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1.
IntroductionAlthough hyperferritinemia may reflect the inflammatory status of patients with non-alcoholic fatty liver disease (NAFLD), approximately 33% of hyperferritinemia cases reflect real hepatic iron overload.AimTo evaluate a non-invasive method for assessing mild iron overload in patients with NAFLD using 3T magnetic resonance imaging (MRI) relaxometry, serum hepcidin, and the expression of ferritin subunits.MethodsThis cross-sectional study assessed patients with biopsy-proven NAFLD. MRI relaxometry was performed using a 3T scanner in all patients, and the results were compared with iron content determined by liver biopsy. Ferritin, hepcidin, and ferritin subunits were assessed and classified according to ferritin levels and to siderosis identified by liver biopsy.ResultsA total of 67 patients with NAFLD were included in the study. MRI revealed mild iron overload in all patients (sensitivity, 73.5%; specificity, 70%). For mild (grade 1) siderosis, the transverse relaxation rate (R2*) threshold was 58.9 s?1 and the mean value was 72.5 s?1 (SD, 33.9), while for grades 2/3 it was 88.2 s?1 (SD, 31.9) (p < 0.001). The hepcidin threshold for siderosis was > 30.2 ng/mL (sensitivity, 87%; specificity, 82%). Ferritin H and ferritin L subunits were expressed similarly in patients with NAFLD, regardless of siderosis. There were no significant differences in laboratory test results between the groups, including glucose parameters and liver function tests.ConclusionsMRI relaxometry and serum hepcidin accurately assessed mild iron overload in patients with dysmetabolic iron overload syndrome.  相似文献   
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Graefe's Archive for Clinical and Experimental Ophthalmology - The purpose of this study was to measure the anti-angiogenic effect of N-desulfated Re–N-acetylated, a chemically modified...  相似文献   
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Odontology - To evaluate the influence of the restorative approach and aging time on dentin bond strength (BS), failure mode (FM), and bottom/top microhardness ratio (B/T) in a large dentin cavity...  相似文献   
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Variation in drug disposition genes might contribute to susceptibility to toxicities and interindividual differences in clinical management on chemotherapy for epithelial ovarian cancer (EOC). This study was designed to explore the association of GST and ABCB1 genetic variation with hematologic and neurologic toxicity, changes in chemotherapy, and disease prognosis in Brazilian women with EOC. A total of 112 women with a confirmed histological diagnosis of EOC treated with carboplatin/paclitaxel were enrolled (2014–2019). The samples were analyzed by multiplex polymerase chain reaction (PCR) for the deletion of GSTM1 and GSTT1 genes. GSTP1 (c.313A>G/rs1695) and ABCB1 (c.1236C>T/rs1128503; c.3435C>T/rs1045642; c.2677G>T>A/rs2032582) single nucleotide polymorphisms (SNPs) were detected by real‐time PCR. Subjects with the GSTP1 c.313A>G had reduced risk of anemia (odds ratio (OR): 0.17, 95% confidence interval (CI): 0.04–0.69, P = 0.01, dominant model) and for thrombocytopenia (OR: 0.27, 95% CI: 0.12–0.64, P < 0.01; OR 0.18, 95% CI 0.03–0.85, P = 0.03, either dominant or recessive model), respectively. The GSTP1 c.313A>G AG genotype was associated with a lower risk of dose delay (OR: 0.35, 95% CI: 0.13–0.90, P = 0.03). The ABCB1 c.1236C>T was associated with increased risk of thrombocytopenia (OR: 0.15, 95% CI: 0.03–0.82, P = 0.03), whereas ABCB1 c.3435C>T had increased risk of grade 2 and 3 neurotoxicity (OR: 3.61, 95% CI: 1.08–121.01, P = 0.03) in recessive model (CC + CT vs. TT). This study suggests that GSTP1 c.313A>G, ABCB1 c.1236C>T, and c.3435C>T SNP detection is a potential predictor of hematological toxicity and neurotoxicity and could help predict the clinical management of women with EOC.

Study Highlights
  • WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?
Variation in drug disposition genes encoding drug‐metabolizing enzymes and transporters might contribute to susceptibility to toxicities and interindividual differences in clinical management such as the need to delay, reduce, or discontinue treatment.
  • WHAT QUESTION DID THIS STUDY ADDRESS?
We studied the association of GST and ABCB1 genetic variation with hematologic and neurologic toxicity, clinical management, and disease prognosis in Brazilian women with epithelial ovarian carcinoma (EOC) who undergo carboplatin and paclitaxel‐based chemotherapy.
  • WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?
GSTP1 c.313A>G is a potential predictor of anemia and thrombocytopenia and associated with a lower risk of dose delay during chemotherapy. In addition, ABCB1 c.1236C>T and c.3435C>T is associated with a higher risk of thrombocytopenia and neurotoxicity.
  • HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?
The polymorphism detection could be a strategy to careful monitoring of patients at increased risk of toxicity and appropriate supportive therapy could decrease the need for changes in treatment, thus improving the likelihood of a beneficial treatment response in women with EOC.

Epithelial ovarian cancer (EOC) is the most common cause of gynecological cancer death, largely due to the advanced stage of the disease at the time of diagnosis. 1 Standard first‐line treatment is cytoreductive surgery and subsequent chemotherapy using a combination of carboplatin and paclitaxel or neoadjuvant chemotherapy and residual tumor resection. 2 Despite a high response rate to chemotherapy, ~ 70% of the women have a relapse within the subsequent 3 years. 3 Platinum and taxane‐based chemotherapy are often associated with severe hematological toxicities, such as anemia, neutropenia, leukopenia, and thrombocytopenia. 4 In addition, neuropathy is a dose‐limiting side effect of paclitaxel. 5 , 6 Interindividual differences in carboplatin and paclitaxel toxicity may be associated with polymorphisms in genes encoding drug‐metabolizing enzymes and transporters, including GSTs and ATP‐binding cassette (ABC) efflux transporters like ABCB1. 4 , 7 , 8 , 9 The GSTs are a family of phase II enzymes involved in detoxification of xenobiotics by conjugation reactions between glutathione and endogenous and exogenous electrophilic compounds, such as chemotherapeutic drugs, including the platinum agents. The GST family consists of several gene subfamilies of which GSTM1, GSTT1, and GSTP1 are the most relevant for drug metabolism. 10 , 11 Functional GSTM1 and GSTT1 enzymes are directly related with the presence of the intact genes, because the absence of activity is the result of a 15 kb and 54 kb deletions that span the entire GSTM1 and GSTT1 genes (GSTM1‐null and GSTT1‐null genotypes), respectively. Consequently, individuals homozygous for the GSTM1 or GSTT1‐null allele have a complete absence of GSTM1 and GSTT1 activity, whereas individuals with two copies of the GSTM1 or GSTT1 genes have reference protein levels. 12 , 13 There is some evidence that these deletion genotypes may play a role in toxicity, response to treatment, and survival in some cancers, 14 , 15 , 16 including cancer of the ovary. 8 In contrast to the commonly studied GSTM1 and GSTT1 genotypes, the GSTP1 c.313A>G (rs1695) is an exonic single nucleotide polymorphism (SNP) that causes an amino acid substitution and results in an isoleucine to valine (Ile > Val) change at codon 105 of the enzyme. The highest level of GSTP1 activity is seen in individuals with the AA genotype (Ile/Ile) and is associated with increased toxicity in different carcinomas, but there are discordant results regarding the effect of GSTP1 c.313A>G on treatment outcomes. 9 , 17 , 18 , 19 , 20 Polymorphisms in ABCB1 or multidrug resistance 1 may affect the function of P‐glycoprotein, a critical transporter for efflux of paclitaxel from cells. 21 , 22 Three SNPs in the coding region of ABCB1 (c.1236C>T, rs1128503; c.3435C>T, rs1045642; and c.2677G>T>A, rs2032582) have been extensively studied. 23 , 24 These common ABCB1 SNPs have been associated with toxicity during carboplatin and paclitaxel‐based chemotherapy, including increased risk of anemia in carriers of the c.1236C>T SNP, a more pronounced neutrophil decrease in patients carrying the c.3435C>T and c.2677G>T>A SNPs and increased risk of peripheral neuropathy associated with the c.3435C>T SNP. 18 , 25 , 26 Similar to studies of GST polymorphisms, the associations of ABCB1 genetic variation with treatment outcomes is inconsistent across studies. 27 , 28 Patients developing severe toxicities often require dose reduction, dose delay, or treatment interruption that require clinical interventions and may affect the disease prognosis. 4 However, no study has been found so far focus on regarding the utility of polymorphisms in the management of chemotherapy and toxicities for ovarian cancer. The current study was designed to examine the association of GST and ABCB1 genetic variants with hematologic and neurologic toxicities, clinical management on chemotherapy, and disease prognosis in Brazilian women with EOC.  相似文献   
8.
