Publications by authors named "Edward R Smith"

193 Publications

HBEGF: an EGF-like growth factor with FGF23-like activity?

Kidney Int 2021 Mar;99(3):539-542

Department of Nephrology, The Royal Melbourne Hospital, Parkville, Australia; Department of Medicine, University of Melbourne, Parkville, Australia.

Renal signaling networks downstream of FGF23 are not well delineated, but elucidating them may offer an opportunity to control target genes independent of FGF23 in states of dysregulated mineral metabolism. Ni et al. identify HBEGF as a paracrine/autocrine factor in the proximal tubules of mice that mimics the inductive effect of FGF23 on the vitamin D-catabolizing enzyme 24-hydroxylase through a common mitogen-activated protein kinase-dependent pathway. An understanding of how these findings relate to human disease is eagerly anticipated.
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http://dx.doi.org/10.1016/j.kint.2020.11.011DOI Listing
March 2021

Neogenin is Highly Expressed in Diffuse Intrinsic Pontine Glioma and Influences Tumor Invasion.

Brain Res 2021 Feb 8:147348. Epub 2021 Feb 8.

Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, 02115 Boston, MA, USA; Department of Neurosurgery, Boston Children's Hospital, Harvard Medical School, 02115 Boston, MA, USA. Electronic address:

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http://dx.doi.org/10.1016/j.brainres.2021.147348DOI Listing
February 2021

Scoliosis with Chiari I malformation without associated syringomyelia.

Spine Deform 2021 Jan 20. Epub 2021 Jan 20.

Department of Orthopaedic Surgery, Boston Children's Hospital, Boston, MA, USA.

Purpose: Many patients with presumed idiopathic scoliosis are found to have Chiari I malformation (CM-I) on MRI. The objective of this study is to report on scoliosis progression in CM-I with no syringomyelia.

Methods: A retrospective review of patients with scoliosis and CM-I was conducted from 1997 to 2015. Patients with syringomyelia and/or non-idiopathic scoliosis were excluded. Clinical and radiographic characteristics were recorded at presentation and latest follow-up. CM-I was defined as the cerebellar tonsil extending 5 mm or more below the foramen magnum on MRI.

Results: Thirty-two patients (72% female) with a mean age of 11 years (range 1-16) at scoliosis diagnosis were included. The average initial curve was 30.3° ± SD 16.3. The mean initial Chiari size was 9.6 mm SD ± 4.0. Fifteen (46.9%) experienced Chiari-related symptoms, and three (9%) patients underwent Posterior Fossa Decompression (PFD) to treat these symptoms. 10 (31%) patients went on to fusion, progressing on average 13.6° (95% CI 1.6-25.6°). No association was detected between decompression and either curve progression or fusion (p = 0.46, 0.60). For those who did not undergo fusion, curve magnitude progressed on average 1.0° (95% CI - 4.0 to 5.9°). There was no association between age, Chiari size, presence of symptoms, initial curve shape, or bracing treatment and fusion.

Conclusion: Patients with CM-I and scoliosis may not require surgical treatment, including PFD and fusion. Scoliosis curvature stabilized in the non-surgical population at an average progression of 1.0°. These results suggest that CM-I with no syringomyelia has minimal effect on scoliosis progression.
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http://dx.doi.org/10.1007/s43390-021-00286-7DOI Listing
January 2021

TGF-β1 is a regulator of the pyruvate dehydrogenase complex in fibroblasts.

Sci Rep 2020 10 21;10(1):17914. Epub 2020 Oct 21.

Department of Nephrology, The Royal Melbourne Hospital (RMH), Grattan Street, Parkville, VIC, 3050, Australia.

TGF-β1 reprograms metabolism in renal fibroblasts, inducing a switch from oxidative phosphorylation to aerobic glycolysis. However, molecular events underpinning this are unknown. Here we identify that TGF-β1 downregulates acetyl-CoA biosynthesis via regulation of the pyruvate dehydrogenase complex (PDC). Flow cytometry showed that TGF-β1 reduced the PDC subunit PDH-E1α in fibroblasts derived from injured, but not normal kidneys. An increase in expression of PDH kinase 1 (PDK1), and reduction in the phosphatase PDP1, were commensurate with net phosphorylation and inactivation of PDC. Over-expression of mutant PDH-E1α, resistant to phosphorylation, ameliorated effects of TGF-β1, while inhibition of PDC activity with CPI-613 was sufficient to induce αSMA and pro-collagen I expression, markers of myofibroblast differentiation and fibroblast activation. The effect of TGF-β1 on PDC activity, acetyl-CoA, αSMA and pro-collagen I was also ameliorated by sodium dichloroacetate, a small molecule inhibitor of PDK. A reduction in acetyl-CoA, and therefore acetylation substrate, also resulted in a generalised loss of protein acetylation with TGF-β1. In conclusion, TGF-β1 in part regulates fibroblast activation via effects on PDC activity.
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http://dx.doi.org/10.1038/s41598-020-74919-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578649PMC
October 2020

Exome sequencing implicates genetic disruption of prenatal neuro-gliogenesis in sporadic congenital hydrocephalus.

Nat Med 2020 11 19;26(11):1754-1765. Epub 2020 Oct 19.

Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.

Congenital hydrocephalus (CH), characterized by enlarged brain ventricles, is considered a disease of excessive cerebrospinal fluid (CSF) accumulation and thereby treated with neurosurgical CSF diversion with high morbidity and failure rates. The poor neurodevelopmental outcomes and persistence of ventriculomegaly in some post-surgical patients highlight our limited knowledge of disease mechanisms. Through whole-exome sequencing of 381 patients (232 trios) with sporadic, neurosurgically treated CH, we found that damaging de novo mutations account for >17% of cases, with five different genes exhibiting a significant de novo mutation burden. In all, rare, damaging mutations with large effect contributed to ~22% of sporadic CH cases. Multiple CH genes are key regulators of neural stem cell biology and converge in human transcriptional networks and cell types pertinent for fetal neuro-gliogenesis. These data implicate genetic disruption of early brain development, not impaired CSF dynamics, as the primary pathomechanism of a significant number of patients with sporadic CH.
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http://dx.doi.org/10.1038/s41591-020-1090-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871900PMC
November 2020

Hydrodynamics across a fluctuating interface.

