bluuebunny/crossref_metadata_2025_split huggingface dataset:
OTME-7. Cancer - immune cell interactions drive transitions to mesenchymal-like state in glioblastoma
Authors: Hara Toshiro , Chanoch-Myers Rony , Mathewson Nathan , Myskiw Chad , Atta Lyla , Bussema Lillian , Eichhorn Stephen , Kinker Gabriela , Rodman Christopher , Gonzalez Nicolas , Wakimoto Hiroaki , Rozenblatt-Rosen Orit , Zhuang Xiaowei , Fan Jean , Hunter Tony , Verma Inder , Wucherpfennig Kai , Regev Aviv , Suvà Mario , Tirosh Itay 
Published: July 2021

Abstract
Communication between cancer cells and immune cells is a key determinant of the glioblastoma ecosystem and its response to therapies, but remains poorly understood. Here we leveraged single-cell RNA-sequencing (scRNA-seq) of human samples and mouse models, deconvolution analysis of bulk specimen from The Cancer Genome Atlas (TCGA) and functional approaches, to dissect cellular cross-talks in glioblastoma. We demonstrate that macrophages induce a transition of glioblastoma cells into mesenchymal-like (MES-like) states. This effect is mediated, both in vitro and in vivo, by macrophage-derived Oncostatin M (OSM) and its cognate receptor OSMR on glioblastoma cells. We show that MES-like glioblastoma states are also associated with increased expression of a mesenchymal program in macrophages and with increased cytotoxicity of T cells, highlighting extensive alterations of the immune microenvironment with potential therapeutic implications.
OTME-13. Integration of metabolic and transcriptional signatures of glioblastoma invasion reveals extracellular matrix reorganization and vasculature remodeling
Authors: Cudalbu Cristina , Bady Pierre , Lai Marta , Xin Lijing , Gusyatiner Olga , Hamou Marie-France , Lepore Mario , Brouland Jean-Philippe , Daniel Roy , Hottinger Andreas , Hegi Monika 
Published: July 2021

Abstract

Background
The invasive behavior of glioblastoma is considered highly relevant for recurrence. However, the invasion zone is difficult to visualize, typically lies outside the resected and irradiated area, and is protected by the blood brain barrier, posing a particular challenge for treatment. We present biological features of invasive growth accompanying tumor progression and invasion based on associated metabolic and transcriptomic changes in patient derived orthotopic xenografts (PDOX) and corresponding patients.

Methods
Patients with suspected glioblastoma were enrolled (NCT02904525) and underwent 1H-MR spectroscopy and imaging (1H-MRS/I, 7T). Tissue obtained at surgery was transplanted orthotopically into immune-compromised mice. Longitudinal follow-up was performed by 1H-MRS/I (14.1T) on the injected and the contralateral side. The PDOX, the corresponding contralateral side, and the original human tumors underwent RNA-sequencing.

Results
The temporal changes of the metabolite profiles characterized the kinetics of invasive growth of PDOX, and were patient specific. Comparison of 1H-MRS derived metabolite signatures, reflecting temporal changes of tumor development and invasion in PDOX, revealed high similarity to spatial metabolite signatures of combined multi-voxel analyses of the patients’ tumors. Associations between the metabolite profiles and the combined transcriptome of the xenografts and the host, reflected molecular signatures of invasion, comprising extracellular matrix degradation and reorganization, growth factor binding, and vascular remodeling.

Conclusion
Integrating metabolic profiles and gene expression of highly invasive PDOX allows in vivo monitoring of progression in the non-enhancing tumor infiltration zone and provides insights into the remodeling of the extracellular matrix that is essential for cell-cell communication and regulation of cellular processes. The changes of the structural and biochemical properties of the extracellular matrix are of importance for the biological behavior of the tumors and may be subjected to therapeutic targeting.
OTME-14. TGF-beta signaling in microtube formation of glioblastoma
Authors: Storevik Simon , Joseph Justin , Magaut Capucine , Henrique Luiz , Mathivet Thomas , Latif Md Abdul , Rudewicz Justine , Guyon Joris , Gambaretti Matteo , Haukås Frida , Trones Amalie , Ystaas Lars Andreas Rømo , Hossain Jubayer , Ninzima Sandra , Zhou Wenjing , Tomar Tushar , Winkler Frank , Kruyt Frank , Bikfalvi Andreas , Bjerkvig Rolf , Daubon Thomas , Miletic Hrvoje 
Published: July 2021

