bluuebunny/crossref_metadata_2025_split huggingface dataset:
CX3CR1/CX3CL1 axis in breast cancer pathology and its therapeutic use
Authors: Singh Rajesh , Singh Santosh Kumar , Mishra Manoj K , Lillard James W 
Published: January 2023

Abstract
Recent reports from the breast cancer (BrCa) suggests that &gt;90% of patients diagnosed at an early stage are successfully treated with surgery, chemotherapy, and radiation or combination. However, chemoresistance, recurrence and metastasis have been noticed in advanced BrCa patients and still remains a challenge. Chemokine receptor-ligand interaction has been noticed to play a significant role in homing to cancer cells to distant sites. Fractalkine (CX3CL1), a structurally distinct chemokine, and its receptor (CX3CR1), are expressed in majority of the cancer including BrCa. Thus, therapeutic strategies that inhibit tumor immune microenvironment of BrCa cells can improve the quality life of patients. In this study, we analyzed the expression and role of the CX3CR1/CX3CL1 axis interface in the progression and invasiveness of BrCa. In vitro investigation of BrCa cell lines MCF-7 and MDA-MB-231 showed higher expression of CX3CR1 analyzed through flow cytometry, RT-PCR, western blot, and immunofluorescence techniques. This was corroborated by our clinical tissue microarray results that showed significantly (p &lt; 0.001) higher expression of CX3CR1 and CX3CL1 in cancerous tissues compared to normal tissues. Furthermore, treatment of BrCa cells with small molecule antagonist JMS-17-2 abrogated the proliferation and metastasis of cancer cells delineating the role CX3CR1-CX3CL1 chemotaxis mediated metastasis of BrCa. This data demonstrates, both biological and clinical significance of CX3CR1 and CX3CL1 expression that may contribute to BrCa metastasis. Inhibition of CX3CR1/CX3CL1 interaction thus could be a promising avenue for researchers to target or treat BrCa.
Validation of a murine multiplex panel to quantitate cytokine release syndrome biomarkers
Authors: Lehmann Jason S. , Mays-Aboagye Kelli , Liao Wen-Cheih , Zhao Amy , Ji Shaoquan , Ni Jessie 
Published: January 2023

Abstract
Cytokine release syndrome (CRS) is a systemic inflammatory response syndrome caused by adverse effects of monoclonal or CAR T cell immunotherapy. CRS can also arise as a complication during infection in response to sepsis. Regardless of its initial etiology, CRS is characterized by an auto-amplifying cascade of leukocyte activation which drives the production and release of several inflammatory biomarkers.
We have developed a murine-specific bead-based multiplex assay panel that simultaneously quantifies up to 13 CRS biomarkers from one sample volume aliquot using commonly available flow cytometers. This panel is manufactured with highly specific antibodies in order to ensure robust assay sensitivities, analytical accuracy, and reproducibility.
The panel was validated with biological samples generated from both in-vitro and in-vivo models of inflammatory cytokine release. Trends in cytokine expression differences between treatment groups were orthogonally confirmed using single target ELISAs.
Taken together, our cytokine release studies and rigorous performance validation establish this multiplex panel as a reliable tool for researchers seeking to mitigate the potentially fatal complications of CRS during infection and immunotherapy treatment.
Biological embedding from adverse childhood experiences in the development of an altered inflammatory state and poor health outcomes in young adults
Authors: Moore Jessy , Wade Terrance J. , Cairney John , O’Leary Deborah D. , MacNeil Adam J. 
Published: January 2023

Abstract
Exposure to emotional, physical, and/or sexual abuse as a child, cumulatively referred to as Adverse Childhood Experiences (ACEs), has been linked with poor health outcomes in early adulthood. Toward a mechanistic explanation for this link, dysregulated inflammation has garnered attention as a potential ‘social-immunological’ axis. Altered immune profiles are associated with ACEs and may contribute to mental health status, cardiovascular disease, and early mortality. Increases in circulating interleukin-6 (IL-6), C-reactive protein (CRP), and tumor necrosis factor α (TNFα) have been detected in individuals exposed to ACEs and are proposed to signal an immunological link to these outcomes. While this sets the stage in characterizing the inflammatory profile, gaps remain in the cast of mediators involved, preventing a more refined mechanistic view. We thus aim to expand the associated immunological cast. A sample of young adults from the Niagara Longitudinal Heart Study self-reported early life trauma (ACEs), and serum levels of a panel of immune biomarkers were quantified. We confirm that levels of IL-6, CRP and TNFα are altered, but also further identify new immune biomarkers that are significantly correlated (p&lt;0.05) with ACEs, including pentraxin, chitinase, and interferons. This further refines the nature of ACE-dependent immunological dysregulation and offers new insights into contributing mechanisms, potential early risk-factor detection, and/or therapeutic targets in those exposed to ACEs. This evidence encourages promotion of public health initiatives and psychosocial preventative interventions aimed at limiting early adversity and its sequalae as an investment in later health status/quality of life.
UHRF1 Controls Thymocyte Fate Decisions Through the Epigenetic Regulation of EGR1 Expression
Authors: Zhang Yiwen , Chen Yingshi , Ma Rong , Wei Lai , Zhang Hui 
Published: January 2023

