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Relation of Serum Copper Status to Survival in COVID-19.
Hackler, J, Heller, RA, Sun, Q, Schwarzer, M, Diegmann, J, Bachmann, M, Moghaddam, A, Schomburg, L
Nutrients. 2021;(6)
Abstract
The trace element copper (Cu) is part of our nutrition and essentially needed for several cuproenzymes that control redox status and support the immune system. In blood, the ferroxidase ceruloplasmin (CP) accounts for the majority of circulating Cu and serves as transport protein. Both Cu and CP behave as positive, whereas serum selenium (Se) and its transporter selenoprotein P (SELENOP) behave as negative acute phase reactants. In view that coronavirus disease (COVID-19) causes systemic inflammation, we hypothesized that biomarkers of Cu and Se status are regulated inversely, in relation to disease severity and mortality risk. Serum samples from COVID-19 patients were analysed for Cu by total reflection X-ray fluorescence and CP was quantified by a validated sandwich ELISA. The two Cu biomarkers correlated positively in serum from patients with COVID-19 (R = 0.42, p < 0.001). Surviving patients showed higher mean serum Cu and CP concentrations in comparison to non-survivors ([mean+/-SEM], Cu; 1475.9+/-22.7 vs. 1317.9+/-43.9 µg/L; p < 0.001, CP; 547.2.5 +/- 19.5 vs. 438.8+/-32.9 mg/L, p = 0.086). In contrast to expectations, total serum Cu and Se concentrations displayed a positive linear correlation in the patient samples analysed (R = 0.23, p = 0.003). Serum CP and SELENOP levels were not interrelated. Applying receiver operating characteristics (ROC) curve analysis, the combination of Cu and SELENOP with age outperformed other combinations of parameters for predicting risk of death, yielding an AUC of 95.0%. We conclude that the alterations in serum biomarkers of Cu and Se status in COVID-19 are not compatible with a simple acute phase response, and that serum Cu and SELENOP levels contribute to a good prediction of survival. Adjuvant supplementation in patients with diagnostically proven deficits in Cu or Se may positively influence disease course, as both increase in survivors and are of crucial importance for the immune response and antioxidative defence systems.
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64CuCl2 PET/CT in Prostate Cancer Relapse.
Piccardo, A, Paparo, F, Puntoni, M, Righi, S, Bottoni, G, Bacigalupo, L, Zanardi, S, DeCensi, A, Ferrarazzo, G, Gambaro, M, et al
Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2018;(3):444-451
Abstract
Our objective was to evaluate the biodistribution, kinetics, and radiation dosimetry of 64CuCl2 in humans and to assess the ability of 64CuCl2 PET/CT to detect prostate cancer (PCa) recurrence in patients with biochemical relapse. Methods: We prospectively evaluated 50 PCa patients with biochemical relapse after surgery or external-beam radiation therapy. All patients underwent 64CuCl2 PET/CT, 18F-choline PET/CT, and multiparametric MRI within 15 d of each other. Experienced readers interpreted the images, and the detection rate (DR) of each imaging modality was calculated. Histopathology, when available; clinical or laboratory response; and multidisciplinary follow-up were used to confirm the site of disease. In parallel, biodistribution, kinetics of the lesions, and radiation dosimetry of 64CuCl2 were evaluated. Results: From a dosimetric point of view, an administered dose of 200 MBq for 64CuCl2 translated into a 5.7-mSv effective dose. Unlike 18F-choline, 64CuCl2 was not excreted or accumulated in the urinary tract, thus allowing thorough pelvic exploration. The maximum 64CuCl2 uptake at the sites of PCa relapse was observed 1 h after tracer injection. In our cohort, 64CuCl2 PET/CT proved positive in 41 of 50 patients, with an overall DR of 82%. The DRs of 18F-choline PET/CT and multiparametric MRI were 56% and 74%, respectively. The difference between the DRs of 64CuCl2 PET/CT and 18F-choline PET/CT was statistically significant (P < 0.001). Interestingly, on considering prostate-specific antigen (PSA) value, 64CuCl2 PET/CT had a higher DR than 18F-choline PET/CT in patients with a PSA of less than 1 ng/mL. Conclusion: The biodistribution of 64CuCl2 is more suitable than that of 18F-choline for exploring the pelvis and prostatic bed. The 64CuCl2 effective dose is like those of other established PET tracers. In patients with biochemical relapse and a low PSA level, 64CuCl2 PET/CT shows a significantly higher DR than 18F-choline PET/CT.