Abstract
Microtubes (MTs) are cytoplasmic extensions of glioma cells serving as important cell communication structures while also promoting invasion and treatment resistance through network formation. MTs are abundant in chemoresistant gliomas, in particular glioblastomas, while they are uncommon in chemosensitive IDH mutated and 1p/19q co-deleted oligodendrogliomas.
By performing a bioinformatics analysis on data from The Cancer Genome Atlas (TCGA) we identified the TGF-b pathway as being distinctly upregulated in glioblastomas compared to oligodendrogliomas, making this a signaling pathway potentially involved in MT formation. Based on patient-derived GBM stem cell line models we demonstrated that stimulation of TGF-b increased MT formation, while inhibition of TGF-b reduced MT formation. MT formation was verified by expression of GAP43 and nestin, which have previously been shown to be important structural proteins of MTs.
Interestingly, we also observed a responder/non-responder relationship between GBM cell lines P3 and GG16/ GG6 regarding MT formation upon TGF-b stimulation. To determine downstream signaling mediators of the TGF-b pathway crucial for MT formation, we subsequently performed RNA sequencing of these cell lines. From the 34 initial candidates common to responders, but absent in non-responders, only 3 genes were left after filtering through TCGA data and in vivo RNA sequencing data of a GBM xenograft model derived from P3.
Thrombospondin 1 (TSP1) emerged as the most interesting candidate as we have previously shown that transcription of this gene is activated by TGF-b/SMAD signaling and TSP1 also promotes invasiveness of GBM. TSP1 was upregulated by TGFB1 stimulation in responder cells and promoted MT formation. Transcriptional activation of TSP1 was absent in the non-responder cell line GG6 and could be reversed in the responder cell line P3 by TSP1 shRNAs in vitro and in vivo. Thus, TSP1 was experimentally verified as an important mediator of microtube formation downstream of TGF-b signaling.
Transcriptome Dynamics of Epidermal Reprogramming during Direct Shoot Regeneration inTorenia fournieri
Authors: Morinaka Hatsune , Mamiya Akihito , Tamaki Hiroaki , Iwamoto Akitoshi , Suzuki Takamasa , Kawamura Ayako , Ikeuchi Momoko , Iwase Akira , Higashiyama Tetsuya , Sugimoto Keiko , Sugiyama Munetaka 
Published: July 2021

abstractShoot regeneration involves reprogramming of somatic cells and de novo organization of shoot apical meristems (SAMs). In the best-studied model system of shoot regeneration using Arabidopsis, regeneration is mediated by the auxin-responsive pluripotent callus formation from pericycle or pericycle-like tissues according to the lateral root development pathway. In contrast, shoot regeneration can be induced directly from fully differentiated epidermal cells of stem explants of Torenia fournieri (Torenia), without intervening the callus mass formation in culture with cytokinin; yet, its molecular mechanisms remain unaddressed. Here, we characterized this direct shoot regeneration by cytological observation and transcriptome analyses. The results showed that the gene expression profile rapidly changes upon culture to acquire a mixed signature of multiple organs/tissues, possibly associated with epidermal reprogramming. Comparison of transcriptomes between three different callus-inducing cultures (callus induction by auxin, callus induction by wounding and protoplast culture) of Arabidopsis and the Torenia stem culture identified genes upregulated in all the four culture systems as candidates of common factors of cell reprogramming. These initial changes proceeded independently of cytokinin, followed by cytokinin-dependent, transcriptional activations of nucleolar development and cell cycle. Later, SAM regulatory genes became highly expressed, leading to SAM organization in the foci of proliferating cells in the epidermal layer. Our findings revealed three distinct phases with different transcriptomic and regulatory features during direct shoot regeneration from the epidermis in Torenia, which provides a basis for further investigation of shoot regeneration in this unique culture system.
Testing Katharine Kolcaba Theory of Comfort
Authors: Sharma Mukesh Chandra , Kalia Raman 
Published: July 2021

