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Monitoring urinary collagen metabolite changes following collagen peptide ingestion and physical activity using ELISA with anti active collagen oligopeptide antibody.
Osawa, Y, Nomura, K, Kimira, Y, Kushibe, S, Takeyama, KI, Nagao, M, Kataoka-Matsushita, A, Koizumi, S, Mano, H
Scientific reports. 2021;(1):13527
Abstract
Active collagen oligopeptides (ACOP) are bioactive collagen-derived peptides detected by a recently-established ELISA. To facilitate studies of the function and metabolism of these products, this study aims to determine which of these peptides is recognized by a novel anti-ACOP antibody used in this ELISA. We then investigate the effect of collagen peptide (CP) ingestion and exercise on urinary ACOP concentrations in a cohort of university student athletes using colorimetric, LC-MS/MS, and ELISA. We observed that the antibody showed strong cross-reactivity to Pro-Hyp and Gly-Pro-Hyp and weak cross-reactivity to commercial CP. CP ingestion increased the urinary level of ACOP over time, which correlated highly with urinary levels of peptide forms of Hyp and Pro-Hyp. Physical activity significantly decreased the urinary ACOP level. This study demonstrates changes in urinary ACOP following oral CP intake and physical activity using ELISA with the novel anti-ACOP antibody. Thus, ACOP may be useful as a new biomarker for collagen metabolism.
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Pretreatment PET/CT imaging of angiogenesis based on 18F-RGD tracer uptake may predict antiangiogenic response.
Li, L, Ma, L, Shang, D, Liu, Z, Yu, Q, Wang, S, Teng, X, Zhang, Q, Hu, X, Zhao, W, et al
European journal of nuclear medicine and molecular imaging. 2019;(4):940-947
Abstract
PURPOSE To explore the relationship between metabolic uptake of the 18F-ALF-NOTA-PRGD2 (18F-RGD) tracer on positron emission tomography/computerized tomography (PET/CT) and the antiangiogenic effect of apatinib in patients with solid malignancies. MATERIALS AND PATIENTS Patients with measurable lesions scheduled for second- or third-line single-agent therapy with apatinib were eligible for this prospective clinical trial. All patients underwent 18F-RGD PET/CT examination before the start of treatment. Standardized uptake values (SUVs) of contoured tumor lesions were computed and compared using independent sample t-tests or the Mann-Whitney U test. Receiver-operating characteristic (ROC) curve analysis was used to determine accuracy in predicting response. Survival curves were compared using the Kaplan-Meier method. RESULTS Of 38 patients who consented to study participation, 25 patients with 42 measurable lesions met the criteria for inclusion in this response assessment analysis. The median follow-up time was 3 months (range, 1-10 months), and the median progression-free survival (PFS) was 3 months (95% confidence interval, 1.04-4.96). The SUVpeak and SUVmean were significantly higher in responding tumors than in non-responding tumors (4.98 ± 2.34 vs 3.59 ± 1.44, p = 0.048; 3.71 ± 1.15 vs 2.95 ± 0.49, P = 0.036). SUVmax did not differ between responding tumors and non-responding tumors (6.58 ± 3.33 vs 4.74 ± 1.83, P = 0.078). An exploratory ROC curve analysis indicated that SUVmean [area under the ROC curve (AUC) = 0.700] was a better parameter than SUVpeak (AUC = 0.689) for predicting response. Using a threshold value of 3.82, high SUVmean at baseline was associated with improved PFS (5.0 vs. 3.4 months, log-rank P = 0.036). CONCLUSION 18F-RGD uptake on PET/CT imaging pretreatment may predict the response to antiangiogenic therapy, with higher 18F-RGD uptake in tumors predicting a better response to apatinib therapy.
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Relation of Left Ventricular Mass and Infarct Size in Anterior Wall ST-Segment Elevation Acute Myocardial Infarction (from the EMBRACE STEMI Clinical Trial).