BackgroundDeveloping a noninvasive clinical test to accurately diagnose kidney allograft rejection is critical to improve allograft outcomes. Urinary exosomes, tiny vesicles released into the urine that carry parent cells’ proteins and nucleic acids, reflect the biologic function of the parent cells within the kidney, including immune cells. Their stability in urine makes them a potentially powerful tool for liquid biopsy and a noninvasive diagnostic biomarker for kidney-transplant rejection.MethodsUsing 192 of 220 urine samples with matched biopsy samples from 175 patients who underwent a clinically indicated kidney-transplant biopsy, we isolated urinary exosomal mRNAs and developed rejection signatures on the basis of differential gene expression. We used crossvalidation to assess the performance of the signatures on multiple data subsets.ResultsAn exosomal mRNA signature discriminated between biopsy samples from patients with all-cause rejection and those with no rejection, yielding an area under the curve (AUC) of 0.93 (95% CI, 0.87 to 0.98), which is significantly better than the current standard of care (increase in eGFR AUC of 0.57; 95% CI, 0.49 to 0.65). The exosome-based signature’s negative predictive value was 93.3% and its positive predictive value was 86.2%. Using the same approach, we identified an additional gene signature that discriminated patients with T cell–mediated rejection from those with antibody-mediated rejection (with an AUC of 0.87; 95% CI, 0.76 to 0.97). This signature’s negative predictive value was 90.6% and its positive predictive value was 77.8%.ConclusionsOur findings show that mRNA signatures derived from urinary exosomes represent a powerful and noninvasive tool to screen for kidney allograft rejection. This finding has the potential to assist clinicians in therapeutic decision making.  相似文献   
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ObjectiveAn ideal scaffold for endodontic regeneration should allow the predictableness of the new tissue organization and limit the negative impact of residual bacteria. Therefore, composition and functionalization of the scaffold play an important role in tissue bioengineering. The objective of this study was to assess the morphological, physicochemical, biological and antimicrobial properties of a new solid chitosan-based scaffold associated with gelatin, microparticulate dentin and genipin.MethodsScaffolds based on chitosan (Ch); chitosan associated with gelatin and genipin (ChGG); and chitosan associated with gelatin, microparticulate dentin and genipin (ChGDG) were prepared by using the freeze-drying method. The morphology of the scaffolds was analyzed by scanning electron microscopy (SEM). The physicochemical properties were assessed for biodegradation, swelling and total released proteins. The biological aspects of the scaffolds were assessed using human cells from the apical papilla (hCAPs). Cell morphology and adhesion to the scaffolds were evaluated by SEM, cytotoxicity and cell proliferation by MTT reduction-assay. Cell differentiation in scaffolds was assessed by using alizarin red assay. The antimicrobial effect of the scaffolds was evaluated by using the bacterial culture method, and bacterial adhesion to the scaffolds was observed by SEM.ResultsAll the scaffolds presented porous structures. The ChCDG had more protein release, adhesion, proliferation and differentiation of hCAPs, and bacteriostatic effect on Enterococcus faecalis than Ch and ChGG (p < 0.05).SignificanceThe chitosan associated with gelatin, microparticulate dentin and genipin has morphological, physicochemical, biological and antibacterial characteristics suitable for their potential use as scaffold in regenerative endodontics.  相似文献   
10.
BackgroundAngiopoietin-1 and 2 (Ang1, Ang2) are important mediators of angiogenesis. Angiopoietin levels are perturbed in cardiovascular disease, but it is unclear whether angiopoietin signaling is causative, an adaptive response, or merely epiphenomenon of disease activity.Methods and ResultsIn a cohort free of cardiovascular disease at baseline (Multi-Ethnic Study of Atherosclerosis [MESA]), relationships between angiopoietins, cardiac morphology, and subsequent incidence of heart failure or cardiovascular death were evaluated. In cohorts with pulmonary arterial hypertension or left heart disease, associations between angiopoietins, invasive hemodynamics, and adverse clinical outcomes were evaluated. In MESA, Ang2 was associated with a higher incidence of heart failure or cardiovascular death (hazard ratio 1.21 per standard deviation, P < .001). Ang2 was associated with increased right atrial pressure (pulmonary arterial hypertension cohort) and increased wedge pressure and right atrial pressure (left heart disease cohort). Elevated Ang2 was associated with mortality in the pulmonary arterial hypertension cohort.ConclusionsAng2 was associated with incident heart failure or death among adults without cardiovascular disease at baseline and with disease severity in individuals with existing heart failure. Our finding that Ang2 is increased before disease onset and that elevations reflect disease severity, suggests Ang2 may contribute to heart failure pathogenesis.  相似文献   
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