J Chem Phys 2020 Oct;153(13):134705

School of Engineering and Materials Science, Queen Mary University of London, London, United Kingdom.

Understanding what happens inside the rippling and dancing surface of a liquid remains one of the great challenges of fluid dynamics. Using molecular dynamics, we can pick apart the interface structure and understand surface tension. In this work, we derive an exact mechanical formulation of hydrodynamics for a liquid-vapor interface using a control volume, which moves with the surface. This mathematical framework provides the local definition of hydrodynamic fluxes at any point on the surface. These are represented not only by the flux of molecules and intermolecular interactions acting across the surface but also as a result of the instantaneous local curvature and movement of the surface itself. By explicitly including the surface dynamics in the equations of motion, we demonstrate an exact balance between kinetic and configurational pressure normal to the surface. The hydrodynamic analysis makes no assumptions regarding the probability distribution function, so it is valid for any system arbitrarily far from thermodynamic equilibrium. The presented equations provide a theoretical basis for the study of time-evolving interface phenomena, such as bubble nucleation, droplet dynamics, and liquid-vapor instabilities.
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http://dx.doi.org/10.1063/5.0022530DOI Listing
October 2020

Clinical status and evolution in moyamoya: which angiographic findings correlate?

Brain Commun 2019 30;1(1):fcz029. Epub 2019 Oct 30.

Department of Neurosurgery, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.

Moyamoya is a progressive steno-occlusive cerebrovascular pathology of unknown aetiology that usually involves the terminal portions of the internal carotid arteries and/or the proximal portions of the anterior and middle cerebral arteries bilaterally. The pre-operative Suzuki staging system and post-operative Matsushima grade are nearly universally used markers of natural history and surgical revascularization results, respectively, but their correlation with clinical and radiographic manifestations of moyamoya has not been systematically evaluated in a large cohort. This study evaluated the strength of correlations between pre- and post-operative angiographic parameters and clinical status among paediatric patients with moyamoya. The participants included 58 patients of mean age 11 years at the time of surgery who underwent bilateral indirect revascularization in the same procedure at Boston Children's Hospital, between January 2010 and December 2015. All included patients had available pre-operative and 1-year post-operative digital subtraction angiography. Clinical data included presenting symptoms, degree of functional incapacity, and peri-operative and long-term complications. Radiographic data included pre-operative Suzuki stage, degree of arterial stenosis, a novel collateral score, the presence of hypovascular territories on digital subtraction angiography, and post-operative Matsushima grade and evolution of stenosis. Chi-squared test and Pearson coefficient were used for correlation studies for categorical variables and Spearman's rho was used for correlation studies for continuous variables. Results showed that Suzuki stage, collateral score and degree of stenosis were insufficient to predict clinical presentation, pre-operative incapacity and radiographic presentation, whereas the presence of hypovascular territories was correlated with all of these. At 1-year follow-up, Matsushima grade was insufficient for predicting peri-operative or long-term complications, nor did it correlate with post-operative incapacity. The presence of hypovascular territories at 1-year follow-up was correlated with the incidence of post-operative ischaemic symptoms.
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http://dx.doi.org/10.1093/braincomms/fcz029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425301PMC
October 2019

Effect of Sevelamer on Calciprotein Particles in Hemodialysis Patients: The Sevelamer Versus Calcium to Reduce Fetuin-A-Containing Calciprotein Particles in Dialysis (SCaRF) Randomized Controlled Trial.

Kidney Int Rep 2020 Sep 29;5(9):1432-1447. Epub 2020 Jun 29.

Department of Nephrology, The Royal Melbourne Hospital, Parkville, Victoria, Australia.

Introduction: Calciprotein particles (CPPs) are potentially modifiable mediators of phosphate toxicity in patients with kidney disease. We compared the effects of calcium carbonate (CC) and the non-calcium-based phosphate binder sevelamer on CPP levels in patients undergoing hemodialysis (HD). We hypothesized that treatment with sevelamer would achieve greater reductions in amorphous calcium phosphate-containing CPP (CPP-1) and hydroxyapatite-containing CPP (CPP-2) owing to reduced calcium loading and anti-inflammatory pleiotropic effects.

Methods: We conducted an open-label, randomized controlled trial (RCT) in which 31 stable prevalent HD patients were allocated to receive either sevelamer hydrochloride (SH), sevelamer carbonate (SC), or CC for 24 weeks. Dual primary endpoints were the between groups differences in serum CPP-1 and CPP-2 levels at 24 weeks in SH + SC-treated versus CC-treated patients. Effects on aortic pulse wave velocity (aPWV), inflammatory cytokines (interleukin-6 and -8), and effects across individual treatment arms were also assessed.

Results: Serum CPP-1, but not CPP-2, levels were lower in those randomly assigned to the sevelamer (SH + SC) group compared with the CC group at 24 weeks (-70%, 95% confidence interval [CI] -90% to -15%,  = 0.02). In subgroup analysis, this effect was confined to those receiving SC (-83.4%, 95% CI -95.7% to -36.8%,  = 0.01). aPWV and interleukin-8 levels were also lower in those who received sevelamer compared with CC at 24 weeks (-2.0 m/s, 95% CI -2.9 to -1.1; -57%, 95% CI -73% to -30%, respectively, both  = 0.01). Conventional markers of mineral metabolism remained stable across all treatment groups.

Discussion: Compared with treatment with CC, use of sevelamer for 24 weeks was associated with lower serum CPP-1 levels and a reduction in aPWV and systemic inflammation.
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http://dx.doi.org/10.1016/j.ekir.2020.06.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486191PMC
September 2020

Single-institution case series of pituitary biopsy for suspected germinoma in the pediatric population: diagnostic utility, operative risks, and biopsy approaches.

Sci Rep 2020 09 17;10(1):15257. Epub 2020 Sep 17.

Department of Neurosurgery, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA, 02115, USA.