Abstract
Thymocyte differentiation is a highly complex process that is accompanied by epigenetic changes. Ubiquitin-like containing PHD ring finger 1 (UHRF1) is a critical epigenetic modifier involved in various cellular processes. Here, we demonstrated that it is highly expressed in T-cell precursors of the thymus. Further, its deficiency results in significantly-reduced thymocyte cellularity and thymus size. Through systematic analysis based on single-cell RNA-sequencing, we found that UHRF1 deficiency thwarts αβ T cell lineage development while biasing γδ lineage differentiation, dampens the progression of immature single-positive cells (ISPs). Further, the analysis of gene-regulatory networks demonstrated that UHRF1 controls the expression of early growth response 1 (EGR1). UHRF1 interacts with DNA methyltransferase 1 (DNMT1) at the CpG promoter region of Egr1 loci and affects the nearby chromatin modifications of H3K9me3 and H3K4me3. Taken together, our results demonstrate that UHRF1 is a key factor that mediates the epigenetic regulation of EGR1 and consequently thymocyte fate decisions.
Tissue plasminogen activator mobilizes neutrophils and T cells that exacerbate hemorrhagic transformation in stroke
Authors: Shi Kaibin , Liu Qiang , Jia Dong-Mei , Yang Xiaoxia , Zou Ming , Shi Samuel , Dong Jing-fei , Sheth Kevin N , Wang Xiaoying , Shi Fu-Dong 
Published: January 2023

Abstract
Hemorrhagic complications represent a major limitation of thrombolytic therapy with tissue plasminogen activator (tPA) in patients with ischemic stroke. Here we report that tPA induces a swift surge of circulating neutrophils and T cells in both ischemic stroke patients and a rat model of focal embolic stroke. tPA exacerbates endothelial injury and increases adhesion and migration of neutrophils and T cells, which are associated with brain hemorrhage in rats subjected to embolic stroke. Genetic ablation of annexin A2 in neutrophils and T cells diminishes the effect of tPA on these cells. Decoupling the interaction between mobilized neutrophils/T cells and the neurovascular unit, achieved by using a sphingosine-1-phosphate receptor 1 modulator RP101075 and a CCL2 synthesis inhibitor bindarit, which block lymphocyte egress and myeloid cell recruitment, respectively, attenuates hemorrhagic transformation and improves neurological function after tPA thrombolysis. Our study suggests that immune invasion of the neurovascular unit represents a previously unrecognized mechanism governing the emergence of tPA-mediated brain hemorrhage, which can be overcome by precise immune modulation during thrombolytic therapy.
Monocytes and monocyte-derived macrophages as mediators of sex differences in allergic asthma
Authors: Heller Nicola M , Diaz Mireya Becerra 
Published: January 2023

Abstract
Allergic asthma is a chronic, immune-mediated lung disease mediated that affects more than 200 million people worldwide. Alveolar macrophages (AM) and monocytes are important cellular contributors to asthma. During allergic lung inflammation, AM polarize to a predominantly M2 phenotype. Recruited monocyte-derived macrophages (MDM), rather than resident AM, have been linked to worse allergic lung inflammation by inducing inflammatory cell recruitment, tissue remodeling and lung fibrosis. There are sex differences in the prevalence and severity of asthma. Women have worse symptoms, longer hospital stays, more asthma-related deaths, and they are more refractory to therapy. Here, we wanted to determine if differences in M2 polarization and chemokine receptors by monocytes and MDM from women compared to men could account for sex differences in asthma pathogenesis. We obtained blood monocytes from healthy and asthmatic female and male donors in parallel. We analyzed the expression of chemokine and IL-4/IL-13 receptors, and in M2 macrophage genes in monocytes and MDM stimulated with IL-4 and IL-13. We found robust differences in CCR2, CCR5, and γC between healthy and asthmatic donors. Moreover, we found sex differences in M2 gene expression between asthmatic women and men. Female cells, in general, induced higher M2 gene expression in response to IL-4. Female monocytes expressed more chemokine receptors that would facilitate recruitment to the asthmatic lung. Our findings provide novel insights into how sex affects monocyte and macrophage polarization in asthmatic patients. These sex differences may represent a new therapeutic avenue for managing pathogenic M2 polarization and preventing monocyte recruitment to the allergic lung.
Mucosal IgE antibody secreting cell (ASC) repertoire analysis suggests an extrafollicular developmental program
Authors: Ramonell Richard Paul , Woodruff Matthew Charles , Saney Celia Lorenza , Duan Meixue , Lee Eun-Hyung 
Published: January 2023

