Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 611
Filter
2.
Nat Cancer ; 5(6): 880-894, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38658775

ABSTRACT

In this prospective, interventional phase 1 study for individuals with advanced sarcoma, we infused autologous HER2-specific chimeric antigen receptor T cells (HER2 CAR T cells) after lymphodepletion with fludarabine (Flu) ± cyclophosphamide (Cy): 1 × 108 T cells per m2 after Flu (cohort A) or Flu/Cy (cohort B) and 1 × 108 CAR+ T cells per m2 after Flu/Cy (cohort C). The primary outcome was assessment of safety of one dose of HER2 CAR T cells after lymphodepletion. Determination of antitumor responses was the secondary outcome. Thirteen individuals were treated in 14 enrollments, and seven received multiple infusions. HER2 CAR T cells expanded after 19 of 21 infusions. Nine of 12 individuals in cohorts A and B developed grade 1-2 cytokine release syndrome. Two individuals in cohort C experienced dose-limiting toxicity with grade 3-4 cytokine release syndrome. Antitumor activity was observed with clinical benefit in 50% of individuals treated. The tumor samples analyzed showed spatial heterogeneity of immune cells and clustering by sarcoma type and by treatment response. Our results affirm HER2 as a CAR T cell target and demonstrate the safety of this therapeutic approach in sarcoma. ClinicalTrials.gov registration: NCT00902044 .


Subject(s)
Immunotherapy, Adoptive , Receptor, ErbB-2 , Receptors, Chimeric Antigen , Sarcoma , Humans , Sarcoma/therapy , Sarcoma/immunology , Middle Aged , Female , Male , Adult , Immunotherapy, Adoptive/methods , Immunotherapy, Adoptive/adverse effects , Aged , Receptors, Chimeric Antigen/immunology , T-Lymphocytes/immunology , Lymphocyte Depletion/methods , Prospective Studies , Vidarabine/analogs & derivatives , Vidarabine/administration & dosage , Vidarabine/therapeutic use , Cyclophosphamide/therapeutic use , Cyclophosphamide/administration & dosage , Treatment Outcome
3.
Arch Pathol Lab Med ; 2024 Mar 29.
Article in English | MEDLINE | ID: mdl-38547914

ABSTRACT

CONTEXT.­: Perivascular epithelioid cell tumors (PEComas) are rare mesenchymal tumors of uncertain histogenesis expressing smooth muscle and melanocytic markers. The clinicopathologic spectrum in young patients is not well documented. OBJECTIVE.­: To describe a multi-institutional series of PEComas in children, adolescents, and young adults. DESIGN.­: PEComas, not otherwise specified (NOS); angiomyolipomas (AMLs); lymphangioleiomyomatosis; and clear cell sugar tumors were retrospectively identified from 6 institutions and authors' files. RESULTS.­: Seventy PEComas in 64 patients (median age, 15 years) were identified. They were more common in females (45 of 64 patients), occurring predominately in kidney (53 of 70), followed by liver (6 of 70). Thirty-four patients had confirmed tuberous sclerosis complex (TSC), 3 suspected TSC mosaicism, 2 Li-Fraumeni syndrome (LFS) and 1 neurofibromatosis type 1. Most common variants were classic (49 of 70) and epithelioid (8 of 70) AML. Among patients with AMLs, most (34 of 47) had TSC, and more TSC patients had multiple AMLs (15 of 36) than non-TSC patients (2 of 13). Two TSC patients developed malignant transformation of classic AMLs: 1 angiosarcomatous and 1 malignant epithelioid. Lymphangioleiomyomatosis (5 of 70) occurred in females only, usually in the TSC context (4 of 5). PEComas-NOS (6 of 70) occurred exclusively in non-TSC patients, 2 of whom had LFS (2 of 6). Three were malignant, 1 had uncertain malignant potential, and 2 were benign. All 4 PEComas-NOS in non-LFS patients had TFE3 rearrangements. CONCLUSIONS.­: Compared to the general population, TSC was more prevalent in our cohort; PEComas-NOS showed more frequent TFE3 rearrangements and possible association with LFS. This series expands the spectrum of PEComas in young patients and demonstrates molecular features and germline contexts that set them apart from older patients.