Daaboul, Y, Korjian, S, Weaver, WD, Kloner, RA, Giugliano, RP, Carr, J, Neal, BJ, Chi, G, Cochet, M, Goodell, L, et al
The American journal of cardiology. 2016;(5):625-31
Abstract
Biomarker measures of infarct size and myocardial salvage index (MSI) are important surrogate measures of clinical outcomes after a myocardial infarction. However, there is variability in infarct size unaccounted for by conventional adjustment factors. This post hoc analysis of Evaluation of Myocardial Effects of Bendavia for Reducing Reperfusion Injury in Patients With Acute Coronary Events (EMBRACE) ST-Segment Elevation Myocardial Infarction (STEMI) trial evaluates the association between left ventricular (LV) mass and infarct size as assessed by areas under the curve for creatine kinase-MB (CK-MB) and troponin I release over the first 72 hours (CK-MB area under the curve [AUC] and troponin I [TnI] AUC) and the MSI. Patients with first anterior STEMI, occluded left anterior descending artery, and available LV mass measurement in EMBRACE STEMI trial were included (n = 100) (ClinicalTrials.govNCT01572909). MSI, end-diastolic LV mass on day 4 cardiac magnetic resonance, and CK-MB and troponin I concentrations were evaluated by a core laboratory. After saturated multivariate analysis, dominance analysis was performed to estimate the contribution of each independent variable to the predicted variance of each outcome. In multivariate models that included age, gender, body surface area, lesion location, smoking, and ischemia time, LV mass remained independently associated with biomarker measures of infarct size (CK-MB AUC p = 0.02, TnI AUC p = 0.03) and MSI (p = 0.003). Dominance analysis demonstrated that LV mass accounted for 58%, 47%, and 60% of the predicted variances for CK-MB AUC, TnI AUC, and MSI, respectively. In conclusion, LV mass accounts for approximately half of the predicted variance in biomarker measures of infarct size. It should be considered as an adjustment variable in studies evaluating infarct size.
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Protective Effects of Soy Oligopeptides in Ultraviolet B-Induced Acute Photodamage of Human Skin.
Zhou, BR, Ma, LW, Liu, J, Zhang, JA, Xu, Y, Wu, D, Permatasari, F, Luo, D
Oxidative medicine and cellular longevity. 2016;:5846865
Abstract
Aim. We explored the effects of soy oligopeptides (SOP) in ultraviolet B- (UVB-) induced acute photodamage of human skin in vivo and foreskin ex vivo. Methods. We irradiated the forearm with 1.5 minimal erythemal dose (MED) of UVB for 3 consecutive days, establishing acute photodamage of skin, and topically applied SOP. Erythema index (EI), melanin index, stratum corneum hydration, and transepidermal water loss were measured by using Multiprobe Adapter 9 device. We irradiated foreskin ex vivo with the same dose of UVB (180 mJ/cm(2)) for 3 consecutive days and topically applied SOP. Sunburn cells were detected by using hematoxylin and eosin staining. Apoptotic cells were detected by using terminal deoxynucleotidyl transferase dUTP nick end labeling assay. Cyclobutane pyrimidine dimers (CPDs), p53 protein, Bax protein, and Bcl-2 protein were detected by using immunohistochemical staining. Results. Compared with UVB group, UVB-irradiated skin with topically applied SOP showed significantly decreased EI. Compared with UVB group, topical SOP significantly increased Bcl-2 protein expression and decreased CPDs-positive cells, sunburn cells, apoptotic cells, p53 protein expression, and Bax protein expressions in the epidermis of UVB-irradiated foreskin. Conclusion. Our study demonstrated that topical SOP can protect human skin against UVB-induced photodamage.
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Safety profile of boceprevir and telaprevir in chronic hepatitis C: real world experience from HCV-TARGET.
