Photopheresis Provides Significant Long-Lasting Benefit in Nephrogenic Systemic Fibrosis.
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ABSTRACT:
SUBMITTER: Zhang R
PROVIDER: S-EPMC5485262 | biostudies-other | 2017
REPOSITORIES: biostudies-other
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Project description:Nephrogenic systemic fibrosis (NSF) was first described in 2000 as a scleromyxedema-like illness in patients on chronic hemodialysis. The relationship between NSF and gadolinium contrast during magnetic resonance imaging was postulated in 2006, and subsequently, virtually all published cases of NSF have had documented prior exposure to gadolinium-containing contrast agents. NSF has been reported in patients from a variety of ethnic backgrounds from America, Europe, Asia and Australia. Skin lesions may evolve into poorly demarcated thickened plaques that range from erythematous to hyperpigmented. With time, the skin becomes markedly indurated and tethered to the underlying fascia. Extracutaneous manifestations also occur. The diagnosis of NSF is based on the presence of characteristic clinical features in the setting of chronic kidney disease, and substantiated by skin histology. Differential diagnosis is with scleroderma, scleredema, scleromyxedema, graft-versus-host disease, etc. NSF has a relentlessly progressive course. While there is no consistently successful treatment for NSF, improving renal function seems to slow or arrest the progression of this condition. Because essentially all cases of NSF have developed following exposure to a gadolinium-containing contrast agent, prevention of this devastating condition involves the careful avoidance of administering these agents to individuals at risk.
| S-EPMC3088938 | biostudies-literature
Project description:Gadolinium-based contrast agents are implicated in several pathologic abnormalities (long-term retention in vital organs such as the skin and the brain) and are the cause of a sometimes fatal condition in patients, nephrogenic systemic fibrosis. Bone marrow-derived fibrocytes and the monocyte chemoattractant protein-1 inflammatory pathway have been implicated as mediators of the adverse effects induced by gadolinium-based contrast agents. Mechanistic studies are scant; therefore, a mouse model of nephrogenic systemic fibrosis was established. Dermal cellularity was increased in contrast-treated green fluorescent protein (GFP) chimeric mice. GFP in the skin and fibrosis were increased in the contrast-treated chimeric animals. Monocyte chemoattractant protein-1 and C-C chemokine receptor 2 were increased in the tissues from contrast-treated mice. C-C chemokine receptor 2-deficient recipients of GFP-expressing marrow had an abrogation of gadolinium-induced pathology and displayed less GFP-positive cells in the skin. Wild-type animals that received C-C chemokine receptor 2-deficient bone marrow had a complete abrogation of dermal pathology. That GFP levels and expression increase in the skin, in tandem with a fibrocyte marker, supports the blood-borne circulating fibrocyte hypothesis of the disease. As of now, fibrocyte trafficking has yet to be demonstrated. Importantly, our data demonstrate that the monocyte chemoattractant protein-1/C-C chemokine receptor 2 axis plays a critical role in the pathogenesis of nephrogenic systemic fibrosis.
| S-EPMC6756957 | biostudies-literature
Project description:Nephrogenic systemic fibrosis (NSF) is an incurable, debilitating disease found exclusively in patients with decreased kidney function and comprises a fibrosing disorder of the skin and systemic tissues. The disease is associated with exposure to gadolinium (Gd)-based contrast agents (GBCA) used in magnetic resonance imaging (MRI). Tissue samples from many patients with NSF contain micron-sized insoluble Gd-containing deposits. However, the precise composition and chemical nature of these particles is unclear.To clarify the precise chemical structure of the Gd-containing deposits in NSF tissues.Autopsy skin tissues from a patient with NSF were examined in situ using synchrotron X-ray fluorescence (SXRF) microscopy and extended X-ray absorption fine structure (EXAFS) spectroscopy and in correlation with light microscopy and the results of scanning electron microscopy /energy dispersive spectroscopy analyses.The insoluble Gd deposits were shown to contain Gd no longer coordinated by GBCA chelator molecules but rather in a sodium calcium phosphate material. SXRF microscopy shows a clear correlation between Gd, Ca and P. EXAFS spectroscopy shows a very different spectrum from the GBCAs, with Gd–P distances at 3·11 A and 3·11 A as well as Gd–Gd distances at an average of 4·05 A, consistent with a GdPO4 structure.This is the first direct evidence for the chemical release of Gd from GBCA in human tissue. This supports the physical–chemical, clinical and epidemiological data indicating a link between stability and dose of GBCA to the development of NSF.