4.
Clin Immunol ; 258: 109874, 2024 01.
Article in English | MEDLINE | ID: mdl-38113962

ABSTRACT

Sle1 and Faslpr are two lupus susceptibility loci that lead to manifestations of systemic lupus erythematosus. To evaluate the dosage effects of Faslpr in determining cellular and serological phenotypes associated with lupus, we developed a new C57BL/6 (B6) congenic lupus strain, B6.Sle1/Sle1.Faslpr/+ (Sle1homo.lprhet) and compared it with B6.Faslpr/lpr (lprhomo), B6.Sle1/Sle1 (Sle1homo), and B6.Sle1/Sle1.Faslpr/lpr (Sle1homo.lprhomo) strains. Whereas Sle1homo.lprhomo mice exhibited profound lymphoproliferation and early mortality, Sle1homo.lprhet mice had a lifespan comparable to B6 mice, with no evidence of splenomegaly or lymphadenopathy. Compared to B6 monogenic lupus strains, Sle1homo.lprhet mice exhibited significantly elevated serum ANA antibodies and increased proteinuria. Additionally, Sle1homo.lprhet T cells had an increased propensity to differentiate into Th1 cells. Gene dose effects of Faslpr were noted in upregulating serum IL-1⍺, IL-2, and IL-27. Taken together, Sle1homo.lprhet strain is a new C57BL/6-based model of lupus, ideal for genetic studies, autoantibody repertoire investigation, and for exploring Th1 effector cell skewing without early-age lymphoproliferative autoimmunity.


Subject(s)
Lupus Erythematosus, Systemic , Mice , Animals , Mice, Inbred C57BL , Lupus Erythematosus, Systemic/genetics , Autoimmunity , Cell Differentiation , Gene Dosage , Mice, Inbred MRL lpr
5.
PLoS Genet ; 19(11): e1011005, 2023 Nov.
Article in English | MEDLINE | ID: mdl-37934770

ABSTRACT

BACKGROUND: Kinesin motor proteins transport intracellular cargo, including mRNA, proteins, and organelles. Pathogenic variants in kinesin-related genes have been implicated in neurodevelopmental disorders and skeletal dysplasias. We identified de novo, heterozygous variants in KIF5B, encoding a kinesin-1 subunit, in four individuals with osteogenesis imperfecta. The variants cluster within the highly conserved kinesin motor domain and are predicted to interfere with nucleotide binding, although the mechanistic consequences on cell signaling and function are unknown. METHODS: To understand the in vivo genetic mechanism of KIF5B variants, we modeled the p.Thr87Ile variant that was found in two patients in the C. elegans ortholog, unc-116, at the corresponding position (Thr90Ile) by CRISPR/Cas9 editing and performed functional analysis. Next, we studied the cellular and molecular consequences of the recurrent p.Thr87Ile variant by microscopy, RNA and protein analysis in NIH3T3 cells, primary human fibroblasts and bone biopsy. RESULTS: C. elegans heterozygous for the unc-116 Thr90Ile variant displayed abnormal body length and motility phenotypes that were suppressed by additional copies of the wild type allele, consistent with a dominant negative mechanism. Time-lapse imaging of GFP-tagged mitochondria showed defective mitochondria transport in unc-116 Thr90Ile neurons providing strong evidence for disrupted kinesin motor function. Microscopy studies in human cells showed dilated endoplasmic reticulum, multiple intracellular vacuoles, and abnormal distribution of the Golgi complex, supporting an intracellular trafficking defect. RNA sequencing, proteomic analysis, and bone immunohistochemistry demonstrated down regulation of the mTOR signaling pathway that was partially rescued with leucine supplementation in patient cells. CONCLUSION: We report dominant negative variants in the KIF5B kinesin motor domain in individuals with osteogenesis imperfecta. This study expands the spectrum of kinesin-related disorders and identifies dysregulated signaling targets for KIF5B in skeletal development.


