Publications by authors named "Andrew J Murphy"

304 Publications

Defective AMPK regulation of cholesterol metabolism accelerates atherosclerosis by promoting HSPC mobilization and myelopoiesis.

Mol Metab 2022 May 10:101514. Epub 2022 May 10.

Diabetes and Metabolic Disease, St. Vincent's Institute of Medical Research, Fitzroy, Australia; Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, Australia; Department of Medicine, University of Melbourne, Melboourne, Australia. Electronic address:

Objectives: Dysregulation of cholesterol metabolism in the liver and hematopoietic stem and progenitor cells (HSPCs) promotes atherosclerosis development. Previously, it has been shown that HMG-CoA-Reductase (HMGCR), the rate-limiting enzyme in the mevalonate pathway, can be phosphorylated and inactivated by the metabolic stress sensor AMP-activated protein kinase (AMPK). However, the physiological significance of AMPK regulation of HMGCR to atherogenesis has yet to be elucidated. The aim of this study was to determine the role of AMPK/HMGCR axis in the development of atherosclerosis.

Methods: We have generated a novel atherosclerotic-prone mouse model with defects in the AMPK regulation of HMGCR (Apoe/Hmgcr KI mice). Atherosclerotic lesion size, plaque composition, immune cell and lipid profiles were assessed in Apoe and Apoe/Hmgcr KI mice.

Results: In this study, we showed that both male and female atherosclerotic-prone mice with a disruption of HMGCR regulation by AMPK (Apoe/Hmgcr KI mice) display increased aortic lesion size concomitant with an increase in plaque-associated macrophages and lipid accumulation. Consistent with this, Apoe/Hmgcr KI mice exhibited an increase in total circulating cholesterol and atherogenic monocytes, Ly6-C subset. Mechanistically, increased circulating atherogenic monocytes in Apoe/Hmgcr KI mice was associated with enhanced egress of bone marrow HSPCs and extramedullary myelopoiesis, driven by a combination of elevated circulating 27-hydroxycholesterol and intracellular cholesterol in HSPCs.

Conclusions: Our results uncovered a novel signalling pathway involving AMPK-HMGCR axis in the regulation of cholesterol homeostasis in HSPCs, and that inhibition of this regulatory mechanism accelerates the development and progression of atherosclerosis. These findings provide a molecular basis to support the use of AMPK activators that currently undergoing Phase II clinical trial such as O-3O4 and PXL 770 for reducing atherosclerotic cardiovascular disease risks.
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http://dx.doi.org/10.1016/j.molmet.2022.101514DOI Listing
May 2022

Histologic type predicts disparate outcomes in pediatric hepatocellular neoplasms: A Pediatric Surgical Oncology Research Collaborative study.

Cancer 2022 May 13. Epub 2022 May 13.

Division of Pediatric Surgery, Children's Hospital, London Health Sciences Center, London, Ontario, Canada.

Background: Hepatocellular carcinoma (HCC) is a rare cancer in children, with various histologic subtypes and a paucity of data to guide clinical management and predict prognosis.

Methods: A multi-institutional review of children with hepatocellular neoplasms was performed, including demographic, staging, treatment, and outcomes data. Patients were categorized as having conventional HCC (cHCC) with or without underlying liver disease, fibrolamellar carcinoma (FLC), and hepatoblastoma with HCC features (HB-HCC). Univariate and multivariate analyses identified predictors of mortality and relapse.

Results: In total, 262 children were identified; and an institutional histologic review revealed 110 cHCCs (42%; 69 normal background liver, 34 inflammatory/cirrhotic, 7 unknown), 119 FLCs (45%), and 33 HB-HCCs (12%). The authors observed notable differences in presentation and behavior among tumor subtypes, including increased lymph node involvement in FLC and higher stage in cHCC. Factors associated with mortality included cHCC (hazard ratio [HR], 1.63; P = .038), elevated α-fetoprotein (HR, 3.1; P = .014), multifocality (HR, 2.4; P < .001), and PRETEXT (pretreatment extent of disease) stage IV (HR, 5.76; P < .001). Multivariate analysis identified increased mortality in cHCC versus FLC (HR, 2.2; P = .004) and in unresectable tumors (HR, 3.4; P < .001). Disease-free status at any point predicted survival.

Conclusions: This multi-institutional, detailed data set allowed a comprehensive analysis of outcomes for children with these rare hepatocellular neoplasms. The current data demonstrated that pediatric HCC subtypes are not equivalent entities because FLC and cHCC have distinct anatomic patterns and outcomes in concert with their known molecular differences. This data set will be further used to elucidate the impact of histology on specific treatment responses, with the goal of designing risk-stratified algorithms for children with HCC.

Lay Summary: This is the largest reported granular data set on children with hepatocellular carcinoma. The study evaluates different subtypes of hepatocellular carcinoma and identifies key differences between subtypes. This information is pivotal in improving understanding of these rare cancers and may be used to improve clinical management and subsequent outcome in children with these rare malignancies.
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http://dx.doi.org/10.1002/cncr.34256DOI Listing
May 2022

ACVR1 antibodies exacerbate heterotopic ossification in fibrodysplasia ossificans progressiva (FOP) by activating FOP-mutant ACVR1.

J Clin Invest 2022 May 5. Epub 2022 May 5.

Skeletal Diseases Therapeutic Focus Area, Regeneron Pharmaceuticals, Inc., Tarrytown, United States of America.

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder whose most debilitating pathology is progressive and cumulative heterotopic ossification (HO) of skeletal muscles, ligaments, tendons, and fascia. FOP is caused by mutations in the type I BMP receptor gene ACVR1, which enable ACVR1 to utilize its natural antagonist, Activin A, as an agonistic ligand. The physiological relevance of this property is underscored by the fact that HO in FOP is exquisitely dependent on activation of FOP-mutant ACVR1 by Activin A, an effect countered by inhibition of Activin A via monoclonal antibody treatment. Hence, we surmised that ACVR1 antibodies that block activation of ACVR1 by ligand should also inhibit HO in FOP and provide an additional therapeutic option for this condition. Therefore, we generated ACVR1 monoclonal antibodies that block ACVR1's activation by its ligands. Surprisingly, in vivo, these ACVR1 antibodies stimulate HO and activate signaling of FOP-mutant ACVR1. This property is restricted to FOP-mutant ACVR1 and results from ACVR1 antibody-mediated dimerization of ACVR1. Conversely, wild type ACVR1 is inhibited by ACVR1 antibodies. These results uncover an additional novel property of FOP-mutant ACVR1 and indicate that ACVR1 antibodies should not be considered as therapeutics for FOP.
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http://dx.doi.org/10.1172/JCI153792DOI Listing
May 2022

Type I interferon antagonism of the JMJD3-IRF4 pathway modulates macrophage activation and polarization.