Little has been reported on the safety and efficacy of pituitary biopsy in the pediatric population for suspected germinoma. An updated review is needed. Patients who underwent biopsy (endoscopic endonasal vs. open craniotomy) for isolated pituitary stalk thickening were identified. Age, pre- and post-operative endocrine status, surgical approach, length of surgery, estimated blood loss, surgical morbidity, length of ICU stay, total length of stay, and pathology reports were reviewed. Nine patients met inclusion criteria. Germinoma diagnosis was rendered in 7 of 9 patients; 1 patient required two biopsy attempts. Two-patients had histology consistent with inflammation and a subsequently self-limited disease course. Average operative time, blood loss, ICU stay and overall length of stay was just over 2 h, 28 mL, 1.6 days and 3.7 days respectively. There were no intraoperative complications and all patients were discharged home. One patient developed new diabetes insipidus post-operatively. Patients who underwent endoscopic biopsy had decreased operative times and shorter hospitalizations. Biopsy for isolated pituitary stalk thickening for suspected germinoma is generally safe with high diagnostic utility. Importantly, 22% of presumed germinomas on imaging yielded alternative diagnoses on biopsy, adding support for pathology-proven data to guide treatment in relevant cases.
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http://dx.doi.org/10.1038/s41598-020-71988-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499298PMC
September 2020

A Randomized Trial on the Effect of Phosphate Reduction on Vascular End Points in CKD (IMPROVE-CKD).

J Am Soc Nephrol 2020 11 11;31(11):2653-2666. Epub 2020 Sep 11.

Australasian Kidney Trials Network, The University of Queensland, Brisbane, Queensland, Australia.

Background: Hyperphosphatemia is associated with increased fibroblast growth factor 23 (FGF23), arterial calcification, and cardiovascular mortality. Effects of phosphate-lowering medication on vascular calcification and arterial stiffness in CKD remain uncertain.

Methods: To assess the effects of non-calcium-based phosphate binders on intermediate cardiovascular markers, we conducted a multicenter, double-blind trial, randomizing 278 participants with stage 3b or 4 CKD and serum phosphate >1.00 mmol/L (3.10 mg/dl) to 500 mg lanthanum carbonate or matched placebo thrice daily for 96 weeks. We analyzed the primary outcome, carotid-femoral pulse wave velocity, using a linear mixed effects model for repeated measures. Secondary outcomes included abdominal aortic calcification and serum and urine markers of mineral metabolism.

Results: A total of 138 participants received lanthanum and 140 received placebo (mean age 63.1 years; 69% male, 64% White). Mean eGFR was 26.6 ml/min per 1.73 m; 45% of participants had diabetes and 32% had cardiovascular disease. Mean serum phosphate was 1.25 mmol/L (3.87 mg/dl), mean pulse wave velocity was 10.8 m/s, and 81.3% had abdominal aortic calcification at baseline. At 96 weeks, pulse wave velocity did not differ significantly between groups, nor did abdominal aortic calcification, serum phosphate, parathyroid hormone, FGF23, and 24-hour urinary phosphate. Serious adverse events occurred in 63 (46%) participants prescribed lanthanum and 66 (47%) prescribed placebo. Although recruitment to target was not achieved, additional analysis suggested this was unlikely to have significantly affected the principle findings.

Conclusions: In patients with stage 3b/4 CKD, treatment with lanthanum over 96 weeks did not affect arterial stiffness or aortic calcification compared with placebo. These findings do not support the role of intestinal phosphate binders to reduce cardiovascular risk in patients with CKD who have normophosphatemia.

Clinical Trial Registry Name And Registration Number: Australian Clinical Trials Registry, ACTRN12610000650099.
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http://dx.doi.org/10.1681/ASN.2020040411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608977PMC
November 2020

Mud in the blood: the role of protein-mineral complexes and extracellular vesicles in biomineralisation and calcification.

J Struct Biol 2020 10 22;212(1):107577. Epub 2020 Jul 22.

Department of Nephrology, The Royal Melbourne Hospital, Melbourne, Australia; Department of Medicine, University of Melbourne, Parkville, Australia.

Protein-mineral interaction is known to regulate biomineral stability and morphology. We hypothesise that fluid phases produce highly dynamic protein-mineral complexes involved in physiology and pathology of biomineralisation. Here, we specifically focus on calciprotein particles, complexes of vertebrate mineral-binding proteins and calcium phosphate present in the systemic circulation and abundant in extracellular fluids - hence the designation of the ensuing protein-mineral complexes as "mud in the blood". These complexes exist amongst other extracellular particles that we collectively refer to as "the particle zoo".
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http://dx.doi.org/10.1016/j.jsb.2020.107577DOI Listing
October 2020

Noninfectious mixed cryoglobulinaemic glomerulonephritis and monoclonal gammopathy of undetermined significance: a coincidental association?

BMC Nephrol 2020 07 23;21(1):293. Epub 2020 Jul 23.

Department of Nephrology, The Royal Melbourne Hospital, Parkville, Australia.

Background: Cryoglobulins are cold-precipitable immunoglobulins that may cause systemic vasculitis including cryoglobulinaemic glomerulonephritis (CGN). Type 1 cryoglobulins consist of isolated monoclonal immunoglobulin (mIg), whereas mixed cryoglobulins are typically immune complexes comprising either monoclonal (type 2) or polyclonal (type 3) Ig with rheumatoid activity against polyclonal IgG. Only CGN related to type 1 cryoglobulins has been clearly associated with monoclonal gammopathy of undetermined significance (MGUS) using the conventional serum-, urine- or tissue-based methods of paraprotein detection.

Case Presentation: We present four patients with noninfectious mixed (type 2 or 3) CGN and MGUS. Two patients had type 2 cryoglobulinaemia, one had type 3 cryoglobulinaemia, and one lacked definitive typing of the serum cryoprecipitate. The serum monoclonal band was IgM-κ in all four cases. Treatments included corticosteroids, cyclophosphamide, plasma exchange, and rituximab. At median 3.5 years' follow-up, no patient had developed a haematological malignancy or advanced chronic kidney disease. Other potential causes of mixed cryoglobulinaemia were also present in our cohort, notably primary Sjögren's syndrome in three cases.

Conclusion: Our study raises questions regarding the current designation of type 2 CGN as a monoclonal gammopathy of renal significance, and the role of clonally directed therapies for noninfectious mixed CGN outside the setting of haematological malignancy.
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http://dx.doi.org/10.1186/s12882-020-01941-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7376917PMC
July 2020

Vascular calcification in skin and subcutaneous tissue in patients with chronic and end-stage kidney disease.