Subject(s)
Kinesins , Osteogenesis Imperfecta , Animals , Humans , Mice , Caenorhabditis elegans/genetics , Caenorhabditis elegans/metabolism , Carrier Proteins/genetics , Down-Regulation , Kinesins/genetics , Kinesins/metabolism , NIH 3T3 Cells , Proteomics , Signal Transduction/genetics , TOR Serine-Threonine Kinases/genetics , TOR Serine-Threonine Kinases/metabolism
6.
Int J Mol Sci ; 24(15)2023 Jul 29.
Article in English | MEDLINE | ID: mdl-37569529

ABSTRACT

Osteosarcoma is the most frequent primary malignant bone tumor with an annual incidence of about 400 cases in the United States. Osteosarcoma primarily metastasizes to the lungs, where FAS ligand (FASL) is constitutively expressed. The interaction of FASL and its cell surface receptor, FAS, triggers apoptosis in normal cells; however, this function is altered in cancer cells. DNA methylation has previously been explored as a mechanism for altering FAS expression, but no variability was identified in the CpG island (CGI) overlapping the promoter. Analysis of an expanded region, including CGI shores and shelves, revealed high variability in the methylation of certain CpG sites that correlated significantly with FAS mRNA expression in a negative manner. Bisulfite sequencing revealed additional CpG sites, which were highly methylated in the metastatic LM7 cell line but unmethylated in its parental non-metastatic SaOS-2 cell line. Treatment with the demethylating agent, 5-azacytidine, resulted in a loss of methylation in CpG sites located within the FAS promoter and restored FAS protein expression in LM7 cells, resulting in reduced migration. Orthotopic implantation of 5-azacytidine treated LM7 cells into severe combined immunodeficient mice led to decreased lung metastases. These results suggest that DNA methylation of CGI shore sites may regulate FAS expression and constitute a potential target for osteosarcoma therapy, utilizing demethylating agents currently approved for the treatment of other cancers.


Subject(s)
Bone Neoplasms , Osteosarcoma , Mice , Animals , fas Receptor/genetics , fas Receptor/metabolism , Bone Neoplasms/metabolism , Osteosarcoma/metabolism , Azacitidine/pharmacology , DNA Methylation , CpG Islands , Cell Line, Tumor
7.
Am J Physiol Renal Physiol ; 325(3): F317-F327, 2023 09 01.
Article in English | MEDLINE | ID: mdl-37439198

ABSTRACT

During development of the spontaneously hypertensive rat (SHR), several distinct but closely related lines were generated. Most lines are resistant to hypertensive renal disease. However, the SHR-A3 line (stroke-prone SHR) experiences end-organ injury (EOI) and provides a model of injury susceptibility that can be used to uncover genetic causation. In the present study, we generated a congenic line in which three distinct disease loci in SHR-A3 are concurrently replaced with homologous loci from an injury-resistant SHR line (SHR-B2). Verification that all three loci were homozygously replaced in this triple congenic line [SHR-A3(Trip B2)] while the genetic background of SHR-A3 was fully retained was obtained by whole genome sequencing. Congenic genome substitution was without effect on systolic blood pressure [198.9 ± 3.34 mmHg, mean ± SE, SHR-A3(Trip B2) = 194.7 ± 2.55 mmHg]. Measures of renal injury (albuminuria, histological injury scores, and urinary biomarker levels) were reduced in SHR-A3(Trip B2) animals, even though only 4.5 Mbases of the 2.8 Gbases of the SHR-B2 genome (0.16% of the genome) was transferred into the congenic line. The gene content of the three congenic loci and the functional effects of gene polymorphism within suggest a role of immunoglobulin in EOI pathogenesis. To prove the role of antibodies in EOI in SHR-A3, we generated an SHR-A3 line in which expression from the immunoglobulin heavy chain gene was knocked out (SHR-A3-IGHKO). Animals in the SHR-A3-IGHKO line lack B cells and immunoglobulin, but the hypertensive phenotype is not affected. Renal injury, however, was reduced in this line, confirming a pathogenic role for immunoglobulin in hypertensive EOI in this model of heritable risk.NEW & NOTEWORTHY Here, we used a polygenic animal model of hypertensive renal disease to show that genetic variation affecting antibody formation underlies hypertensive renal disease. We proved the genetic thesis by generating an immunoglobulin knockout in the susceptible animal model.


