bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of enriched environment on micturition activity in freely moving C57BL/6J mice
Authors: Soeda Fumio , Toda Akihisa , Masuzaki Kazuya , Miki Risa , Koga Takayuki , Fujii Yukiko , Takahama Kazuo 
Published: March 2021

AbstractObjectivesAn enriched environment (EE) has been known to promote structural changes in the brain and enhance learning and emotional performance. However, little is known about the effect of an EE on brain stem functions, such as the micturition function. In this study, we examined whether an EE affects micturition activity in mice.MethodsMale C57BL/6J mice were used. We assessed the micturition activity of freely moving mice using a novel system developed in‐house.ResultsDuring the dark period, but not light, the EE significantly increased voiding frequency, total voided volume, mean voided volume, voiding duration, mean flow rate, and maximum flow rate compared with the control environment. This EE effect on micturition function was associated with habituation to novel environments in the open‐field test, but not with amelioration of motor coordination in the rotarod test. Interestingly, even after the mice were withdrawn from the EE, the improvements in micturition function persisted, while other behavioral changes were abolished. The relative value of voiding frequency and total voided volume during the light period, expressed as a percentage of 24 hours, increased with age when mice were reared in a standard environment. However, this age‐related change was not observed in mice reared in an EE.ConclusionsThese results suggest that an EE may promote micturition activity during the active phase of C57BL/6J mice, and its effects persist even after withdrawal from the EE. Furthermore, an EE may mitigate dysfunctions in micturition activity, such as polyuria, during the resting phase in aged mice.
Significant decrease in delirium referrals after changing hypnotic from benzodiazepine to suvorexant
Authors: Tachibana Masako , Inada Toshiya , Ichida Masaru , Kojima Shihori , Arai Takafumi , Naito Keiko , Ozaki Norio 
Published: March 2021

AbstractBackgroundThe use of benzodiazepines (BZDs) causes delirium, especially in elderly people. For this reason, suvorexant has been recommended as the first‐line hypnotic in elderly patients. The aim of this study was to determine whether the first‐line use of suvorexant, instead of BZDs, decreases referrals for delirium in elderly patients.MethodsSince May 2016 at Nagoya Ekisaikai Hospital, suvorexant has been recommended as the first‐line hypnotic instead of BZDs. In May 2017, suvorexant was adopted as the first‐line hypnotic. The number of delirium cases referred to psychiatry was compared among three consecutive periods: period A (May 2015–April 2016), during which BZDs were mainly used for insomnia; period B (May 2016–April 2017), during which the use of suvorexant was recommended instead of BZDs; and period C (May 2017–April 2018), during which suvorexant was principally adopted as the first‐line hypnotic for insomnia. Potential confounding factors that may affect the development of delirium were also examined during the three periods.ResultsThe number of delirium referral cases in elderly patients in each period decreased, from 133 in period A to 86 in period B and 53 in period C. The rate of delirium referral cases decreased significantly every year (P = 9.02 × 10−10). Almost no significant confounding factors other than hypnotics were detected during the three periods.ConclusionThe referrals for delirium in elderly patients decreased significantly after the hypnotic was changed from BZDs to suvorexant.
Withdrawal of the multifibre agreement and Indian textile industry: Concerns, efforts, and achievements
Authors: Bhandari Anup Kumar 
Published: March 2021