Abstract
The aim of this study was to test Katharine Kolcaba's theory of comfort by evaluating the effectiveness of integrative comfort care interventions on discomfort experienced by children (aged 5–10 years) during the postoperative period. An experimental approach, pretest-and-posttest control group design, was used for evaluating the effectiveness of integrative comfort care interventions on discomfort experienced by children. Sample was composed of 200 children, selected using purposive sampling technique with random assignment to experimental and control groups. Kolcaba's Comfort Theory was used to assess the child's condition and then plan and deliver integrative comfort care interventions. The steps that followed for data collection, planning, and implementing effective care were based on the presuppositions of the theory. The tools used for data collection were demographics, a Comfort Behaviors Checklist, and the Comfort Daisies tool. Comfort care interventions were delivered through nursing process approach. These interventions were addressed across physical, psychological, social, spiritual, and environmental aspects. After the application of theory, the analysis revealed improvement in the comfort level of the subjects. Mann–Whitney U test was used to find out the significant difference in posttest postoperative discomfort scores among subjects in the experimental and control groups. Findings were significant at <.001. The findings revealed that subjects who received integrative comfort care interventions using the comfort theory experienced more comfort as compared with the subjects in the control group.
Virtual Surgical Planning for Intracranial Intraosseous Meningioma Reconstruction
Authors: Shah Rema , Lu Xiaona , Dinis Jacob , Junn Alexandra , Alperovich Michael 
Published: July 2021

Objective:
To assess the use of custom-made intracranial implants and three-dimensional cutting guides to direct the intracranial, intraorbital, and temporal reconstruction process for intraosseous meningioma.

Methods:
A retrospective analysis was conducted on 6 patients who were operated on by the senior author for intraosseous meningioma between 2017 and 2020. Three-dimensional models of the maxillofacial skeleton were created from preoperative virtual planned reconstruction and postoperative computed tomography scan images in the Mimics and 3-Matics software. Orbital reconstruction and temporal implant accuracy assessments were performed through the Materialise Mimics software.

Results:
Orbital cone volume had a mean discrepancy between the planned and actual orbital volume of 1.5% ± 1.6%. The reconstructed postoperative orbital volume was within 1.3% ± 2.0% of the unaffected orbit. Temporal bone reconstructions had a mean implant accuracy of 81.0%.

Conclusions:
Our results show that the postextirpative intracranial applications of virtual surgical planning are particularly suited for high fidelity reconstructions such as orbital reconstructions, as well as temporal reconstructions with intraoperative adjustments. Custom implants and virtual three-dimensional planning is particularly ideal and promising for intraosseous meningiomas given the involvement of complex intracranial and intraorbital bony structures.
Proof-of-concept pilot study on comprehensive spatiotemporal intra-patient heterogeneity for colorectal cancer with liver metastasis
Authors: Kyrochristos Ioannis D. , Glantzounis Georgios K. , Goussia Anna , Eliades Alexia , Achilleos Achilleas , Tsangaras Kyriakos , Hadjidemetriou Irene , Elpidorou Marilena , Ioannides Marios , Koumbaris George , Mitsis Michail , Patsalis Philippos C. , Roukos Dimitrios H. 
Published: July 2021

