders. Rest and exercise echocardiography were performed to describe cardiac remodelling, pulmonary artery pressure (PAP), and pulmonary vascular resistance (PVR). Total blood volume (BV) and haemoglobin mass were determined in all people. With the increase in the altitude of residency, the right heart dilated with an impairment in right ventricle systolic function, while the left heart exhibited a progressive concentric remodelling with Grade I diastolic dysfunction but without systolic dysfunction. Those modifications were greater in moderate–severe CMS patients. The mean PAP was higher both at rest and during exercise in healthy highlanders at 5100 m. The moderate–severe CMS subjects had a higher PVR at rest and a larger increase in PAP during exercise. The right heart remodelling was correlated with PAP, total BV, and SpO2.

Conclusion

Healthy dwellers at 5100 m exhibit both right heart dilatation and left ventricle concentric remodelling with diastolic dysfunction. Those modifications are even more pronounced in moderate–severe CMS subjects and could represent the limit of the heart's adaptability before progression to heart failure.
Bordetella pertussis outer membrane vesicles as virulence factor vehicles that influence bacterial interaction with macrophages
Authors: Blancá Bruno , Alvarez Hayes Jimena , Surmann Kristin , Hugo Valdez , Hentschker Christian , Lamberti Yanina , Völker Uwe , Rodriguez María Eugenia
Published: August 2022

Gram-negative pathogenic bacteria constitutively shed outer membrane vesicles (OMVs) which play a significant role in the host–pathogen interaction, eventually determining the outcome of the infection. We previously found that Bordetella pertussis, the etiological agent of whooping cough, survives the innate interaction with human macrophages remaining alive inside these immune cells. Adenylate cyclase (CyaA), one of the main toxins of this pathogen, was found involved in the modulation of the macrophage defense response, eventually promoting bacterial survival within the cells. We here investigated whether B. pertussis OMVs, loaded with most of the bacterial toxins and CyaA among them, modulate the macrophage response to the bacterial infection. We observed that the pre-incubation of macrophages with OMVs led to a decreased macrophage defense response to the encounter with the bacteria, in a CyaA dependent way. Our results suggest that CyaA delivered by B. pertussis OMVs dampens macrophages protective function by decreasing phagocytosis and the bactericidal capability of these host cells. By increasing the chances of bacterial survival to the innate encounter with the macrophages, B. pertussis OMVs might play a relevant role in the course of infection, promoting bacterial persistence within the host and eventually, shaping the whole infection process.
Risks of Melanoma and Nonmelanoma Skin Cancers Pre– and Post–Inflammatory Bowel Disease Diagnosis
Authors: Narous Mariam , Nugent Zoann , Singh Harminder , Bernstein Charles N
Published: August 2022

Background

We compared risks of nonmelanoma skin cancers (NMSCs) and melanoma preceding and following a diagnosis of inflammatory bowel disease (IBD) and to evaluate the effect of thiopurines and anti-tumor necrosis factor α (anti-TNF-α) on skin cancer risk in IBD.

Methods

This was a retrospective, historical cohort study using the population-based University of Manitoba IBD Epidemiology Database (11 228 IBD cases and 104 725 matched controls) linked to the Manitoba Cancer Registry. Logistic and Cox regression analyses were performed to calculate skin cancer risks prior to and after IBD diagnosis.

Results

Persons with ulcerative colitis (UC) were more likely to have basal cell carcinoma (BCC) predating their UC diagnosis (odds ratio, 1.32; 95% confidence interval [CI], 1.08-1.60). Risks of squamous cell carcinoma (SCC), other NMSCs, or melanoma prior to IBD diagnosis were not significantly increased. Post-IBD diagnosis, risks of BCC (hazard ratio, 1.53; 95% CI, 1.37-1.70) and SCC (hazard ratio, 1.61; 95% CI, 1.29-2.01) were significantly increased across all IBD groups except for SCC in UC. There was no significant association between melanoma and IBD post–IBD diagnosis. The risks of BCC and melanoma were increased in thiopurine and anti-TNF users, and risk of SCC was increased in only thiopurine users. Nested cohort analysis of persons with IBD with censoring at both thiopurines and anti-TNF use confirmed a higher baseline risk of BCC and no effect on SCC, comparable to pre-IBD diagnosis findings.