BMC Nephrol 2020 07 16;21(1):279. Epub 2020 Jul 16.

Department of Nephrology, The Royal Melbourne Hospital, 300 Grattan St, Parkville, Victoria, 3050, Australia.

Background: Vascular calcification (VC) is well described in large- and medium-sized vessels in patients with chronic kidney disease (CKD), especially in those with end-stage kidney disease (ESKD) on dialysis. Medial calcification is particularly prevalent in this population and contributes to arterial stiffness and increased cardiovascular mortality and morbidity. Apart from in the setting of calciphylaxis, few studies have assessed skin and subcutaneous calcification and associations with abnormalities of bone and mineral metabolism in patients with CKD.

Methods: We performed a single-centre observational study to evaluate incisional skin tissue samples from three anatomical sites in patients with different stages of CKD undergoing elective surgery. We compared these samples to skin samples of a control cohort without CKD. Staining for calcification was performed with von Kossa method. A subgroup of skin samples were assessed by RT-PCR for upregulation of pro-calcific gene transcripts for tissue non-specific alkaline phosphatase (TNAP) and Runt-related transcription factor 2 (RUNX2).

Results: Forty-five patients were evaluated, 34 with CKD (including ESKD) and 11 control patients. VC was identified in 15 skin samples (13 CKD/ESKD and 2 controls). VC was present in the dermal and subcutaneous tissues of the neck, abdomen and arm samples. Two different histological types of VC were identified: speckled medial calcification and internal elastic lamina calcification. Presence of perieccrine calcification was identified in 14 samples, 10 with concurrent VC. There were no significant differences in serum parathyroid hormone, phosphate or calcium in patients with or without VC. Expression of TNAP or RUNX2 was not increased in samples from patients with ESKD or those with histological evidence of calcification.

Conclusion: This study reports the novel finding of dermal and subcutaneous calcification in multiple anatomical locations in 38% of patients with advanced CKD/ESKD undergoing elective surgery but free from calciphylaxis.
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http://dx.doi.org/10.1186/s12882-020-01928-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7364566PMC
July 2020

Calciprotein particles: A mineral biomarker in need of better measurement.

Authors:
Edward R Smith

Atherosclerosis 2020 06 8;303:43-45. Epub 2020 May 8.

Department of Nephrology, The Royal Melbourne Hospital, Melbourne, Australia; Department of Medicine, University of Melbourne, Parkville, Australia. Electronic address:

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http://dx.doi.org/10.1016/j.atherosclerosis.2020.04.017DOI Listing
June 2020

Calciprotein particles: mineral behaving badly?

Curr Opin Nephrol Hypertens 2020 07;29(4):378-386

Helmholtz-Institute for Biomedical Engineering, RWTH Aachen University Hospital, Aachen, Germany.

Purpose Of Review: Calciprotein particles (CPP) are formed in supersaturated solutions of calcium, phosphate and the mineral-binding protein fetuin-A. CPP have garnered considerable interest as potential mediators of mineral stress, but little consideration has been given to their origin, clearance and role in metabolism.

Recent Findings: CPP are made whilst buffering the mineral absorbed from the intestine after a meal or during remodelling of bone matrix. The postprandial rise in circulating CPP rise may be sensed by osteoblasts/osteocytes in bone, stimulating the secretion of the master phosphatonin fibroblast growth factor 23. Amorphous calcium phosphate-containing CPP are rapidly cleared by endothelial cells in the liver whereas crystalline apatite-containing CPP are filtered by phagocytic cells of the reticuloendothelial system. Impaired excretory function in kidney disease may lead to accumulation of CPP and its precursors with possible pathological sequalae. Inability to stabilize CPP in fetuin-A-deficiency states can result in intraluminal precipitation and inflammatory cascades if other mineralisation regulatory networks are compromised.

Summary: CPP allow efficient transport and clearance of bulk calcium phosphate as colloids without risk of precipitation. As circulating factors, CPP may couple dietary mineral exposure with endocrine control of mineral metabolism in bone, signalling the need to dispose of excess phosphate from the body.
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http://dx.doi.org/10.1097/MNH.0000000000000609DOI Listing
July 2020

Dysregulation of the EphrinB2-EphB4 ratio in pediatric cerebral arteriovenous malformations is associated with endothelial cell dysfunction in vitro and functions as a novel noninvasive biomarker in patients.

Exp Mol Med 2020 04 14;52(4):658-671. Epub 2020 Apr 14.

Vascular Biology Program, Boston Children's Hospital, Boston, MA, USA.

We investigated (1) EphrinB2 and EphB4 receptor expression in cerebral AVMs, (2) the impact of an altered EphrinB2:EphB4 ratio on brain endothelial cell function and (3) potential translational applications of these data. The following parameters were compared between AVM endothelial cells (AVMECs) and human brain microvascular endothelial cells (HBMVECs): quantified EphrinB2 and EphB4 expression, angiogenic potential, and responses to manipulation of the EphrinB2:EphB4 ratio via pharmacologic stimulation/inhibition. To investigate the clinical relevance of these in vitro data, Ephrin expression was assessed in AVM tissue (by immunohistochemistry) and urine (by ELISA) from pediatric patients with AVM (n = 30), other cerebrovascular disease (n = 14) and control patients (n = 29), and the data were subjected to univariate and multivariate statistical analyses. Compared to HBMVECs, AVMECs demonstrated increased invasion (p = 0.04) and migration (p = 0.08), impaired tube formation (p = 0.06) and increased EphrinB2:EphB4 ratios. Altering the EphrinB2:EphB4 ratio (by increasing EphrinB2 or blocking EphB4) in HBMVECs increased invasion (p = 0.03 and p < 0.05, respectively). EphrinB2 expression was increased in AVM tissue, which correlated with increased urinary EphrinB2 levels in AVM patients. Using the optimal urinary cutoff value (EphrinB2 > 25.7 pg/μg), AVMs were detected with high accuracy (80% vs. controls) and were distinguished from other cerebrovascular disease (75% accuracy). Post-treatment urinary EphrinB2 levels normalized in an index patient. In summary, AVMECs have an EphrinB2:EphB4 ratio that is increased compared to that of normal HBMVECs. Changing this ratio in HBMVECs induces AVMEC-like behavior. EphrinB2 is clinically relevant, and its levels are increased in AVM tissue and patient urine. This work suggests that dysregulation of the EphrinB2:EphB4 signaling cascade and increases in EphrinB2 may play a role in AVM development, with potential utility as a diagnostic and therapeutic target.
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http://dx.doi.org/10.1038/s12276-020-0414-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7210966PMC
April 2020

Nature's remedy to phosphate woes: calciprotein particles regulate systemic mineral metabolism.