| S-EPMC4334379 | biostudies-literature
Project description:BackgroundThe risk for nephrogenic systemic fibrosis (NSF) after exposure to newer versus older gadolinium-based contrast agents (GBCAs) remains unclear.PurposeTo synthesize evidence about NSF risk with newer versus older GBCAs across the spectrum of kidney function.Data sourcesMEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Web of Science for English-language references from inception to 5 March 2020.Study selectionRandomized controlled trials, cohort studies, and case-control studies that assessed NSF occurrence after GBCA exposure.Data extractionData were abstracted by 1 investigator and verified by a second. Investigator pairs assessed risk of bias by using validated tools.Data synthesisOf 32 included studies, 20 allowed for assessment of NSF risk after exposure to newer GBCAs and 12 (11 cohort studies and 1 case-control study) allowed for comparison of NSF risk between newer and older GBCAs. Among 83 291 patients exposed to newer GBCAs, no NSF cases developed (exact 95% CI, 0.0001 to 0.0258 case). Among the 12 studies (n = 118 844) that allowed risk comparison between newer and older GBCAs, 37 NSF cases developed after exposure to older GBCAs (exact CI, 0.0001 to 0.0523 case) and 4 occurred (3 confounded) after exposure to newer GBCAs (exact CI, 0.0018 to 0.0204 case). Data were scant for patients with acute kidney injury or those at risk for chronic kidney disease.LimitationsStudy heterogeneity prevented meta-analysis. Risk of bias was high in most studies because of inadequate exposure and outcome ascertainment.ConclusionAlthough NSF occurrence after exposure to newer GBCAs is very rare, the relatively scarce data among patients with acute kidney injury and those with risk factors for chronic kidney disease limit conclusions about safety in these populations.Primary funding sourceU.S. Department of Veterans Affairs. (PROSPERO: CRD42019135783).
| S-EPMC7847719 | biostudies-literature
Project description:Contemporary treatment of node-positive (N+) colon cancer consists of adjuvant chemotherapy; however, randomized data supporting this practice were derived from lesions T2 or greater. Minimal data exist regarding the use and need for adjuvant chemotherapy in T1N+ disease.The aim of this study was to determine treatment trends and the effects of adjuvant chemotherapy on T1N+ colon cancers by using the National Cancer Database.This was a retrospective study. Baseline demographics, tumor, and cancer treatment characteristics were compared. Groups were matched on the propensity to receive chemotherapy. Adjusted long-term survival stratified by chemotherapy use was compared by using the Kaplan-Meier method with the log-rank test. Predictors of not receiving chemotherapy were identified by using a multivariable logistic regression model.Data were collected from the National Cancer Database, which collects cancer data from over 1500 cancer centers.We identified patients from 1998 to 2006 with T1N+ disease, excluding those with metastatic disease or previous cancer. Patients were stratified based on whether or not they received chemotherapy.The primary outcome measure of this study was long-term survival.Three thousand one hundred thirty-seven patients had T1N+ disease; 70.6% (n = 2216) received chemotherapy, and utilization significantly increased from 1998 to 2011 (p < 0.001). Unadjusted analysis revealed that patients treated with chemotherapy were statistically younger and healthier, and had shorter postoperative lengths of stay (all p < 0.001). Unadjusted 5-year survival was higher in patients receiving chemotherapy (87.9% vs 63.0% in patients with no chemotherapy; p < 0.001) and this persisted after propensity matching with (83.4% and 63.0% in patients with or without chemotherapy; p < 0.001). Only age (OR, 0.29; p < 0.001) predicted not receiving chemotherapy.Limitations include potential selection bias as well as the inability to compare disease-free survival/recurrence.Adjuvant chemotherapy appears to significantly improve long-term survival in patients receiving chemotherapy in T1N+ disease. Thus, the use of chemotherapy in T1N+ disease is justified and provides a highly significant survival benefit.