ABSTRACTPurposeThe mechanisms underlying high drug resistance and relapse rates after multi-modal treatment in patients with colorectal cancer (CRC) and liver metastasis (LM) remain poorly understood. We evaluate the potential translational implications of intra-patient heterogeneity (IPH) comprising primary and matched metastatic intratumor heterogeneity (ITH) coupled with circulating tumor DNA (ctDNA) variability.Patients and methodsAccording to our IPH-based protocol, 18 eligible patients with CRC-LM, who underwent complete tumor resection after neo-adjuvant treatment, with a total of 122 multi-regional tumor and perioperative liquid biopsies were analyzed via next-generation sequencing (NGS) of a custom 77-gene panel. The primary endpoints were the extent of IPH and the frequency of actionable mutations.ResultsThe proportion of patients with ITH were 53% and 56% in primary CRC and LM respectively, while 35% of patients harbored de novo mutations in LM indicating spatiotemporal tumor evolution and the necessity of multiregional analysis. Among the 56% of patients with alterations in liquid biopsies, de novo mutations in cfDNA were identified in 25% of patients, which were undetectable in both CRC and LM. All 17 patients with driver alterations harbored actionable mutations, with an average of 3.2 oncogenic events per patient, for molecularly targeted drugs either approved or under evaluation in ongoing clinical trials or in pre-clinical studies.ConclusionsOur proof-of-concept prospective study provides initial evidence and warrants the conduction of precision oncology trials to test the potential clinical utility of IPH-driven matched therapy.
An Approach for Open Multivariate Analysis of Integrated Clinical and Environmental Exposures Data
Authors: Fecho Karamarie , Haaland Perry , Krishnamurthy Ashok , Lan Bo , Ramsey Stephen A. , Schmitt Patrick L. , Sharma Priya , Sinha Meghamala , Xu Hao 
Published: July 2021

ABSTRACTThe Integrated Clinical and Environmental Exposures Service (ICEES) provides regulatory-compliant open access to sensitive patient data that have been integrated with public exposures data. ICEES was designed initially to support dynamic cohort creation and bivariate contingency tests. The objective of the present study was to develop an open approach to support multivariate analyses using existing ICEES functionalities and abiding by all regulatory constraints. We first developed an open approach for generating a multivariate table that maintains contingencies between clinical and environmental variables using programmatic calls to the open ICEES application programming interface. We then applied the approach to data on a large cohort (N = 22,365) of patients with asthma or related conditions and generated an eight-feature table. Due to regulatory constraints, data loss was incurred with the incorporation of each successive feature variable, from a starting sample size of N = 22,365 to a final sample size of N = 4,556 (20.5%), but data loss was < 10% until the addition of the final two feature variables. We then applied a generalized linear model to the subsequent dataset and focused on the impact of seven select feature variables on asthma exacerbations, defined as annual emergency department or inpatient visits for respiratory issues. We identified five feature variables—sex, race, obesity, prednisone, and airborne particulate exposure—as significant predictors of asthma exacerbations. We discuss the advantages and disadvantages of ICEES open multivariate analysis and conclude that, despite limitations, ICEES can provide a valuable resource for open multivariate analysis and can serve as an exemplar for regulatory-compliant informatics solutions to open patient data, with capabilities to explore the impact of environmental exposures on health outcomes.
Prevalence and Correlates of Parosmia and Phantosmia among Smell Disorders
Authors: Pellegrino Robert , Mainland Joel D. , Kelly Christine E. , Parker Jane K. , Hummel Thomas 
Published: July 2021

AbstractAmong those many individuals who suffer from a reduced odor sensitivity (hyposmia/anosmia) some individuals also experience disorders that lead to odor distortion, such as parosmia (i.e., distorted odor with a known source), or odor phantoms (i.e., odor sensation without an odor source). We surveyed a large population with at least one olfactory disorder (N = 2031) and found that odor distortions were common (46%), with respondents reporting either parosmia (19%), phantosmia (11%), or both (16%). In comparison to respondents with hyposmia or anosmia, respondents with parosmia were more likely to be female, young, and suffered from post-viral olfactory loss (p < 0.001), while phantosmia occurred most frequently in middle-aged respondents (p < 0.01) and was more likely to be caused by head trauma than parosmia (p < 0.01). A higher prevalence of odor distortion was observed 3 months to a year after their olfactory symptom onset (p < 0.001), which coincides with the timeline of physiological recovery. Additionally, we observed that the frequency and duration of distortions negatively affects quality of life, with parosmia showing a higher range of severity than phantosmia (p < 0.001). Previous research often grouped these distortions together, but our results show that they have distinct patterns of demographics, medical history, and loss in quality of life.
Analysis of feature influence on Covid-19 Death Rate Per Country Using a Novel Orthogonalization Technique
Authors: Gonnet Gaston , Stewart John , Lafleur Joseph , Keith Stephen , McLellan Mark , Jiang-Gorsline David , Snider Tim 
Published: July 2021