Cell Rep 2022 04;39(3):110719

The Department of Medicine, University of Melbourne, The Royal Melbourne Hospital, Parkville, VIC 3050, Australia; Haematopoiesis and Leukocyte Biology, Baker IDI Heart and Diabetes Institute, Melbourne, VIC 3004, Australia. Electronic address:

Metabolic adaptations can directly influence the scope and scale of macrophage activation and polarization. Here we explore the impact of type I interferon (IFNβ) on macrophage metabolism and its broader impact on cytokine signaling pathways. We find that IFNβ simultaneously increased the expression of immune-responsive gene 1 and itaconate production while inhibiting isocitrate dehydrogenase activity and restricting α-ketoglutarate accumulation. IFNβ also increased the flux of glutamine-derived carbon into the tricarboxylic acid cycle to boost succinate levels. Combined, we identify that IFNβ controls the cellular α-ketoglutarate/succinate ratio. We show that by lowering the α-ketoglutarate/succinate ratio, IFNβ potently blocks the JMJD3-IRF4-dependent pathway in GM-CSF and IL-4 activated macrophages. The suppressive effects of IFNβ on JMJD3-IRF4-dependent responses, including M2 polarization and GM-CSF-induced inflammatory pain, were reversed by supplementation with α-ketoglutarate. These results reveal that IFNβ modulates macrophage activation and polarization through control of the cellular α-ketoglutarate/succinate ratio.
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http://dx.doi.org/10.1016/j.celrep.2022.110719DOI Listing
April 2022

Expression in Wilms Tumor Is Regulated by Promoter Mutation or Hypermethylation, WT1, and N-MYC.

Cancers (Basel) 2022 Mar 25;14(7). Epub 2022 Mar 25.

Department of Surgery, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Mail Stop 133, Memphis, TN 38105, USA.

Increased mRNA is associated with disease relapse in favorable histology Wilms tumor (WT). This study sought to understand the mechanism of increased expression by determining the association between and WT1 and N-MYC, two proteins important in Wilms tumor pathogenesis that have been shown to regulate expression. Three out of 45 (6.7%) WTs and the corresponding patient-derived xenografts harbored canonical gain-of-function mutations in the promoter. This study identified near ubiquitous hypermethylation of the promoter region in WT compared to normal kidney. WTs with biallelic inactivating mutations in (7/45, 15.6%) were found to have lower expression by RNA-seq and qRT-PCR and lower telomerase activity determined by the telomerase repeat amplification protocol. Anaplastic histology and increased percentage of blastema were positively correlated with higher expression and telomerase activity. In vitro shRNA knockdown of resulted in decreased expression of , reduced colony formation, and decreased proliferation of WiT49, an anaplastic WT cell line with wild-type . CRISPR-Cas9-mediated knockout of resulted in decreased expression of telomere-related gene pathways. However, an inducible -knockout mouse model showed no relationship between knockout and expression in normal murine nephrogenesis, suggesting that WT1 and TERT are coupled in transformed cells but not in normal kidney tissues. N-MYC overexpression resulted in increased promoter activity and transcription. Thus, multiple mechanisms of activation are involved in WT and are associated with anaplastic histology and increased blastema. This study is novel because it identifies potential mechanisms of activation in Wilms tumor that could be of therapeutic interests.
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http://dx.doi.org/10.3390/cancers14071655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8996936PMC
March 2022

Neutrophil Migratory Patterns: Implications for Cardiovascular Disease.

Front Cell Dev Biol 2022 2;10:795784. Epub 2022 Mar 2.

Department of Surgery, Division of Cardiac Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, United States.

The body's inflammatory response involves a series of processes that are necessary for the immune system to mitigate threats from invading pathogens. Leukocyte migration is a crucial process in both homeostatic and inflammatory states. The mechanisms involved in immune cell recruitment to the site of inflammation are numerous and require several cascades and cues of activation. Immune cells have multiple origins and can be recruited from primary and secondary lymphoid, as well as reservoir organs within the body to generate an immune response to certain stimuli. However, no matter the origin, an important aspect of any inflammatory response is the web of networks that facilitates immune cell trafficking. The vasculature is an important organ for this trafficking, especially during an inflammatory response, mainly because it allows cells to migrate towards the source of insult/injury and serves as a reservoir for leukocytes and granulocytes under steady state conditions. One of the most active and vital leukocytes in the immune system's arsenal are neutrophils. Neutrophils exist under two forms in the vasculature: a marginated pool that is attached to the vessel walls, and a demarginated pool that freely circulates within the blood stream. In this review, we seek to present the current consensus on the mechanisms involved in leukocyte margination and demargination, with a focus on the role of neutrophil migration patterns during physio-pathological conditions, in particular diabetes and cardiovascular disease.
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http://dx.doi.org/10.3389/fcell.2022.795784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8924299PMC
March 2022

Hematopoietic Progenitors and the Bone Marrow Niche Shape the Inflammatory Response and Contribute to Chronic Disease.

Int J Mol Sci 2022 Feb 17;23(4). Epub 2022 Feb 17.

Haematopoiesis and Leukocyte Biology Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC 3004, Australia.

It is now well understood that the bone marrow (BM) compartment can sense systemic inflammatory signals and adapt through increased proliferation and lineage skewing. These coordinated and dynamic alterations in responding hematopoietic stem and progenitor cells (HSPCs), as well as in cells of the bone marrow niche, are increasingly viewed as key contributors to the inflammatory response. Growth factors, cytokines, metabolites, microbial products, and other signals can cause dysregulation across the entire hematopoietic hierarchy, leading to lineage-skewing and even long-term functional adaptations in bone marrow progenitor cells. These alterations may play a central role in the chronicity of disease as well as the links between many common chronic disorders. The possible existence of a form of "memory" in bone marrow progenitor cells is thought to contribute to innate immune responses via the generation of trained immunity (also called innate immune memory). These findings highlight how hematopoietic progenitors dynamically adapt to meet the demand for innate immune cells and how this adaptive response may be beneficial or detrimental depending on the context. In this review, we will discuss the role of bone marrow progenitor cells and their microenvironment in shaping the scope and scale of the immune response in health and disease.
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http://dx.doi.org/10.3390/ijms23042234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8879433PMC
February 2022

Malignant Peripheral Nerve Sheath Tumors-A Comprehensive Review of Pathophysiology, Diagnosis, and Multidisciplinary Management.

Children (Basel) 2022 Jan 1;9(1). Epub 2022 Jan 1.