| S-EPMC4336178 | biostudies-literature
Project description:BackgroundNephrogenic systemic fibrosis (NSF) is a rare but serious disorder disease affecting patients with advanced renal disease. Although multiple studies have indicated an association between gadolinium-based contrast agents (GBCAs) and NSF, some studies published after 2007 found no association. We therefore performed a meta-analysis to evaluate the association and analyze related (co)factors.MethodsStudies for analysis were identified by searching PubMed, Embase, and the Cochrane Central Register of Controlled Trials through December 2014. Pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated using the fixed-effects model. Statistical heterogeneity was assessed by Q statistics and the I2 test. Publication bias was evaluated using Begg's test, Egger's test, funnel plot, and classic fail-safe N. Study quality was assessed using the Newcastle-Ottawa Scale. We also conducted sensitivity analyses, subgroup analyses and a cumulative meta-analysis. All statistical analyses were performed using Comprehensive Meta-Analysis 2.0.ResultsA total of 14 studies (6,398 patients) met the inclusion criteria, but 3 were excluded since they reported no NSF events. Meta-analysis of controlled trials indicated a significant association between GBCAs and NSF development (OR = 16.504; 95% CI: 7.455-36.533; P < 0.001) and between gadodiamide and NSF (OR = 20.037; 95% CI: 3.725-107.784; P < 0.001). No statistical heterogeneity was observed across studies (P = 0.819, I2 = 0%; P = 0.874, I2 = 0%, respectively). Cumulative analysis demonstrated that the pooled ORs for association between GBCAs and NSF decreased post-2007 compared to pre-2007 (OR = 26.708; 95% CI: 10.273-69.436; P<0.001).ConclusionsAlthough this updated meta-analysis found a significant association between GBCAs and the incidence of NSF in patients with advanced renal disease, the association decreased after 2007. More studies, especially randomized controlled trials, are warranted to examine the potential association between GBCAs other than gadodiamide and NSF.
| S-EPMC4468111 | biostudies-literature
Project description:Osteoarthritis (OA) is the most prevalent joint disorder associated with severe chronic pain. Although synovial inflammation is well correlated with pain severity, the molecular mechanism responsible for OA pain remains unclear. Here, we show that extracellular miR-21 released from synovial tissue mediates knee OA pain in surgical OA model rats. miR-21 was the most abundant among increased microRNAs (miRNAs) in the synovial tissue. miR-21 was released into extracellular space from the synovial tissue and increased in the synovial fluid. A single intra-articular injection of miR-21 inhibitor exerted long-term analgesia of knee OA pain, whereas miR-21 injection in naive rats caused knee joint pain. miR-21 mutant, which lacks the Toll-like receptor (TLR) binding motif, but not in the seed sequence, did not cause joint pain, suggesting a non-canonical mode of action different from translational repression. Consistent with this, the algesic effect of miR-21 was blocked by antagonizing TLR7. The TLR7 antagonist also exerted a long-lasting analgesic effect on knee OA pain. Therefore, extracellular miR-21 released from synovial tissue mediates knee OA pain through TLR7 activation in surgical OA model rats. Extracellular miRNA in the joint may be a plausible target for pain therapy, providing a novel analgesic strategy for OA.
| S-EPMC6920297 | biostudies-literature
Project description:A proteomic analysis of the secretome of cultured dermal fibroblasts from patients with systemic sclerosis (SSc) and nephrogenic systemic fibrosis (NSF) was performed to identify proteins that reflect the fibrotic process. Confluent culture supernatants from three cell strains each of normal, SSc, and NSF dermal fibroblasts were pooled separately, and each pool was labeled with a specific fluorochrome. The three pools were electrophoresed together on two-dimension SDS gels, and protein differential expression was evaluated by quantitative fluorescence analysis. The secretome analysis identified 1694 spots per sample, among which 890 spots (52%) were differentially increased or decreased (more than twofold) in SSc fibroblasts, and 985 spots (58%) were differentially increased or decreased in NSF fibroblasts compared with normal fibroblasts. Mass spectrometry analysis was then used to identify the proteins that had increased by the greatest extent in both NSF and SSc secretomes. Three reticulocalbin family members were among the 10 most up-regulated proteins. Confocal microscopy results validated the differential increase of reticulocalbin-1 in affected SSc and NSF skin, and Western blot findings demonstrated its presence in SSc sera. The secretomes of both SSc and NSF fibroblasts display a pattern of shared changes compared with the normal fibroblast secretome. The differentially increased proteins reflect an activated fibroblast phenotype and may represent a specific "fibrosis signature" that can be used as a biomarker for fibrotic diseases.
