bluuebunny/crossref_metadata_2025_split huggingface dataset:
Second messenger signalling bypasses CGRP receptor blockade to provoke migraine attacks in humans
Authors: Do Thien Phu , Deligianni Christina , Amirguliyev Sarkhan , Snellman Josefin , Lopez Cristina Lopez , Al-Karagholi Mohammad Al-Mahdi , Guo Song , Ashina Messoud 
Published: August 2023

Abstract
There are several endogenous molecules that can trigger migraine attacks when administered to humans. Notably, calcitonin gene-related peptide (CGRP) has been identified as a key player in a signalling cascade involved in migraine attacks, acting through the second messenger cyclic adenosine monophosphate (cAMP) in various cells, including intracranial vascular smooth muscle cells. However, it remains unclear whether intracellular cAMP signalling requires CGRP receptor activation during a migraine attack in humans. To address this question, we conducted a randomized, double-blind, placebo-controlled, parallel trial using a human provocation model involving the administration of CGRP and cilostazol in individuals with migraine pretreated with erenumab or placebo. Our study revealed that migraine attacks can be provoked in patients by cAMP-mediated mechanisms using cilostazol, even when the CGRP receptor is blocked by erenumab. Furthermore, the dilation of cranial arteries induced by cilostazol was not influenced by the CGRP receptor blockade. These findings provide clinical evidence that cAMP-evoked migraine attacks do not require CGRP receptor activation. This discovery opens up new possibilities for the development of mechanism-based drugs for the treatment of migraine.
Regulatory Issues of Data and Algorithms for the Data-Driven Economy
Authors: Liu Kung-Chung 
Published: August 2023

Abstract
Data and algorithms are the lifeblood of the data-driven economy. Big data and big algo are bringing new challenges and legal issues to the fore. This article deals with some aspects of these issues and tries to put forward an analytical framework for typifying, securing access to and use of data, and ultimately maximizing the generation and flow of data. This article then deals with algorithms and endeavours to propose six principles for auditing algorithms and a brand new international governance framework for algorithms and their auditing via a treaty and relevant mechanisms.
Performance analysis of a geothermal heat-powered resorption cooling system: a case study for cold storage of apple fruit
Authors: Pastakkaya Bilsay 
Published: August 2023

Abstract
Renewable energy use in agricultural applications is essential for sustainable production. Resorption cooling systems can be operated for agricultural cooling applications by using thermal energy derived from geothermal springs with sufficient temperature. Since the resorption cycle uses ammonia-water solution, cold storage and industrial cooling processes below 0°C can be actualized efficiently. In this article, a geothermal powered resorption system for cold storage of apple fruit is investigated. Technical features and cooling performance of the resorption system are analysed and compared to the other conventional cooling systems. Results showed that, geothermal powered resorption cooling systems can annually cover the cooling load of the cold storage application with adequate cooling temperature and capacity. Moreover, the use of the geothermal powered resorption system enables to set up safer and more economic cooling applications with the similar cooling performance compared with the alternative sorption cooling systems, and provides substantial economic benefits by reducing the cooling costs in agricultural production with lower operational costs.
Tissue Distribution of mtDNA Copy Number And Expression Pattern of An mtDNA-Related Gene in Three Teleost Fish Species
Authors: Li B , Wang H , Jiang C , Zeng X , Zhang T , Liu S , Zhuang Z 
Published: August 2023