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Concentration of selenium, zinc, copper, Cu/Zn ratio, total antioxidant status and c-reactive protein in the serum of patients with psoriasis treated by narrow-band ultraviolet B phototherapy: A case-control study.
Wacewicz, M, Socha, K, Soroczyńska, J, Niczyporuk, M, Aleksiejczuk, P, Ostrowska, J, Borawska, MH
Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS). 2017;:109-114
Abstract
BACKGROUND Psoriasis is a common, an inflammatory skin disease. Trace elements may play an active role in the pathogenesis of psoriasis. OBJECTIVE The aim of this study was to estimate the concentration of selenium (Se), zinc (Zn), copper (Cu) and Cu/Zn ratio as well as total antioxidant status (TAS) and c-reactive protein (CRP) in the serum of patients with psoriasis. METHODS In this case-control study sixty patients with psoriasis and fifty-eight healthy people were examined. Serum levels of Se, Zn and Cu were determined by atomic absorption spectrometry. Cu/Zn ratio was calculated. TAS was measured spectrophotometrically. CRP was analyzed by immunoturbidimetric method. Clinical activity of psoriasis was evaluated using Psoriasis Area and Severity Index (PASI). RESULTS Serum concentration of Se in patients with psoriasis (71.89±16.90μg/L) was lower as compared to the control group (79.42±18.97μg/L) and after NB-UVB. Cu level of patients was higher (1.151±0.320mg/L) as compared to controls (1.038±0.336mg/L), but Zn level did not differ. We observed higher Cu/Zn ratio (p<0.05) in examined patients than in the control group and after NB-UVB. We found decrease TAS before and after NB-UVB. CRP levels was found to be normal range. A significant correlation coefficient between CRP and Cu/Zn was observed. CONCLUSIONS The study showed some disturbances in the serum levels of trace elements and TAS in psoriatic patients.
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Selenium, Zinc, Copper, and Total Antioxidant Status in the Serum of Patients with Chronic Tonsillitis.
Michalska-Mosiej, M, Socha, K, Soroczyńska, J, Karpińska, E, Łazarczyk, B, Borawska, MH
Biological trace element research. 2016;(1):30-4
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Antioxidants can play a significant role in chronic inflammatory process. The aim of this study was to evaluate the content of selenium (Se), zinc (Zn), copper (Cu), and total antioxidant status (TAS) of patients with chronic tonsillitis (CT). The study group consisted of 84 patients with CT from 18 to 62 years old and the control group of 67 healthy people aged 19-65 years. Se, Zn, and Cu concentration in serum samples were determined by atomic absorption spectrometry. Serum TAS was measured spectrophotometrically, using the test by Randox Laboratories-Us Ltd. The mean content of Se and Zn in the serum of patients with CT (61.122 ± 12.73 μg/L, 0.887 ± 0.26 mg/L, respectively) was lower compared to the control group (77.969 ± 12.73 μg/L, 0.993 ± 0.32 mg/L, respectively). The mean serum concentration of Cu in patients with CT (1.219 ± 0.35 mg/L) was higher compared to its serum concentration in healthy people (1.033 ± 0.37 mg/L). Serum TAS of patients with CT (1.171 ± 0.33 mmol/L) was lower in comparison with healthy volunteers (1.333 ± 0.42 mmol/L). The serum concentration of Se, Zn, and TAS in patients with CT was lower, whereas the concentration of Cu was higher compared to healthy volunteers. Smoking has an influence on reducing the concentration of Se and TAS of patients with CT.
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Neurodevelopment and brain growth in classic Menkes disease is influenced by age and symptomatology at initiation of copper treatment.
Kaler, SG
Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS). 2014;(4):427-30
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Abstract
Menkes disease is an X-linked recessive disorder of brain copper metabolism caused by mutations in an essential mammalian copper transport gene, ATP7A. Untreated affected individuals suffer failure to thrive and neurodevelopmental delays that usually commence at 6-8 weeks of age. Death by age three years is typical. While provision of working copies of ATP7A to the brain by viral vectors is a promising strategy under development, the only treatment currently available is subcutaneous copper injections. These can normalize circulating blood levels and may replete brain copper depending on the molecular context, e.g., the severity of ATP7A mutation and potential presence of mosaicism. In this paper, we summarize somatic growth and neurodevelopmental outcomes for 60 subjects enrolled in a recently concluded phase I/II clinical trial of copper histidine for Menkes disease (ClinicalTrials.gov Identifier: NCT00001262). Primary outcomes indicate highly statistically significant improvements in gross motor, fine motor/adaptive, personal-social, and language neurodevelopment in the cohort of subjects who received early treatment prior to onset of symptoms (n=35). Correlating with these findings, quantitative parameters of somatic growth indicated statistically significant greater growth in head circumference for the initially asymptomatic group, whereas weight and height/length at age three years (or at time of death) did not differ significantly. Mortality at age 3 was higher (50%) in subjects older and symptomatic when treatment commenced compared to the asymptomatic group (28.6%). We conclude that early copper histidine for Menkes disease is safe and efficacious, with treatment outcomes influenced by the timing of intervention, and ATP7A mutation.