Conclusions

The risk of BCC preceding a diagnosis of UC is higher than in non-UC controls, compared with a generally increased risk of all NMSCs post–IBD diagnosis. Thiopurine and anti-TNF therapy increase the risks for skin cancers in persons with IBD after their diagnoses.
Utilization of Community Science Data to Explore Habitat Suitability of Basal Termite Genera
Authors: Goodman Aaron , Allen Jonah , Brim Jinna , Codella Alessa , Hahn Brittney , Jojo Hassan , BondocGawa Mafla-Mills Zoila , Bondoc Mafla Salka’Tuwa , Oduro Agnes , Wilson Megan , Ware Jessica
Published: August 2022

The advent of community-science databases in conjunction with museum specimen locality information has exponentially increased the power and accuracy of ecological niche modeling (ENM). Increased occurrence data has provided colossal potential to understand the distributions of lesser known or endangered species, including arthropods. Although niche modeling of termites has been conducted in the context of invasive and pest species, few studies have been performed to understand the distribution of basal termite genera. Using specimen records from the American Museum of Natural History (AMNH) as well as locality databases, we generated ecological niche models for 12 basal termite species belonging to six genera and three families. We extracted environmental data from the Worldclim 19 bioclimatic dataset v2, along with SoilGrids datasets and generated models using MaxEnt. We chose Optimal models based on partial Receiving Operating characteristic (pROC) and omission rate criterion and determined variable importance using permutation analysis. We also calculated response curves to understand changes in suitability with changes in environmental variables. Optimal models for our 12 termite species ranged in complexity, but no discernible pattern was noted among genera, families, or geographic range. Permutation analysis revealed that habitat suitability is affected predominantly by seasonal or monthly temperature and precipitation variation. Our findings not only highlight the efficacy of largely community-science and museum-based datasets, but our models provide a baseline for predictions of future abundance of lesser-known arthropod species in the face of habitat destruction and climate change.
Partition-based 3 + 2-axis tool path generation for freeform surface machining using a non-spherical tool
Authors: Hao Jiancheng , Li Zhaoyu , Li Xiangyu , Xie Fubao , He Dong , Tang Kai
Published: August 2022

When machining a complex freeform part, using a non-spherical tool could significantly improve the machining efficiency, as one can adaptively adjust the tool posture to maximize its contact area with the part surface. However, since adjusting the tool posture requires changing the tool orientation, a five-axis machine tool is needed, which is extremely expensive as compared to a conventional three-axis machine tool. Moreover, for a complex freeform surface with high curvature variation, to match its curvature change, the tool axis has to drastically change accordingly, thus inducing high velocity and acceleration on the machine tool’s rotary axes. To address these issues, in this paper we propose a partition-based 3 + 2-axis strategy for machining a general complex freeform surface with a non-spherical tool. As only a finite small number of distinct tool orientations are needed for 3 + 2-axis machining, an indexed three-axis machine tool suffices, thus relieving the need of an expensive five-axis machine tool. In addition, the much-increased rigidity of the three linear axes of the machine tool will greatly improve the kinematics and dynamics of the machine tool and thus enhance the machining accuracy. Experiments in both computer simulation and physical machining are carried out, whose results confirm that, when compared to using a conventional spherical cutter, by using a non-spherical cutter and adaptively adjusting the contacting tool posture and the feed direction, significant improvement in machining efficiency could be achieved, e.g., more than 50% achieved in our experiments.
β-cell dynamics in type 2 diabetes and in dietary and exercise interventions
Authors: Lv Chengan , Sun Yuchen , Zhang Zhe Yu , Aboelela Zeyad , Qiu Xinyuan , Meng Zhuo-Xian
Published: August 2022

Pancreatic β-cell dysfunction and insulin resistance are two of the major causes of type 2 diabetes (T2D). Recent clinical and experimental studies have suggested that the functional capacity of β-cells, particularly in the first phase of insulin secretion, is a primary contributor to the progression of T2D and its associated complications. Pancreatic β-cells undergo dynamic compensation and decompensation processes during the development of T2D, in which metabolic stresses such as endoplasmic reticulum stress, oxidative stress, and inflammatory signals are key regulators of β-cell dynamics. Dietary and exercise interventions have been shown to be effective approaches for the treatment of obesity and T2D, especially in the early stages. Whilst the targeted tissues and underlying mechanisms of dietary and exercise interventions remain somewhat vague, accumulating evidence has implicated the improvement of β-cell functional capacity. In this review, we summarize recent advances in the understanding of the dynamic adaptations of β-cell function in T2D progression and clarify the effects and mechanisms of dietary and exercise interventions on β-cell dysfunction in T2D. This review provides molecular insights into the therapeutic effects of dietary and exercise interventions on T2D, and more importantly, it paves the way for future research on the related underlying mechanisms for developing precision prevention and treatment of T2D.
The Woman at the Well as a Witness in John Revisited
Authors: Wasserman Tommy
Published: August 2022