Kidney Int 2020 04;97(4):648-651

Department of Nephrology, The Royal Melbourne Hospital, Melbourne, Australia; Department of Medicine, University of Melbourne, Parkville, Australia. Electronic address:

Calciprotein particles, colloidal complexes of calcium phosphate and plasma protein fetuin-A, have emerged as mediators of multiple biological effects attributed to phosphate. A new study postulates that circulating calciprotein particles, not phosphate, regulate the production of the major bone-derived phosphatonin, fibroblast growth factor-23. The signaling events coupling calciprotein particles sensing in bone to fibroblast growth factor-23 secretion remain to be established.
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http://dx.doi.org/10.1016/j.kint.2019.12.018DOI Listing
April 2020

A phase I/II study of veliparib (ABT-888) with radiation and temozolomide in newly diagnosed diffuse pontine glioma: a Pediatric Brain Tumor Consortium study.

Neuro Oncol 2020 06;22(6):875-885

Cincinnati Children's Hospital, Cincinnati, Ohio.

Background: A Pediatric Brain Tumor Consortium (PBTC) phase I/II trial of veliparib and radiation followed by veliparib and temozolomide (TMZ) was conducted in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG). The objectives were to: (i) estimate the recommended phase II dose (RP2D) of veliparib with concurrent radiation; (ii) evaluate the pharmacokinetic parameters of veliparib during radiation; (iii) evaluate feasibility of intrapatient TMZ dose escalation; (iv) describe toxicities of protocol therapy; and (v) estimate the overall survival distribution compared with historical series.

Methods: Veliparib was given Monday through Friday b.i.d. during radiation followed by a 4-week rest. Patients then received veliparib at 25 mg/m2 b.i.d. and TMZ 135 mg/m2 daily for 5 days every 28 days. Intrapatient dose escalation of TMZ was investigated for patients experiencing minimal toxicity.

Results: Sixty-six patients (65 eligible) were enrolled. The RP2D of veliparib was 65 mg/m2 b.i.d. with radiation. Dose-limiting toxicities during radiation with veliparib therapy included: grade 2 intratumoral hemorrhage (n = 1), grade 3 maculopapular rash (n = 2), and grade 3 nervous system disorder (generalized neurologic deterioration) (n = 1). Intrapatient TMZ dose escalation during maintenance was not tolerated. Following a planned interim analysis, it was concluded that this treatment did not show a survival benefit compared with PBTC historical controls, and accrual was stopped for futility. The 1- and 2-year overall survival rates were 37.2% (SE 7%) and 5.3% (SE 3%), respectively.

Conclusion: Addition of veliparib to radiation followed by TMZ and veliparib was tolerated but did not improve survival for patients with newly diagnosed DIPG.

Trial Registration: NCT01514201.
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http://dx.doi.org/10.1093/neuonc/noaa016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7283021PMC
June 2020

Chiari I malformations with syringomyelia: long-term results of neurosurgical decompression.

Spine Deform 2020 04 13;8(2):233-243. Epub 2020 Jan 13.

Department of Orthopaedic Surgery, University Hospital Cleveland Medical Center, Cleveland, OH, USA.

Study Design: Retrospective case series.

Objectives: The objective was to assess the long-term outcomes on scoliosis following Chiari-I (CM-I) decompression in patients with CM-I and syringomyelia (SM). A secondary objective was to identify risk factors of scoliosis progression.

Background: The association between CM-I with SM and scoliosis is recognized, but it remains unclear if CM-I decompression alters the long-term evolution of scoliosis in patients with associated syringomyelia.

Methods: A retrospective review of children with scoliosis, CM-I, and SM during 1997-2015 was performed. Congenital, syndromic, and neuromuscular scoliosis were excluded. Clinical and radiographic characteristics were recorded at presentation, pre-decompression, after 1-year, and latest follow-up. A scale to measure syringomyelia area on MRI was used to evaluate SM changes post-decompression.

Results: 65 children with CM-I, SM, and scoliosis and a mean age of 8.9 years (range 0.7-15.8) were identified. Mean follow-up was 6.9 years (range 2.0-20.4). Atypical curves were present in 28 (43%) children. Thirty-eight patients (58%) underwent decompression before 10 years. Syringomyelia size reduced a mean of 70% after decompression (p < 0.001). Scoliosis improved in 26 (40%), stabilized in 17 (26%), and progressed in 22 (34%) cases. Early spinal fusion was required in 7 (11%) patients after a mean of 0.5 ± 0.37 years and delayed fusion in 16 (25%) patients after 6.0 ± 3.24 years. The remaining 42 (65%) patients were followed for a median of 6.1 years (range 2.0-12.3) without spine instrumentation or fusion. Fusion patients experienced less improvement in curve magnitude 1-year post-decompression (p < 0.001) and had larger curves at presentation (43° vs. 34°; p = 0.004).

Conclusions: Syringomyelia size decreased by 70% after CM-I decompression and scoliosis stabilized or improved in two-thirds of patients. Greater curve improvement within the first year post-decompression and smaller curves at presentation decreased the risk of spinal fusion. Neurosurgical decompression is recommended in children with CM-I, SM, and scoliosis with the potential to treat all three conditions.

Level Of Evidence: Level IV.
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http://dx.doi.org/10.1007/s43390-019-00009-zDOI Listing
April 2020

Monitoring skin temperature at the wrist in hospitalised patients may assist in the detection of infection.

Intern Med J 2020 06 5;50(6):685-690. Epub 2020 May 5.

Department of Nephrology, The Royal Melbourne Hospital, Melbourne, Victoria, Australia.

Background: Measuring temperature has always been a key observation in the diagnosis of infection. No studies have examined the usefulness of measuring temperature at the wrist to detect infection.