SynopsisTeleosts are the most speciose vertebrates and have diverse swimming performance. Based on swimming duration and speed, teleosts are broadly divided into sustained, prolonged, and burst swimming fish. Teleosts with different swimming performance have different energy requirements. In addition, energy requirement also varies among different tissues. As mitochondrial DNA (mtDNA) copy number is correlated with ATP production, we speculated that mtDNA copy number varies among fish with different swimming performance, as well as among different tissues. In other species, mtDNA copy number is regulated by tfam (mitochondrial transcription factor A) through mtDNA compaction and mito-genome replication initiation. In order to clarify the tissue distribution of mtDNA copy number and expression pattern of tfam in teleosts with disparate swimming performance, we selected representative fish with sustained swimming (Pseudocaranx dentex), prolonged swimming (Takifugu rubripes), and burst swimming (Paralichthys olivaceus). We measured mtDNA copy number and tfam gene expression in 10 tissues of these three fish. The results showed the mtDNA content pattern of various tissues was broadly consistent among three fish, and high-energy demanding tissues contain higher mtDNA copy number. Slow-twitch muscles with higher oxidative metabolism possess a greater content of mtDNA than fast-twitch muscles. In addition, relatively higher mtDNA content in fast-twitch muscle of P. olivaceus compared to the other two fish could be an adaptation to their frequent burst swimming demands. And the higher mtDNA copy number in heart of P. dentex could meet their oxygen transport demands of long-distance swimming. However, tfam expression was not significantly correlated with mtDNA copy number in these teleosts, suggesting tfam may be not the only factor regulating mtDNA content among various tissues. This study can lay a foundation for studying the role of mtDNA in the adaptive evolution of various swimming ability in teleost fish.
Development and implementation of an interoperability tool across state public health agency’s disease surveillance and immunization information systems
Authors: Rajamani Sripriya , Chakoian Hanna , Bieringer Aaron , Lintelmann Anna , Sanders Jeffrey , Ostadkar Rachel , Saupe Amy , Grilli Genny , White Katie , Solarz Sarah , Melton Genevieve B 
Published: August 2023

Abstract
Public health information systems have historically been siloed with limited interoperability. The State of Minnesota’s disease surveillance system (Minnesota Electronic Disease Surveillance System: MEDSS, ∼12 million total reportable events) and immunization information system (Minnesota Immunization Information Connection: MIIC, ∼130 million total immunizations) lacked interoperability between them and data exchange was fully manual. An interoperability tool based on national standards (HL7 and SOAP/web services) for query and response was developed for electronic vaccination data exchange from MIIC into MEDSS by soliciting stakeholder requirements (n = 39) and mapping MIIC vaccine codes (n = 294) to corresponding MEDSS product codes (n = 48). The tool was implemented in March 2022 and incorporates MIIC data into a new vaccination form in MEDSS with mapping of 30 data elements including MIIC demographics, vaccination history, and vaccine forecast. The tool was evaluated using mixed methods (quantitative analysis of user time, clicks, queries; qualitative review with users). Comparison of key tasks demonstrated efficiencies including vaccination data access (before: 50 clicks, &gt;2 min; after: 4 clicks, 8 s) which translated directly to staff effort (before: 5 h/week; after: ∼17 min/week). This case study demonstrates the contribution of improving public health systems interoperability, ultimately with the goal of enhanced data-driven decision-making and public health surveillance.
BSBM-03 A NOVEL COMBINED IMMUNOTHERAPY TO IMPROVE THERAPEUTIC RESPONSES IN SYMPTOMATIC BRAIN METASTASIS BASED ON TARGETING A SUBPOPULATION OF IMMUNOSUPPRESSIVE ASTROCYTES
Authors: Priego Neibla , de Pablos-Aragoneses Ana , Perea-García María , Álvaro-Espinosa Laura , Hernández-Oliver Carolina , Martínez-Saez Elena , Pérez-Núñez Ángel , Hernández-Laín Aurelio , Sanz-Pamplona Rebeca , Schmitz Marc , Crocker Stephen J , Serrano Diego , Calvo Alfonso , Palazón Asís ,   RENACER Red Nacional de Metástasis Cerebral, Valiente Manuel 
Published: August 2023

Abstract
The diagnosis of brain metastasis involves high morbidity and mortality. Recently, immune checkpoint blockade antibodies (ICB) have shown clinical benefits mainly when applied to asymptomatic brain metastasis patients. However, variability is broad and responses to this therapy drop considerably when treating clinically relevant disease. Although potentially involved in the lack of response to immunotherapy, corticoids do not seem to fully explain this situation. Thus, it is currently unknown how to effectively target symptomatic brain metastases with immunotherapy. We previously reported a clinically relevant protumoral program driven by STAT3 activation in a subpopulation of reactive astrocytes during advanced stages of the disease. By further exploiting astrocyte heterogeneity, we have found a potential strategy to improve the number of responders to immunotherapy in symptomatic brain metastasis. Specifically, we have developed a comprehensive strategy including genetic and pharmacologic approaches to define a novel immunosuppressive axis involving astrocyte-secreted TIMP1 signaling on CD63+ CD8+ T cells. Based on these findings, we developed a combined immunotherapy to boost the systemic activation of T cells with ICB while blocking local TIMP1-dependent immunosuppression in various preclinical models. Furthermore, the detection of TIMP1 in the CSF provides a biomarker to select patients who would benefit the most from the combined immunotherapy. Even more, our data using Patient Derived Organotypic Cultures from fresh brain metastasis neurosurgeries confirmed that our therapeutic strategy is valid for symptomatic brain metastases from any primary source. In conclusion, our study has identified a novel combined immunotherapy that could be especially relevant for symptomatic brain metastases. Our findings have emerged from a strong scientific rationale whereby a specific subpopulation of astrocytes is shown to activate the local immunosuppressive environment for brain-infiltrating CD8+ T cells.
BSBM-04 MULTIPLE MYELOMA METASTASIS TO THE PINEAL GLAND: A CASE REPORT FROM LONG ISLAND, NEW YORK, USA
Authors: Torres Marielle , Bazer Danielle , Kowalska Agnieszka 
Published: August 2023

