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Laparoscopic sleeve gastrectomy alters 1H-NMR-measured lipoprotein and glycoprotein profile in patients with severe obesity and nonalcoholic fatty liver disease.
Cabré, N, Gil, M, Amigó, N, Luciano-Mateo, F, Baiges-Gaya, G, Fernández-Arroyo, S, Rodríguez-Tomàs, E, Hernández-Aguilera, A, Castañé, H, París, M, et al
Scientific reports. 2021;(1):1343
Abstract
Patients with morbid obesity frequently present non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH) associated with pro-atherogenic alterations. Laparoscopic sleeve gastrectomy (LSG) is an effective treatment for weight reduction, and for the remission of hepatic alterations. Using 1H-nuclear magnetic resonance (1H-NMR), we investigated the effects of LSG on lipoprotein and glycoprotein profile in patients with morbid obesity and liver disease. We included 154 patients with morbid obesity (49 non-NASH, 54 uncertain NASH, 51 definite NASH). A blood sample was obtained before surgery and, in patients with definite NASH, one year after surgery. Patients with NASH had increased concentrations of medium and small VLDL particles, VLDL and IDL cholesterol concentrations, IDL, LDL, and HDL triglyceride concentrations, and elevated glycoprotein levels. These changes were more marked in patients with type 2 diabetes mellitus. LSG produced significant decreases in the concentration of VLDL particles, VLDL cholesterol and triglycerides, an increase in the concentration LDL particles and LDL cholesterol concentrations, and a decrease in protein glycation. We conclude that patients with obesity and NASH had significant alterations in circulating levels of lipoproteins and glycoproteins that were associated with the severity of the disease. Most of these changes were reversed post-LSG.
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Estimating the age of the p.Cys433Arg variant in the MYOC gene in patients with primary open-angle glaucoma.
Marques, AM, Ananina, G, Costa, VP, de Vasconcellos, JPC, de Melo, MB
PloS one. 2018;(11):e0207409
Abstract
The aim of this study was to estimate the age of the Cys433Arg (c.1297T>C, p.Cys433Arg) variant by comparing the genotypes of individuals affected and not affected by primary open angle glaucoma juvenile onset (JOAG). Our sample consisted of 35 JOAG-affected individuals from three families, 16 unrelated patients with the MYOC p.Cys433Arg variant and 16 unaffected individuals. Genomic DNA was amplified by PCR; nine short tandem repeats were genotyped through automated electrophoresis and three single nucleotide polymorphisms through Sanger sequencing. The determination of haplotypes was performed using Arlequin software and age estimation was performed using DMLE+ 2.3 and BDMC21 softwares. Four markers constituted the haplotypes associated with the p.Cys433Arg variant. The software DMLE+2.3 predicted an age of 43 generations for this variant with a 95% confidence interval ranging from 28 to 76 generations (560-1520 years) and BDMC21 predicted an age of 59 generations (1180 years) (95% CI: 40 to 100).
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A prospective multicentre phase III validation study of AZGP1 as a biomarker in localized prostate cancer.
Zhang, AY, Grogan, JS, Mahon, KL, Rasiah, K, Sved, P, Eisinger, DR, Boulas, J, Vasilaris, A, Henshall, SM, Stricker, PD, et al
Annals of oncology : official journal of the European Society for Medical Oncology. 2017;(8):1903-1909
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Abstract
BACKGROUND Prostate cancers (PCs) with similar characteristics at the time of diagnosis can have very different disease outcomes. Conventional biomarkers of PC still lack precision in identifying individuals at high risk of PC recurrence. While many candidate biomarkers are proposed in the literature, few are in clinical practice as they lack rigorous validation. This study prospectively enrolled an independent phase III cohort to evaluate the clinical utility of zinc-alpha 2-glycoprotein (AZGP1) as a prognostic biomarker in localized PC. PATIENTS AND METHODS In our multicentre, prospective phase III study, AZGP1 status in 347 radical prostatectomy specimens was assayed by immunohistochemistry in a NATA-accredited laboratory. The AZGP1 score was assessed in a multivariable model incorporating established prognostic factors. We also report extended outcomes from our previous phase II study. The primary endpoint was biochemical relapse-free survival (BRFS). Secondary endpoints were metastasis-free survival (MFS) and PC-specific survival (PCSS). RESULTS In the phase II cohort, with a median follow-up of 15.8 years, low/absent AZGP1 expression was an independent predictor of poor BRFS (HR, 1.4; 95% CI, 1.1-1.9; P = 0.03), MFS (HR, 2.8; 95% CI, 1.2-6.6; P = 0.02) and PCSS (HR, 3.8; 95% CI, 1.5-9.5; P = 0.005). These results were validated in our prospective phase III cohort. Low/absent AZGP1 expression independently predicted for BRFS (HR, 1.9; 95% CI, 1.1-3.3; P = 0.02), with shorter MFS (HR, 2.0; 95% CI, 1.1-3.4; P = 0.02). AZGP1 improved the discriminatory value when incorporated into existing prognostic risk models. CONCLUSION Our study provides prospective phase III validation that absent/low AZGP1 expression provides independent prognostic value in PC. This study provides robust evidence for the incorporation of this biomarker into clinical practice.