Department of Surgery, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft tissue sarcomas (STS) with nerve sheath differentiation and a tendency to metastasize. Although occurring at an incidence of 0.001% in the general population, they are relatively common in individuals with neurofibromatosis type 1 (NF1), for whom the lifetime risk approaches 10%. The staging of MPNSTs is complicated and requires close multi-disciplinary collaboration. Their primary management is most often surgical in nature, with non-surgical modalities playing a supportive, necessary role, particularly in metastatic, invasive, or widespread disease. We, therefore, sought to provide a comprehensive review of the relevant literature describing the characteristics of these tumors, their pathophysiology and risk factors, their diagnosis, and their multi-disciplinary treatment. A close partnership between surgical and medical oncologists is therefore necessary. Advances in the molecular characterization of these tumors have also begun to allow the integration of targeted RAS/RAF/MEK/ERK pathway inhibitors into MPNST management.
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http://dx.doi.org/10.3390/children9010038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8774267PMC
January 2022

Complications associated with totally implantable access ports in children less than 1 year of age.

J Pediatr Surg 2021 Dec 10. Epub 2021 Dec 10.

Department of Surgery, Boston Children's Hospital/Harvard Medical School, Boston, MA 02115, United States; Department of Pediatric Oncology, Dana-Farber Cancer Institute/Harvard Medical School, Boston, MA 02115, United States.

Background: Long term central venous access is necessary for the treatment of several conditions affecting young children. Totally implantable access ports (ports) offer the advantage of containing no external components, thus simplifying their care and maintenance. However, there is no consensus on the safety of port placement in infants (birth to 1-year of age). The aim of this study was to describe complications associated with port placement in infants, including which specific factors may be associated with risk for developing complications among these patients, and thereby assess the safety of port placement in this young population.

Methods: A two-institution, retrospective cohort study identified patients under 1-year old who underwent port placement. Intraoperative, early postoperative (within 30 days), and late postoperative (greater than 30 days) complications were recorded. Multivariate logistic regression models were employed to assess factors associated with port-related complications.

Results: Among 121 patients who received a port, 36 (30%) experienced a complication with a median time to complication of 299.5 days [IQR 67.5-440.75]. Of those, 26 required unplanned port removal. Only 3 patients (2.5%) experienced an intraoperative complication, and 3 patients (2.5%) experienced a complication within 30 days of port placement. A diagnosis of cancer was found to be protective against early catheter malfunction (OR=0.31, p = 0.03). A non-statistically significant trend associated with increased complications for large caliber devices (>6.0Fr) and weight <7-kg (OR 2.20, p = 0.06 and OR=2.26, p = 0.11 respectively) was observed.

Conclusions: Port placement appears to be safe for most infants with low or acceptable rates of intra- or post-operative complications. Smaller patient size (< 7 kg) and larger-sized catheters (> 6.0Fr) may be associated with an increased risk for complications among this population.
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http://dx.doi.org/10.1016/j.jpedsurg.2021.12.004DOI Listing
December 2021

Glutaminase 2 knockdown reduces hyperammonemia and associated lethality of urea cycle disorder mouse model.

J Inherit Metab Dis 2022 May 4;45(3):470-480. Epub 2022 Feb 4.

Regeneron Pharmaceuticals, Tarrytown, New York, USA.

Amino acids, the building blocks of proteins in the cells and tissues, are of fundamental importance for cell survival, maintenance, and proliferation. The liver plays a critical role in amino acid metabolism and detoxication of byproducts such as ammonia. Urea cycle disorders with hyperammonemia remain difficult to treat and eventually necessitate liver transplantation. In this study, ornithine transcarbamylase deficient (Otc ) mouse model was used to test whether knockdown of a key glutamine metabolism enzyme glutaminase 2 (GLS2, gene name: Gls2) or glutamate dehydrogenase 1 (GLUD1, gene name: Glud1) could rescue the hyperammonemia and associated lethality induced by a high protein diet. We found that reduced hepatic expression of Gls2 but not Glud1 by AAV8-mediated delivery of a short hairpin RNA in Otc mice diminished hyperammonemia and reduced lethality. Knockdown of Gls2 but not Glud1 in Otc mice exhibited reduced body weight loss and increased plasma glutamine concentration. These data suggest that Gls2 hepatic knockdown could potentially help alleviate risk for hyperammonemia and other clinical manifestations of patients suffering from defects in the urea cycle.
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http://dx.doi.org/10.1002/jimd.12474DOI Listing
May 2022

Humanization of T cell-mediated immunity in mice.

Sci Immunol 2021 Dec 17;6(66):eabj4026. Epub 2021 Dec 17.

Regeneron Pharmaceuticals, 777 Old Saw Mill River Rd, Tarrytown, NY 10591, USA.

Despite the enormous promise of T cell therapies, the isolation and study of human T cell receptors (TCRs) of dedicated specificity remains a major challenge. To overcome this limitation, we generated mice with a genetically humanized system of T cell immunity. We used VelociGene technology to replace the murine TCRαβ variable regions, along with regions encoding the extracellular domains of co-receptors CD4 and CD8, and major histocompatibility complex (MHC) class I and II, with corresponding human sequences. The resulting “VelociT” mice have normal myeloid and lymphoid immune cell populations, including thymic and peripheral αβ T cell subsets comparable with wild-type mice. VelociT mice expressed a diverse TCR repertoire, mounted functional T cell responses to lymphocytic choriomeningitis virus infection, and could develop experimental autoimmune encephalomyelitis. Immunization of VelociT mice with human tumor-associated peptide antigens generated robust, antigen-specific responses and led to identification of a TCR against tumor antigen New York esophageal squamous cell carcinoma-1 with potent antitumor activity. These studies demonstrate that VelociT mice mount clinically relevant T cell responses to both MHC-I– and MHC-II–restricted antigens, providing a powerful new model for analyzing T cell function in human disease. Moreover, VelociT mice are a new platform for de novo discovery of therapeutic human TCRs.
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http://dx.doi.org/10.1126/sciimmunol.abj4026DOI Listing
December 2021

KDM6B promotes activation of the oncogenic CDK4/6-pRB-E2F pathway by maintaining enhancer activity in MYCN-amplified neuroblastoma.

Nat Commun 2021 12 10;12(1):7204. Epub 2021 Dec 10.

Department of Surgery, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.

