Cardiovascular effects of overt and subclinical hyperthyroidism:focus on differentiated thyroid cancer

Thyroid hormone stimulates cardiac inotropy and chronotropy via direct genomic and non-genomic mechanisms. Hyperthyroidism magnifies these effects, resulting in an increase in heart rate, ejection fraction and blood volume. Hyperthyroidism also affects thrombogenesis and this may be linked to a probable tendency towards thrombosis in patients with hyperthyroidism. Patients with hyperthyroidism are therefore at higher risk for atrial fibrillation, heart failure and cardiovascular mortality. Similarly, TSH suppressive therapy for differentiated thyroid cancer is associated with increased cardiovascular risk. In this review, we present the latest insights on the cardiac effects of thyroid suppression therapy for the treatment of thyroid cancer. Finally, we will show new clinical data on how to implement this knowledge into the clinical practice of preventive medicine

Advanced glycation end products:An emerging biomarker for adverse outcome in patients with peripheral artery disease

AbstractPatients with peripheral artery disease (PAD) suffer from widespread atherosclerosis. Partly due to the growing awareness of cardiovascular disease, the incidence of PAD has increased considerably during the past decade. It is anticipated that algorithms to identify high risk patients for cardiovascular events require being updated, making use of novel biomarkers. Advanced glycation end products (AGEs) are moieties formed non-enzymatically on long-lived proteins under influence of glycemic and oxidative stress reactions. We elaborate about the formation and effects of AGEs, and the methods to measure AGEs. Several studies have been performed with AGEs in PAD. In this review, we evaluate the emerging evidence of AGEs as a clinical biomarker for patients with PAD

F-18-FDG PET/CT Scans Can Identify Sub-Groups of NSCLC Patients with High Glucose Uptake in the Majority of Their Tumor Lesions

Background: Reprogrammed glucose metabolism is a hallmark of cancer making it an attractive therapeutic target, especially in cancers with high glucose uptake such as non-small cell lung cancer (NSCLC). Tools to select patients with high glucose uptake in the majority of tumor lesions are essential in the development of anti-cancer drugs targeting glucose metabolism. Type 2 diabetes mellitus (T2DM) patients may have tumors highly dependent on glucose uptake. Surprisingly, this has not been systematically studied. Therefore, we aimed to determine which patient and tumor characteristics, including concurrent T2DM, are related to high glucose uptake in the majority of tumor lesions in NSCLC patients as measured by 2-deoxy-2-[fluorine-18]fluoro-D-glucose (F-18-FDG) positron emission tomography (PET)/computed tomography (CT) scans. Methods: Routine primary diagnostic F-18-FDG PET/CT scans of consecutive NSCLC patients were included. Mean standardized uptake value (SUVmean) of F-18-FDG was determined for all evaluable tumor lesions and corrected for serum glucose levels according to the European Association of Nuclear Medicine Research Ltd guidelines. Patient characteristics potentially determining degree of tumor lesion glucose uptake in the majority of tumor lesions per patient were investigated. Results: The cohort consisted of 102 patients, 28 with T2DM and 74 without T2DM. The median SUVmean per patient ranged from 0.8 to 35.2 (median 4.2). T2DM patients had higher median glucose uptake in individual tumor lesions and per patient compared to non-diabetic NSCLC patients (SUVmean 4.3 vs 2.8, P = 1 mL per patient (odds ratio 0.8, 95% confidence interval 0.7-0.9). Conclusions: F-18-FDG PET/CT scans can identify sub-groups of NSCLC patients with high glucose uptake in the majority of their tumor lesions. T2DM patients had higher tumor lesion glucose uptake than non-diabetic patients. However, this was not independent of other factors such as the histological subtype and number of tumor lesions per patient

Genome-wide association study of cardiovascular disease in testicular cancer patients treated with platinum-based chemotherapy

Genetic variation may mediate the increased risk of cardiovascular disease (CVD) in chemotherapy-treated testicular cancer (TC) patients compared to the general population. Involved single nucleotide polymorphisms (SNPs) might differ from known CVD-associated SNPs in the general population. We performed an explorative genome-wide association study (GWAS) in TC patients. TC patients treated with platinum-based chemotherapy between 1977 and 2011, age ≤55 years at diagnosis, and ≥3 years relapse-free follow-up were genotyped. Association between SNPs and CVD occurrence during treatment or follow-up was analyzed. Data-driven Expression Prioritized Integration for Complex Trait (DEPICT) provided insight into enriched gene sets, i.e., biological themes. During a median follow-up of 11 years (range 3-37), CVD occurred in 53 (14%) of 375 genotyped patients. Based on 179 SNPs associated at p ≤ 0.001, 141 independent genomic loci associated with CVD occurrence. Subsequent, DEPICT found ten biological themes, with the RAC2/RAC3 network (linked to endothelial activation) as the most prominent theme. Biology of this network was illustrated in a TC cohort (n = 60) by increased circulating endothelial cells during chemotherapy. In conclusion, the ten observed biological themes highlight possible pathways involved in CVD in chemotherapy-treated TC patients. Insight in the genetic susceptibility to CVD in TC patients can aid future intervention strategies