There is a major emphasis on testimony and witnesses in the Gospel of John, and scholars have analysed this trait in the context of a literary trial, or a cosmic lawsuit. The Samaritan woman (John 4) who testifies concerning Jesus is an unexpected witness. Could the author expect his contemporary readers to receive her testimony? This article surveys the status of women as witnesses in in the Graeco-Roman world in general and first-century Judaism in particular. There was a strong expectation that women should not testify in law-courts, where they were instead represented by male guardians with few exceptions. An analysis of John 4:4–42 gives further clues for the evaluation of the Samaritan woman as a legal witness. First, she expresses surprise that Jesus talks with her as a Samaritan. Second, the disciples are astonished that Jesus speaks to a woman. Third, the information about her previous marriages would likely further diminish her status as a witness. In conclusion, the presentation of the Samaritan woman as a key witness in John does not reflect the convention of contemporary culture, whether Graeco-Roman or Jewish. On the contrary, in regard to divine law, she is elevated to a status equal to male witnesses. A two-level reading of the Fourth Gospel further suggests that this feature reflects a different attitude toward women in early Christianity, if not a particular community connected with the Johannine writings.
National identity and anti-immigrant sentiment: Experimental evidence from Mexico
Authors: Acevedo Jesse , Meseguer Covadonga
Published: August 2022

In this article, we explore how historical patterns of identity construction shape today’s attitudes towards immigrants in Mexico. Immigrants in Mexico constitute a very small percentage of the country’s population. Yet some immigrants, in particular those of Asian origin, face a strong anti-immigrant sentiment as measured in terms of opinions and opposition to their social and political incorporation. We trace contemporary anti-Chinese sentiment back to historical processes of Mexican colonisation, which resulted in a particular politics of Chinese incorporation at the turn of the 19th century. This incorporation was violently contested during and after the revolution, leading to a construction of a national identity based on openly excluding the Chinese community. Using experimental evidence, we show that anti-Asian prejudice today is well explained by looking at ethnic traits and civic norms that are endorsed by natives as being constitutive of Mexican national identity.
Revisiting the evidences for spectral anomalies in distant blazars: New data on the photon-ALP mixing
Authors: Cenedese Francesco , Franceschini Alberto , Galanti Giorgio
Published: August 2022

We re-examine possible dependencies on redshift of the spectral parameters of blazars observed at very-high energies (VHEs) with Imaging Atmospheric Cherenkov telescopes. This is relevant to assess potential effects with the source distance of the photon to axion-like particle mixing that would deeply affect the propagation of VHE photons across the Universe. We focus our spectral analysis on 38 BL Lac objects (32 high-peaked and 6 intermediate-peaked) up to redshift z ≃ 0.5, and a small sample of 5 Flat Spectrum Radio Quasars up to z = 1 treated independently to increase the redshift baseline. The 78 independent spectra of these sources are first of all carefully corrected for the gamma–gamma interaction with photons of the Extragalactic Background Light that are responsible for the major redshift-dependent opacity effect. Then, the corrected spectra are fitted with simple power laws to infer the intrinsic spectral indices Γem at VHE, to test the assumption that such spectral properties are set by the local rather than the global cosmological environment. We find some systematic anticorrelations with redshift of Γem that might indicate, although with low-significance, a spectral anomaly potentially requiring a revision of the photon propagation process. More conclusive tests with higher statistical significance will require the observational improvements offered by the forthcoming new generation of Cherenkov arrays (CTA, ASTRI, LHAASO).
Understanding the spatial variation of Mg ii and ionizing photon escape in a local LyC leaker
Authors: Seive Thomas , Chisholm John , Leclercq Floriane , Zeimann Gregory
Published: August 2022