AbstractMultifibre agreement (MFA)–endorsed safe textile export markets were abolished in 2005. For India, scholars anticipated both enormous potential gain from the post‐MFA free market and the threat of inevitably increasing competition. Researchers also emphasized selected channels to succeed, including effective exploitation of scale economies and technological upgradation, for fruitful market gain in this regard. Against this backdrop, we study the Indian textile industry from 1999–2000 through 2014–2015 to examine (1) the role of economies of scale to achieve efficiency gain and therefore competitiveness, (2) the industry's efforts toward technological upgradation, and (3) its overall sustainability through net export expansion, profitability, and total factor productivity (TFP) growth. Results show that (1) size‐efficiency nexus is positively significant and therefore the industry can achieve further efficiency gain and competitiveness by expanding scale of operations at the firm level; (2) despite considerable increase in R&D investments, the industry's overall production technological status has deteriorated in the post‐MFA regime and therefore has substantial scope of improvement, possibly through more effectively using the prevailing technological upgradation funds scheme (TUFS) and other official arrangements; and (3) although India achieves sizeable net export expansion and TFP gains, the industry's profitability scenario seems bleak and requires further attention for its better sustainability.
The Carboniferous chronostratigraphic scale: history, status and prospectus
Authors: Lucas Spencer G. , Schneider Joerg W. , Nikolaeva Svetlana , Wang Xiangdong 
Published: March 2021

Abstract
The Carboniferous chronostratigraphic scale is a hierarchy of two subsystems, six series and seven stages developed during nearly two centuries of research. Carboniferous stage nomenclature developed with the proposal of numerous regional stages/substages based primarily on palaeobotanical, foraminiferal and ammonoid biostratigraphy, especially in Western Europe, the former Soviet Union, China and the USA. From the regional stages, seven ‘global stages’ have been identified (in ascending order): Tournaisian, Visean, Serpukhovian, Bashkirian, Moscovian, Kasimovian and Gzhelian. Three of the four ratified Carboniferous GSSPs use conodont evolutionary events as the primary signal for correlation – bases of Tournaisian, Bashkirian and base of Asselian. The GSSP of the Visean base has a foraminiferal event as its primary signal. Issues in the development of a Carboniferous chronostratigraphic scale include the rank of chronostratigraphic units, provinciality, conodont biostratigraphy, palaeobotanical biostratigraphy and the development of astrochronology and other methods of chronology and correlation.
Which Holds the Key to BRCAness: Inability to Repair the Break, Protect the Fork, or Prevent the Gap?
Authors: Canman Christine E. 
Published: March 2021

Abstract
Defects in genes crucial for the process of DNA repair by homology-directed DNA repair (HDR), such as BRCA1 and BRCA2, are well-known contributors to cancer pathogenesis as well as an Achilles' heel that can be exploited therapeutically. BRCA1/2-deficient cells are exquisitely sensitive to agents that stall replication forks, such as PARP inhibitors and platinating drugs, presumably due to the inability to repair double-stranded breaks that form as a consequence of replication fork collapse. BRCA1/2 also promote tolerance to DNA replication stress by protecting replication forks from nucleolytic degradation. Both biological endpoints involve the deposition of RAD51 onto single-stranded DNA (ssDNA) for homology searching and strand exchange during HDR repair, as well as protection of newly synthesized DNA from nucleolytic degradation (i.e., replication fork protection). In this issue of Cancer Research, Panzarino and colleagues performed multiple separation-of-function studies and identify the lesion most associated with intolerance to replication stress in BRCA1/2-deficient cells is persistent ssDNA gaps in newly synthesized DNA, resulting from a failure to restrain DNA replication. Mechanisms that suppress gap formation are closely associated with chemoresistance, and the authors’ findings challenge the paradigm that lack of HR repair or fork protection underlie the phenotype known as BRCAness.
See related article by Panzarino et al., p. 1388
Targeting EYA3 in Ewing Sarcoma Retards Tumor Growth and Angiogenesis
Authors: Wang Yuhua , Pandey Ram Naresh , Roychoudhury Kaushik , Milewski David , Kalin Tanya V. , Szabo Sara , Pressey Joseph G. , Hegde Rashmi S. 
Published: March 2021