AbstractWe have developed a new technique of Feature Importance, a topic of machine learning, to analyze the possible causes of the Covid-19 pandemic based on country data. This new approach works well even when there are many more features than countries and is not affected by high correlation of features. It is inspired by the Gram-Schmidt orthogonalization procedure from linear algebra. We study the number of deaths, which is more reliable than the number of cases at the onset of the pandemic, during Apr/May 2020. This is while countries started taking measures, so more light will be shed on the root causes of the pandemic rather than on its handling.The analysis is done against a comprehensive list of roughly 3,200 features. We find that globalization is the main contributing cause, followed by calcium intake, economic factors, environmental factors, preventative measures, and others. This analysis was done for 20 different dates and shows that some factors, like calcium, phase in or out over time. We also compute row explainability, i.e. for every country, how much each feature explains the death rate. Finally we also study a series of conditions, e.g. comorbidities, immunization, etc. which have been proposed to explain the pandemic and place them in their proper context. While there are many caveats to this analysis, we believe it sheds light on the possible causes of the Covid-19 pandemic.One-Sentence SummaryWe use a novel feature importance technique to find that globalization, followed by calcium intake, economic factors, environmental factors, and some aspects of societal quality are the main country-level data that explain early Covid-19 death rates.
RAFFT: Efficient prediction of RNA folding pathways using the fast Fourier transform
Authors: Opuu Vaitea , Merleau Nono S. C. , Messow Vincent , Smerlak Matteo 
Published: July 2021

AbstractWe propose a novel heuristic to predict RNA secondary structure formation pathways that has two components: (i) a folding algorithm and (ii) a kinetic ansatz. This heuristic is inspired by the kinetic partitioning mechanism, by which molecules follow alternative folding pathways to their native structure, some much faster than others. Similarly, our algorithm RAFFT starts by generating an ensemble of concurrent folding pathways ending in multiple metastable structures, which is in contrast with traditional thermodynamic approaches that find single structures with minimal free energies. When we constrained the algorithm to predict only 50 structures per sequence, nearnative structures were found for RNA molecules of length ≤ 200 nucleotides. Our heuristic has been tested on the coronavirus frameshifting stimulation element (CFSE): an ensemble of 68 distinct structures allowed us to produce complete folding kinetic trajectories, whereas known methods require evaluating millions of sub-optimal structures to achieve this result. Thanks to the fast Fourier transform on which RAFFT is based, these computations are efficient, with complexity 𝒪(L2 log L).
Comprehensive evaluation of machine learning models and gene expression signatures for prostate cancer prognosis using large population cohorts
Authors: Li Ruidong , Zhu Jianguo , Zhong Wei-De , Jia Zhenyu 
Published: July 2021

AbstractOvertreatment remains the pervasive problem in prostate cancer (PCa) management due to the highly variable and often indolent course. Molecular signatures derived from gene expression profiling have played critical roles in PCa treatment decision-making. Many gene expression signatures have been developed to improve the risk stratification of PCa and some of them have already been translationally applied to clinical practice, however, no comprehensive evaluation was performed to compare the performances of the signatures. In this study, we conducted a systematic and unbiased evaluation of 15 machine learning (ML) algorithms and 30 published PCa gene expression-based prognostic signatures leveraging 10 transcriptomics datasets with 1,558 primary PCa patients from public data repositories. The results revealed that survival analysis models outperformed binary classification models for risk assessment, and the performances of the survival analysis methods - Cox model regularized with ridge penalty (Cox-Ridge) and partial least squares regression for Cox model (Cox-PLS) – were generally more robust than the other methods. Based on the Cox-Ridge algorithm, a few top prognostic signatures that have comparable or even better performances than the commercial panels have been identified. The findings from the study will greatly facilitate the identification of existing prognostic signatures that are promising for further validations in prospective studies and promote the development of robust prognostic models to guide clinical decision-making. Moreover, the study provided a valuable data resource from large primary PCa cohorts, which can be used to develop, validate, and evaluate novel statistical methodologies and molecular signatures to improve PCa management.