Abstract
Allergic fungal rhinosinusitis (AFRS) is a subset of chronic rhinosinusitis with nasal polyposis (CRSwNP). AFRS is primarily associated with a type 2 inflammatory profile including eosinophilic mucosal infiltration and high serum and mucosal titers of IgE. Patients with AFRS have increased frequencies of IgE ASCs within NP structures, although it is unclear if these cells originate from a germinal center (GC) reaction or undergo local mucosal extrafollicular differentiation and class switch recombination (CSR). To better understand the origin of these cells, CD19+ and CD19− ASCs from human NPs (n = 3) were isolated for integrated single cell RNAseq and adaptive immune receptor repertoire (AIRRseq) profiling. Resulting AIRRseq data were piped into the ImMunoGeneTics (IMGT) V-Quest platform for comprehensive B cell receptor analysis. Interestingly, mutational frequency analysis showed that IgE ASCs have a lower V region mutation frequency (7.4 +/− 2.7%) compared with IgG (9.2 +/− 3.5%) and IgA (9.4 +/− 3.4%) ASCs from the same individuals. Additionally, IgE ASCs have an intermediate frequency of mutations in activation-induced deaminase WRC hotspots when compared with other isotypes. Finally, IgH repertoire lineage analysis does not indicate clonal expansion of NP IgE ASCs. These data suggest NP IgE ASCs compared to IgG and IgA ASCs from patients with AFRS may undergo a distinct developmental program that includes extrafollicular differentiation and CSR.
Characterization of milk-specific immunoglobulins of oral immunotherapy participants
Authors: Zhao Wei Wendy , Ke Danbing , Cohen Casey , Lejtenyi Duncan , Ben-Shoshan Moshe , Grunebaum Eyal , Upton Julia , Mazer Bruce 
Published: January 2023

Abstract
Since the standard treatment for food allergies such as cow’s milk allergy is strict avoidance and epinephrine injection upon anaphylaxis, alternative treatments are needed. Allergic reactions including anaphylaxis are presumed to be due to high-affinity immunoglobulin (Ig)E antibodies against cow’s milk proteins (CMP) such as casein. Currently, our laboratory is leading a pan-Canadian randomized controlled trial of milk oral immunotherapy (OIT). Participants in the OIT receive increasing doses of cow’s milk until 200ml of milk is tolerated without allergic reactions, followed by 12 months of follow-up while continuing to ingest milk and dairy at least twice a week. Using enzyme-linked immunosorbent assay (ELISA) to detect antibodies specific for casein, we determined that female participants have higher casein-specific IgE and IgG4 than male participants. We then aimed to assess whether the sex-dependent change in the affinity of immunoglobulins throughout OIT. Using a modified ELISA that assays for relative binding affinity, we found that the affinity of IgE for casein decreases in approximately half of the participants following the 12-months observation period, compared to the baseline. This is associated with an increase in tolerance and significant protection against minor symptoms or adverse reactions following milk ingestion. The results suggest that oral immunotherapy may induce changes in the affinity binding of allergen-specific IgE and contribute to the improvement of symptoms associated with allergy desensitization to milk.
Safe, rapid suppression of IgE-mediated allergy with monovalent (mv) anti-human (hu) FceRIa monoclonal antibody (mAb)
Authors: Khodoun Marat , Peipp Matthias , Morris Suzanne C , Angerman Elizabeth , Potter Crystal , Herr Andrew , Mulloy James , Wunderlich Mark , Finkelman Fred D 
Published: January 2023

Abstract

Background
Mast cells and FceRI, the high affinity IgE receptor (R), are central to allergy pathogenesis. Strong FceRI crosslinking induces severe allergy while low-level crosslinking removes IgE from mast cells and desensitizes them.