The H3K27me2/me3 histone demethylase KDM6B is essential to neuroblastoma cell survival. However, the mechanism of KDM6B action remains poorly defined. We demonstrate that inhibition of KDM6B activity 1) reduces the chromatin accessibility of E2F target genes and MYCN, 2) selectively leads to an increase of H3K27me3 but a decrease of the enhancer mark H3K4me1 at the CTCF and BORIS binding sites, which may, consequently, disrupt the long-range chromatin interaction of MYCN and E2F target genes, and 3) phenocopies the transcriptome induced by the specific CDK4/6 inhibitor palbociclib. Overexpression of CDK4/6 or Rb1 knockout confers neuroblastoma cell resistance to both palbociclib and the KDM6 inhibitor GSK-J4. These data indicate that KDM6B promotes an oncogenic CDK4/6-pRB-E2F pathway in neuroblastoma cells via H3K27me3-dependent enhancer-promoter interactions, providing a rationale to target KDM6B for high-risk neuroblastoma.
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http://dx.doi.org/10.1038/s41467-021-27502-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8664842PMC
December 2021

Mammary tumour cells remodel the bone marrow vascular microenvironment to support metastasis.

Nat Commun 2021 11 26;12(1):6920. Epub 2021 Nov 26.

ACRF Cancer Biology and Stem Cells Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.

Bone marrow is a preferred metastatic site for multiple solid tumours and is associated with poor prognosis and significant morbidity. Accumulating evidence indicates that cancer cells colonise specialised niches within the bone marrow to support their long-term propagation, but the precise location and mechanisms that mediate niche interactions are unknown. Using breast cancer as a model of solid tumour metastasis to the bone marrow, we applied large-scale quantitative three-dimensional imaging to characterise temporal changes in the bone marrow microenvironment during disease progression. We show that mouse mammary tumour cells preferentially home to a pre-existing metaphyseal domain enriched for type H vessels. Metastatic lesion outgrowth rapidly remodelled the local vasculature through extensive sprouting to establish a tumour-supportive microenvironment. The evolution of this tumour microenvironment reflects direct remodelling of the vascular endothelium through tumour-derived granulocyte-colony stimulating factor (G-CSF) in a hematopoietic cell-independent manner. Therapeutic targeting of the metastatic niche by blocking G-CSF receptor inhibited pathological blood vessel remodelling and reduced bone metastasis burden. These findings elucidate a mechanism of 'host' microenvironment hijacking by mammary tumour cells to subvert the local microvasculature to form a specialised, pro-tumorigenic niche.
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http://dx.doi.org/10.1038/s41467-021-26556-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8626461PMC
November 2021

Retention of the NLRP3 Inflammasome-Primed Neutrophils in the Bone Marrow Is Essential for Myocardial Infarction-Induced Granulopoiesis.

Circulation 2022 01 17;145(1):31-44. Epub 2021 Nov 17.

Department of Surgery, The Ohio State University Wexner Medical Center, Columbus (G.S., R.M.J., B.A., K.H.P., J.J., A.D., J.M., P.R.N.).

Background: Acute myocardial infarction (MI) results in overzealous production and infiltration of neutrophils to the ischemic heart. This is mediated in part by granulopoiesis induced by the S100A8/A9-NLRP3-IL-1β signaling axis in injury-exposed neutrophils. Despite the transcriptional upregulation of the NLRP3 (Nod Like Receptor Family Pyrin Domain-Containing 3) inflammasome and associated signaling components in neutrophils, the serum levels of IL-1β (interleukin-1β), the effector molecule in granulopoiesis, were not affected by MI, suggesting that IL-1β is not released systemically. We hypothesize that IL-1β is released locally within the bone marrow (BM) by inflammasome-primed and reverse-migrating neutrophils.

Methods: Using a combination of time-dependent parabiosis and flow cytometry techniques, we first characterized the migration patterns of different blood cell types across the parabiotic barrier. We next induced MI in parabiotic mice by permanent ligation of the left anterior descending artery and examined the ability of injury-exposed neutrophils to permeate the parabiotic barrier and induce granulopoiesis in noninfarcted parabionts. Last, using multiple neutrophil adoptive and BM transplant studies, we studied the molecular mechanisms that govern reverse migration and retention of the primed neutrophils, IL-1β secretion, and granulopoiesis. Cardiac function was assessed by echocardiography.

Results: MI promoted greater accumulation of the inflammasome-primed neutrophils in the BM. Introducing a time-dependent parabiotic barrier to the free movement of neutrophils inhibited their ability to stimulate granulopoiesis in the noninfarcted parabionts. Previous priming of the NLRP3 inflammasome is not a prerequisite, but the presence of a functional CXCR4 (C-X-C-motif chemokine receptor 4) on the primed-neutrophils and elevated serum S100A8/A9 levels are necessary for homing and retention of the reverse-migrating neutrophils. In the BM, the primed-neutrophils secrete IL-1β through formation of gasdermin D pores and promote granulopoiesis. Pharmacological and genetic strategies aimed at the inhibition of neutrophil homing or release of IL-1β in the BM markedly suppressed MI-induced granulopoiesis and improved cardiac function.

Conclusions: Our data reveal a new paradigm of how circulatory cells establish a direct communication between organs by delivering signaling molecules (eg, IL-1β) directly at the sites of action rather through systemic release. We suggest that this pathway may exist to limit the off-target effects of systemic IL-1β release.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.121.056019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8716427PMC
January 2022

Deletion of GPR21 improves glucose homeostasis and inhibits the CCL2-CCR2 axis by divergent mechanisms.

BMJ Open Diabetes Res Care 2021 11;9(2)

Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia

Introduction: A potential role for the orphan G protein-coupled receptor, GPR21, in linking immune cell infiltration into tissues and obesity-induced insulin resistance has been proposed, although limited studies in mice are complicated by non-selective deletion of .

Research Design And Methods: We hypothesized that a -selective knockout mouse model, coupled with type 2 diabetes patient samples, would clarify these issues and enable clear assessment of GPR21 as a potential therapeutic target.

Results: High-fat feeding studies in mice revealed improved glucose tolerance and modest changes in inflammatory gene expression. monocytes and intraperitoneal macrophages had selectively impaired chemotactic responses to monocyte chemoattractant protein (MCP)-1, despite unaltered expression of . Further genotypic analysis revealed that chemotactic impairment was due to dysregulated monocyte polarization. Patient samples revealed elevated expression in peripheral blood mononuclear cells in type 2 diabetes, which was correlated with both %HbA1c and fasting plasma glucose levels.

Conclusions: Collectively, human and mouse data suggest that GPR21 influences both glucose homeostasis and MCP-1/CCL2-CCR2-driven monocyte migration. However, a bone marrow transplantation and high-fat feeding study in mice revealed no effect on glucose homeostasis, suggesting that there is no (or limited) overlap in the mechanism involved for monocyte-driven inflammation and glucose homeostasis.
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http://dx.doi.org/10.1136/bmjdrc-2021-002285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8593704PMC
November 2021

Validating an opioid prescribing algorithm in post-operative pediatric surgical oncology patients.