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All-trans retinoic acid-triggered antimicrobial activity against Mycobacterium tuberculosis is dependent on NPC2.
Wheelwright, M, Kim, EW, Inkeles, MS, De Leon, A, Pellegrini, M, Krutzik, SR, Liu, PT
Journal of immunology (Baltimore, Md. : 1950). 2014;(5):2280-2290
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Abstract
A role for vitamin A in host defense against Mycobacterium tuberculosis has been suggested through epidemiological and in vitro studies; however, the mechanism is unclear. In this study, we demonstrate that vitamin A-triggered antimicrobial activity against M. tuberculosis requires expression of NPC2. Comparison of monocytes stimulated with all-trans retinoic acid (ATRA) or 1,25-dihydroxyvitamin D3 (1,25D3), the biologically active forms of vitamin A and vitamin D, respectively, indicates that ATRA and 1,25D3 induce mechanistically distinct antimicrobial activities. Stimulation of primary human monocytes with ATRA did not result in expression of the antimicrobial peptide cathelicidin, which is required for 1,25D3 antimicrobial activity. In contrast, ATRA triggered a reduction in the total cellular cholesterol concentration, whereas 1,25D3 did not. Blocking ATRA-induced cellular cholesterol reduction inhibits antimicrobial activity as well. Bioinformatic analysis of ATRA- and 1,25D3-induced gene profiles suggests that NPC2 is a key gene in ATRA-induced cholesterol regulation. Knockdown experiments demonstrate that ATRA-mediated decrease in total cellular cholesterol content and increase in lysosomal acidification are both dependent upon expression of NPC2. Expression of NPC2 was lower in caseous tuberculosis granulomas and M. tuberculosis-infected monocytes compared with normal lung and uninfected cells, respectively. Loss of NPC2 expression ablated ATRA-induced antimicrobial activity. Taken together, these results suggest that the vitamin A-mediated antimicrobial mechanism against M. tuberculosis requires NPC2-dependent expression and function, indicating a key role for cellular cholesterol regulation in the innate immune response.
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Gross cystic disease fluid protein 15 (GCDFP-15) expression in breast cancer subtypes.
Darb-Esfahani, S, von Minckwitz, G, Denkert, C, Ataseven, B, Högel, B, Mehta, K, Kaltenecker, G, Rüdiger, T, Pfitzner, B, Kittel, K, et al
BMC cancer. 2014;:546
Abstract
BACKGROUND Gross cystic disease fluid protein 15 (GCDFP-15), which is regulated by the androgen receptor (AR), is a diagnostic marker for mammary differentiation in histopathology. We determined the expression of GCDFP-15 in breast cancer subtypes, its potential prognostic and predictive value, as well as its relationship to AR expression. METHODS 602 pre-therapeutic breast cancer core biopsies from the phase III randomized neoadjuvant GeparTrio trial (NCT00544765) were investigated for GCDFP-15 expression by immunohistochemistry. Expression data were correlated with disease-free (DFS) and overall survival (OS) time as well as pathological complete response (pCR) to neoadjuvant chemotherapy. RESULTS 239 tumors (39.7%) were GCDFP-15 positive. GCDFP-15 expression was positively linked to hormone receptor (HR) and HER2 positive tumor type, while most triple negative carcinomas were negative (p < 0.0001). GCDFP-15 was also strongly correlated to AR expression (p 0.001), and to the so-called molecular apocrine subtype (HR-/AR+, p < 0.0001). Higher rates of GCDFP-15 positivity were seen in tumors of lower grade (<0.0001) and negative nodal status (p = 0.008). GCDFP-15 positive tumors tended to have a more favourable prognosis than GCDFP-15 negative tumors (DFS (p = 0.052) and OS (p = 0.044)), which was not independent from other factors in multivariate analysis. GCDFP-15 expression was not linked to pCR. Histological apocrine differentiation was frequent in molecular apocrine carcinomas (60.7%), and was associated with GCDFP-15 within this group (p = 0.039). CONCLUSIONS GCDFP-15 expression is higher in tumors with favorable prognostic features. GCDFP-15 expression is further a frequent feature of AR positive tumors and the molecular apocrine subtype. It might have reduced sensitivity as a diagnostic marker for mammary differentiation in triple negative tumors as compared to HR or HER2 positive tumor types.
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Energy flux, more so than energy balance, protein intake, or fitness level, influences insulin-like growth factor-I system responses during 7 days of increased physical activity.