Abstract
EWSR1/FLI1, the most common fusion gene in Ewing sarcoma, upregulates expression of the Eyes Absent 3 (EYA3) transactivator–phosphatase protein. The purpose of this study was to investigate molecular and cellular mechanisms through which EYA3 might promote Ewing sarcoma tumor growth and to determine whether the EYA3 tyrosine phosphatase activity represents a viable therapeutic target. We used genetic and pharmacologic modulation of EYA3 in cell line–based xenografts to examine how loss of EYA3 tyrosine phosphatase activity affects tumor growth and angiogenesis. Molecular mechanisms were evaluated in vivo and in vitro through analyses of tumor tissue and multicellular tumor spheroids. Our results show that both loss of EYA3 in Ewing sarcoma cells and pharmacologic inhibition of the EYA3 tyrosine phosphatase activity inhibit tumor growth and tumor angiogenesis. EYA3 regulates levels of VEGFA in Ewing tumors, as well as promoting DNA damage repair and survival of Ewing sarcoma tumor cells. Target engagement is demonstrated in tumor tissue through elevated levels of the EYA3 substrate H2AX-pY142 upon loss of EYA3 or with Benzarone treatment. The efficacy of EYA3 tyrosine phosphatase inhibition in attenuating tumor growth and angiogenesis is corroborated in an Ewing sarcoma patient-derived tumor xenograft. Together, the results presented here validate EYA3 as a target for the development of novel Ewing sarcoma therapeutic strategies, and set the stage for evaluating the efficacy of combining the antiangiogenic and anti-cell survival effects of EYA3 inhibition with cytotoxic chemotherapy.
Abstract IA008: Age-related stromal changes drive tumorigenesis
Authors: Stewart Sheila A 
Published: March 2021

Abstract
The stromal compartment plays a pivotal role in tumor progression. This is best illustrated in breast cancer bone metastases, where the stromal compartment supports tumor growth, albeit through poorly defined mechanisms. p38MAPKa is frequently expressed in tumor cells and surrounding stromal cells and its expression levels correlate with poor prognosis. Using a clinically relevant breast cancer metastasis model, we show that orally administered, small-molecule inhibitors of p38MAPKa or its downstream kinase, MK2, each limited outgrowth of metastatic breast cancer cells in the bone and visceral organs. Further we find that this effect is primarily mediated by inhibition of the p38MAPKa pathway within the stromal compartment. Beyond effectively limiting metastatic tumor growth, we also find that these inhibitors reduce tumor-associated and chemotherapy-induced bone loss, which is a devastating comorbidity for cancer patients that drastically impact their quality of life. Interestingly we find that p38MAPKa’s ability to limit tumor growth within the bone is dependent on CD4 T cells while MK2 does not require these cells to limit tumor progression, demonstrating that it is not a straightforward pathway. To determine which cell types within the bone contribute to tumor growth and bone loss, we have carried out single cell RNA-sequencing of stromal cells located within the bone metastatic lesion and cells outside the lesion. We find numerous differences that could explain how the stromal compartment contributes to tumor progression and bone loss and how inhibition of p38MAPKa or MK2 contribute. These data underscore the vital role stromal-derived factors play in tumor progression and identify the p38MAPK-MK2 pathway as a promising therapeutic target for metastatic disease and prevention of tumor-induced bone loss.
Citation Format: Sheila A Stewart. Age-related stromal changes drive tumorigenesis [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr IA008.
Abstract PO013: Blood-brain barrier dysfunction leads to neuronal loss in glioma pathology
Authors: Mata-Martínez Pablo , Segura-Collar Berta , Garranzo-Asensio Maria , Sepúlveda-Sánchez Juan M. , Hernández-Lain Aurelio , Sánchez-Gómez Pilar , Gargini Ricardo 
Published: March 2021