| S-EPMC2947261 | biostudies-literature
Project description:Background and purpose: A major gap in the field of ischemic preconditioning (IPC) is whether or not long-lasting neuroprotection can be achieved. Moreover, the specific mechanisms underlying IPC and how they can be translated into the clinic remain uncertain. To fill these gaps, we tested the hypothesis that IPC exerts long-lasting structural and functional neuroprotection against ischemic stroke through the master gatekeeper of antioxidant defenses, nuclear factor erythroid 2-related factor 2 (Nrf2). We also tested whether the brain could be pharmaceutically preconditioned with a potent and blood-brain barrier-permeable Nrf2 activator, 2-cyano-3,12-dioxo-oleana-1,9(11)-dien-28-trifluoethyl amide (CDDO-TFEA).Methods: IPC was induced by transient middle cerebral artery occlusion (MCAO) for 12 min, and ischemic stroke was generated by MCAO for 60 min in wild-type (WT) or Nrf2 knockout (KO) mice. Sensorimotor function, learning/memory skills, and brain tissue loss were measured up to 35 days after stroke. Primary rodent cortical neurons from wildtype (WT) and Nrf2 KO mice were subjected to lethal oxygen-glucose deprivation (OGD) or a brief OGD episode as a preconditioning (PC) stimulus before OGD. Cell viability/death, lipid electrophile generation, and Nrf2 activation were measured. CDDO-TFEA or its vehicle was administered in vivo for three consecutive days before MCAO. Tissue loss and neurological tests were performed 35 days after stroke.Results: IPC significantly reduced sensorimotor deficits, post-stroke cognitive impairments, and brain tissue loss, 35 days after MCAO in WT mice. These enduring protective effects of IPC were inhibited in Nrf2 KO mice. In neuronal cultures, PC also endowed primary neurons with ischemic tolerance against OGD-induced cell death, an effect that was abolished by loss of Nrf2 expression in KO neurons. PC induced the generation of low levels of lipid electrophiles and led to activation of the Nrf2 pathway. The mechanism underlying IPC may be translatable, as exogenous administration of the Nrf2 activator CDDO-TFEA significantly reduced neurological dysfunction and ischemic brain damage after MCAO.Conclusions: IPC provides long-lasting neuroprotection against ischemic brain injury and post-stroke cognitive dysfunction. Nrf2 activation plays a key role in this beneficial outcome and is a promising therapeutic target for the attenuation of ischemic brain injury.
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Project description:Cancer immunotherapy has been the subject of extensive research, but highly effective and broadly applicable methods remain elusive. Moreover, a general approach to engender endogenous patient-specific cellular therapy, without the need for a priori knowledge of tumor antigen, ex vivo cellular manipulation, or cellular manufacture, could dramatically reduce costs and broaden accessibility. Here, we describe a biotechnology based on synthetic, biodegradable nanoparticles that can genetically reprogram cancer cells and their microenvironment in situ so that the cancer cells can act as tumor-associated antigen-presenting cells (tAPCs) by inducing coexpression of a costimulatory molecule (4-1BBL) and immunostimulatory cytokine (IL-12). In B16-F10 melanoma and MC38 colorectal carcinoma mouse models, reprogramming nanoparticles in combination with checkpoint blockade significantly reduced tumor growth over time and, in some cases, cleared the tumor, leading to long-term survivors that were then resistant to the formation of new tumors upon rechallenge at a distant site. In vitro and in vivo analyses confirmed that locally delivered tAPC-reprogramming nanoparticles led to a significant cell-mediated cytotoxic immune response with systemic effects. The systemic tumor-specific and cell-mediated immunotherapy response was achieved without requiring a priori knowledge of tumor-expressed antigens and reflects the translational potential of this nanomedicine.
| S-EPMC7049107 | biostudies-literature