Aim: We sought to determine whether a watch measuring wrist temperature could accurately identify patients who are infected.

Methods: Prospective cross-sectional pilot study of temperature monitoring in an unselected patients in a tertiary referral adult nephrology unit.

Results: One hundred and four data recording sessions revealed 88 useful data sets, with recording failures in the others. Patients were retrospectively classified as having no infection (Group A, n = 60), clinically diagnosed infection with less than 24 h of treatment with antibiotics (Group B, n = 5), and clinically diagnosed infection with greater than 24 h on antibiotics (Group C, n = 23). There was a significantly higher average maximum temperature in Group B (mean (SEM)) 38°C (0.6) compared with Groups A (36.1°C (0.1)) and C (36.3°C (0.3)). Based on receiver operating characteristics (ROC) a cut-off temperature of ≥37.5°C gave sensitivity 80% and specificity 98%. Mean electrodermal activity was significantly higher in Groups B and C.

Conclusions: ROC of peripheral skin temperature measurements suggest that such a device may identify many patients requiring treatment for infection. This proof of principle study showed value in using a wearable device in the detection of infection and its potential as an early warning or monitoring device.
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http://dx.doi.org/10.1111/imj.14748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318648PMC
June 2020

Diagnostic Tests for Vascular Calcification.

Adv Chronic Kidney Dis 2019 11;26(6):445-463

Department of Nephrology, The Royal Melbourne Hospital, Parkville, VIC, Australia; Department of Medicine, University of Melbourne, Parkville, VIC, Australia.

Vascular calcification (VC) is the heterogeneous endpoint of multiple vascular insults, which varies by arterial bed, the layer of the arterial wall affected, and is propagated by diverse cellular and biochemical mechanisms. A variety of in vivo and ex vivo techniques have been applied to the analysis of VC in preclinical studies, but clinical examination has principally relied on a number of noninvasive and invasive imaging modalities for detection and quantitation. Most imaging methods suffer from suboptimal spatial resolution, leading to the inability to distinguish medial from intimal VC and insufficient sensitivity to detect microcalcifications that are indicative of active mineral deposition and of vulnerable plaques which may be prone to rupture. Serum biomarkers lack specificity for VC and cannot discriminate pathology. Overall, uncertainties surrounding the sensitivity and specificity of different VC testing modalities, the absence of a clear cause-effect relationship, and lack of any evidence-based diagnostic or therapeutic protocols in relation to VC testing in chronic kidney disease has yielded weak or ungraded recommendations for their use in clinical practice. While VC is recognized as a key manifestation of chronic kidney disease-mineral and bone disorder and those with an increasing burden of VC are considered to be at higher cardiovascular risk, routine screening is not currently recommended.
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http://dx.doi.org/10.1053/j.ackd.2019.07.001DOI Listing
November 2019

The effect of increasing dialysate magnesium on calciprotein particles, inflammation and bone markers: post hoc analysis from a randomized controlled clinical trial.

Nephrol Dial Transplant 2019 Nov 25. Epub 2019 Nov 25.

Department of Nephrology, Royal Melbourne Hospital, University of Melbourne, Melbourne, Victoria, Australia.

Background: The formation of calciprotein particles (CPPs) may be an important component of the humoral defences against ectopic calcification. Although magnesium (Mg) has been shown to delay the transition of amorphous calcium-/phosphate-containing primary CPP (CPP-1) to crystalline apatite-containing secondary CPP (CPP-2) ex vivo, effects on the endogenous CPP pool are unknown.

Methods: We used post hoc analyses from a randomized double-blind parallel-group controlled clinical trial of 28 days treatment with high dialysate Mg of 2.0 mEq/L versus standard dialysate Mg of 1.0 mEq/L in 57 subjects undergoing maintenance hemodialysis for end-stage kidney disease. CPP load, markers of systemic inflammation and bone turnover were measured at baseline and follow-up.

Results: After 28 days of treatment with high dialysate Mg, serum total CPP (-52%), CPP-1 (-42%) and CPP-2 (-68%) were lower in the high Mg group (all P < 0.001) but were unchanged in the standard dialysate Mg group. Tumour necrosis factor-α (-20%) and interleukin-6 (-22%) were also reduced with high dialysate Mg treatment (both P < 0.01). High dialysate Mg resulted in higher levels of bone-specific alkaline phosphatase (a marker of bone formation) (+17%) but lower levels of tartrate-resistant acid phosphatase 5 b (a marker of bone resorption; -33%) (both P < 0.01). Inflammatory cytokines and bone turnover markers were unchanged in the standard dialysate Mg group over the same period.

Conclusions: In this exploratory analysis, increasing dialysate Mg was associated with reduced CPP load and systemic inflammation and divergent changes in markers of bone formation and resorption.
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http://dx.doi.org/10.1093/ndt/gfz234DOI Listing
November 2019

Indirect bypass for maternal symptomatic moyamoya in the first trimester of pregnancy: case report.

J Neurosurg Pediatr 2019 Nov 22:1-6. Epub 2019 Nov 22.

1Vascular Biology Program and.

There are no practice guidelines for the treatment of moyamoya disease in pregnant women. The need for such guidelines, however, is evidenced by the numerous case reports, case series, and systematic reviews in the literature highlighting an at-risk period for female moyamoya patients of childbearing age. Here the authors review and interpret the existing literature as it applies to their index patient and expand the literature in support of treating select patients during pregnancy. The authors describe what is to their knowledge the first case reported in the literature of a patient successfully treated with indirect surgical revascularization during the first trimester, who went on to deliver a healthy term baby without complications.
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http://dx.doi.org/10.3171/2019.9.PEDS19360DOI Listing
November 2019

Serum Calcification Propensity and Clinical Events in CKD.

Clin J Am Soc Nephrol 2019 11 28;14(11):1562-1571. Epub 2019 Oct 28.

Center for Translational Metabolism and Health, Institute for Public Health and Medicine, and

Background And Objectives: Patients with CKD are at high risk for cardiovascular disease, ESKD, and mortality. Vascular calcification is one pathway through which cardiovascular disease risks are increased. We hypothesized that a novel measure of serum calcification propensity is associated with cardiovascular disease events, ESKD, and all-cause mortality among patients with CKD stages 2-4.

