BackgroundIn children with proliferative lupus nephritis, response to induction treatment is based on clinical parameters. The added benefit of repeat kidney biopsy in defining therapy response ...remains unclear. Emerging adult data suggests a discordancy between clinical and histological outcomes. In children, we hypothesize that histologic reassessment after induction therapy correlates better with clinical remission.MethodsA single-center retrospective observational cohort study was conducted in childhood-onset proliferative lupus nephritis with a repeat biopsy after 5-9 months of induction therapy from 2007 to 2019. LN response was determined clinically. Histologic activity and damage were calculated using National Institutes of Health activity and chronicity indices. Lupus nephritis class transformation and changes in the degree of immune complex deposition were determined. Descriptive statistics and comparison tests were used before and after induction treatment.ResultsA total of 44 patients were identified. Complete clinical response was achieved in 43% (19/44) after induction and 69% (29/42) at one year. None of the complete responders after induction had histologic activity index of > 2 on repeat biopsy (figure 1). Activity index after induction in complete responders (median 1, range 0-2) was lower than in partial or non-responders (median 2, range 0-10) (p-value < 0.005). Complete clinical response was associated with transformation to a non-proliferative class in 79% (15/19) and a reduction in immune complex deposition in 68% (13/19) on repeat biopsy.ConclusionsUnlike adult-onset lupus nephritis, clinical and histologic remission are more congruent after induction therapy in childhood-onset disease. There was good correlation between clinical response and activity index.Lay SummaryLupus nephritis can cause kidney failure. The need to balance risks and benefits of immunosuppression requires stringent monitoring. In adults with lupus, available diagnostics are insufficient to gauge response to initial ”induction” therapy and repeat biopsy studies are necessary to rigorously test novel biomarkers. Here we show that repeat biopsy in children performed 1/2 year into therapy correlates well with clinical response, but there is a subset of children with sub-clinical scarring that would be missed without repeat biopsy - this subset may be at risk long-term for kidney failure.Abstract 1108 Figure 1Findings at first biopsy (baseline, at time of nephritis diagnosis) and repeat biopsy (5-7 months into therapy) stratified by clinical response at time of repeat biopsy (CR, complete response; PR, partial response; NR, no response). Shown are medians (lines), means (large circles), and ranges (activity index scored 0 to 24 and chronicity index scored 0 to 12 based on ISN/RPS schema).
Objective To identify features associated with multisystem involvement and therapeutic failure in patients with skin Langerhans cell histiocytosis (LCH). Study design We reviewed medical records of ...71 consecutive patients with LCH with skin involvement evaluated at Texas Children's Hospital and analyzed clinical features, laboratory results, and the presence of circulating cells with the BRAF-V600E mutation with respect to initial staging and clinical outcomes. Results Skin disease in patients older than 18 months of age at diagnosis was associated with the presence of multisystem disease (OR, 9.65; 95% CI, 1.17-79.4). Forty percent of patients referred for presumed skin-limited LCH had underlying multisystem involvement, one-half of these with risk-organ involvement. Patients with skin-limited LCH had a 3-year progression-free survival of 89% after initial therapy, and none developed multisystem disease. Patients with skin/multisystem involvement had a 3-year progression-free survival of 44% with vinblastine/prednisone therapy, and risk-organ involvement did not correlate with failure to achieve nonactive disease. Circulating cells with BRAF-V600E were detected at higher frequency in patients with multisystem involvement (8 of 11 skin/multisystem vs 1 of 13 skin-limited; P = .002). Conclusion Skin-limited LCH necessitates infrequent therapeutic intervention and has a lower risk of progression relative to skin plus multisystem LCH. The less-aggressive clinical course and lack of circulating cells with the BRAF-V600E mutation in skin-limited LCH suggest a different mechanism of disease origin compared with multisystem or risk-organ disease.
Similar to humans, the risk of cerebrovascular disease in stroke-prone spontaneously hypertensive rats (SHR-A3/SHRSP) arises from naturally occurring genetic variation. In the present study, we show ...the involvement of genetic variation affecting the store-operated calcium signaling gene, Stim1, in the pathogenesis of stroke in SHR. Stim1 is a key lymphocyte activation signaling molecule and contains functional variation in SHR-A3 that diverges from stroke-resistant SHR-B2. We created a SHR-A3 congenic line in which Stim1 was substituted with the corresponding genomic segment from SHR-B2. Compared with SHR-A3 rats, Stim1 congenic SHR-A3 (SHR-A3(Stim1-B2)) have reduced cerebrovascular disease in response to salt loading including lower neurological deficit scores and cerebral edema. Microbleeds and major hemorrhages occurred in over half of SHR-A3 rats. These lesions were absent in SHR-A3(Stim1-B2) rats. Loss of Stim1 function in mice and humans is associated with antibody-mediated autoimmunity due to defects in T lymphocyte helper function to B cells. We investigated autoantibody formation using a high-density protein array to detect the presence of IgG and IgM autoantibodies in SHR-A3. Autoantibodies to key cerebrovascular stress proteins were detected that were reduced in the congenic line.