Hypothesis
IgE-mediated allergy can be safely suppressed by a mv anti-FceRIa mAb that persistently crosslinks FceRI to a limited extent.

Methods
We tested our hypothesis with: 1) divalent (dv) anti-huFceRIa mAbs that bind FceRI regardless of its association with IgE; 2) mv Fab/Fc derivatives of these mAbs, which do not directly crosslink FceRI; 3) mice that express hu, instead of mouse FceRIa; hu FceRIa mice that also have a mutant, hyperresponsive IL-4 receptor; and immunodeficient, human stem cell factor/IL-3/GM-CSF-secreting mice that develop large numbers of activated human mast cells following hu cord blood cell reconstitution; and 4) IL-4 and propranolol treatment that increases sensitivity to mast cell-released mediators.

Results
1) A single injection of mv anti-huFceRIa mAb protects our mice against IgE-mediated anaphylaxis and food allergy. 2) A rapid desensitization approach increases the safety of administration of this mv mAb. 3) The mv mAb decreases mast cell responsiveness to FceRI crosslinking and causes loss of most IgE. 4) Protection is maintained and increased by repeated injection of mv anti-huFceRIa mAb. 5) FcgRs are required for FceRI crosslinking by mv anti-FceRIa mAb. 6) Rapid desensitization with mv anti-FceRIa mAb provides a better combination of safety and efficacy than rapid desensitization with dv anti-FceRIa mAb or with a relevant allergen.

Conclusion
Desensitization with mv anti-huFceRIa mAb is a promising therapy for the suppression of hu IgE-mediated allergy.
A Randomized, Double-Blind, Placebo-Controlled Study of Daily Cannabidiol for the Treatment of Canine Osteoarthritis
Authors: Halpert Matthew , Verrico Chris , Wesson Shonda , Konduri Vanaja , Hofferek Colby , Vazquez-Perez Jonathan , Blair Emek , Dunner Kenneth , Salimpour Pedram , Decker William K 
Published: January 2023

Abstract
Hemp-derived cannabidiol (CBD) is the major non-psychoactive component of cannabis and has been promoted as a potential treatment for a wide variety of disparate inflammatory conditions. Here we evaluated CBD for its ability to modulate the production of pro-inflammatory cytokines in vitro and in murine models of induced inflammation and further validated the ability of a liposomal formulation to increase bioavailability in mice and in humans. Subsequently, the therapeutic potential of both naked and liposomally-encapsulated CBD was explored in a 4-week, randomized placebo-controlled, double-blinded study in a spontaneous canine model of osteoarthritis. In vitro and in mouse models, CBD significantly attenuated the production of pro-inflammatory cytokines IL-6 and TNF-a while elevating levels of anti-inflammatory IL-10. In the veterinary study, CBD significantly decreased pain and increased mobility in a dose-dependent fashion among animals with an affirmative diagnosis of osteoarthritis. Liposomal CBD (20 mg/day) was as effective as the highest dose of non-liposomal CBD (50 mg/day) in improving clinical outcomes. Hematocrit, comprehensive metabolic profile, and clinical chemistry indicated no significant detrimental impact of CBD administration over the four week analysis period. This study supports the safety and therapeutic potential of hemp-derived CBD for relieving arthritic pain and suggests follow-up investigations in humans is warranted.
Lipopolysaccharide (LPS) protects from a normally lethal dose of respiratory viral infection and affects post-airway disease in a dose dependent manner
Authors: Resiliac Jenny , Rohlfing Michelle , Santoro Jennifer , Hussain Syed-Rehan A , Grayson Mitchell 
Published: January 2023

Abstract

Rationale
Respiratory diseases are major public health concerns and leading causes of death and disability in the world. Understanding anti-viral immune responses is crucial to alleviate morbidity and mortality of respiratory infections. Previous data using our Sendai virus (SeV, murine parainfluenza virus type 1) mouse model suggested pretreatment of C57BL6 wild-type (WT) mice with 3μg lipopolysaccharide (LPS) reduced mortality from a normally lethal dose of SeV (2×106pfu) by half. This study was undertaken to identify the minimal effective dose for survival from the normally lethal SeV and determine its effects on subsequent airway disease.

Methods
WT mice were intranasally (i.n.) inoculated with 30 μL of 0.01–3 μg LPS or PBS 24 hours before lethal dose of SeV i.n. and survival determined. In surviving mice, invasive measurement of airway hyper-reactivity (AHR) was determined on d21 post-viral inoculation.