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Tetrathiomolybdate-associated copper depletion decreases circulating endothelial progenitor cells in women with breast cancer at high risk of relapse.
Jain, S, Cohen, J, Ward, MM, Kornhauser, N, Chuang, E, Cigler, T, Moore, A, Donovan, D, Lam, C, Cobham, MV, et al
Annals of oncology : official journal of the European Society for Medical Oncology. 2013;(6):1491-8
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BACKGROUND Bone marrow-derived endothelial progenitor cells (EPCs) are critical for metastatic progression. This study explores the effect of tetrathiomolybdate (TM), an anti-angiogenic copper chelator, on EPCs in patients at high risk for breast cancer recurrence. PATIENTS AND METHODS This phase 2 study enrolled breast cancer patients with stage 3 and stage 4 without evidence of disease (NED), and stage 2 if triple-negative. TM 100 mg orally was administered to maintain ceruloplasmin <17 mg/dl for 2 years or until relapse. The primary end point was change in EPCs. RESULTS Forty patients (28 stage 2/3, 12 stage 4 NED) were enrolled. Seventy-five percent patients achieved the copper depletion target by 1 month. Ninety-one percent of triple-negative patients copper-depleted compared with 41% luminal subtypes. In copper-depleted patients only, there was a significant reduction in EPCs/ml by 27 (P = 0.04). Six patients relapsed while on study, of which only one patient had EPCs maintained below baseline. The 10-month relapse-free survival was 85.0% (95% CI 74.6%-96.8%). Only grade 3/4 toxicity was hematologic: neutropenia (3.1% of cycles), febrile neutropenia (0.2%), and anemia (0.2%). CONCLUSIONS TM is safe and appears to maintain EPCs below baseline in copper-depleted patients. TM may promote tumor dormancy and ultimately prevent relapse.
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Overcoming platinum resistance through the use of a copper-lowering agent.
Fu, S, Naing, A, Fu, C, Kuo, MT, Kurzrock, R
Molecular cancer therapeutics. 2012;(6):1221-5
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Low levels of human copper transporter 1 (hCtr1) mRNA are associated with a shorter progression-free survival after platinum-based therapy. Pretreatment with a copper-lowering agent such as trientine enhanced hCtr1-mediated platinum uptake. Therefore, we conducted a pilot study (NCT01178112) of carboplatin and trientine with the goal of resensitizing patients with advanced cancer to platinum chemotherapy. This case report reviews the outcomes of 5 patients with platinum-resistant high-grade epithelial ovarian cancer enrolled on the study to date. Overall, they tolerated treatment well. Severe adverse events that occurred in 2 patients were myelosuppression, notably anemia requiring transfusion. Dose-limiting toxicity was not observed within the first 28 days (cycle 1). After 2 cycles of therapy, partial remission was achieved in 1 patient (10+ months), stable disease in 3 patients (2, 3.5+, and 5 months, respectively), and 1 patient had progressive disease. These cases provide preliminary clinical evidence that the role of decreasing copper levels in reversing platinum resistance merits additional clinical investigation. Evaluation of this novel strategy is warranted in larger studies to assess the efficacy of this approach for treating platinum-resistant advanced epithelial ovarian cancer in patients with high copper levels.
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A pilot trial of the anti-angiogenic copper lowering agent tetrathiomolybdate in combination with irinotecan, 5-flurouracil, and leucovorin for metastatic colorectal cancer.