Abstract
The blood-brain barrier (BBB) defines the physiological function of the brain. Its disruption is common in multiple neuropathological diseases. Accumulating evidence suggest that BBB alterations occur in early stages of neurodegenerative diseases, being associated with neuronal loss processes. The vascular abnormalities and BBB leakage characterize the progression of gliomas, however it is unclear their correlation with the neurodegeneration observed in such tumors.
Methods: To establish the different gene signatures we have performed an in-silico analysis using glioma data sets and we have validated the results in a cohort of 26 gliomas (high and low grade) and 7 controls from non-tumor donors. We have also used patient-derived xenografts (PDXs) to correlate the degree of BBB disruption (measured by IgG extravasation immunofluorescence staining) with the neuronal loss (evaluated by NeuN immunofluorescence staining) and with the motor impairment (assessed by a rotarod test). Results: We measured the expression of a series of signatures associated with different biological processes, relevant for glioma development. The “Synapse” and the “BBB dysfunction” signatures were inversely correlated during glioma development. Thus, the most aggressive tumors were associated with BBB breakdown and neuronal dysfunction. These phenotypes correlate with the mesenchymal subtype of gliomas and with a shorter survival. The vascular normalization induced by the isocitrate dehydrogenase 1 (IDH1) mutations rescued the neuronal loss, reducing the motor impairment and increasing the overall survival of PDX-bearing mice. Conclusions: Our data demonstrate that vascular normalization can revert the neuronal loss and the aggressiveness in those tumors, which is linked to the appearance of motor dysfunction symptoms. Overall, we propose that disruption of the BBB is associated with neurodegeneration in glioma patients. These results could help us to understand the progression of this pathology as well as other neurodegenerative diseases and therefore to improve their therapeutic approaches.
Citation Format: Pablo Mata-Martínez, Berta Segura-Collar, Maria Garranzo-Asensio, Juan M. Sepúlveda-Sánchez, Aurelio Hernández-Lain, Pilar Sánchez-Gómez, Ricardo Gargini. Blood-brain barrier dysfunction leads to neuronal loss in glioma pathology [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr PO013.
Abstract PO045: Impact of fibroblast mediated stromal protection on evolution of resistance to targeted therapies in NSCLC
Authors: Desai Bina 
Published: March 2021

Abstract
BACKGROUND: Clinical introduction of tyrosine kinases inhibitors (TKIs) for ALK+ non-small cell lung cancer (NSCLC) has improved patient survival, but it did not translate into cures as acquired resistance inevitably emerges in patients with advanced and metastatic cancers. Cancer associated fibroblasts (CAFs) have emerged as the major determinant of environmental protection. While the ability of stroma to protect tumor cells from TKI is well documented in-vitro, whether the impact of stromal protection is relevant in 3D context and in-vivo remains unresolved. Thus, we hypothesized that stromal protection impacts the initial response of tumor cells to targeted therapies.
METHODS: Cancer cell lines were cultured in presence of CAF conditioned media (CM) and treated with TKIs to monitor cell viability. To interrogate molecular mechanism, loss and gain of function experiments were performed using pharmacological inhibitors and recombinant human protein respectively. To address the relevance of stromal protection in-vivo, we worked with tumor xenograft mouse model. We also used mathematical modelling to understand the tumor dynamics, using inferences from xenograft mouse models to build agent-based models.
RESULTS: We observed that patient derived matched normal tissue associated fibroblast (NAFs) and CAFs, both confers various level of protection to tumor cells against TKIs. Addition of rh Hepatocyte growth factor (HGF) protein mimicked the effect of CAF CM and addition of small molecule inhibitors of cMET abolished the CAF-mediated protection to tumor cells against TKIs. Our xenograft experiment showed the significant increase in stroma/tumor ratio during the initial tumor response to targeted therapy and we observed increase in tumor proliferating cells in proximity to stroma. Our math model for stroma and pre-existing resistant population showed delay in development of resistance to TKI.
CONCLUSION: Fibroblast-mediated stromal protection is critically dependent on HGF-cMET axis. Dual inhibition of ALK and MET signaling abolished the fibroblast-mediated protection and increased the cell sensitivity to ALK TKIs, suggesting the crucial role of microenvironment-mediated resistance in NSCLC. To study tumor dynamics using mathematical models, we addressed that space could be key to understand the impact of stromal protection in-vivo. Our study shows that understanding the signaling changes carried by fibroblast in response to therapy may lead to potential better combination therapy.
Citation Format: Bina Desai. Impact of fibroblast mediated stromal protection on evolution of resistance to targeted therapies in NSCLC [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr PO045.
Abstract PO047: Sensory nerves enhance breast cancer migration through PlexinB3 signaling
Authors: Le Thanh T. , Oudin Madeleine J. 
Published: March 2021