Subject(s)
Hypertension , Stroke , Rats , Animals , Rats, Inbred SHR , Antibody Formation , Kidney/metabolism , Blood Pressure/genetics , Genetic Variation , Stroke/genetics , Stroke/metabolism , Stroke/pathology
8.
Genes Dis ; 10(1): 254-266, 2023 Jan.
Article in English | MEDLINE | ID: mdl-37013056

ABSTRACT

Osteosarcoma is a malignant bone tumor that commonly occurs in the pediatric population. Despite the use of chemotherapy and surgery, metastasis remains to be the leading cause of death in patients with osteosarcoma. We have previously reported that cytoplasmic mislocalization of p27 is associated with a poor outcome in osteosarcoma. In this study, we further show that lysyl oxidase (LOX) expression was associated with p27 mislocalization. LOX is an enigmatic molecule that acts as a tumor suppressor or a metastatic promoter; however, its role in osteosarcoma is still unclear. Hence, we performed both in vitro and in vivo analyses to dissect the role of LOX in osteosarcoma. The result of our survival analysis indicated that LOX expression significantly correlated with a poor outcome in osteosarcoma with or without controlling for the initial metastasis status (P < 0.05). Functionally, we found that higher LOX expression promoted osteosarcoma cell proliferation, migration, and invasiveness in vitro and produced a higher number of mice with pulmonary metastases in an orthotopic xenograft mouse model. Mechanistically, phospho-FAK was increased in osteosarcoma cells with high LOX expression. Our results further showed that FAK inhibition significantly reduced tumor cell proliferation and migration in vitro as well as LOX-mediated metastasis in mice. Together, our findings suggest that there is a novel link between p27 mislocalization and LOX expression. LOX plays a pivotal role in osteosarcoma metastasis by upregulating FAK phosphorylation. FAK inhibition may constitute a promising therapeutic strategy to reduce the development of metastasis in osteosarcoma with LOX overexpression.

9.
Aust Endod J ; 49(1): 213-236, 2023 Apr.
Article in English | MEDLINE | ID: mdl-35665985

ABSTRACT

This systematic review (PROSPERO-CRD42020147333) aimed to compare the effects of conservative, ultraconservative and truss access cavities with traditional access cavities on the load capacity of root-canal-treated teeth. Online databases were searched until December 2021, and 25 ex vivo studies in which the effects of different access cavities on load capacity of permanent teeth had been investigated were included. Quality assessment was completed using a modified risk of bias tool for in vitro studies adapted from previous studies. Meta-analysis was performed using the maximum-likelihood-based random-effects model with similar groups. Conservative access cavities significantly improved the load capacity of maxillary premolars (p < 0.01 [-1.32, -0.028]) and molars (p < 0.05 [-0.89, -0.02]) compared to traditional access cavities. Additionally, truss access cavities significantly improved the load capacity of mandibular molars with (p < 0.05, [-1.18, -0.02]) mesio-occluso-distal cavity preparations. Higher levels of evidence are needed to determine the long-term implications of minimal preparations for treatment outcomes.


Subject(s)
Dental Pulp Cavity , Root Canal Therapy , Likelihood Functions , Dental Cavity Preparation , Molar/surgery
10.
Surv Ophthalmol ; 68(4): 815-820, 2023.
Article in English | MEDLINE | ID: mdl-35970231

ABSTRACT

An 8-year-old boy presented with acute visual loss in the right eye and nausea, vomiting, and diplopia. Imaging revealed a right orbital apex mass. Biopsy showed Langerhans cell histiocytosis (LCH), and the patient was diagnosed with isolated orbital LCH causing an orbital apex syndrome. A 12-month cytarabine chemotherapy course was begun, during which the patient developed bilateral optic disc edema. He was diagnosed with cytarabine-induced intracranial hypertension, which was successfully treated with acetazolamide. The cytarabine course was completed with complete resolution of the LCH lesion. The ophthalmologic relevance of this rare disorder is discussed.