Gordon, SC, Muir, AJ, Lim, JK, Pearlman, B, Argo, CK, Ramani, A, Maliakkal, B, Alam, I, Stewart, TG, Vainorius, M, et al
Journal of hepatology. 2015;(2):286-93
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Abstract
BACKGROUND & AIMS The safety profiles of boceprevir and telaprevir in the treatment of chronic hepatitis C, administered in academic and community centres across the United States, were evaluated. METHODS In 90 medical centres, patients with chronic HCV received pegylated interferon, ribavirin, and either telaprevir or boceprevir per local standard of care. Demographic, adverse event, clinical, and virological data were collected during treatment and follow-up. RESULTS A total of 2084 patients (97% HCV genotype 1) received at least one dose of a protease inhibitor. At baseline, 38% of patients had cirrhosis, and 57% had received at least one prior treatment for hepatitis C. Serious adverse events occurred in 12% of patients receiving protease inhibitor therapy. Overall, 66% of patients experienced anaemia, leading to frequent ribavirin dose reductions (42%) and erythropoietin use (37%); 11% received blood transfusion. More than 90% of patients had adverse events that led to a prescription, treatment, or dosage change, and 39% of patients discontinued treatment early, most commonly because of adverse events (18%) or lack of efficacy (16%). Hepatic decompensation events occurred in 3% of all patients. Age, female gender, cirrhosis, HCV genotype 1 subtype, creatinine clearance, platelet levels, albumin levels and haemoglobin levels were independent predictors of anaemia. Five deaths occurred. Overall, 52% of all patients achieved a sustained virologic response. CONCLUSIONS In academic and community centres, where chronic hepatitis C patients commonly have advanced liver disease, triple therapy was associated with a high rate of adverse events and involved frequent treatment modifications and adverse event management.
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Faldaprevir and pegylated interferon α-2a/ribavirin in individuals co-infected with hepatitis C virus genotype-1 and HIV.
Dieterich, D, Nelson, M, Soriano, V, Arastéh, K, Guardiola, JM, Rockstroh, JK, Bhagani, S, Laguno, M, Tural, C, Ingiliz, P, et al
AIDS (London, England). 2015;(5):571-81
Abstract
OBJECTIVE Faldaprevir is a potent, once-daily hepatitis C virus (HCV) NS3/4A protease inhibitor. STARTVerso4 assessed the efficacy and safety of faldaprevir and response-guided pegylated interferon α-2a/ribavirin (PegIFN/RBV) in individuals with HCV/HIV co-infection. DESIGN A phase 3 open-label study (NCT01399619). METHODS Individuals (N = 308) co-infected with HCV genotype 1 (treatment-naive or prior interferon relapsers) and HIV [96% on antiretroviral therapy (ART)] received faldaprevir 120 mg (N = 123) or 240 mg (N = 185) and PegIFN/RBV. Those receiving a protease inhibitor or efavirenz ART were assigned to faldaprevir 120 or 240 mg, respectively. Individuals achieving early treatment success (ETS; HCV RNA <25 IU/ml at week 4 and undetectable at week 8) were randomized to 24 or 48 weeks of PegIFN/RBV. The primary endpoint was sustained virologic response 12 weeks after treatment (SVR12). RESULTS SVR12 was achieved in 221 (72%) individuals, and the rates were comparable across faldaprevir doses. ETS was achieved in 80%, and of these 86% achieved SVR12, with comparable rates with 24 and 48 weeks of PegIFN/RBV (87 and 94%, respectively). In multivariate analysis, age below 40 years, IL28B CC genotype, and baseline HCV RNA below 800 000 IU/ml were associated with SVR12 (P = 0.027, P < 0.0001, and P = 0.0002, respectively), whereas treatment (ART regimen and faldaprevir dose), liver cirrhosis, and genotype 1 subtype were not. The safety profile was comparable to that of faldaprevir in HCV-monoinfected individuals. CONCLUSIONS High SVR12 rates were achieved with faldaprevir and PegIFN/RBV in HIV/HCV co-infected individuals, regardless of faldaprevir dose and background ART, HCV genotype 1 subtype, or cirrhosis status. SVR rates mirrored those obtained with similar regimens in HCV monoinfected individuals.
