bluuebunny/crossref_metadata_2025 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

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

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

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

Synopsis

Teleosts 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

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, >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

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

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

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

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

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

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

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.
SPCR-05 ENVIRONMENTAL ENRICHMENT AMONG BRAINTUMOR SURVIVORS
Authors: Figuracion Karl Cristie , Hunt David , Donald Christine Mac , Thompson Hilaire
Published: August 2023

Individuals from underserved communities who received photon radiation are at a disproportionately increased risk of accelerated aging and symptom burden that significantly impacts independence and overall functioning. There is limited knowledge of environmental factors that mitigate these long-term sequelae. The aim of the study is to explore if higher levels of environmental enrichment (EE) are neuroprotective against accelerated brain aging experienced by brain tumor (BT) survivors who received radiation.

METHODS: The study employed a retrospective cohort design among persons with low-grade glioma treated with radiation approximately 5 years from the original diagnosis (N=39). EE consists of social network/engagement, physical activity, and employment status/financial stability measured by the Berkman-Syme Social Network Index, International Physical Activity Questionnaire, Vocational Index Scale, and Socioeconomic Questionnaires, respectively. EE at enrollment is classified into high, moderate, or low levels. Montreal Cognitive Assessment and Symbol Digit Modality Test at enrollment measure cognitive function. Karnofsky Performance Status Scale and the MD Anderson Symptom Inventory – BT module at enrollment are used to measure functional status. Cortical volume is measured using temporal brain MRI images from the time of diagnosis, 3 and 5 years after diagnosis. Images are processed using FreeSurfer segmentation software. Linear mixed models will estimate mean cerebral atrophy and explore the association to cognitive and functional data across time adjusted for covariates.

RESULTS: Research analysis in progress. Thirty-nine participants have been enrolled in the study. The median age is 44, 22 are male, and 27 are female. There are 18 Individuals diagnosed with Astrocytoma and 19 with Oligodendroglioma. Thirty-three percent of individuals have low EE, 43.5% have moderate EE, and 23% have high EE.

CONCLUSION: BT survivors are at an increased risk of accelerated aging and progressive neurological decline. EE may serve as a positive stimulation that improves neuroplasticity and reduces accelerated aging after brain radiation.
Pediatric Provider and Staff Burnout in Federally Qualified Community Health Centers
Authors: Hill Cameron , Justo Stacy , Park Hannah , Bair-Merritt Megan , Morris Anita , Feinberg Emily , Sheldrick R. Christopher
Published: August 2023

This study examined changes in provider and staff burnout in 4 Boston-area federally qualified community health centers (FQHCs) participating in a pediatric behavioral health integration project. Utilizing the Maslach Burnout Inventory—Human Services Survey for Medical Personnel (MBI-HSSMP), the study found that emotional exhaustion among primary care providers (M = 20.5; confidence interval [CI], 17.8-23.2) was higher (P = .001) than that among behavioral health clinicians (M = 13.6; CI, 10.4-16.8) and (P = .00005) community health workers (M = 10.8; CI, 7.3-14.2). Emotional exhaustion among staff increased (P = .04) from baseline (M = 16.8; CI, 15.0-18.6) to follow-up (M = 20.8; CI, 17.5-24.2), but burnout at follow-up was lower than national averages. FQHCs are integral in caring for marginalized patients; therefore, supporting a stable workforce by minimizing burnout is essential.
Appointment Pathways
Authors: Keister Adrian C. , Munden Derek R. , Bailey Brian S.
Published: August 2023

Patients have multiple outpatient appointments for various reasons. Analyzing patients' related appointments provides insight into referral patterns, leading to recommendations for ideal care and more efficient planning. We model these appointments with causal graphs via Judea Pearl's causal graph approach. Once we define the causal relationships in the appointment data, we leverage a graph database and visualization software to investigate valuable patterns and relationships in patient care over time. The Pathways tool allows yield management at specialty, provider, or appointment levels. Leaders use this tool to anticipate a patient's downstream appointments; the tool provides staffing insights and the impact of growing demand.
Neurocognitive Outcomes in Multiethnic Pediatric Brain Tumor Patients Treated With Proton Versus Photon Radiation
Authors: Unnikrishnan Soumya , Yip Anthony T. , Qian Alexander S. , Salans Mia A. , Yu Justin D. , Huynh-Le Minh-Phuong , Reyes Anny , Stasenko Alena , McDonald Carrie , Kaner Ryan , Crawford John R. , Hattangadi-Gluth Jona A.
Published: August 2023

Background:

We analyzed post-radiation (RT) neurocognitive outcomes in an ethnically diverse pediatric brain tumor population undergoing photon radiotherapy (XRT) and proton radiotherapy (PRT).