Abstract
The tumor microenvironment plays an essential role in the process of metastasis. However, the role of the peripheral nervous system, a crucial component of the tumor microenvironment, in cancer progression remains poorly understood. In breast cancer, nerve presence has been correlated with more invasive disease and worse prognosis. Yet, there is still a lack of detailed investigation into the specific types of nerves that are present in breast cancer as well as the mechanism by which nerve-cancer crosstalk contributes to breast cancer metastasis. We identified sensory nerves as more abundant in triple-negative human breast cancer tumors relative to healthy breast by mining gene expression datasets and immunostaining. Interestingly, the sensory nerve bundle structure in normal breast is disrupted in breast tumor, resulting in discrete nerve fibers throughout the tumor. To investigate the role of these sensory nerves in cancer progression, we cocultured primary sensory neurons from dorsal root ganglia of mice and human triple-negative breast cancer cells (MDA-MB-231). We found that cancer cells tend to attach and move along nerve fibers. These cells also have higher migration speed and proliferation rate when compared to both monoculture and conditioned media control. We then set out to investigate whether sensory nerves impact gene expression in tumors using RNA sequencing. By utilizing published algorithms, we were able to separate the transcriptome of human cancer cells and mouse neurons in coculture. Differential analysis shows that cancer cells in coculture upregulate genes related to cell migration, adhesion, and proliferation pathways, which further validates our experimental findings. We identified the Sema5A-PlexinB3 ligand-receptor pair as a potential mechanism of nerve-cancer crosstalk, where neurons provide Sema5A that interacts with upregulated PlexinB3 receptors on cancer cells. Knockdown of Plexin-B3 in tumor cells reduced the effect of sensory nerves on breast cancer cell migration. In vivo experiments injecting sensory nerves and tumor cells into the mammary gland of mice are ongoing. Overall, these studies demonstrate that sensory nerve density is high in TNBC and that sensory nerves promote tumor cell migration and proliferation via direct cell-cell interactions. We also show for the first time that nerves can induce gene expression changes in cancer cells. In the long-term, these findings could lead to novel treatments for metastatic disease that target nerve-cancer crosstalk.
Citation Format: Thanh T. Le, Madeleine J. Oudin. Sensory nerves enhance breast cancer migration through PlexinB3 signaling [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr PO047.
Abstract IA-06: Artificial intelligence in cancer imaging
Authors: Aerts Hugo 
Published: March 2021

Abstract
Medical imaging in oncology has traditionally been restricted to the diagnosis and staging of cancer. But technological advances in Artificial Intelligence (AI), deep learning in particular, are moving imaging modalities into the heart of patient care. Imaging can address a critical barrier in precision medicine as solid tumors can be spatial and temporal heterogeneous, and the standard approach to tumor sampling, often invasive needle biopsy, is unable to fully capture the spatial state of the tumor. Radiomics refers to the automatic quantification of this radiographic phenotype. Radiomic methods heavily rely on AI technologies to quantify phenotypic characteristics that can be used to develop non-invasive biomarkers. In this talk, Dr. Aerts will discuss recent developments from his group and collaborators performing research at the intersection of radiology, bioinformatics, and data science. Also, he will discuss recent work of building a computational image analysis system to extract a rich radiomics set and use these features to build radiomic signatures. The presentation will conclude with a discussion of future work on building integrative systems incorporating both molecular and phenotypic data to improve cancer therapies.
Citation Format: Hugo Aerts. Artificial intelligence in cancer imaging [abstract]. In: Proceedings of the AACR Virtual Special Conference on Artificial Intelligence, Diagnosis, and Imaging; 2021 Jan 13-14. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(5_Suppl):Abstract nr IA-06.