Design, Setting, Participants, & Measurements: Among 3404 participants from the prospective, longitudinal Chronic Renal Insufficiency Cohort Study, we quantified calcification propensity as the transformation time (T) from primary to secondary calciprotein particles, with lower T corresponding to higher calcification propensity. We used multivariable-adjusted Cox proportional hazards regression models to assess the associations of T with risks of adjudicated atherosclerotic cardiovascular disease events (myocardial infarction, stroke, and peripheral artery disease), adjudicated heart failure, ESKD, and mortality.

Results: The mean T was 313 (SD 79) minutes. Over an average 7.1 (SD 3.1) years of follow-up, we observed 571 atherosclerotic cardiovascular disease events, 633 heart failure events, 887 ESKD events, and 924 deaths. With adjustment for traditional cardiovascular disease risk factors, lower T was significantly associated with higher risk of atherosclerotic cardiovascular disease (hazard ratio [HR] per SD lower T, 1.14; 95% confidence interval [95% CI], 1.05 to 1.25), ESKD within 3 years from baseline (HR per SD lower T, 1.68; 95% CI, 1.52 to 1.86), and all-cause mortality (HR per SD lower T, 1.16; 95% CI, 1.09 to 1.24), but not heart failure (HR per SD lower T, 1.06; 95% CI, 0.97 to 1.15). After adjustment for eGFR and 24-hour urinary protein, T was not associated with risks of atherosclerotic cardiovascular disease, ESKD, and mortality.

Conclusions: Among patients with CKD stages 2-4, higher serum calcification propensity is associated with atherosclerotic cardiovascular disease events, ESKD, and all-cause mortality, but this association was not independent of kidney function.

Podcast: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2019_10_28_CJN04710419.mp3.
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http://dx.doi.org/10.2215/CJN.04710419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6832040PMC
November 2019

Dynamic Changes in Arteriovenous Malformations (AVMs): Spontaneous Growth and Resolution of AVM-Associated Aneurysms in Two Pediatric Patients.

Pediatr Neurosurg 2019 9;54(6):394-398. Epub 2019 Oct 9.

Department of Neurosurgery, Boston Children's Hospital, Boston, Massachusetts, USA,

Arteriovenous malformations (AVMs) of the central nervous system are dynamic lesions that can change with time. One of the most clinically important concerns is the development and potential rupture of AVM-associated aneurysms. In this report, we review pediatric cases of de novo development of AVM-associated aneurysms in 2 children and present the relevant clinical and radiographic records. These 2 cases, coupled with a review of the current literature, offer insight into the risks of AVMs in children and underline the importance of timely treatment of appropriate cases.
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http://dx.doi.org/10.1159/000501041DOI Listing
April 2020

The pleiotropy associated with de novo variants in CHD4, CNOT3, and SETD5 extends to moyamoya angiopathy.

Genet Med 2020 02 2;22(2):427-431. Epub 2019 Sep 2.

Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.

Purpose: Moyamoya angiopathy (MMA) is a cerebrovascular disease characterized by occlusion of large arteries, which leads to strokes starting in childhood. Twelve altered genes predispose to MMA but the majority of cases of European descent do not have an identified genetic trigger.

Methods: Exome sequencing from 39 trios were analyzed.

Results: We identified four de novo variants in three genes not previously associated with MMA: CHD4, CNOT3, and SETD5. Identification of additional rare variants in these genes in 158 unrelated MMA probands provided further support that rare pathogenic variants in CHD4 and CNOT3 predispose to MMA. Previous studies identified de novo variants in these genes in children with developmental disorders (DD), intellectual disability, and congenital heart disease.

Conclusion: These genes encode proteins involved in chromatin remodeling, and taken together with previously reported genes leading to MMA-like cerebrovascular occlusive disease (YY1AP1, SMARCAL1), implicate disrupted chromatin remodeling as a molecular pathway predisposing to early onset, large artery occlusive cerebrovascular disease. Furthermore, these data expand the spectrum of phenotypic pleiotropy due to alterations of CHD4, CNOT3, and SETD5 beyond DD to later onset disease in the cerebrovascular arteries and emphasize the need to assess clinical complications into adulthood for genes associated with DD.
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http://dx.doi.org/10.1038/s41436-019-0639-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673309PMC
February 2020

Fully automated, real-time, calibration-free, continuous noninvasive estimation of intracranial pressure in children.

J Neurosurg Pediatr 2019 Aug 23:1-11. Epub 2019 Aug 23.

1Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge.

Objective: In the search for a reliable, cooperation-independent, noninvasive alternative to invasive intracranial pressure (ICP) monitoring in children, various approaches have been proposed, but at the present time none are capable of providing fully automated, real-time, calibration-free, continuous and accurate ICP estimates. The authors investigated the feasibility and validity of simultaneously monitored arterial blood pressure (ABP) and middle cerebral artery (MCA) cerebral blood flow velocity (CBFV) waveforms to derive noninvasive ICP (nICP) estimates.

Methods: Invasive ICP and ABP recordings were collected from 12 pediatric and young adult patients (aged 2-25 years) undergoing such monitoring as part of routine clinical care. Additionally, simultaneous transcranial Doppler (TCD) ultrasonography-based MCA CBFV waveform measurements were performed at the bedside in dedicated data collection sessions. The ABP and MCA CBFV waveforms were analyzed in the context of a mathematical model, linking them to the cerebral vasculature's biophysical properties and ICP. The authors developed and automated a waveform preprocessing, signal-quality evaluation, and waveform-synchronization "pipeline" in order to test and objectively validate the algorithm's performance. To generate one nICP estimate, 60 beats of ABP and MCA CBFV waveform data were analyzed. Moving the 60-beat data window forward by one beat at a time (overlapping data windows) resulted in 39,480 ICP-to-nICP comparisons across a total of 44 data-collection sessions (studies). Moving the 60-beat data window forward by 60 beats at a time (nonoverlapping data windows) resulted in 722 paired ICP-to-nICP comparisons.