Subject(s)
Histiocytosis, Langerhans-Cell , Orbital Diseases , Papilledema , Male , Humans , Child , Histiocytosis, Langerhans-Cell/diagnosis , Histiocytosis, Langerhans-Cell/drug therapy , Histiocytosis, Langerhans-Cell/pathology , Orbital Diseases/diagnosis , Orbital Diseases/drug therapy , Orbital Diseases/pathology , Cytarabine/adverse effects , Diplopia , Papilledema/chemically induced , Papilledema/diagnosis , Papilledema/drug therapy
11.
Rheumatology (Oxford) ; 62(3): 1335-1342, 2023 03 01.
Article in English | MEDLINE | ID: mdl-35961024

ABSTRACT

OBJECTIVE: The objective of this study was to evaluate the utility of urine CD163 for detecting disease activity in childhood-onset SLE (cSLE) patients. METHODS: Sixty consecutive pediatric patients fulfilling four or more ACR criteria for SLE and 20 healthy controls were recruited for testing of urinary CD163 using ELISA. SLE disease activity was assessed using the SLEDAI-2K. RESULTS: Urine CD163 was significantly higher in patients with active LN than inactive SLE patients and healthy controls, with receiver operating characteristics area under the curve values ranging from 0.93 to 0.96. LN was ascertained by kidney biopsy. Levels of CD163 significantly correlated with the SLEDAI, renal SLEDAI, urinary protein excretion and C3 complement levels. Urine CD163 was also associated with high renal pathology activity index and chronicity index, correlating strongly with interstitial inflammation and interstitial fibrosis based on the examination of concurrent kidney biopsies. CONCLUSION: Urine CD163 emerges as a promising marker for identifying cSLE patients with active kidney disease. Longitudinal studies are warranted to validate the clinical utility of urine CD163 in tracking kidney disease activity in children with lupus.


Subject(s)
Lupus Erythematosus, Systemic , Lupus Nephritis , Child , Humans , Antigens, CD , Biomarkers/urine , Kidney/pathology , Lupus Erythematosus, Systemic/pathology , Lupus Nephritis/pathology
12.
AJNR Am J Neuroradiol ; 43(11): 1667-1673, 2022 11.
Article in English | MEDLINE | ID: mdl-36265894

ABSTRACT

BACKGROUND AND PURPOSE: Juvenile xanthogranuloma is a rare clonal, myeloid, neoplastic disorder. Typically, juvenile xanthogranuloma is a self-limited disorder of infancy, often presenting as a solitary red-brown or yellow skin papule/nodule. A small subset of patients present with extracutaneous, systemic juvenile xanthogranuloma, which may include the CNS. The goal of this retrospective study was to evaluate and categorize the neuroimaging findings in a representative cohort of pediatric patients with CNS juvenile xanthogranuloma. MATERIALS AND METHODS: The brain and/or spine MR imaging data of 14 pediatric patients with pathology-proven juvenile xanthogranuloma were categorized and evaluated for the location; the signal intensity of xanthogranulomas on T1WI, T2WI, DWI, and a matching ADC map for the pattern and degree of contrast enhancement; and the presence of perilesional edema, cysts, or necrosis. RESULTS: Fourteen pediatric patients (8 girls, 6 boys; mean age, 84 months) were included in the study. Patients presented with a wide variety of different symptoms, including headache, seizure, ataxia, strabismus, hearing loss, facial paresis, and diabetes insipidus. Juvenile xanthogranuloma lesions were identified in a number of different sites, including supra- and infratentorial as well as intracranial and spinal leptomeningeal. Five patients were categorized into the neuroradiologic pattern unifocal CNS juvenile xanthogranuloma; 8, into multifocal CNS juvenile xanthogranuloma; and 1, into multifocal CNS juvenile xanthogranuloma with intracranial and spinal leptomeningeal disease. In most cases, xanthogranulomas were small-to-medium intra-axial masses with isointense signal on T1WI (compared with cortical GM), iso- or hyperintense signal on T2WI, had restricted diffusion and perilesional edema. Almost all xanthogranulomas showed avid contrast enhancement. However, we also identified less common patterns with large lesions, nonenhancing lesions, or leptomeningeal disease. Four cases had an additional CT available. On CT, all xanthogranulomas were homogeneously hyperdense (solid component) without evident calcifications. CONCLUSIONS: CNS juvenile xanthogranuloma may demonstrate heterogeneous neuroimaging appearances potentially mimicking other diseases, such as primary brain neoplasms, metastatic disease, lymphoma and leukemia, other histiocytic disorders, infections, or granulomatous diseases.