J Pediatr Surg 2020 Oct 6. Epub 2020 Oct 6.

Department of Surgery, St. Jude Children's Research Hospital, Memphis, TN; Division of Pediatric Surgery, Department of Surgery, University of Tennessee Health Science Center, Memphis, TN.

Purpose: We developed an algorithm to decrease opioid prescriptions for pediatric oncology patients at discharge following surgery, based on a retrospective analysis to decrease variability and over-prescribing. The aim of this study was to prospectively test the algorithm.

Methods: Opioid-naïve patients undergoing surgery for tumor resection at a single institution were included. A prescribing algorithm was developed based on surgical approach, day of discharge, and inpatient opioid use. Prospectively collected data included outpatient opioid consumption and patient/family satisfaction. Total home dose prescribed was equal to that used in the 8 or 24 h, depending on length of stay and operative approach, prior to discharge, divided into 0.15 mg/kg doses.

Results: The algorithm was used in 121 patients and correctly predicted outpatient opioid requirements for 102 patients (84.3%). For 15 (12.4%) patients, the algorithm over-estimated opioid need by an average of 0.38 OME/kg. Four (3.3%) patients required additional opioids. Using this algorithm, we decreased overall opioid prescriptions from 6.17 to 0.21 OME/kg (p < 0.001), and all but one patient/family reported being satisfied with post-operative pain control.

Conclusion: Using an algorithm based on inpatient opioid use, outpatient opioid needs can be accurately predicted, thereby reducing excess opioid prescriptions without detriment to patient satisfaction.

Type Of Study: Prospective Quality Initiative Study.

Level Of Evidence: Level III.
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http://dx.doi.org/10.1016/j.jpedsurg.2020.09.040DOI Listing
October 2020

Single-cell RNA transcriptome landscape of hepatocytes and non-parenchymal cells in healthy and NAFLD mouse liver.

iScience 2021 Nov 6;24(11):103233. Epub 2021 Oct 6.

Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, New York 10591, USA.

Nonalcoholic fatty liver disease (NAFLD) is a global health-care problem with limited therapeutic options. To obtain a cellular resolution of pathogenesis, 82,168 single-cell transcriptomes (scRNA-seq) across different NAFLD stages were profiled, identifying hepatocytes and 12 other non-parenchymal cell (NPC) types. scRNA-seq revealed insights into the cellular and molecular mechanisms of the disease. We discovered a dual role for hepatic stellate cells in gene expression regulation and in the potential to trans-differentiate into myofibroblasts. We uncovered distinct expression profiles of Kupffer cells versus monocyte-derived macrophages during NAFLD progression. Kupffer cells showed stronger immune responses, while monocyte-derived macrophages demonstrated a capability for differentiation. Three chimeric NPCs were identified including endothelial-chimeric stellate cells, hepatocyte-chimeric endothelial cells, and endothelial-chimeric Kupffer cells. Our work identified unanticipated aspects of mouse with NAFLD at the single-cell level and advanced the understanding of cellular heterogeneity in NAFLD livers.
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http://dx.doi.org/10.1016/j.isci.2021.103233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8560975PMC
November 2021

Macrophage polarization state affects lipid composition and the channeling of exogenous fatty acids into endogenous lipid pools.

J Biol Chem 2021 12 23;297(6):101341. Epub 2021 Oct 23.

Baker Heart and Diabetes Institute, Melbourne, Australia; Department of Immunology, Monash University, Melbourne, Australia. Electronic address:

Adipose-tissue-resident macrophages (ATMs) maintain metabolic homeostasis but also contribute to obesity-induced adipose tissue inflammation and metabolic dysfunction. Central to these contrasting effects of ATMs on metabolic homeostasis is the interaction of macrophages with fatty acids. Fatty acid levels are increased within adipose tissue in various pathological and physiological conditions, but appear to initiate inflammatory responses only upon interaction with particular macrophage subsets within obese adipose tissue. The molecular basis underlying these divergent outcomes is likely due to phenotypic differences between ATM subsets, although how macrophage polarization state influences the metabolism of exogenous fatty acids is relatively unknown. Herein, using stable isotope-labeled and nonlabeled fatty acids in combination with mass spectrometry lipidomics, we show marked differences in the utilization of exogenous fatty acids within inflammatory macrophages (M1 macrophages) and macrophages involved in tissue homeostasis (M2 macrophages). Specifically, the accumulation of exogenous fatty acids within triacylglycerols and cholesterol esters is significantly higher in M1 macrophages, while there is an increased enrichment of exogenous fatty acids within glycerophospholipids, ether lipids, and sphingolipids in M2 macrophages. Finally, we show that functionally distinct ATM populations in vivo have distinct lipid compositions. Collectively, this study identifies new aspects of the metabolic reprogramming that occur in distinct macrophage polarization states. The channeling of exogenous fatty acids into particular lipid synthetic pathways may contribute to the sensitivity/resistance of macrophage subsets to the inflammatory effects of increased environmental fatty acid levels.
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http://dx.doi.org/10.1016/j.jbc.2021.101341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8604758PMC
December 2021

Indocyanine Green-Guided Pediatric Tumor Resection: Approach, Utility, and Challenges.

Front Pediatr 2021 20;9:689612. Epub 2021 Sep 20.

Department of Surgery, St. Jude Children Research Hospital, Memphis, TN, United States.

Incomplete tumor resection increases the risk of local recurrence. However, the standard of care approach to distinguishing tumor tissue is less than optimal, as it depends on a conglomeration of preoperative imaging and visual and tactile indicators in real time. This approach is associated with a significant risk of inadequate resection; therefore, a novel approach that delineates the accurate intraoperative definition of pediatric tumors is urgently needed. To date, there is no reliable method for the intraoperative assessment of tumor extent and real-time differentiation between tumor- involved tissues and tumor-free tissues. Use of intraoperative frozen sections is challenging, time consuming, and covers a small surface area. Increased vascular permeability and impaired lymphatic drainage in the tumor microenvironment leads to an enhanced permeability and retention effect of small molecules. ICG is a fluorescent dye that when administered intravenously accumulates passively in the tumor because of EPR, thereby providing some tumor contrast for intraoperative real-time tumor recognition. Preclinical and clinical studies suggest that the tumor-to-background fluorescence ratio is optimized when imaging is obtained 24 h after dye injection, and many studies suggest using a high dose of ICG to optimize dye retention in the tumor tissue. However, in childhood cancers, little is known about the ideal dosing, applications, and challenges of ICG-guided tumor resection. This retrospective study examines the feasibility of ICG-guided tumor resection in common childhood solid tumors such as neuroblastoma, sarcomas, hepatic tumors, pulmonary metastases, and other rare tumors. Pediatric dosing and challenges related to the optimization of tumor-to-background ratio are also examined.
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http://dx.doi.org/10.3389/fped.2021.689612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8489593PMC
September 2021

A One-Year Cross Sectional Analysis of Emergency Medical Services Utilization and Its Association with Hypertension in Pregnancy.