Ionizing photons must have escaped from high-redshift galaxies, but the neutral high-redshift intergalactic medium makes it unlikely to directly detect these photons during the Epoch of Reionization. Indirect methods of studying ionizing photon escape fractions present a way to infer how the first galaxies may have reionized the Universe. Here, we use HET/LRS2 observations of J0919 + 4906, a confirmed z≈ 0.4 emitter of ionizing photons to achieve spatially resolved (12.5 kpc in diameter) spectroscopy of Mg iiλ2796, Mg iiλ2803, [O ii]λλ3727, 3729, [Ne iii]λ3869, H γ, [O iiI]λ4363, H β, [O iii]λ4959, [O iii]λ5007, and H α. From these data, we measure Mg ii emission, which is a promising indirect tracer of ionizing photons, along with nebular ionization and dust attenuation in multiple spatially resolved apertures. We find that J0919 + 4906 has significant spatial variation in its Mg ii escape and thus ionizing photon escape fraction. Combining our observations with photoionization models, we find that the regions with the largest relative Mg ii emission and Mg ii escape fractions have the highest ionization and lowest dust attenuation. Some regions have an escape fraction that matches that required by models to reionize the early Universe, while other regions do not. We observe a factor of 36 spatial variation in the inferred LyC escape fraction, which is similar to recently observed statistical samples of indirect tracers of ionizing photon escape fractions. These observations suggest that spatial variations in neutral gas properties lead to large variations in the measured LyC escape fractions. Our results suggest that single sightline observations may not trace the volume-averaged escape fraction of ionizing photons.
The feasibility of constraining DM interactions with high-redshift observations by JWST
Authors: Kurmus Ali , Bose Sownak , Lovell Mark , Cyr-Racine Francis-Yan , Vogelsberger Mark , Pfrommer Christoph , Zavala Jesús
Published: August 2022

Observations of the high redshift universe provide a promising avenue for constraining the nature of the dark matter (DM). This will be even more true with the advent of the James Webb Space Telescope (JWST). We run cosmological simulations of galaxy formation as part of the Effective Theory of Structure Formation (ETHOS) project to compare high redshift galaxies in cold dark matter (CDM) and alternative DM models which have varying relativistic coupling and self-interaction strengths. The interacting DM scenarios produce a cutoff in the linear power spectrum on small-scales, followed by a series of ‘dark acoustic oscillations’. We find that DM interactions suppress the abundance of galaxies below $M_\star \sim 10^8\, {\rm M}_\odot$ for the models considered. The cutoff in the power spectrum delays structure formation relative to CDM. Objects in ETHOS that end up at the same final masses as their CDM counterparts are characterized by a more vigorous phase of early star formation. While galaxies with $M_\star \lesssim 10^6\, {\rm M_\odot }$ make up more than 60 per cent of star formation in CDM at z ≈ 10, they contribute only about half the star formation density in ETHOS. These differences diminish with decreasing redshift. We find that the effects of DM self-interactions are negligible compared to effects of relativistic coupling (i.e. the effective initial conditions for galaxy formation) in all properties of the galaxy population we examine. Finally, we show that the clustering strength of galaxies at high redshifts depends sensitively on DM physics, although these differences are manifest on scales that may be too small to be measurable by JWST.
BSCI-02 CSF PROTEOMICS AS A MINIMALLY-INVASIVE STRATEGY FOR DISTINGUISHING BRAIN METASTASES FROM OTHER PRIMARY BRAIN MALIGNANCIES
Authors: Mansouri Alireza , Mikolajewicz Nicholas , Khan Shahbaz , Glantz Michael , Moffat Jason , Zadeh Gelareh , Kislinger Thomas
Published: August 2022

BACKGROUND

Accurate diagnosis and prognostication of intra-axial brain tumors hinges on invasive brain sampling, which carries risk of morbidity. Minimally invasive sampling of proximal fluids, also known as liquid biopsy, can mitigate this risk. Although the cerebrospinal fluid (CSF) is the ideal liquid biopsy source, the traditionally high volumes required for impactful analyses have deterred progress. The objective of this study was to identify diagnostic and prognostic CSF proteomic signatures in glioblastoma (GBM), brain metastases (BM), and central nervous system lymphoma (CNSL).

METHODS

CSF samples were retrospectively retrieved from the Penn State Neuroscience Biorepository and profiled using shotgun proteomics with low sample volumes. Proteomic signatures were identified using machine learning classifiers and survival analyses.

RESULTS

Using 30µL CSF volumes, we recovered 800 unique peptides across 73 samples [20 normal pressure hydrocephalus (NPH, non-tumor control), 22 GBM, 17 BM, and 14 CNSL]. Externally-validated proteomic-based classifiers identified malignancy with AUROC of 0.94 and distinguished individual tumor entities from others with AUROC ≥0.96. More clinically relevant triplex classifiers, comprised of just 3 peptides, distinguished individual tumor entities with AUROC ≥0.90. Novel biomarkers were identified among the top classifiers, including TFF3 and CACNA2D2, and characterized using single-cell RNA sequencing data. Survival analyses validated previously implicated prognostic signatures, including blood brain barrier disruption.