Stroke-prone spontaneously hypertensive rats (SHR-A3) develop strokes and progressive kidney disease as a result of naturally occurring genetic variations. We recently identified genetic variants in ...immune signaling pathways that contribute to end-organ injury. The present study was designed to test the hypothesis that a dysregulated immune response promotes stroke susceptibility. We salt-loaded 20 wk old male SHR-A3 rats and treated them with the immunosuppressant mycophenolate mofetil (MMF, 25 mg/kg/day po) (
= 8) or vehicle (saline) (
= 9) for 8 wk. Blood pressure (BP) was measured weekly by telemetry. Compared with vehicle-treated controls, MMF-treated SHR-A3 rats had improved survival and lower neurological deficit scores (1.44 vs. 0.125;
< 0.02). Gross morphology of the brain revealed cerebral edema in 8 of 9, and microbleeds and hemorrhages in 5 of 9 vehicle-treated rats. These lesions were absent in MMF-treated rats. Brain CD68 expression, indicating macrophage/microglial activation, was upregulated in vehicle-treated rats with microbleeds and hemorrhages but was undetectable in the brains of MMF-treated rats. MMF also prevented renal injury in SHR-A3 rats, evidenced by reduced proteinuria (albumin:creatinine) from 7.52 to 1.05 mg/mg (
< 0.03) and lower tubulointerstitial injury scores (2.46 vs. 1.43;
< 0.01). Salt loading resulted in a progressive increase in BP, which was blunted in rats receiving MMF. Our findings provide evidence that abnormal immune activation predisposes to cerebrovascular and renal injury in stroke-prone SHR-A3 rats.
MYCN activation is a hallmark of advanced neuroblastoma (NB) and a known master regulator of metabolic reprogramming, favoring NB adaptation to its microenvironment. We found that the expression of ...the main regulators of the molecular clock loops is profoundly disrupted in MYCN-amplified NB patients, and this disruption independently predicts poor clinical outcome. MYCN induces the expression of clock repressors and downregulates the one of clock activators by directly binding to their promoters. Ultimately, MYCN attenuates the molecular clock by suppressing BMAL1 expression and oscillation, thereby promoting cell survival. Reestablishment of the activity of the clock activator RORα via its genetic overexpression and its stimulation through the agonist SR1078, restores BMAL1 expression and oscillation, effectively blocks MYCN-mediated tumor growth and de novo lipogenesis, and sensitizes NB tumors to conventional chemotherapy. In conclusion, reactivation of RORα could serve as a therapeutic strategy for MYCN-amplified NBs by blocking the dysregulation of molecular clock and cell metabolism mediated by MYCN.
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.
Pipes have been used for thousands of years, the first record of copper piping dates to the Egyptians in 3000 BC. In today's time, pipelines play a dramatic role in our everyday life and is a ...backbone of our society. Replacing and renewing our vast piping system is extremely important to maintain and grow the infrastructure around us. Trenchless methods (TM) can renew pre-existing piping, replace, and offer installation of new pipe(s). Two very common TMs are cured-in-place piping (CIPP) and spray-applied pipe lining (SAPL). These are great alternatives compared to open cut pipeline installation (OCPI) due to minimizing environmental impact and the total cost associated with renewing or replacing a pipe. Owners and engineers involved in a project which contain pipe renewal and or replacement should consider the time and social cost associated with each method. Cost alone should not be the one and only deciding factor. The objective of this review is to compare and contrast CIPP and SAPL pipeline renewal methods with references found over these renewal methods. This will be demonstrated with the use of a table that will consist of these parameters; environmental, mechanical properties, performance, cost, and methods. The method used for selecting specific articles/papers is intended to locate major factors that play a role in pipeline renewal using publications from the past years. Results show that reviewing, comparing, and understanding current research relating to pipeline renewal will allow for safer applications, increased efficiency, and pipeline longevity.