Prehosp Emerg Care 2021 Nov 3:1-10. Epub 2021 Nov 3.

Received July 18, 2021 from Department of Obstetrics and Gynecology, The Ohio State University Wexner Medical Center, Columbus, OH, USA (MLH); College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA (OO); Department of Biomedical Informatics, The Ohio State University, Columbus, OH, USA (EMM, EMH); City of Columbus (Ohio), Division of Fire, Columbus, OH, USA (AJM); Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA (HAF); Department of Emergency Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA (AL, ARP). Revision received September 28, 2021; accepted for publication September 29, 2021.

To evaluate the prehospital obstetric population that utilizes emergency medical services (EMS) and their association with hypertensive disorders of pregnancy. We conducted a retrospective evaluation of one year of all medical calls from a large, municipal, midwestern fire department. Inclusion criteria included all pregnant patients transported to a hospital by EMS. Descriptive statistics were calculated to evaluate prehospital event information (e.g., zip code, time, and duration of call), patient characteristics, and clinical management data regarding blood pressure. Census data were used to compare neighborhood information with poverty rates. Of the 1,575 identified patients, 64.4% (1015/1575) presented with obstetric complaints, 57.4% (700/1220) were in their third trimester and 72.7% (686/944) were multiparous. The median call duration was 17 (interquartile range 12-22) minutes. In the areas where EMS usage was highest, one quarter of individuals lived below the poverty level. Of the studied population, 32.0% (504/1575) were found to be hypertensive; 14.9% (75/504) of hypertensive patients were found to have severe hypertension. Only one patient (1/1575, 0.06%) presented with a chief complaint of hypertension; the rest were discovered by EMS. The highest rates of hypertension were noted in wealthier areas of the city. Patients with severe hypertension were more likely to present with seizures, consistent with eclampsia. Hypertension is common in the obstetric population using EMS. Prehospital management of hypertensive disorders of pregnancy may focus on identification and treatment of severe pre-eclampsia or eclampsia. Areas with longer call times may consider treatment of severe hypertension. Prehospital treatment of hypertensive disorders of pregnancy could be optimized.
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http://dx.doi.org/10.1080/10903127.2021.1988775DOI Listing
November 2021

Five-in-One: Simultaneous isolation of multiple major liver cell types from livers of normal and NASH mice.

J Cell Mol Med 2021 10 23;25(20):9878-9883. Epub 2021 Sep 23.

Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA.

NASH is a chronic liver disease that affects 3%-6% of individuals and requires urgent therapeutic developments. Isolating the key cell types in the liver is a necessary step towards understanding their function and roles in disease pathogenesis. However, traditional isolation methods through gradient centrifugation can only collect one or a few cell types simultaneously and pose technical difficulties when applied to NASH livers. Taking advantage of identified cell surface markers from liver single-cell RNAseq, here we established the combination of gradient centrifugation and antibody-based cell sorting techniques to isolate five key liver cell types (hepatocytes, endothelial cells, stellate cells, macrophages and other immune cells) from a single mouse liver. This method yielded high purity of each cell type from healthy and NASH livers. Our five-in-one protocol simultaneously isolates key liver cell types with high purity under normal and NASH conditions, enabling for systematic and accurate exploratory experiments such as RNA sequencing.
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http://dx.doi.org/10.1111/jcmm.16933DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8505823PMC
October 2021

Neutrophils in cardiovascular disease: Warmongers, peacemakers or both?

Cardiovasc Res 2021 Sep 17. Epub 2021 Sep 17.

Dept. of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.

Neutrophils, the most abundant of all leukocytes and the first cells to arrive at the sites of sterile inflammation/injury act as a double-edged sword. On one hand, they inflict a significant collateral damage to the tissues and on the other hand they help facilitate wound healing by a number of mechanisms. Recent studies have drastically changed the perception of neutrophils from being simple one-dimensional cells with an un-restrained mode of action to a cell type that display maturity and complex behavior. It is now recognized that neutrophils are transcriptionally active and respond to plethora of signals by deploying a wide variety of cargo to influence the activity of other cells in the vicinity. Neutrophils can regulate macrophage behavior, display innate immune memory, and play a major role in the resolution of inflammation in a context-dependent manner. In this review, we provide an update on the factors that regulate neutrophil production and the emerging dichotomous role of neutrophils in the context of cardiovascular diseases, particularly in atherosclerosis and the ensuing complications, myocardial infarction and heart failure. Deciphering the complex behavior of neutrophils during inflammation and resolution may provide novel insights and in turn facilitate the development of potential therapeutic strategies to manage cardiovascular disease.
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http://dx.doi.org/10.1093/cvr/cvab302DOI Listing
September 2021

Indocyanine green-guided nephron-sparing surgery for pediatric renal tumors.

J Pediatr Surg 2021 Aug 23. Epub 2021 Aug 23.

Department of Surgery, MS 133, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA; Division of Pediatric Surgery, University of Tennessee Health Science Center, 910 Madison Ave, Memphis, TN 38163, USA.

Background: Indocyanine green (ICG), a water-soluble tricarbocyanine fluorophore, is being increasingly used for tumor localization based on its passive intra-tumoral accumulation due to enhanced permeability and retention in tumor tissue. Therefore, we hypothesized that ICG can provide contrast to facilitate accurate, real-time recognition of renal tumors at the time of nephron-sparing surgery in children.

Methods: This retrospective study examined the feasibility of ICG in guiding nephron-sparing surgery for pediatric renal tumors.

Results: We reviewed the medical records of 8 pediatric patients with renal tumors in 12 kidneys. Intraoperative localization of tumor with near infrared guidance was successful in all 12 kidneys. However, we consistently found an inverse pattern of near infrared signal in which the normal kidney demonstrated increased fluorescent signal relative to the kidney tumor.

Conclusions: Fluorescence-guided renal tumor delineation is unique because it has an inverse pattern of near infrared signal in which the normal kidney demonstrates increased signal relative to the adjacent tumor. Nevertheless fluorescence-guided distinguishing of renal tumor from surrounding normal kidney is feasible.
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http://dx.doi.org/10.1016/j.jpedsurg.2021.08.006DOI Listing
August 2021

Why do subcutaneous ports get stuck? A case-control study.