Subject(s)
Xanthogranuloma, Juvenile , Male , Female , Child , Humans , Xanthogranuloma, Juvenile/diagnostic imaging , Retrospective Studies , Magnetic Resonance Imaging , Neuroimaging , Head/pathology
13.
BMC Pediatr ; 22(1): 526, 2022 09 04.
Article in English | MEDLINE | ID: mdl-36058901

ABSTRACT

BACKGROUND: Jaundice within the first 1-2 weeks of a neonate's life will generally self-resolve; however, if it lasts longer than this time frame it warrants further work up. Direct or conjugated hyperbilirubinemia can suggest neonatal cholestasis, which in turn reflects marked reduction in bile secretion and flow. The differential diagnosis for neonatal cholestasis is broad. Neonatal choledocholithiasis is a rare cause of neonatal cholestasis, but should be considered on the differential diagnosis for patients presenting with elevated conjugated bilirubin. CASE PRESENTATION: We describe an infant who presented with neonatal cholestasis. He subsequently underwent work up for biliary atresia, as this is one of the more time-sensitive diagnoses that must be made in neonates with conjugated hyperbilirubinemia. He was ultimately found to have choledocholithiasis on magnetic resonance cholangiopancreatography. He was managed conservatively with optimizing nutrition and ursodeoxycholic acid therapy. CONCLUSIONS: We found that conservative management, specifically optimizing nutrition and treating with ursodeoxycholic acid, can be a sufficient approach to facilitating resolution of the choledocholithiasis and conjugated hyperbilirubinemia.


Subject(s)
Biliary Atresia , Choledocholithiasis , Cholestasis , Infant, Newborn, Diseases , Jaundice, Neonatal , Liver Diseases , Biliary Atresia/complications , Biliary Atresia/diagnosis , Choledocholithiasis/diagnosis , Choledocholithiasis/diagnostic imaging , Cholestasis/diagnosis , Cholestasis/etiology , Humans , Hyperbilirubinemia/diagnosis , Hyperbilirubinemia/etiology , Infant , Infant, Newborn , Jaundice, Neonatal/complications , Jaundice, Neonatal/etiology , Male , Ursodeoxycholic Acid/therapeutic use
15.
Front Immunol ; 13: 885307, 2022.
Article in English | MEDLINE | ID: mdl-35720325

ABSTRACT

Objectives: Serial kidney biopsy for repeat evaluation and monitoring of lupus nephritis (LN) in childhood-onset Systemic Lupus Erythematosus (cSLE) remains challenging, thus non-invasive biomarkers are needed. Here, we evaluate the performance of ten urine protein markers of diverse nature including cytokines, chemokines, and adhesion molecules in distinguishing disease activity in cSLE. Methods: Eighty-four pediatric patients meeting ≥4 ACR criteria for SLE were prospectively enrolled for urine assay of 10 protein markers normalized to urine creatinine, namely ALCAM, cystatin-C, hemopexin, KIM-1, MCP-1, NGAL, PF-4, Timp-1, TWEAK, and VCAM-1 by ELISA. Samples from active renal (LN) and active non-renal SLE patients were obtained prior to onset/escalation of immunosuppression. SLE disease activity was evaluated using SLEDAI-2000. 59 patients had clinically-active SLE (SLEDAI score ≥4 or having a flare), of whom 29 patients (34.5%) were classified as active renal, and 30 patients (35.7%) were active non-renal. Twenty-five healthy subjects were recruited as controls. Results: Urine concentrations of ALCAM, KIM-1, PF4 and VCAM-1 were significantly increased in active LN patients versus active non-renal SLE, inactive SLE and healthy controls. Five urine proteins differed significantly between 2 (hemopexin, NGAL, MCP1) or 3 (Cystatin-C, TWEAK) groups only, with the highest levels detected in active LN patients. Urine ALCAM, VCAM-1, PF4 and hemopexin correlated best with total SLEDAI as well as renal-SLEDAI scores (p < 0.05). Urine ALCAM, VCAM-1 and hemopexin outperformed conventional laboratory measures (anti-dsDNA, complement C3 and C4) in identifying concurrent SLE disease activity among patients (AUCs 0.75, 0.81, 0.81 respectively), while urine ALCAM, VCAM-1 and PF4 were the best discriminators of renal disease activity in cSLE (AUCs 0.83, 0.88, 0.78 respectively), surpassing conventional biomarkers, including proteinuria. Unsupervised Bayesian network analysis based on conditional probabilities re-affirmed urine ALCAM as being most predictive of active LN in cSLE patients. Conclusion: Urinary ALCAM, PF4, and VCAM-1 are potential biomarkers for predicting kidney disease activity in cSLE and hold potential as surrogate markers of nephritis flares in these patients.