Abstract

BACKGROUND
Multiple myeloma (MM) is one of the most common bone cancers in older adults, occurring as a neoplasm that emerges from a clone of differentiated plasma cells, ultimately resulting in proliferation of a monoclonal immunoglobulin. The plasma cells accumulate in the bone marrow, often producing osseous lesions. Although rare, extramedullary proliferation of these plasma cells can occur. Extramedullary proliferation has been identified in 10-16% of MM patients, most often in the lymph nodes, spleen, liver, and kidney, but has been identified in every organ system.

RESULTS
We present a rare case of a 71 year-old female with MM, diagnosed in 2010 and treated with several chemotherapy agents and steroids, found to have metastasis to her pineal gland after initially presenting with altered mentation. Her course was complicated by obstructive hydrocephalus requiring ventriculostomy. Metastasis was confirmed with biopsy from the pineal gland. Metastasis to the pineal gland is rare and typically secondary to primary lung cancer, but other primary lesions including breast, kidney, cervical, esophageal, gastric, colon, and skin have been identified. Literature review has only yielded two case reports of MM metastasis to the pineal gland.

CONCLUSION
Though metastasis to the pineal gland is rare, and MM an unlikely primary source, patients known to have MM presenting with neurologic symptoms should be evaluated for extramedullary lesions in the brain.
BSBM-11 COMBINING IMMUNOTHERAPY AND WHOLE-BRAIN RADIATION THERAPY IN A NOVEL SYNGENEIC LUNG CANCER BRAIN METASTASIS PRECLINICAL MODEL: DOES TIMING OF ADMINISTRATION MATTER?
Authors: Blethen Kathryn , Sprowls Samuel , Arsiwala Tasneem , Wolford Cullen , Panchal Dhruvi , Fladeland Ross , Glass Morgan , Dykstra Leah , Kielkowski Brooke , Blackburn Jillian , Lockman Paul 
Published: August 2023

Abstract
Approximately 50% of all brain metastasis cases originate from primary lung tumors. Whole-brain radiation therapy (WBRT) is a common treatment for patients with multiple brain metastases, but patients rarely survive longer than one year after diagnosis. Recent studies demonstrate improved outcomes with combinatorial radiotherapy and immunotherapy, but the optimal timing of immunotherapy administration is unclear. Eliciting a robust immune response post-immunotherapy is vital for therapeutic efficacy. Our work shows that the BBB is disrupted and proinflammatory cytokines are increased in the brain 12 hours post-WBRT in immunocompetent but not immunocompromised mice. Additionally, efflux transporter activity is decreased at this time point. This study utilizes a novel Lewis Lung Carcinoma cell line, LLC-Br, which was developed in our laboratory to preferentially metastasize to the brain. Mice were treated with immune checkpoint inhibitors (ICIs) before or after WBRT then we evaluated tumor progression, survival, and blood-tumor barrier (BTB) permeability. We hypothesized administration of ICI following WBRT would increase survival, decrease tumor burden, and increase BTB permeability in our preclinical syngeneic lung cancer brain metastasis model.
BSBM-18 SINGLE-CELL PROFILING TUMOR-INFILTRATING IMMUNE CELLS REVEALS CXCL13+ FOLLICULAR HELPER-LIKE CD4+ T CELLS IN HUMAN BRAIN TUMORS
Authors: Lu Benjamin , Lucca Liliana , DiStasio Marcello , Liu Yang , Pham Giang , Buitrago-Pocasangre Nicholas , Arnal-Estape Anna , Moliterno Jennifer , Chiang Veronica , Omuro Antonio , Hafler David 
Published: August 2023