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Baseline Polymorphisms and Emergence of Drug Resistance in the NS3/4A Protease of Hepatitis C Virus Genotype 1 following Treatment with Faldaprevir and Pegylated Interferon Alpha 2a/Ribavirin in Phase 2 and Phase 3 Studies.
Berger, KL, Scherer, J, Ranga, M, Sha, N, Stern, JO, Quinson, AM, Kukolj, G
Antimicrobial agents and chemotherapy. 2015;(10):6017-25
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Analysis of data pooled from multiple phase 2 (SILEN-C1 to 3) and phase 3 studies (STARTVerso1 to 4) of the hepatitis C virus (HCV) nonstructural protein 3/4A (NS3/4A) protease inhibitor faldaprevir plus pegylated interferon alpha/ribavirin (PR) provides a comprehensive evaluation of baseline and treatment-emergent NS3/4A amino acid variants among HCV genotype-1 (GT-1)-infected patients. Pooled analyses of GT-1a and GT-1b NS3 population-based pretreatment sequences (n = 3,124) showed that faldaprevir resistance-associated variants (RAVs) at NS3 R155 and D168 were rare (<1%). No single, noncanonical NS3 protease or NS4A cofactor baseline polymorphism was associated with a reduced sustained virologic response (SVR) to faldaprevir plus PR, including Q80K. The GT-1b NS3 helicase polymorphism T344I was associated with reduced SVR to faldaprevir plus PR (P < 0.0001) but was not faldaprevir specific, as reduced SVR was also observed with placebo plus PR. Among patients who did not achieve SVR and had available NS3 population sequences (n = 507 GT-1a; n = 349 GT-1b), 94% of GT-1a and 83% of GT-1b encoded faldaprevir treatment-emergent RAVs. The predominant GT-1a RAV was R155K (88%), whereas GT-1b encoded D168 substitutions (78%) in which D168V was predominant (67%). The novel GT-1b NS3 S61L substitution emerged in 7% of virologic failures as a covariant with D168V, most often among the faldaprevir breakthroughs; S61L in combination with D168V had a minimal impact on faldaprevir susceptibility compared with that for D168V alone (1.5-fold difference in vitro). The median time to loss of D168 RAVs among GT-1b-infected patients who did not have a sustained virologic response at 12 weeks posttreatment (non-SVR12) after virologic failure was 5 months, which was shorter than the 14 months for R155 RAVs among GT-1a-infected non-SVR12 patients, suggesting that D168V is less fit than R155K in the absence of faldaprevir selective pressure.
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The human immune system recognizes neopeptides derived from mitochondrial DNA deletions.
Duvvuri, B, Duvvuri, VR, Wang, C, Chen, L, Wagar, LE, Jamnik, V, Wu, J, Yeung, RS, Grigull, J, Watts, TH, et al
Journal of immunology (Baltimore, Md. : 1950). 2014;(10):4581-91
Abstract
Mutations in mitochondrial (mt) DNA accumulate with age and can result in the generation of neopeptides. Immune surveillance of such neopeptides may allow suboptimal mitochondria to be eliminated, thereby avoiding mt-related diseases, but may also contribute to autoimmunity in susceptible individuals. To date, the direct recognition of neo-mtpeptides by the adaptive immune system has not been demonstrated. In this study we used bioinformatics approaches to predict MHC binding of neopeptides identified from known deletions in mtDNA. Six such peptides were confirmed experimentally to bind to HLA-A*02. Pre-existing human CD4(+) and CD8(+) T cells from healthy donors were shown to recognize and respond to these neopeptides. One remarkably promiscuous immunodominant peptide (P9) could be presented by diverse MHC molecules to CD4(+) and/or CD8(+) T cells from 75% of the healthy donors tested. The common soil microbe, Bacillus pumilus, encodes a 9-mer that differs by one amino acid from P9. Similarly, the ATP synthase F0 subunit 6 from normal human mitochondria encodes a 9-mer with a single amino acid difference from P9 with 89% homology to P9. T cells expanded from human PBMCs using the B. pumilus or self-mt peptide bound to P9/HLA-A2 tetramers, arguing for cross-reactivity between T cells with specificity for self and foreign homologs of the altered mt peptide. These findings provide proof of principal that the immune system can recognize peptides arising from spontaneous somatic mutations and that such responses might be primed by foreign peptides and/or be cross-reactive with self.