Procedure:

Post-RT neurocognitive outcomes from 49 pediatric patients (37% Hispanic/Latino) with primary brain tumors were analyzed. Tests included cognitive outcomes, behavioral outcomes, and overall intelligence. For each outcome, proportion of patients with cognitive impairment (scores <1.5 SD) was calculated. The Fisher exact tests compared proportion of patients with impairment and t tests compared T-scores between XRT (n=32) and PRT (n=17) groups. Linear regression assessed associations between radiation modality and outcomes.

Results:

Median follow-up was 3.2 and 1.8 years in the XRT and PRT groups, respectively. The median RT dose was 54.0 Gy. We found impairment in 16% to 42% of patients across most neurocognitive domains except executive function. There was no difference in scores between XRT and PRT groups. Regression analyses revealed no association of neurocognitive outcomes with radiation modality. Non-Hispanic patients had better Verbal Comprehension Index and General Ability Index scores than Hispanic patients (P<0.05).

Conclusions:

Among pediatric patients with brain tumors receiving RT, all cognitive domains were affected except executive function. Radiation modality was not associated with neurocognitive outcomes. Hispanic patients may be more vulnerable to posttreatment cognitive effects that warrant further study.
Creating a Community of Nurse Educator Scholars
Authors: Schuler Monika S. , Vottero Beth , Altmiller Gerry
Published: August 2023

Background:

Engaging in scholarship is a critical component of being an effective nurse educator and can have a significant impact on the nursing profession as a whole.

Problem:

Nurse educators are expected to teach and simultaneously engage in scholarship. Barriers include heavy workloads and lack of resources including faculty mentors. Evidence supports that organized work groups support success.

Approach:

Members of the Quality and Safety Education for Nurses (QSEN) Academic Task force were queried about scholarly activity as a result of engagement with fellow task force members.

Outcomes:

Scholarly outcomes included numerous peer-reviewed publications, teaching tips, presentations, and grants.

Conclusion:

Participating in national work groups can serve as a platform for fostering a community of scholars to make meaningful contributions to the profession.
The Genetic Landscape of Fibroepithelial Lesions of the Breast
Authors: Dadmanesh Farnaz , Li Xiaomo , Leong Matthew , Maluf Horacio , Balzer Bonnie
Published: August 2023

Fibroepithelial lesions of the breast encompass a broad spectrum of lesions from fibroadenomas and their variants to phyllodes tumors, including their clinical range of benign, borderline, and malignant. Classification of this spectrum of neoplasms has historically and currently been based purely on morphology, although the nomenclature has shifted over the years largely due to the significant histologic overlap that exists primarily within the cellular fibroadenomas to borderline malignant phyllodes tumor categories. A review of the current diagnostic challenge, proposed ancillary studied and their value in prognostic significance, is provided. This article highlights the most recent molecular and genetic findings as well as the limitations of the studies, in the context of practical and available applications for the diagnostician and managerial implications for the clinician.
A unique human cord blood CD8+CD45RA+CD27+CD161+T cell subset identified by flow cytometric data analysis using Seurat
Authors: Reyes Julen Gabirel Araneta , Ni Duan , Santner-Nanan Brigitte , Pinget Gabriela Veronica , Kraftova Lucie , Ashhurst Thomas Myles , Marsh-Wakefield Felix , Wishart Claire Leana , Tan Jian , Hsu Peter , King Nicholas Jonathan Cole , Macia Laurence , Nanan Ralph
Published: August 2023