Results: Greater than 80% of all nICP estimates fell within ± 7 mm Hg of the reference measurement. Overall performance in the nonoverlapping data window approach gave a mean error (bias) of 1.0 mm Hg, standard deviation of the error (precision) of 5.1 mm Hg, and root-mean-square error of 5.2 mm Hg. The associated mean and median absolute errors were 4.2 mm Hg and 3.3 mm Hg, respectively. These results were contingent on ensuring adequate ABP and CBFV signal quality and required accurate hydrostatic pressure correction of the measured ABP waveform in relation to the elevation of the external auditory meatus. Notably, the procedure had no failed attempts at data collection, and all patients had adequate TCD data from at least one hemisphere. Last, an analysis of using study-by-study averaged nICP estimates to detect a measured ICP > 15 mm Hg resulted in an area under the receiver operating characteristic curve of 0.83, with a sensitivity of 71% and specificity of 86% for a detection threshold of nICP = 15 mm Hg.

Conclusions: This nICP estimation algorithm, based on ABP and bedside TCD CBFV waveform measurements, performs in a manner comparable to invasive ICP monitoring. These findings open the possibility for rational, point-of-care treatment decisions in pediatric patients with suspected raised ICP undergoing intensive care.
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http://dx.doi.org/10.3171/2019.5.PEDS19178DOI Listing
August 2019

A national analysis of 9655 pediatric cerebrovascular malformations: effect of hospital volume on outcomes.

J Neurosurg Pediatr 2019 Aug 2:1-10. Epub 2019 Aug 2.

2Department of Neurosurgery, Children's Hospital Boston.

Objective: Comprehensive multicenter data on the surgical treatment of pediatric cerebrovascular malformations (CVMs) in the US are lacking. The goal of this study was to identify national trends in patient demographics and assess the effect of hospital case volume on outcomes.

Methods: Admissions for CVMs (1997-2012) were identified from the nationwide Kids' Inpatient Database. Admissions with and without craniotomy were reviewed separately. Patients were categorized by whether they were treated at low-, medium-, or high-volume centers (< 10, 10-40, > 40 cases/year, respectively). A generalized linear model was used to evaluate the association of hospital pediatric CVM case volume and clinical variables assessing outcomes.

Results: Among the 9655 patients, 1828 underwent craniotomy and 7827 did not. Patient age and race differed in the two groups, as did the rate of private medical payers. High-volume hospitals had fewer nonroutine discharges (11.2% [high] vs 16.4% [medium] vs 22.3% [low], p = 0.0001). For admissions requiring craniotomy, total charges ($106,282 [high] vs $126,215 [medium] vs $134,978 [low], p < 0.001) and complication rates (0.09% [high] vs 0.11% [medium] vs 0.16% [low], p = 0.001) were lower in high-volume centers.

Conclusions: This study revealed that further investigation may be needed regarding barriers to surgical treatment of pediatric CVMs. The authors found that surgical treatment of pediatric CVM at high-volume centers is associated with significantly fewer complications, better dispositions, and lower costs, but for noncraniotomy patients, low-volume centers had lower rates of complications and death and lower costs. These findings may support the consideration of appropriate referral of CVM patients requiring surgery or with intracranial hemorrhage toward high-volume, specialized centers.
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http://dx.doi.org/10.3171/2019.5.PEDS19155DOI Listing
August 2019

αKlotho-FGF23 interactions and their role in kidney disease: a molecular insight.

Cell Mol Life Sci 2019 Dec 26;76(23):4705-4724. Epub 2019 Jul 26.

Department of Nephrology, The Royal Melbourne Hospital, Melbourne, Australia.

Following the serendipitous discovery of the ageing suppressor, αKlotho (αKl), several decades ago, a growing body of evidence has defined a pivotal role for its various forms in multiple aspects of vertebrate physiology and pathology. The transmembrane form of αKl serves as a co-receptor for the osteocyte-derived mineral regulator, fibroblast growth factor (FGF)23, principally in the renal tubules. However, compelling data also suggest that circulating soluble forms of αKl, derived from the same source, may have independent homeostatic functions either as a hormone, glycan-cleaving enzyme or lectin. Chronic kidney disease (CKD) is of particular interest as disruption of the FGF23-αKl axis is an early and common feature of disease manifesting in markedly deficient αKl expression, but FGF23 excess. Here we critically discuss recent findings in αKl biology that conflict with the view that soluble αKl has substantive functions independent of FGF23 signalling. Although the issue of whether soluble αKl can act without FGF23 has yet to be resolved, we explore the potential significance of these contrary findings in the context of CKD and highlight how this endocrine pathway represents a promising target for novel anti-ageing therapeutics.
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http://dx.doi.org/10.1007/s00018-019-03241-yDOI Listing
December 2019

Quantitative Analysis of Different Cell Entry Routes of Actively Targeted Nanomedicines Using Imaging Flow Cytometry.

Cytometry A 2019 08 11;95(8):843-853. Epub 2019 Jul 11.

Vascular Biology Program, Boston Children's Hospital, Boston, Massachusetts, 02115.

A rapid, high-throughput, and quantitative method for cell entry route characterization is still lacking in nanomedicine research. Here, we report the application of imaging flow cytometry for quantitatively analyzing cell entry routes of actively targeted nanomedicines. We first engineered ICAM1 antibody-directed fusogenic nanoliposomes (ICAM1-FusoNLPs) and ICAM1 antibody-directed endocytic nanolipogels (ICAM1-EndoNLGs) featuring highly similar surface properties but different cell entry routes: receptor-mediated membrane fusion and receptor-mediated endocytosis, respectively. By using imaging flow cytometry, we characterized their intracellular delivery into human breast cancer MDA-MB-231 cells. We found that ICAM1-FusoNLPs mediated a 2.8-fold increased cell uptake of fluorescent payload, FITC-dextran, with a 2.4-fold increased intracellular distribution area in comparison with ICAM1-EndoNLGs. We also investigated the effects of incubation time and endocytic inhibitors on the cell entry routes of ICAM1-FusoNLP and ICAM1-EndoNLG. Our results indicate that receptor-mediated membrane fusion is a faster and more efficient cell entry route than receptor-mediated endocytosis, bringing with it a significant therapeutic benefit in a proof-of-principle nanomedicine-mediated siRNA transfection experiment. Our studies suggest that cell entry route may be an important design parameter to be considered in the development of next-generation nanomedicines. © 2019 International Society for Advancement of Cytometry.
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http://dx.doi.org/10.1002/cyto.a.23848DOI Listing
August 2019