DISCUSSION

Reliable classification of intra-axial malignancies using low CSF volumes is feasible, which has ramifications for longitudinal tumor surveillance. Novel biomarkers identified here necessitate future validation. Based on emerging evidence, upfront implantation of CSF reservoirs in brain tumor patients warrants consideration.
BSCI-03 THE ROLE OF LONP1 IN DRIVING ENHANCED PMT IN THE ‘LEADING EDGE’ NICHE IN GLIOBLASTOMA
Authors: Douglas Christopher , Lomeli Naomi , Bota Daniela
Published: August 2022

Glioblastoma (GBM), a high grade brain tumor, possesses poor overall survival with less than 5% surviving past five years. Previously, the TCGA classifications for GBM have included the mesenchymal, proneural, classical and neural subtypes with their own respective expression profiles and survival. Recent omics analysis has revealed other key aspects of GBM pathology, including intratumoral heterogeneity spanning all subtypes and enhanced stemness and treatment resistance and other hallmarks of proneural mesenchymal transition (PMT) following treatment with first-line standard of care treatment with radiation therapy and temozolomide (TMZ). Invading glioma stem cells (GSC) with high Nestin and hypoxia-inducible factor 1 alpha (HIF-1α) expression have been theorized to contribute to recurrence. HIF-1α acts as a master regulator driving increased stemness, invasiveness and angiogenesis. Interestingly, HIF-1α and nuclear respiratory factor-2 both upregulate Lon peptidase 1 (LonP1) in response to increased hypoxia or reactive oxygen species (ROS) production. LonP1 has been shown to drive increased metastasis, tumor growth and epithelial-mesenchymal transition (EMT), an analog of PMT, in colon cancer, melanoma and other cancer types. In a recently elucidated GBM organoid model, we present new findings demonstrating the importance of LonP1 in driving enhanced, transient PMT near the ‘invading edge’. This includes the enhanced expression of several key drivers of PMT and phenotypic hallmarks, such as increased invasiveness, proliferation and poorer survival.
BSCI-05 REPURPOSING PROPOFOL FOR THE TREATMENT OF BRAIN METASTASES
Authors: Penning Donald , Cazacu Simona , Nizar Raphael , Goldstein Hodaya , Kazimirsky Gila , Brown Stephen , Rogers Lisa , Brodie Chaya
Published: August 2022

BACKGROUND

Recent clinical studies suggest beneficial effects of propofol anesthesia on tumor progression and patient survival in solid tumors but reported benefits are modest. One potential reason is the relatively short, single exposure to propofol, limited to the surgical period. Brain metastases (BM) are the most common brain tumors in adults. Metastatic tumors develop following infiltration of the brain from primary tumors such as lung, breast, melanoma, and colorectal cancers. BM are treated with combination therapies, including surgery, radiotherapy, chemotherapy, and immunotherapy, however the prognosis of most patients with BM remains dismal. In this report we investigated the effects of propofol plus radiation on cancer stem cells derived from human lung cancer brain metastases (BM-CSCs) and their cross-talk with microglia.

OBJECTIVES

Our hypothesis is that propofol can be repurposed as a treatment of BM in addition to its anesthetic uses. To test this, we first examined the cytotoxic effects of propofol on cancer stem cells established from BM-CSCs alone and with radiation. Also, we studied the effects of propofol on the cross-talk of BM-CSCs and microglia.

RESULTS

We found that propofol 1) exerted inhibitory effect on BM-CSCs self-renewal, stemness and cell proliferation; 2) increased cell death of cancer cells but not normal neural elements; 3) sensitized BM-CSCs to radiation; 4) inhibited the pro-tumorigenic BM-CSCs/ microglia cross-talk by promoting M1 phenotypes of co-cultured microglia.

CONCLUSIONS

Propofol exerted anti-tumor effects on BM-CSCs including inhibition of cell renewal, proliferation, and mesenchymal transition. Propofol at sensitized BM-GSCs to radiation and at higher concentrations induced cell death. Propofol exerted anti-tumor cytotoxicity also by inhibiting the pro-tumorigenic CSC-microglia cross-talk via secreted extracellular vesicles (EVs). Propofol effects can be exploited as a general anesthetic of choice during tumor resection and should be examined as an anti-tumor agent in sub-anesthetic doses either alone or in combination with radiation.
BSCI-13 DEVELOPMENT OF NOVEL ANTI-BRAIN METASTASIS INHIBITORS
Authors: Kieliszek Agata , Mobilio Daniel , Bassey-Archibong Blessing , Johnson Jarrod , McKenna Dillon , Venugopal Chitra , Magolan Jakob , Singh Sheila
Published: August 2022