Advances in single cell analysis, especially cytometric approaches, have profoundly innovated immunological research. This has resulted in an expansion of high dimensional data, posing great challenges for comprehensive and unbiased analysis. Conventional manual analysis thus becomes untenable, while most computational methods lack flexibility and interoperability, hampering usability. Here, for the first time, we adapted Seurat, a single cell RNA sequencing (scRNA-seq) analysis package, for end-to-end flow cytometric data analysis. We showcased its robust analytical capacity by analyzing the adult blood and cord blood T cell profiles, which was validated by Spectre, another cytometric data analysis package, and manual analysis. Importantly, a unique CD8+CD45RA+CD27+CD161+T cell subset, was identified in cord blood and characterized using flow cytometry and scRNA-seq analysis from a published dataset. Collectively, Seurat possesses great potential for cytometric data analysis. It facilitates thorough interpretations of high dimensional data using a single pipeline, implementing data-driven investigation in clinical immunology.
The importance of DNA sequence for nucleosome positioning in transcriptional regulation
Authors: Sahrhage Malte , Paul Niels Benjamin , Beißbarth Tim , Haubrock Martin
Published: August 2023

Nucleosome positioning is a key factor for transcriptional regulation. Nucleosomes regulate the dynamic accessibility of chromatin and interact with the transcription machinery at every stage. Influences to steer nucleosome positioning are diverse, and the according importance of the DNA sequence in contrast to active chromatin remodeling has been subject of long discussion. In this study, we evaluate the functional role of DNA sequence for all major elements along the process of transcription. We developed a random forest classifier based on local DNA structure that assesses the sequence-intrinsic support for nucleosome positioning. On this basis, we created a simple data resource that we applied genome-wide to the human genome. In our comprehensive analysis, we found a special role of DNA in mediating the competition of nucleosomes with cis-regulatory elements, in enabling steady transcription, for positioning of stable nucleosomes in exons and for repelling nucleosomes during transcription termination. In contrast, we relate these findings to concurrent processes that generate strongly positioned nucleosomes in vivo that are not mediated by sequence, such as energy-dependent remodeling of chromatin.

GRAPHICAL ABSTRACT
Pathogenic mutations of human phosphorylation sites affect protein-protein interactions
Authors: Rrustemi Trendelina , Meyer Katrina , Roske Yvette , Uyar Bora , Akalin Altuna , Imami Koshi , Ishihama Yasushi , Daumke Oliver , Selbach Matthias
Published: August 2023

Despite their lack of a defined 3D structure, intrinsically disordered regions (IDRs) of proteins play important biological roles. Many IDRs contain short linear motifs (SLiMs) that mediate protein-protein interactions (PPIs), which can be regulated by post-translational modifications like phosphorylation. 20% of pathogenic missense mutations are found in IDRs, and understanding how such mutations affect PPIs is essential for unraveling disease mechanisms. Here, we employed peptide-based interaction proteomics to investigate 36 disease-causing mutations affecting phosphorylation sites. Our results unveiled significant differences in interactomes between phosphorylated and non-phosphorylated peptides, often due to disrupted phosphorylation-dependent SLiMs. We focused on a mutation of a serine phosphorylation site in the transcription factor GATAD1, which causes dilated cardiomyopathy. We found that this phosphorylation site mediates interaction with 14-3-3 family proteins. Follow-up experiments revealed the structural basis of this interaction and suggest that 14-3-3 binding affects GATAD1 nucleocytoplasmic transport by masking a nuclear localisation signal. Our results demonstrate that pathogenic mutations of human phosphorylation sites can significantly impact protein-protein interactions, offering fresh insights into potential molecular mechanisms underlying pathogenesis.
Island demographics and trait associations in white-tailed deer
Authors: Cars Brooklyn S. , Kessler Camille , Hoffman Eric A. , Côté Steeve D. , Koelsch Daniel , Shafer Aaron B.A
Published: August 2023

When a population is isolated and composed of few individuals, genetic drift is the paramount evolutionary force that results in the loss of genetic diversity. Inbreeding might also occur, resulting in genomic regions that are identical by descent, manifesting as runs of homozygosity (ROHs) and the expression of recessive traits. Likewise, the genes underlying traits of interest can be revealed by comparing fixed SNPs and divergent haplotypes between affected and unaffected individuals. Populations of white-tailed deer (Odocoileus virginianus) on islands of Saint Pierre and Miquelon (SPM, France) have high incidences of leucism and malocclusions, both considered genetic defects; on the Florida Keys islands (USA) deer exhibit smaller body sizes, a polygenic trait. Here we aimed to reconstruct island demography and identify the genes associated with these traits in a pseudo case-control design. The two island populations showed reduced levels of genomic diversity and a build-up of deleterious mutations compared to mainland deer; there was also significant genome-wide divergence in Key deer. Key deer showed higher inbreeding levels, but not longer ROHs, consistent with long-term isolation. We identified multiple trait-related genes in ROHs includingLAMTOR2which has links to pigmentation changes, andNPVFwhich is linked to craniofacial abnormalities. Our mixed approach of linking ROHs, fixed SNPs and haplotypes matched a high number (∼50) of a-priori body size candidate genes in Key deer. This suite of biomarkers and candidate genes should prove useful for population monitoring, noting all three phenotypes show patterns consistent with a complex trait and non-Mendelian inheritance.
Effects of calibrated blue–yellow (–S+[L+M], +S–[L+M]) changes in light on the human circadian clock
Authors: Blume Christine , Cajochen Christian , Schöllhorn Isabel , Slawik Helen C. , Spitschan Manuel
Published: August 2023