Rarick, KR, Pikosky, MA, Grediagin, A, Smith, TJ, Glickman, EL, Alemany, JA, Staab, JS, Young, AJ, Nindl, BC
Journal of applied physiology (Bethesda, Md. : 1985). 2007;(5):1613-21
Abstract
The purpose of this study was to determine the impact of dietary factors and exercise-associated factors on the response of IGF-I and its binding proteins (IGFBPs) during a period of increased physical activity. Twenty-nine men completed a 4-day (days 1-4) baseline period of a controlled energy balanced diet while maintaining their normal physical activity level followed by 7 days (days 5-11) of a 1,000 kcal/day increase in physical activity above their normal activity levels. Two subject groups, one sedentary (Sed, mean Vo(2peak): 39 mlxkg(-1)xmin(-1), n = 7) and one fit (FIT1, mean Vo(2peak): 56 ml.kg(-1)xmin(-1), n = 8) increased energy intake to maintain energy balance throughout the 7-day intervention. In two other fit subject groups (FIT2, n = 7 and FIT3, n = 7), energy intake remained at baseline resulting in a 1,000 kcal/day exercise-induced energy deficit. Of these, FIT2 received an adequate protein diet (0.9 g/kg), and FIT3 received a high-protein diet (1.8 g/kg). For all four groups, IGF-I, IGFBP-3, and the acid labile subunit (ALS) were significantly decreased by day 11 (27 +/- 4%, 10 +/- 2%, and 19 +/- 4%, respectively) and IGFBP-2 significantly increased by 49 +/- 21% following day 3. IGFBP-1 significantly increased only in the two negative energy balance groups, FIT2 (38 +/- 6%) and FIT3 (46 +/- 8%). Differences in initial fitness level and dietary protein intake did not alter the IGF-I system response to an acute increase in physical activity. Decreases in IGF-I were observed during a moderate increase in physical activity despite maintaining energy balance, suggesting that currently unexplained exercise-associated mechanisms, such as increased energy flux, regulate IGF-I independent of energy deficit.
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Biomarkers predict radiographic progression in early rheumatoid arthritis and perform well compared with traditional markers.
Young-Min, S, Cawston, T, Marshall, N, Coady, D, Christgau, S, Saxne, T, Robins, S, Griffiths, I
Arthritis and rheumatism. 2007;(10):3236-47
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OBJECTIVE To evaluate the performance of biochemical and traditional markers in predicting radiographic progression in rheumatoid arthritis (RA). METHODS One hundred thirty-two patients with early RA were treated with nonbiologic therapies for 2 years and studied longitudinally. Genomic DNA was analyzed for presence of the shared epitope. Levels of matrix metalloproteinases (matrix metalloproteinase 1 [MMP-1], MMP-13, and MMP-3), tissue inhibitor of metalloproteinases 1 (TIMP-1), and cartilage oligomeric matrix protein (COMP) were assessed in serially obtained serum samples. The presence of pyridinoline (Pyr), deoxypyridinoline, glycosylated Pyr (Glc-Gal-Pyr), and C-telopeptide of type II collagen (CTX-II) was assessed in urine samples. Radiographs obtained at entry and at 2 years were evaluated using the modified Larsen score. RESULTS Baseline and 2-year radiographs were available from 118 patients. Larsen scores worsened during the 2 years in 50 patients, while 68 patients had no radiographic progression. Levels of a variety of biochemical markers, i.e., MMP-3, CTX-II, COMP, TIMP-1, Pyr, and Glc-Gal-Pyr, correlated significantly with radiographic progression at entry and longitudinally as assessed by area under the curve (AUC). By multivariate analysis, a model including MMP-3 and CTX-II was identified as providing the best prediction of radiographic progression at entry (predictive accuracy by receiver operating characteristic [ROC] AUC = 0.76 [95% confidence interval 0.66-0.85]), while a combination of MMP-3, CTX-II, and swollen joint count formed the best longitudinal AUC model (predictive accuracy by ROC AUC = 0.81 [95% confidence interval 0.73-0.89]). Patient-reported measures (Health Assessment Questionnaire, pain scores) were of limited use. In a subset of 50 patients who were treated with methotrexate (MTX) during the followup period, median serum MMP-3 levels decreased after the initiation of MTX therapy (P = 0.0003). CONCLUSION These results indicate that biochemical markers are useful predictors of radiographic progression in RA and that serum MMP-3 levels decrease significantly with MTX therapy. Multivariate models that include MMP-3 and CTX-II perform better than existing traditional markers in predicting radiographic outcome in RA.
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Bisphosphonate treatment does not affect serum levels of osteoprotegerin and RANKL in hypercalcemic cancer patients.
Zojer, N, Brenner, K, Beke, D, Kudlacek, S, Hawa, G, Woloszczuk, W, Hofbauer, LC, Pecherstorfer, M
Anticancer research. 2005;(5):3607-12
Abstract
Bisphosphonates are the standard treatment for hypercalcemia of malignancy. We hypothesized that bisphosphonate treatment and the subsequent fall in serum calcium might induce changes in the RANK/RANKL/OPG system, which plays a pivotal role in the regulation of bone resorption. Soluble RANKL and OPG levels were measured in the serum of 15 hypercalcemic patients at baseline and on 5 consecutive days following treatment with the amino-bisphosphonate ibandronate. At day 0, the median soluble OPG level was elevated (p=0.0021) in the hypercalcemic group as compared to normal controls, while the median serum RANKL level was not significantly different. Ibandronate treatment and the resulting decrease (p<0.0001) in serum calcium levels did not affect the serum concentrations of OPG, serum RANKL, or the serum RANKL/OPG ratio. In comparison with day 0, these factors did not change significantly at any time-point analyzed.