The current standard of care (surgery and radiation) for brain metastases (BM) is inadequate as BM have a 90% mortality rate within one year of diagnosis, posing a large unmet clinical need. The Singh lab has generated a large in-house biobank of patient-derived BM cell lines that are established from BM patient tumor samples. We use these BM cell lines to generate murine orthotopic xenograft models of BM and interrogate the biological processes that lead to BM. These models have successfully recapitulated all the stages of their respective BM cascades and additionally captured a “pre-metastatic” population of BM cells that have just seeded the brains of mice before forming mature, clinically detectable tumors. Pre-metastatic cell populations are impossible to detect in human patients but represent a therapeutic window wherein metastasizing cells can be targeted and eradicated before establishing clinically detectable and difficult to treat brain tumors. RNA sequencing of pre-metastatic BM cells revealed a unique deregulated transcriptomic profile that is specific to pre-metastatic cells despite the tumor of origin. Connectivity Map analysis was applied to the gene expression signatures of pre-metastatic BM cells to identity a compound (Drug A) which selectively inhibits BM cell proliferation but is not blood-brain barrier (BBB) penetrant and has not been previously considered in the context of brain metastasis. We synthesized a BBB-penetrant analogue of Drug A and found, using our patient-derived xenograft (PDX) models, that it increased survival benefit relative to both placebo and Drug A. Beginning with this promising scaffold, we will conduct structure-activity hypothesis-driven medicinal chemistry campaigns to optimize this scaffold for brain permeation while maintaining selective anti-BM activity. Development of novel small molecules that target pre-metastatic BM cells could slow or prevent the formation of BM and dramatically improve the prognosis of at-risk cancer patients.
BSCI-14 THE ROLE OF ICAM1 IN GLIOBLASTOMA TUMOUR ASSOCIATED MACROPHAGES UNDER HYPOXIC CONDITIONS
Authors: Devaraja Kaviya , Mansouri Sheila , Zadeh Gelareh
Published: August 2022

BACKGROUND

Glioblastoma (GBM) is an aggressive and highly fatal brain cancer in adults. Existing treatment methods are ineffective and we are in need of new treatments that extend the overall survival and improve quality-of-life. Cell adhesion molecules (CAMs) are proteins that enable cells to communicate with one another and the surrounding environment. Intracellular adhesion molecule 1 (ICAM1) is a CAM expressed by TAMs in GBM. Tumour associated macrophages (TAMs) are thought to enhance tumour growth and proliferation, particularly within the characteristic hypoxic tumour microenvironment (TME) of GBM. I hypothesize that the expression of ICAM1 on the surface of TAMs contributes to GBM cell invasiveness, especially in the hypoxic TME, by enhancing the interaction between tumour cells and macrophages, thereby facilitating the migration and invasion of the tumour cells.

METHODOLOGY

Assess the expression levels of ICAM1 in primary and immortalized human and mouse macrophages under hypoxic conditions. Analyze the effect of ICAM1 deficiency on macrophage behaviour including migration, proliferation, and adhesion to tumour cells. Intracranially inject GL261 glioma cells in ICAM1 deficient and wild type mice.

RESULTS

ICAM1 is highly expressed in different cell types within the GBM microenvironment, including TAMs. The expression is particularly enhanced when primary or immortalized macrophages are treated with tumour cell-conditioned medium and is further exacerbated upon incubation of these cells in hypoxic conditions. The migration levels of bone marrow derived macrophage mouse cell type is higher in wild type cells than in ICAM1 deficient cells and higher when co-cultured with tumour cell condition media. ICAM1 deficient mice succumbed to GBM more quickly compared with wild type.