Evening exposure to short-wavelength light can acutely affect the circadian clock located in the suprachiasmatic nuclei, sleep, and alertness. The intrinsically photosensitive retinal ganglion cells (ipRGCs) expressing the photopigment melanopsin are thought to be the primary drivers of these effects. Much less is known about the contribution of the colour-sensitive cones. Using calibrated silent-substitution changes in light colour along the blue-yellow axis, we investigated whether mechanisms of colour vision affect the human circadian system and sleep. In a 32.5-h repeated within-subjects protocol, 16 healthy participants (8 women, 18-35 years old) were exposed to three different light scenarios for 1 h starting 30 min after habitual bedtime: a control condition (“background”, 93.5 photopic lux), intermittently flickering yellow-bright light (1 Hz, 30s on-off, 123.5 photopic lux), and intermittently flickering blue-dim light (1 Hz, 30s on-off; 67.0 photopic lux). Importantly, there was no difference in melanopsin excitation (163.2±2.1 lux melanopic EDI) between the three lighting conditions, allowing us to determine the unique contribution of the blue-yellow colour system. Our analyses did not yield conclusive evidence for differences between the three lighting conditions regarding circadian melatonin phase delays, melatonin suppression, subjective sleepiness, psychomotor vigilance, or sleep. Thus, in this study, we found no evidence that evening light changing along the blue-yellow dimension under moderate light levels typical for room illumination has a major impact on the human circadian clock or sleep. Our work underscores the previously demonstrated primary role of melanopsin-containing ipRGCs in mediating these effects.
Non-sequential alignment of binding sites for fast peptide screening
Authors: Guyon Frédéric , Moroy Gautier
Published: August 2023

Motivation

Peptides are molecules involved in many essential biological activities by interacting with proteins in the body. They can also be used as therapeutic molecules, particularly to disrupt protein-protein interactions involved in disease. However, it is difficult to identify potential therapeutic peptides if the structure of the protein-protein complex to be inhibited has not been solved.

Results

The PepIT program was developed to propose peptides that can interact with a given protein. PepIT is based on a non-sequential alignment algorithm to identify peptide binding sites that share geometrical and physicochemical properties with a surface region of the target protein. PepIT compares the entire surface of the target protein with the peptide binding sites of the Propedia dataset, which contains more than 19,000 high-resolution protein-peptide structures. Once a peptide binding site similar to a portion of the protein surface is found, the peptide bound to the binding site is repositioned on the corresponding portion of the protein surface.

Availability and implementation

The PepIT source code is freely available athttps://github.com/DSIMB/pepit

Supplementary information

Supplementary data are available online.
Meta-analysis of herbicide non-target effects on pest natural enemies
Authors: Zilnik Gabriel , Bergeron Paul , Chuang Angela , Diepenbrock Lauren , Hanel Aldo , Middleton Eric , Moretti Erica , Schmidt-Jeffris Rebecca
Published: August 2023