Abstract
While therapies enhancing antitumor T cell function have clinical efficacy for patients with brain metastases, patients with high-grade gliomas fail to benefit. How the brain tumor microenvironment differentially shapes T cell function remains unknown. We performed droplet-based single-cell RNA and T cell receptor sequencing on immune cells from tumor and blood of patients with newly diagnosed non-small cell lung cancer brain metastases (n=10) and high-grade glioma (n=12). In total, we examined 220,049 high-quality immune cells, including 159,043 T cells. Tumor-infiltrating T cells in metastases were more abundant (p=0.005), more clonally expanded (p=0.039), and had a less diverse clonal repertoire (p=0.033). While no differences were observed among CD8+ T cells, a population of CXCL13+CD4+ T cells was more abundant in metastases (6.03% vs. 1.82%, p=0.004). This population expressed genes encoding transcriptional factors (BCL6, MAF), co-inhibitory receptors (PDCD1, LAG3, TIGIT), and effector cytokines (IL21, IL4, IFNG) characteristic of follicular helper T cells though notably lacked expression for the canonical chemokine receptor CXCR5. CXCL13+CD4+ T cells were highly expanded, had minimal clonal overlap with other populations, largely confined to the tumor, associated with germinal center B cell and plasma cell signatures, and resembled T cell populations predictive of anti-PD-1 therapy response in extracranial disease. Based on the expression of potential ligand-receptors and downstream signaling targets, CXCL13+CD4+ T cells were predicted to interact with B cells and antigen-presenting cells, as seen in tertiary lymphoid structures. To investigate the relevance of CXCL13+CD4+ T cells in glioblastoma, we analyzed bulk RNA sequencing data from The Cancer Genome Atlas (n=160) and observed a trend towards longer overall survival in patients with high follicular helper-like expression. In summary, we identified a follicular helper-like CD4+ T cell population that is preferentially found in brain metastases and may be a feature of productive antitumor immune responses in human brain tumors.
BSLD-03 MIMICKING CAFS, PIAL CELLS SUPPORTLEPTOMENINGEAL METASTASIS
Authors: Snyder Jenna , Remsik Jan , Boire Adrienne 
Published: August 2023

Abstract
Leptomeningeal metastasis (LM), the spread of cancer into cerebrospinal fluid (CSF)-filled coverings of the brain and spinal cord, is a dismal complication of cancer leading to rapid neurologic disability and death. While a diverse array of primary tumors may result in LM, recent work from our laboratory (Chi Y et al 2020 Science) demonstrates a conserved transcriptional signature, independent of primary tumor, suggesting that tumor-microenvironmental interactions play a dominant role in this pathology. We have proteomically interrogated CSF collected from breast (n = 45), lung (n = 30), and melanoma (n = 27) patients with and without LM. We detect robust expression of inflammatory cytokines in all LM+ samples, 15 of these cytokines including IL8, IL6, and CXCL1 are conserved across tumor types in the presence of LM. Because cancer cells in the CSF do not express mRNA associated with these cytokines, we hypothesized that these inflammatory cytokines may originate from the microenvironment. Within the leptomeninges, LM cells adhere to and interact with the innermost layer of the meninges, the pia mater, which contains fibroblast-like cells. Co-culture of cancer cells with pial cells induced changes in the pial cell transcriptome and secretome, leading to increased IL8, IL6, and CXCL1 production. This communication between cancer cells and pial cells is preserved in the absence of direct cell-cell contact. These pial cells support cancer cell growth in vivo, as measured by co-implantation experiments. In addition, bulk RNA sequencing of mouse pial cells shows an inflammatory signature upregulated in the presence of LM. Taken together, these observations support a cancer-associated-fibroblast like role for pial cells in the setting of LM. Our work extends the CAF phenotype beyond classical fibroblasts to include pial cells, suggesting novel therapeutic opportunities within CNS malignancies.
LMAP-07 POTENTIAL MECHANISM OF IMMUNE ESCAPE RELATED TO TUMOR-ASSOCIATED MACROPHAGE IN GLIOBLASTOMA AFTER COMBINED THERAPY WITH RADIOTHERAPY AND IMMUNE CHECKPOINT BLOCKER
Authors: Zhang Chi , Wang Fei , Khan Rubayat 
Published: August 2023