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Telaprevir in the treatment of acute hepatitis C virus infection in HIV-infected men.
Fierer, DS, Dieterich, DT, Mullen, MP, Branch, AD, Uriel, AJ, Carriero, DC, van Seggelen, WO, Hijdra, RM, Cassagnol, DG, ,
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2014;(6):873-9
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BACKGROUND There is an international epidemic of hepatitis C virus (HCV) infection among human immunodeficiency virus (HIV)-infected men who have sex with men. Sustained virologic response (SVR) rates with pegylated interferon and ribavirin treatment are higher in these men during acute HCV than during chronic HCV, but treatment is still lengthy and SVR rates are suboptimal. METHODS We performed a pilot study of combination therapy with telaprevir, pegylated interferon, and ribavirin in acute genotype 1 HCV infection in HIV-infected men. Men who were treated prior to the availability of, or ineligible for, telaprevir were the comparator group. The primary endpoint was SVR12, defined as an HCV viral load <5 IU/mL at least 12 weeks after completing treatment. RESULTS In the telaprevir group, 84% (16/19) of men achieved SVR12 vs 63% (30/48) in the comparator group. Among men with SVR, median time to undetectable viral load was week 2 in the telaprevir group vs week 4 in the comparator group, and 94% vs 53% had undetectable viral loads at week 4. Most patients (81%) who achieved SVR in the telaprevir group received ≤12 weeks of treatment and there were no relapses after treatment. The overall safety profile was similar to that known for telaprevir-based regimens. CONCLUSIONS Incorporating telaprevir into treatment of acute genotype 1 HCV in HIV-infected men halved the treatment duration and increased the SVR rate. Larger studies should be done to confirm these findings. Clinicians should be alert to detect acute HCV infection of HIV-infected men to take advantage of this effective therapy and decrease further transmission in this epidemic.
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Weight loss during telaprevir-based triple therapy due to telaprevir-induced appetite loss.
Nomura, H, Miyagi, Y, Tanimoto, H, Kawano, A, Yamashita, N
Internal medicine (Tokyo, Japan). 2014;(22):2567-73
Abstract
OBJECTIVE The sustained virological response (SVR) rate has improved to >70% for patients with hepatitis C virus genotype 1 treated with the triple therapy of telaprevir (TVR), pegylated interferon (PEG-IFN)-α, and ribavirin (RBV). However, this therapy has various adverse effects, although there have been no reports of it decreasing body weight. METHODS A total of 175 patients with chronic hepatitis C received one of three IFN-based regimens (35 received the PEG-IFN/RBV/TVR (PRT) regimen, 70 received the PEG-IFN/RBV (PR) regimen, and 70 received the IFN-β/RBV (FR) regimen) and body weight was followed for 12 weeks. RESUTS Decreases in body weight up to week 12 were significantly greater in the PRT group than in the PR or FR groups (p<0.001). The proportion of patients who experienced weight loss ≥5.0 kg by week 12 in the PRT group was significantly higher than in the PR or FR groups (p<0.001) regardless of baseline ghrelin level. The question 18 score (appetite) of the Beck Depression Inventory-II at week 12 was significantly higher in the PRT group than in the PR or FR groups (p<0.001). A multivariate analysis revealed PRT, the ghrelin level before treatment (<7.0 fmol/mL), and the question 18 score in week 12 (2 or 3) to be independent factors associated with a decrease in body weight ≥5.0 kg from week 0 to week 12. CONCLUSION PEG-IFN/RBV/TVR therapy yielded high SVR rates, but it was associated with a decreased body weight due to TVR-induced appetite loss.