A critical component of integrated pest management is minimizing disruption of biological control by reducing use of pesticides with significant non-target effects on natural enemies. Insecticide non-target effects testing for natural enemies has become increasingly common, but research examining the non-target effects of herbicides on natural enemies is scarce and recommendations regarding herbicide selectivity are non-existent. We used meta-analysis to summarize laboratory bioassays testing non-target effects of herbicides on arthropod natural enemies and identify patterns in taxon susceptibility and active ingredient toxicity. Data was extracted from 103 papers representing 801 total observations. Herbicides increased natural enemy mortality and decreased longevity, reproduction, and predation. Mesostigmatan mites and hemipterans were the most sensitive to herbicides and spiders, neuropterans, and hymenopterans were the least sensitive. Mortality was higher in juvenile predators versus parasitoids, but did not differ between adults; parasitoid juveniles are likely better protected within the host. In terms of acute mortality, metribuzin, glufosinate, and oxyfluorfen were the most harmful herbicides. Only nicosulfuron, rimsulfuron, pendimethalin, phenmedipham, atrazine, and urea did not increase natural enemy mortality. The large effect size of glufosinate is particularly concerning, as it is the most likely replacement herbicide for glyphosate in many crops. Many active ingredients remain under-studied. Our analysis indicates that herbicides have a strong potential to disrupt biological control in cropping systems.

Simple Summary

Reducing the use of pesticides that harm natural enemies of crop pests is important to pest management. Currently, there is limited information on how herbicides might affect natural enemies. The researchers found that herbicides increased natural enemy mortality and reduced their longevity and efficacy as predators. Some potential glyphosate replacement herbicides were more harmful than glyphosate. There was little or no data available for many herbicides and beneficial insects, indicating that much more research is needed on this topic.
Physiological roles of endocytosis and presynaptic scaffold in vesicle replenishment at fast and slow central synapses
Authors: Mahapatra Satyajit , Takahashi Tomoyuki
Published: August 2023

After exocytosis, release sites are cleared of vesicular residues to replenish with transmitter-filled vesicles. Endocytic and scaffold proteins are thought to underlie this site-clearance mechanism. However, the physiological significance of this mechanism at diverse mammalian central synapses remains unknown. Here, we tested this in a physiologically optimized condition using action potential evoked EPSCs at fast calyx synapse and relatively slow hippocampal CA1 synapse, in post-hearing mice brain slices at 37°C and in 1.3 mM [Ca2+]. Pharmacological block of endocytosis enhanced synaptic depression at the calyx synapse, whereas it attenuated synaptic facilitation at the hippocampal synapse. Block of scaffold protein activity likewise enhanced synaptic depression at the calyx but had no effect at the hippocampal synapse. At the fast calyx synapse, block of endocytosis or scaffold protein activity significantly enhanced synaptic depression as early as 10 ms after the stimulation onset. Unlike previous reports, neither endocytic blockers nor scaffold protein inhibitors prolonged the recovery from short-term depression. We conclude that the release-site clearance by endocytosis can be a universal phenomenon supporting vesicle replenishment at both fast and slow synapses, whereas the presynaptic scaffold mechanism likely plays a specialized role in vesicle replenishment predominantly at fast synapses.
Cross-family small GTPase ubiquitination by the intracellular pathogenLegionella pneumophila
Authors: Steinbach Adriana M. , Bhadkamkar Varun L. , Jimenez-Morales David , Stevenson Erica , Jang Gwendolyn M. , Krogan Nevan J. , Swaney Danielle L. , Mukherjee Shaeri
Published: August 2023

The intracellular bacterial pathogenLegionella pneumophila(L.p.) manipulates eukaryotic host ubiquitination machinery to form its replicative vacuole. While nearly 10% ofL.p.’s arsenal of ∼330 secreted effector proteins have been biochemically characterized as ubiquitin ligases or deubiquitinases, a comprehensive measure of temporally resolved changes in the endogenous host ubiquitinome during infection has not been undertaken. To elucidate howL.phijacks ubiquitin signaling within the host cell, we undertook a proteome-wide analysis of changes in protein ubiquitination during infection. We discover thatL.p.infection results in increased ubiquitination of host proteins regulating subcellular trafficking and membrane dynamics, most notably 63 of ∼160 mammalian Ras superfamily small GTPases. We determine that these small GTPases predominantly undergo non-degradative monoubiquitination, and link ubiquitination to recruitment to theLegionella-containing vacuole membrane. Finally, we find that the bacterial effectors SidC/SdcA play a central, but likely indirect, role in cross-family small GTPase ubiquitination. This work highlights the extensive reconfiguration of host ubiquitin signaling by bacterial effectors during infection and establishes simultaneous ubiquitination of small GTPases across the Ras superfamily as a novel consequence ofL.p.infection. This work positionsL.p.as a tool to better understand how small GTPases can be regulated by ubiquitination in uninfected contexts.