Gartner, EM, Griffith, KA, Pan, Q, Brewer, GJ, Henja, GF, Merajver, SD, Zalupski, MM
Investigational new drugs. 2009;(2):159-65
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Tetrathiomolybdate (TM) is an oral copper chelator under development as an anti-angiogenic agent. We evaluated TM in combination with irinotecan, 5-fluorouracil, and leucovorin (IFL). Serum vascular endothelial growth factor (VEGF), basic fibroblast growth factor, interleukin 6 (IL-6), and IL-8 were measured to evaluate the anti-angiogenic effect. Twenty-four patients with metastatic colorectal cancer were treated. The combination with IFL was well tolerated and dose intensity of IFL was maintained during combination therapy with TM. By intention to treat analysis, the overall response rate (RR) was 25% (95% CI 9.8-46.7) and the median time to progression (TTP) was 5.6 months (95% CI 2.7-7.7). VEGF levels were correlated with TTP, as were changes in VEGF, IL-8, and IL-6. TM can be safely added to IFL without compromising dose intensity or diminishing the expected RR. Changes in serum VEGF, IL-8, and IL-6 after treatment may directly reflect changes in CRC tissue angiogenesis.
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[Effects of kakisu (persimmon vinegar) on plasma antioxidant power and urinary 8-isoprostane level].
Mure, K, Takeshita, T, Morioka, I, Arita, M
Nihon eiseigaku zasshi. Japanese journal of hygiene. 2007;(1):32-8
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OBJECTIVES To clarify the antioxidative effects of kakisu (persimmon vinegar), plasma antioxidant power and urinary oxidative stress level in healthy subjects were measured using enzyme immunological assays. METHODS Eighty-one subjects (age 30-69, 58.4 +/- 0.8) were randomly divided into two groups using a crossover design. Group A drank kakisu for 56 days starting in March, whereas group B drank kakisu for 54 days starting in June. Copper reducing equivalent level in plasma was measured as antioxidant power, and urinary 8-isoprostane (8-iso-prostaglandin F2alpha) level was measured as oxidative stress marker. RESULTS Baseline plasma antioxidant power and urinary 8-isoprostane level showed no significant correlation among the subjects in this study. By drinking kakisu for 8 weeks, total antioxidant power significantly increased, and urinary 8-isoprostane level decreased. Total antioxidant power increased more markedly in group A than in group B. In contrast, urinary oxidative stress level decreased more markedly in group B than in group A. Smoking habits significantly correlated with urinary 8-isoprostane level. Males were more sensitive to the antioxidative effects of kakisu than females. CONCLUSIONS Kakisu has antioxidative effects that increase plasma antioxidant power and reduce urinary 8-isoprostane level. Further study is needed to clarify the influence of season and gender on such antioxidative effects.
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The value of serum zinc, copper, ceruloplasmin levels in patients with gastrointestinal tract cancers.
Boz, A, Evliyaoğlu, O, Yildirim, M, Erkan, N, Karaca, B
The Turkish journal of gastroenterology : the official journal of Turkish Society of Gastroenterology. 2005;(2):81-4
Abstract
BACKGROUND/AIMS: Gastrointestinal cancers are frequent diseases of particular importance for surgeons with regard to their management and follow-up. Neoplastic diseases activate antioxidant defense systems. As a result, concentrations of redoxal enzymes and their co-factor elements appear to change. The levels of zinc (Zn), copper (Cu) and ceruloplasmin have been found to be critical parameters. In addition, it seems to be important to consider the Cu/Zn ratio in such cases. In this study, changes in the levels of Cu, Zn and ceruloplasmin in patients with gastrointestinal system cancers was evaluated, and the proportion of Cu to Zn (Cu/Zn) is discussed. METHODS In this clinical trial, levels of Cu and Zn were defined with calorimetric methods and ceruloplasmin levels were measured with immunohistochemical methods in a control group of 20 healthy individuals and in 25 patients who underwent surgery for gastrointestinal system cancer. The blood samples were taken preoperatively in gastrointestinal system cancer patients. RESULTS This study has shown that while the decrease in Zn levels and the increase in ceruloplasmin levels in patients with gastrointestinal system cancers were found to be significant (p<0. 001, p=0. 014) when compared to the control group, the increase in the level of Cu was also found to be significant (p=0. 019). In the patient group, the correlations between serum Cu and serum ceruloplasmin proved to be significant (r=991, p<0. 001). The Cu/Zn ratio, when compared with Zn, ceruloplasmin and Cu, showed significant results (r= 0. 562, r= 0. 500, r=0. 506, p<0. 001). CONCLUSIONS This study shows that serum Cu, Zn and ceruloplasmin levels show changes in gastrointestinal system cancers, but further research is needed to demonstrate the importance and significance of these parameters and their relation with other contributing neoplastic factors.