Subject(s)
Cystatins , Lupus Erythematosus, Systemic , Lupus Nephritis , Activated-Leukocyte Cell Adhesion Molecule , Antigens, CD , Bayes Theorem , Benchmarking , Biomarkers/urine , Cell Adhesion Molecules, Neuronal , Child , Fetal Proteins , Hemopexin , Humans , Lipocalin-2 , Lupus Erythematosus, Systemic/diagnosis , Lupus Nephritis/diagnosis , Platelet Factor 4 , Proteins , Vascular Cell Adhesion Molecule-1
16.
Pediatr Nephrol ; 37(12): 3139-3145, 2022 12.
Article in English | MEDLINE | ID: mdl-35347402

ABSTRACT

BACKGROUND: The revised 2018 ISN/RPS Classification System for lupus nephritis (LN) includes calculations for both activity index (A.I.) and chronicity index (C.I.). Unchanged were the thresholds of < 25%, 25-50%, and > 50% crescents to distinguish between mild, moderate, and severe activity/chronicity. We aimed to evaluate these thresholds for percent crescents in childhood-onset LN. METHODS: Eighty-six subjects < 21 years of age were enrolled from the Pediatric Glomerulonephritis with Crescents Registry, a retrospective multi-center cohort sponsored by the Pediatric Nephrology Research Consortium. Thresholds of 10%, 25%, and 50% for both cellular/fibrocellular and fibrous crescents were interrogated for primary outcomes of kidney failure, eGFR, and eGFR slope. RESULTS: Median age at time of initial biopsy was 14 years (range 1-21). Median follow-up time was 3 years (range 1-11). Cumulative incidence of kidney failure was 6% at 1 year and 10% at latest follow-up. Median eGFR slope was - 18 mL/1.73 m2/min (IQR - 51 to + 8) at 1 year and - 3 mL/min/1.73 m2/year (IQR - 19 to + 6) at latest follow-up. We found no difference in kidney failure at the proposed < 25% and 25-50% cellular crescents thresholds, and thus added a new provisional threshold of 10% that better predicted outcomes in children. Moreover, use of 10% and 25% thresholds for fibrous crescents showed a fourfold and sevenfold increase in risk of kidney failure. CONCLUSIONS: In children with crescentic LN, use of 10% and 25% thresholds for cellular crescents better reflects disease activity, while these thresholds for fibrous crescents better discriminates kidney disease outcomes. A higher resolution version of the Graphical abstract is available as Supplementary information.


Subject(s)
Lupus Nephritis , Nephrology , Renal Insufficiency , Humans , Child , Infant , Child, Preschool , Adolescent , Young Adult , Adult , Lupus Nephritis/diagnosis , Lupus Nephritis/epidemiology , Kidney Glomerulus/pathology , Kidney/pathology
17.
Neuroradiol J ; 35(4): 497-503, 2022 Aug.
Article in English | MEDLINE | ID: mdl-34873956

ABSTRACT

BACKGROUND: In the pediatric population, dermoid cysts are among the most frequent lesions of the scalp and skull. Imaging plays a key role in characterizing scalp and skull lesions in order to narrow the differential diagnoses. In general, dermoids are described as heterogeneous T1-/T2-hypo- to hyperintense lesions on magnetic resonance imaging. METHODS: The goal of this retrospective study is to evaluate the diffusion weighted imaging findings while reviewing the conventional T1-/T2-/T1+C-weighted MR characteristics in a pathology-proven series of 14 dermoids of the pediatric scalp and skull. RESULTS: In our pediatric cohort (eight boys, six girls, age range 3-95 months), half of the dermoids were homogeneous T1-hypointense and homogeneous T2-hyperintense. We found a mixture of restricted (45.5%) and increased diffusion (54.5%) in dermoids. The vast majority of dermoids (91.7%) showed rim enhancement. Most dermoids (57.1%) were located at the midline and adjacent to one of its sutures. CONCLUSIONS: This study suggests that dermoids may have more variable imaging appearances than hitherto assumed and are frequently seen in close proximity or adjacent to the anterior fontanelle.