CONCLUSIONS

It is evident that the hypoxic tumour microenvironment increases the expression of ICAM1 in macrophages. The tumour microenvironment increases migration levels of macrophages. The expression of ICAM1 in TAMs in hypoxic TME promotes GBM cell invasiveness, proliferation, aggressiveness and migration.
BSCI-15 INVESTIGATING CD8 T CELL EXHAUSTION STATES WITHIN THE TME AND DRAINING LYMPH NODE OF PRIMARY BRAIN TUMORS AND BRAIN METASTASES
Authors: Waibl Polania Jessica , Hoyt-Miggelbrink Alexandra , Tomaszewski William , Fecci Peter
Published: August 2022

Brain metastases affect nearly 20% of all cancer patients. Likewise, glioblastoma (GBM) is the most common primary brain cancer in adults and remains universally lethal. Current immunotherapeutic efficacy is hindered by immunosuppression present in the brain tumor microenvironment (TME). T-cells, critical for tumor clearance, take on a functionally exhausted phenotype. Importantly, two exhaustion states, progenitor (Tpe) and terminal (Tte), have been identified in models of chronic infection and cancer. This distinction is particularly relevant, as Tpe can remain responsive to immune checkpoint blockade (ICB), while Tte cannot. To date, the dynamics and characteristics of these exhausted populations in primary tumors and brain metastases remain unclear. Using intracranially implanted murine models of GBM (CT2A) and metastatic melanoma (B16F10), Tpe and Tte were identified by flow cytometry as PD1+SLAMF6+ and PD1+TIM3+, respectively. Functional differences between subsets were evaluated via intracellular staining of IFNγ, TNFα, IL2, CD107a, and Ki67. To determine the role of antigen, we performed adoptive lymphocyte transfers of tumor-specific and non-tumor-specific transgenic T-cells into a TRP2 or OVA overexpressing intracranial CT2A or B16 tumor, respectively. Tte displayed higher cytotoxic molecule expression than Tte, consistent with chronic infection models. Key exhaustion-associated transcription factors were identified in exhaustion subsets, including Tox, Tcf7, T-bet, and Eomes. Tox and Tcf7 expression identified Tpe within tumor-draining lymph nodes, suggesting a potential origin outside of the tumor, and the capacity for rescued function. We observed a decline in the Tpe population over time, with an associated rise in Tte within both tumor types. Notably, the ratio of Tpe to Tte was higher at all time points in B16F10 compared to CT2A. Tte appeared only in tumor-specific T-cells of the TME, further confirming the tumor-antigen dependence of T cell exhaustion. Tpe may arise outside the TME in tumor-specific T-cells. Further study may reveal a means and time window for rescuing T-cell function with ICB for brain tumors.
BSCI-17 TOPIRAMATE DECREASES RADIATION-INDUCED CYTOTOXIC EDEMA IN HER2+ BRAIN METASTASES VIA AQUAPORIN 4 INHIBITION
Authors: Contreras-Zárate Maria J , Alvarez-Eraso Karen , Littrell Zachary , Kwak Gina , Ormond Ryan , Karam Sana D , Kabos Peter , Cittelly Diana
Published: August 2022

Brain metastasis (BM) occurs in 30-40 % of breast cancer patients with Her2+ tumors, and radiation is part of the standard treatment for BM. About 10% of BM patients treated with radiation develop brain edema. We have shown that combination of Ado-trastuzumab Emtansine (T-DM1)-the main targeted therapy for metastatic Her2+ Breast Cancer- and radiation increases the risk of developing radionecrosis by 13.5-fold (Stump et al., 2019). We also showed that T-DM1 enhances radiation-induced astrocytic toxicity and cytotoxic edema through upregulation of aquaporin-4 water-transporter (AQP4). Here, we determined whether blockage of AQP4 would prevent astrocytic swelling –cytotoxic edema- in vitro and in vivo models of Her2+ BM. Results: Electron microscopy of brain cortex from mice treated with 35 Gy (single dose), showed acute astrocytic end-feet swelling and a significant increase in AQP4 expression compared with non-irradiated mice. Consistent with prior findings in murine astrocytes, primary human astrocytes (huAST) also upregulated AQP4 levels 24 h post-radiation (8 Gy), and T-DM1 treatment exacerbated this effect. AQP4 upregulation was concomitant with 4.8 fold increase in the astrocytic area (indicative of cytotoxic edema). The FDA-approved anti-epileptic and migraine prevention drug, Topiramate (TPM), which works as an AQP4 inhibitor, blocked radiation-induced astrocytic swelling in huAST in vitro. Thus, we tested whether pre-treatment with TPM could prevent radiation-induced edema in a mouse model of HER2+BMs. Mice were injected intracardially JmT1BR3 brain metastatic cells and ten days later randomized based on the total head flux to (1) Radiation + vehicle, (2) Radiation + TPM (2 days prior to irradiation), (3) Non-Radiation + vehicle, and (4) Non-radiation + TPM. TPM decreased brain-water content (a marker of brain edema) in irradiated mice as compared with vehicle-treated mice, without alteration of metastatic burden 21 days post-injection. These results suggest TPM could be repurposed as a preventive agent of radiation-induced brain edema.
BSCI-18 ESTROGEN-DEPLETION DECREASES PROGRESSION OF ER¯ BRAIN METASTASES BY PROMOTING AN ANTI-TUMORAL LOCAL IMMUNE RESPONSE
Authors: Contreras-Zarate Maria , Alvarez-Eraso Karen , Littrell Zachary , Tsuji Nicole , Karam Sana , Ormond D Ryan , Kabos Peter , Cittelly Diana
Published: August 2022