Results
LPS mediated survival and AHR were dose dependent (p&lt;0.0001 comparing all groups, Mantel-Cox for survival and ANOVA for AHR). Mice receiving lower doses of LPS (0.03 and 0.1 μg) had increased survival (92±8% and 67±10% survival, respectively) and decreased AHR compared to those with the highest doses (n≥5 mice per dose with up to 4 experimental repeats).

Conclusion
LPS mediated survival from a lethal paramyxoviral infection is greatest with lower doses of LPS (0.1–0.03 μg). These doses have been associated with development of atopic disease (Eisenbarth SC, J Exp Med. 2002). We are currently undertaking studies to determine the mechanism(s) through which low dose LPS inhibits mortality from normally lethal SeV dose and how this reduces post-SeV atopy.
Microbial exposure increases the magnitude and diversity of peritoneal inflammatory cell infiltrates and cytokine storm during sepsis
Authors: Martin Matthew D , Akal Peter Kassis , Schelzel George , Swanson Whitney , Sjaastad Frances V , Kucaba Tamara A , Badovinac Vladimir P , Griffith Thomas S 
Published: January 2023

Abstract
Sepsis – defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection - remains a major healthcare burden and cause of death in the United States and worldwide. While there has been a vast expansion in knowledge regarding the impact of sepsis on the immune system, virtually all preclinical sepsis research to date has relied on using mice housed under specific pathogen-free (SPF) conditions. Environmental pathogen exposure is one important difference between basic human and laboratory mouse biology that must be considered when using mice to evaluate immune system fitness. Interestingly, B6 mice that have been cohoused with pet store mice (to permit microbial transfer and immune system maturation; “CoH” mice) exhibit exaggerated acute hyperinflammation, morbidity, and mortality during cecal ligation and puncture (CLP)-induced polymicrobial sepsis compared to SPF B6 mice. To understand the mechanism of this increased acute response, we examined peritoneal immune cell composition in SPF and CoH mice before and after sepsis induction. CoH mice have more ‘large’ MHC IIloF4/80hi and ‘small’ MHC IIhiF4/80lo peritoneal macrophages (LPM and SPM) and neutrophils than SPF mice at baseline. Upon the induction of polymicrobial-induced peritonitis, there was increased recruitment of neutrophils, monocytes, T cells, and NK cells into the peritoneum of CoH mice vs. SPF mice. This increased immune cell influx correlated with increased CXCL1 and CCL2 in peritoneal lavage samples from CoH mice. CoH mice devoid of neutrophils or LPM exhibit reduced cytokine storm and improved outcomes after sepsis induction. These data suggest the cells of the innate immune system govern the magnitude of the acute septic response.
The effects of functional platelet-derived extracellular mitochondria on the inflammatory phenotype of neutrophils
Authors: Boudreau Luc H , Foulem Robert D , Léger Jacob L 
Published: January 2023

Abstract
Unregulated inflammation has been associated with chronic inflammatory auto-immune diseases, such as rheumatoid arthritis, multiple sclerosis and atherosclerosis. Polymorphonuclear neutrophils (PMNL) are amongst the immune cells involved in the acute inflammatory response used to fight bacterial infections. Once activated, PMNL release inflammatory mediators in the extracellular milieu to recruit various immune cells required to fight the invading pathogens. Platelets (PLTs) are also implicated in the body’s inflammatory response. Interestingly, activated PLTs can release fully functional mitochondria in the extracellular milieu. Known as the powerhouse of the cell, the mitochondria share similar characteristics with bacteria. Therefore, we hypothesize that PLTs-derived mitochondria present in the extracellular milieu, acting in a similar way as bacteria, induce a sterile inflammatory response that involves the PMNL. The objective of this study was to investigate the sterile inflammatory response of PMNL caused by the exposure of PLTs-derived extracellular mitochondria. Following the co-incubation of PMNL with various physiological doses of PLTs-derived mitochondria, a characterization of the interaction between PMNL and PLTs-derived mitochondria and an investigation of the inflammatory proprieties of PMNL was performed. We have shown that PLTs-derived mitochondria associate with PMNL, resulting in a 2.47-fold mitochondrial-dependent increase in oxygen consumption. Data also shows that PLTs-derived mitochondria significantly induce the release of PMNL microparticles. The knowledge gained from this study provides insight into the mechanism of sterile inflammation in auto-immune diseases.