Abstract Wilms' tumors (WT), which accountfor 6% of all childhood cancers, arise from dysregulated differentiation of nephrogenic progenitor cells from embryonic kidneys. Though there is an ...improvement in the prognosis of WT, still 10% of patients with WT die due to recurrence. Thus more effective treatment approaches are necessary. We previously characterized the inflammatory microenvironment in human WT and observed the robust expression of COX-2. The aim of this study was to extend our studies to analyze the role of COX-2 pathway components in WT progression using a mouse model of WT. Herein, COX-2 pathway components such as COX-2, HIF1-α, p-ERK1/2, and p-STAT3 were upregulated in mouse and human tumor tissues. In our RPPA analysis, COX-2 was up-regulated in M15 cells after Wt1 gene was knocked down. Flow cytometry analysis showed the increased infiltration of immune suppressive inflammatory cells such as pDC's and Treg cells in tumors. The chemotactic chemokines responsible for the infiltration of these cells were also induced in CCR5 and CXCR4 dependent manner respectively. The immunosuppressive cytokines IL-10, TGF-β, and TNF-α were also up-regulated. Furthermore, more pronounced Th2 and Treg induced cytokine response was observed than Th1 response in tumors. Basing on all these evidences it is speculated that COX-2 pathway may be a beneficial target for the treatment of WT. It may be most effective as an adjuvant therapy together with other inhibitors. Thus, our current study provides a good rationale for initiating animal studies to confirm the efficacy of COX-2 inhibitors in decreasing tumor cell growth in vivo.
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•Reef-type PGE deposit in the Halls Creek Orogen, east Kimberley, Western Australia.•High-temperature fluid-driven overprint of the Paleoproterozoic deposit.•Chromite texture and ...composition reflect both magmatic and metamorphic processes.•Bulk rock PGE is almost exclusively controlled by PGM.•Sulfide stable isotope ratios correlate with bulk rock PGE concentration.
The Central and Western Zones of the Halls Creek Orogen (HCO) of the East Kimberley region of Western Australia host various Paleoproterozoic layered mafic–ultramafic intrusions. The 1856 ± 2 Ma layered mafic–ultramafic Panton Intrusion of the Central Zone contains a reef-type platinum-group element (PGE) mineralisation associated with metamorphosed chromitite horizons. Here we investigate the compositional variation of chromite within the A chromitite layer, or Main Chromitite Layer (MCL), base metal sulphides (BMS), and the associated PGE distribution. Electron-microprobe analysis (EMPA) and laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) data reveal complex chemical zoning of the chromite reflecting post-magmatic sub-solidus re-equilibration and fluid–rock interaction during metamorphism of the host rocks. The sulphur isotopic composition of the BMS (δ34S: −1.67 to 2.89‰) suggests negligible contamination of the parental melt by crustal sulphur and thus favours BMS formation due to fractional crystallisation. Furthermore, pentlandite compositions indicate the highest ƒS2 in the centre of the MCL, which coincides with a considerably heavier sulphur isotope composition compared to pentlandite in the surrounding ultramafic host rock. Alteration of the BMS during amphibolite facies hydration of the Panton Intrusion resulted in the formation of secondary bornite and digenite from the chalcopyrite as well as desulphurisation of pyrrhotite and pentlandite to secondary magnetite. The bulk rock PGE concentrations are controlled by the distribution of platinum-group minerals (PGM) due to the low PGE concentrations in BMS. PGM are present as inclusions in chromite, suggesting that they formed under sulphur-undersaturated conditions. Additional PGM are present within the interstitial serpentine-chlorite matrix suggesting that they precipitated during fluid-rock interaction and hydration of the silicate matrix. Likely sources for the remobilised PGE include PGM inclusions in altered rim zones of magmatic chromite and PGE released due to desulphurisation of BMS despite their low PGE concentrations.
Systemic sclerosis (SSc) is a connective tissue disease that results in excessive accumulation of collagen in the skin and internal organs. Overall, SSc has a rare morbidity (276 cases per million ...adults in the United States), but has a 10-year survival rate of 55%. Currently, the modified Rodnan skin score (mRSS) is assessed by palpation on 17 sites on the body. However, the mRSS assessed score is subjective and may be influenced by the experience of the rheumatologists. In addition, the inherent elasticity of skin may bias the mRSS assessment in the early stage of SSc, such as oedematous. Optical coherence elastography (OCE) is a rapidly emerging technique, which can assess mechanical contrast in tissues with micrometer spatial resolution. In this work, the OCE technique is applied to assess the mechanical properties of skin in both control and bleomycin (BLM) induced SSc-like disease noninvasively. Young's modulus of the BLM-SSc skin was found be significantly higher than that of normal skin, in both the in vivo and in vitro studies (p<0.05). Thus, OCE is able to differentiate healthy and fibrotic skin using mechanical contrast. It is a promising new technology for quantifying skin involvement in SSc in a rapid, unbiased, and noninvasive manner.
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