Subject(s)
Dermoid Cyst , Scalp , Child , Child, Preschool , Female , Humans , Infant , Magnetic Resonance Imaging , Male , Retrospective Studies , Skull
18.
Haematologica ; 107(4): 887-898, 2022 04 01.
Article in English | MEDLINE | ID: mdl-34092059

ABSTRACT

Tatton-Brown-Rahman syndrome (TBRS) is an overgrowth disorder caused by germline heterozygous mutations in the DNA methyltransferase DNMT3A. DNMT3A is a critical regulator of hematopoietic stem cell (HSC) differentiation and somatic DNMT3A mutations are frequent in hematologic malignancies and clonal hematopoiesis. Yet, the impact of constitutive DNMT3A mutation on hematopoiesis in TBRS is undefined. In order to establish how constitutive mutation of DNMT3A impacts blood development in TBRS we gathered clinical data and analyzed blood parameters in 18 individuals with TBRS. We also determined the distribution of major peripheral blood cell lineages by flow cytometric analyses. Our analyses revealed non-anemic macrocytosis, a relative decrease in lymphocytes and increase in neutrophils in TBRS individuals compared to unaffected controls. We were able to recapitulate these hematologic phenotypes in multiple murine models of TBRS and identified rare hematological and non-hematological malignancies associated with constitutive Dnmt3a mutation. We further show that loss of DNMT3A in TBRS is associated with an altered DNA methylation landscape in hematopoietic cells affecting regions critical to stem cell function and tumorigenesis. Overall, our data identify key hematopoietic effects driven by DNMT3A mutation with clinical implications for individuals with TBRS and DNMT3A-associated clonal hematopoiesis or malignancies.


Subject(s)
DNA (Cytosine-5-)-Methyltransferases , Intellectual Disability , Animals , DNA (Cytosine-5-)-Methyltransferases/genetics , DNA Methyltransferase 3A , Germ Cells/pathology , Hematopoiesis/genetics , Humans , Intellectual Disability/genetics , Intellectual Disability/pathology , Mice
19.
J Laryngol Otol ; 136(11): 1034-1038, 2022 Nov.
Article in English | MEDLINE | ID: mdl-34674779

ABSTRACT

BACKGROUND: Burnout, anxiety and depression are commonly reported among surgical residents and faculty members. Resident training programmes are encouraged to implement structured wellness initiatives, to address emotional stress. METHODS: Thirty otolaryngology residents and faculty members were invited to participate in this prospective pilot trial. Participants were randomised to either the intervention group, which involved completing 10 mobile meditation sessions, or the control group. Outcomes were measured with the Generalized Anxiety Disorder scale-7, Patient Health Questionnaire and Professional Quality of Life scale. RESULTS: Nineteen participants completed the study. Participants in the intervention group had a significantly greater mean change in Generalized Anxiety Disorder scale-7 score (-2.7 ± 3.335 vs 0.33 ± 1.225; p = 0.04). There was no significant difference in average change in Patient Health Questionnaire-9 scores or Professional Quality of Life scale sub-scores between the intervention and control groups. CONCLUSION: Short meditation sessions can significantly improve anxiety in surgical residents and faculty members, and they offer a simple, attainable and effective wellness intervention.


Subject(s)
Internship and Residency , Meditation , Humans , Quality of Life , Depression/therapy , Prospective Studies , Anxiety/prevention & control , Faculty
20.
Pediatr Blood Cancer ; 68(12): e29327, 2021 12.
Article in English | MEDLINE | ID: mdl-34520106

ABSTRACT

Liposarcoma is arare soft tissue sarcoma in children. While prognosis, clinical behavior, and response to therapy among the various histologic subtypes are well described in adults, data in children are limited. Here, we describe our experience treating 14 children with liposarcoma at a large, academic pediatric center and review the available pediatric literature. This comprehensive report adds treatment, survival, and genomic data to pediatric liposarcoma literature.


Subject(s)
Liposarcoma , Sarcoma , Adult , Child , Humans , Liposarcoma/genetics , Liposarcoma/therapy , Prognosis
SELECTION OF CITATIONS
SEARCH DETAIL
...