J Pediatr Surg 2021 Aug 8. Epub 2021 Aug 8.

Department of Surgery, St. Jude Children's Research Hospital, 262 Danny Thomas Place Mail Stop 133, Memphis, TN 38105, USA; Department of Surgery, University of Tennessee Health Science Center, Memphis, TN 38105, USA. Electronic address:

Purpose: We sought to identify clinical features associated with difficult subcutaneous port removals in children.

Methods: Ports placed between April 2014 and September 2017 at our institution were prospectively tracked for difficult removals. A case-control analysis was performed. Patients with ports that were difficult to remove (stuck; cases) were compared to biological sex and age-matched controls in a ratio of 1:3. Logistic regression determined the association between case/control status and clinical features adjusting for biological sex and age as covariates. A multivariable analysis was performed to identify independent associations.

Results: 57 stuck ports (28 extreme [10 endovascular intervention] and 29 moderate) and 171 controls were analyzed. Stuck ports were associated with a diagnosis of acute lymphoblastic leukemia (86% cases versus 22.2% controls; p < 0.001) and a longer placement duration (median 2.6 years [interquartile range (IQR) 2.5-2.6] versus 0.8 years [IQR 0.5-1.4]; p < 0.001). On univariate analysis, procedural and device features associated with stuck ports included subclavian access (71.9% cases versus 48.5% controls; p = 0.0126), a polyurethane versus silicone catheter (96.5% cases versus 79.9% controls; p = 0.001), and a rough catheter appearance at removal (92.6% cases versus 9.4% controls; p < 0.0001). A diagnosis of ALL and duration of line placement were associated with having a stuck port on multivariate analysis.

Conclusion: Polyurethane central venous catheters placed for the two-year treatment of acute lymphoblastic leukemia may become difficult to remove. This constellation of factors warrants more extensive preoperative discussion of risk, endovascular backup availability, and scheduling for longer operating room time.
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http://dx.doi.org/10.1016/j.jpedsurg.2021.08.003DOI Listing
August 2021

Management of intravascular thrombus in cases of bilateral Wilms tumor or horseshoe kidney.

J Pediatr Surg 2021 Aug 5. Epub 2021 Aug 5.

Department of Surgery, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Mail Stop 133, Memphis, TN 38105, United States; Division of Pediatric Surgery, Department of Surgery, University of Tennessee Health Science Center, Memphis, TN 38105, United States. Electronic address:

Purpose: To describe the oncologic and surgical management of bilateral Wilms tumor or Wilms tumor arising in a horseshoe kidney with intravenous tumor thrombus to help pediatric surgeons negotiate this rare and difficult anatomic circumstance.

Methods: A single-institution, retrospective medical record review identified 4 cases of bilateral WT and one case of WT arising in a horseshoe kidney with intravenous tumor thrombus between 2009 and 2021. The presentation, imaging, chemotherapy regimen, intraoperative approach, and surgical and oncologic outcomes were reviewed for each of these patients.

Results: All patients received a total of 12 weeks of neoadjuvant chemotherapy. In two patients, a staged approach to the bilateral tumors was undertaken with the first side being operated on after six weeks of therapy and the other side undergoing surgery after an additional six weeks of therapy. Of five patients, four underwent nephron-sparing surgery of all tumors and one underwent unilateral radical nephroureterectomy with contralateral nephron-sparing surgery. Tumor thrombectomy was performed in four of five cases; one patient demonstrated a complete response of the intravenous tumor thrombus to neoadjuvant chemotherapy and did not require thrombectomy. Three patients received adjuvant flank radiotherapy. Three patients developed medically managed stage II or III chronic kidney disease and no patient required renal replacement therapy or kidney transplant to date.

Conclusion: Nephron-sparing surgery is feasible and safe to perform in selected cases of bilateral Wilms tumor with intravascular thrombus by utilizing three-drug neoadjuvant chemotherapy, staged approaches to each kidney when appropriate, and detailed preoperative and/or intraoperative mapping of renal venous anatomy. Successful nephron-sparing surgery with tumor thrombectomy is dependent on a branched renal venous system or the presence of accessory renal veins.
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http://dx.doi.org/10.1016/j.jpedsurg.2021.07.025DOI Listing
August 2021

Cell type-selective targeted delivery of a recombinant lysosomal enzyme for enzyme therapies.

Mol Ther 2021 12 14;29(12):3512-3524. Epub 2021 Aug 14.

Regeneron Pharmaceuticals, Tarrytown, NY 10591, USA. Electronic address:

Lysosomal diseases are a class of genetic disorders predominantly caused by loss of lysosomal hydrolases, leading to lysosomal and cellular dysfunction. Enzyme replacement therapy (ERT), where recombinant enzyme is given intravenously, internalized by cells, and trafficked to the lysosome, has been applied to treat several lysosomal diseases. However, current ERT regimens do not correct disease phenotypes in all affected organs because the biodistribution of enzyme uptake does not match that of the affected cells that require the enzyme. We present here targeted ERT, an approach that utilizes antibody-enzyme fusion proteins to target the enzyme to specific cell types. The antibody moiety recognizes transmembrane proteins involved in lysosomal trafficking and that are also preferentially expressed in those cells most affected in disease. Using Pompe disease (PD) as an example, we show that targeted ERT is superior to ERT in treating the skeletal muscle phenotypes of PD mice both as a protein replacement therapeutic and as a gene therapy.
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http://dx.doi.org/10.1016/j.ymthe.2021.08.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8636175PMC
December 2021

Late-onset kidney failure in survivors of childhood cancer: a report from the Childhood Cancer Survivor Study.

Eur J Cancer 2021 09 11;155:216-226. Epub 2021 Aug 11.

Department of Surgery, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.

Background: The incidence of and risk factors for late-onset kidney failure among survivors over the very long term remains understudied.

Materials And Methods: A total of 25,530 childhood cancer survivors (median follow-up 22.3 years, interquartile range 17.4-28.8) diagnosed between 1970 and 1999, and 5045 siblings from the Childhood Cancer Survivor Study were assessed for self-reported late-onset kidney failure, defined as dialysis, renal transplantation, or death attributable to kidney disease. Piecewise exponential models evaluated associations between risk factors and the rate of late-onset kidney failure.