Abstract
Immune checkpoint blockers (ICBs) have revolutionized the treatment of cancer. Radiotherapy (RT) has been demonstrated to increase the survival benefit of ICBs in some cancers through its local and systemic immunomodulation, although its efficacy in glioblastoma (GBM) is very limited. With a thorough investigation of the immune responses to single and dual treatment utilizing single-cell RNA-seq analyses on the synergy of RT and anti-PD-L1 antibody (aPD-L1), we studied the potential mechanism of immune escape in GBM even when RT and ICB are combined. Our findings demonstrated a statistically significant longer survival of mice treated with RT and aPD-L1 combined than either single modality of treatment in an orthotopic syngeneic GBM model achieving a 70% cure rate. In the tumor tissues collected from the mouse brain that failed dual treatment, i.e., immune escaped, immune cell profiling still demonstrated much lower T regulatory cells and higher CD8+ cytotoxic T cells infiltrated to tumor, and elevated CD8+/CD4+ and CD8+/Treg ratios in the dual therapy group compared to single therapies, as expected with synergistic effects of dual treatment. RT with aPD-L1 markedly reduced CD8+ and CD4+ T exhaustion cells and elevated T-memory cells in comparison to single modality groups. Nevertheless, compared to the RT alone or no treatment control group, dual therapy failed to decrease the proportion of Arginase1-positive glioma-associated macrophages (GAM) in macrophage/monocytes in tumor microenvironment, which were considerably increased if treated with aPD-L1 only. Moreover, the combination of RT with aPD-L1 did not alter immunosuppressive gene expression in the macrophage/monocyte groups. In conclusion, our research demonstrated that RT and aPD-L1 together may elicit a potent and durable antitumor immune response in the GBM mouse model through regulating lymphocytes but not macrophages. Our findings point to the urgent need for research into GAM-modulating drug and their potential to prevent immunological escape.
SDPS-47 CIRCULATING TUMOR CELL ANALYSIS FROM THE CEREBROSPINAL FLUID INFORMS EARLY DIAGNOSIS, TREATMENT AND PROGNOSIS IN LEPTOMENINGEAL CARCINOMATOSIS
Authors: Sandri Andrea , Bazhenov Nadia , Orosco Heather , Turpin Tiffany , Shatsky Rebecca , Schulte Jessica , Piccioni David 
Published: August 2023

Abstract

INTRODUCTION
Leptomeningeal carcinomatosis (LMC) is an aggressive pattern of recurrence with limited survival. Early detection by traditional CSF (cerebrospinal fluid) cytology is poor. We evaluated CSF circulating tumor cells (CTCs) with a commercially available assay (CNSideTM) and subsequent molecular profiling on captured CTCs, to determine if CTC analysis would lead to early detection, identification of therapeutic targets, and improved treatment outcomes.

METHODS
We analyzed 58 patients with carcinoma who were referred to Neuro-oncology clinic for evaluation for LMC, and underwent comprehensive work-up with CSF sampling (traditional cytology and CTCs), brain and spine MRI, and neurologic examination, and were followed for survival.

RESULTS
28/58 were diagnosed with LMC (breast n=16, Lung n=9, other n=3). 24/28 were female. Median KPS was 80. 15/16 breast cancer patients were HER2- on initial systemic cancer diagnosis. The mean time to LMC from cancer diagnosis was 70 months. In the patients with LMC, CTCs were positive in 96%, compared to traditional cytology, which was positive in 64%. Molecular analysis of the CTCs in 15 patients with HER2- primary tumors detected HER2+ amplification in 3/15 patients. 14/28 patients received first line therapy for LMC with radiation + systemic chemotherapy + intrathecal chemotherapy, and 8/28 received systemic chemotherapy + intrathecal chemotherapy. 6/28 received other combinations. The overall median progression-free survival (PFS) was 5.3 months and the overall survival (OS) was 7.7 months from LMC diagnosis (breast PFS 4.5 months, OS 6.3 months; Lung PFS 5.3 months, OS 23.5 months).

CONCLUSION
CTC detection had superior sensitivity compared to traditional cytology, allowing for earlier detection of LMC and consequently earlier treatment. Molecular analysis of CTCs can allow for identification of therapeutic targets specific to the CSF, such as intrathecal trastuzumab for HER2+ LMC. PFS and OS in our cohort with this approach suggested improved survival compared to historical controls.