We have shown that 17-β-Estradiol (E2) promotes brain metastasis (BM) of estrogen receptor negative (ER¯) BC cells by inducing neuroinflammatory ER+ astrocytes in the brain niche to secrete pro-metastatic factors critical for early brain colonization. E2-depletion prevented brain colonization of human xenografts (MDA231BR/NSG) and syngeneic (E0711/C57Bl6, 4T1/Balb-c) ER¯ models. Yet, whether E2-depletion can be used to decrease progression of established BM and how E2-dependent modulation of brain immune response contributes to the pro-metastatic effects of E2 remains unclear. To assess whether E2-depletion could decrease BM progression in a model that mimics standard of care for BM, E0771-GFP-luc cells were injected intracardially in syngeneic ovariectomized (OVX)-female C57Bl6 mice supplemented with E2. Seven days after injection (when micrometastases are established), mice received a single 15Gy dose brain irradiation and were randomized to continue receiving E2, E2 withdrawal (E2WD) or E2WD plus the aromatase-inhibitor letrozole (EWD+LET). Endpoint BM (but not systemic metastases) were significantly decreased in E2WD+Letrozole treated mice as compared to E2-treated mice. This effect was abolished when E0711 cells were injected in severely immunocompromised NSG mice or in the absence of brain irradiation, suggesting EWD+LET decreases BM progression through boosting radiation-induced anti-tumor immunity. Accordingly, there were no differences in BM progression in E2, EWD or E2WD+let treated mice in a xenograft model (F2-7 TNBC cells) in NSG mice, even in the presence of brain irradiation. Brain immune-profiling of brain irradiated E2, EWD and EWD+Let C57BL6 mice carrying E0771 BMs shows that brains of EWD+LET-treated mice had a significantly lower fraction of CD4 T cells and an increase in CD8 T cells, suggesting that EWD+letrozole decrease brain metastatic burden in part through modulation of T cells. These results suggest E2-depletion therapies could be used in combination with brain irradiation to decrease progression of BMs and promote an anti-tumoral immune response.
BSCI-21 COX4I1 EXPRESSION IN BRAIN METASTASES
Authors: Saad Mahak , Jones Karra , Loeffler Bradley , Mott Sarah , Griguer Corinne , Monga Varun
Published: August 2022

BACKGROUND

COX4I1 (Cytochrome C oxidase, subunit 4, isoform 1) is a mitochondrial enzyme involved in the process of switching from glycolysis to oxidative phosphorylation. A previously published prospective biomarker study in glioblastoma cells found that Cytochrome C oxidase (CcO) activity was associated with resistance to treatment with both radiation and temozolomide (TMZ). The current study was designed to retrospectively assess COX4I1 expression in brain metastases from various primary cancers.

METHODS

This single-institution, blinded, retrospective biomarker study evaluated 24 patients with paired brain metastases and primary cancers including lung cancer, malignant melanoma, breast cancer, colorectal cancer, renal cell carcinoma, and urothelial carcinoma. COX4I1 immunohistochemical expression in primary and metastatic samples was assessed using the H-score method. A paired t-test was used to assess the difference in total H-score between primary and brain metastasis tissue samples. Cox regression was used to assess the association between COX4I1 expression and overall survival (OS). For OS, time was calculated from metastatic tissue sample retrieval to death due to any cause.

RESULTS

Brain metastasis tissue samples were found to have a significantly lower total H-score, on average, when compared to primary cancer tissue samples (p=0.01, mean difference of -33.3). 83.3% of tissue samples from metastases were not radiated. 58.3% of patients were on systemic treatment 6 months prior to tumor resection of brain metastases. COX4I1 expression was not associated with overall survival.

CONCLUSIONS

There is significantly increased COX4I1 expression in primary cancers as compared to brain metastases. Anti-cytochrome C oxidase therapies may be beneficial for treatment of primary tumors. No patient or treatment variables were significantly associated with overall survival in paired patients.

KEYWORDS

COX4I1, cytochrome c oxidase, brain metastases