Results: A total of 206 survivors and 10 siblings developed late-onset kidney failure, a 35-year cumulative incidence of 1.7% (95% confidence interval [CI] = 1.4-1.9) and 0.2% (95% confidence interval [CI] = 0.1-0.4), respectively, corresponding to an adjusted rate ratio (RR) of 4.9 (95% CI = 2.6-9.2). High kidney dose from radiotherapy (≥15Gy; RR = 4.0, 95% CI = 2.1-7.4), exposure to high-dose anthracycline (≥250 mg/m; RR = 1.6, 95% CI = 1.0-2.6) or any ifosfamide chemotherapy (RR = 2.6, 95% CI = 1.2-5.7), and nephrectomy (RR = 1.9, 95% CI = 1.0-3.4) were independently associated with elevated risk for late-onset kidney failure among survivors. Survivors who developed hypertension, particularly in the context of prior nephrectomy (RR = 14.4, 95% CI = 7.1-29.4 hypertension with prior nephrectomy; RR = 5.9, 95% CI = 3.3-10.5 hypertension without prior nephrectomy), or diabetes (RR = 2.2, 95%CI = 1.2-4.2) were also at elevated risk for late-onset kidney failure.

Conclusions: Survivors of childhood cancer are at increased risk for late-onset kidney failure. Kidney dose from radiotherapy ≥15 Gy, high-dose anthracycline, any ifosfamide, and nephrectomy were associated with increased risk of late-onset kidney failure among survivors. Successful diagnosis and management of modifiable risk factors such as diabetes and hypertension may mitigate the risk for late-onset kidney failure. The association of late-onset kidney failure with anthracycline chemotherapy represents a novel finding that warrants further study.
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http://dx.doi.org/10.1016/j.ejca.2021.06.050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8429192PMC
September 2021

Butyrophilin-like 2 regulates site-specific adaptations of intestinal γδ intraepithelial lymphocytes.

Commun Biol 2021 07 26;4(1):913. Epub 2021 Jul 26.

Regeneron Pharmaceuticals Inc., Tarrytown, NY, USA.

Tissue-resident γδ intraepithelial lymphocytes (IELs) orchestrate innate and adaptive immune responses to maintain intestinal epithelial barrier integrity. Epithelia-specific butyrophilin-like (Btnl) molecules induce perinatal development of distinct Vγ TCR IELs, however, the mechanisms that control γδ IEL maintenance within discrete intestinal segments are unclear. Here, we show that Btnl2 suppressed homeostatic proliferation of γδ IELs preferentially in the ileum. High throughput transcriptomic characterization of site-specific Btnl2-KO γδ IELs reveals that Btnl2 regulated the antimicrobial response module of ileal γδ IELs. Btnl2 deficiency shapes the TCR specificities and TCRγ/δ repertoire diversity of ileal γδ IELs. During DSS-induced colitis, Btnl2-KO mice exhibit increased inflammation and delayed mucosal repair in the colon. Collectively, these data suggest that Btnl2 fine-tunes γδ IEL frequencies and TCR specificities in response to site-specific homeostatic and inflammatory cues. Hence, Btnl-mediated targeting of γδ IEL development and maintenance may help dissect their immunological functions in intestinal diseases with segment-specific manifestations.
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http://dx.doi.org/10.1038/s42003-021-02438-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8313535PMC
July 2021

Immune-based therapies in cardiovascular and metabolic diseases: past, present and future.

Nat Rev Immunol 2021 10 20;21(10):669-679. Epub 2021 Jul 20.

Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.

Cardiometabolic disorders were originally thought to be driven primarily by changes in lipid metabolism that cause the accumulation of lipids in organs, thereby impairing their function. Thus, in the setting of cardiovascular disease, statins - a class of lipid-lowering drugs - have remained the frontline therapy. In the past 20 years, seminal discoveries have revealed a central role of both the innate and adaptive immune system in driving cardiometabolic disorders. As such, it is now appreciated that immune-based interventions may have an important role in reducing death and disability from cardiometabolic disorders. However, to date, there have been a limited number of clinical trials exploring this interventional strategy. Nonetheless, elegant preclinical research suggests that immune-targeted therapies can have a major impact in treating cardiometabolic disease. Here, we discuss the history and recent advancements in the use of immunotherapies to treat cardiometabolic disorders.
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http://dx.doi.org/10.1038/s41577-021-00580-5DOI Listing
October 2021

T-Cell Expression and Release of Kidney Injury Molecule-1 in Response to Glucose Variations Initiates Kidney Injury in Early Diabetes.

Diabetes 2021 08 18;70(8):1754-1766. Epub 2021 Mar 18.

Mater Young Adult Health Centre, Mater Misericordiae Ltd, South Brisbane, Queensland, Australia.

Half of the mortality in diabetes is seen in individuals <50 years of age and commonly predicted by the early onset of diabetic kidney disease (DKD). In type 1 diabetes, increased urinary albumin-to-creatinine ratio (uACR) during adolescence defines this risk, but the pathological factors responsible remain unknown. We postulated that early in diabetes, glucose variations contribute to kidney injury molecule-1 (KIM-1) release from circulating T cells, elevating uACR and DKD risk. DKD risk was assigned in youth with type 1 diabetes ( = 100; 20.0 ± 2.8 years; males/females, 54:46; HbA 66.1 [12.3] mmol/mol; diabetes duration 10.7 ± 5.2 years; and BMI 24.5 [5.3] kg/m) and 10-year historical uACR, HbA, and random blood glucose concentrations collected retrospectively. Glucose fluctuations in the absence of diabetes were also compared with streptozotocin diabetes in mice. Kidney biopsies were used to examine infiltration of KIM-1-expressing T cells in DKD and compared with other chronic kidney disease. Individuals at high risk for DKD had persistent elevations in uACR defined by area under the curve (AUC; uACR, 29.7 ± 8.8 vs. 4.5 ± 0.5; < 0.01 vs. low risk) and early kidney dysfunction, including ∼8.3 mL/min/1.73 m higher estimated glomerular filtration rates (modified Schwartz equation; < 0.031 vs. low risk) and plasma KIM-1 concentrations (∼15% higher vs. low risk; < 0.034). High-risk individuals had greater glycemic variability and increased peripheral blood T-cell KIM-1 expression, particularly on CD8 T cells. These findings were confirmed in a murine model of glycemic variability both in the presence and absence of diabetes. KIM-1 T cells were also infiltrating kidney biopsies from individuals with DKD. Healthy primary human proximal tubule epithelial cells exposed to plasma from high-risk youth with diabetes showed elevated collagen IV and sodium-glucose cotransporter 2 expression, alleviated with KIM-1 blockade. Taken together, these studies suggest that glycemic variations confer risk for DKD in diabetes via increased CD8 T-cell production of KIM-1.
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http://dx.doi.org/10.2337/db20-1081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8385614PMC
August 2021
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