HDL Cholesterol Efflux Capacity is Impaired in Severe Short-Term Hypothyroidism Despite Increased HDL Cholesterol

Context: Severe hypothyroidism has profound effects on lipoprotein metabolism including high-density lipoprotein (HDL) cholesterol elevations but effects on HDL function metrics are unknown. Objective: To determine the impact of severe short-term hypothyroidism on HDL particle characteristics, HDL cholesterol efflux capacity (CEC), and HDL antioxidative capacity. Design: Observational study with variables measured during severe short-term hypothyroidism (median TSH 81 mU/L) and after 20 weeks of thyroid hormone supplementation (median TSH 0.03 mU/L) (Netherlands Trial Registry ID 7228). Setting: University hospital setting in The Netherlands. Patients: Seventeen patients who had undergone a total thyroidectomy for differentiated thyroid carcinoma. Main outcome measures: HDL particle characteristics (nuclear magnetic resonance spectrometry), CEC (human THP-1-derived macrophage foam cells and apolipoprotein B-depleted plasma), and HDL anti-oxidative capacity (inhibition of low-density lipoprotein oxidation). Results: During hypothyroidism plasma total cholesterol, HDL cholesterol and apolipoprotein A-I were increased (P = 0.001). HDL particle concentration was unchanged, but there was a shift in HDL subclasses toward larger HDL particles (P <0.001). CEC was decreased (P = 0.035), also when corrected for HDL cholesterol (P <0.001) or HDL particle concentration (P = 0.011). HDL antioxidative capacity did not change. Conclusion: During severe short-term hypothyroidism CEC, an important antiatherogenic metric of HDL function, is impaired. HDL cholesterol and larger HDL particles are increased but HDL particle concentration is unchanged. Combined, these findings suggest that HDL quality and quantity are not improved, reflecting dysfunctional HDL in hypothyroidism

Otimização da produção de lacase pelo fungo Trametes sp. para a biorremediação de bisfenol A em meio aquoso

Orientadora : Prof. Dr. Jörg Wolfgang MetzgerCoorientadores: Profª. Drª. Arislete Dantas de Aquino e Prof. Dr. José Domingos FontanaDissertação (mestrado) - Universidade Federal do Paraná, Setor de Tecnologia, Programa de Mestrado Profissional em Meio Ambiente Urbano e Industrial, em parceria com o Serviço Nacional de Aprendizagem Industrial e a Universität Stuttgart. Defesa: Curitiba, 28/08/2017Inclui referências : f. 114-134Resumo: O bisfenol A (BFA) é um monômero empregado na fabricação de resinas epóxi e plásticos policarbonatados, e também como insumo para outros fins industriais. Este composto é classificado como um interferente endócrino capaz de causar perturbações no sistema endócrino, imunológico e nervoso dos seres vivos, além de causar sérios distúrbios ambientais. Os tratamentos físico-químicos para remoção deste tipo de poluente são dispendiosos. Assim, tratamentos com o emprego de enzimas fúngicas como as lacases podem ser uma alternativa promissora para este fim. Este trabalho teve como objetivo otimizar a produção da enzima lacase por meio do cultivo do fungo Trametes sp. com a adição de extratos de lignina bruta e indutores químicos, e sua aplicação na biorremediação de BFA em meio aquoso. O estudo da produção da lacase teve início com a aplicação de seis extratos de lignina bruta de bracatinga, peroba, pinus, bagaço de cana-de-açúcar, casca de soja e casca de trigo, em concentração de 1 g L-1 nos experimentos. Os extratos de peroba e bagaço de cana-de-açúcar apresentaram maior potencial indutor frente aos demais, de modo que foram empregados na otimização da produção de lacase por meio de um delineamento de experimentos fatorial fracionáro5-2, juntamente com os potenciais indutores químicos: dioxano, siringol e sulfato de cobre, estes na concentração de 1 mmol L-1. A biorremediação do BFA foi realizada pela aplicação de 500 U L-1 de lacase bruta em meio tamponado em pH 5 contendo 100 mg L-1 do contaminante que foi quantificado por cromatografia líquida (HPLC-DAD). A técnica analítica de espectrofotometria UV-Vis derivativa foi avaliada para a determinação do BFA em solução multicomponente. A faixa de pH ótimo para a lacase foi observada entre os valores de 4 a 6, na qual a atividade enzimática se manteve estável por um período de 72h. O melhor efeito indutor obtido na otimização da produção de lacase ocorreu pela interação dos cinco indutores atingindo uma atividade de 45.185 + 321 U L-1 em 24 dias de cultivo. Também ocorreu um forte efeito indutor com os extratos de bagaço de cana-de-açúcar e de peroba juntamente com o CuSO4, e com o extrato de peroba, dioxano e CuSO4 que obtiveram resultados de 35.926 + 642 U L-1 e 35.556 + 1.111 U L-1, respectivamente. A biorremediação do BFA pela lacase bruta se mostrou eficiente, sendo que na primeira hora de reação foi reduzida cerca de 50% da concentração inicial, e após 10 h de reação já não foi mais possível detectar a presença do contaminante em solução aquosa. A avaliação da técnica de espectrofotometria UV-Vis derivativa foi positiva para a análise do BFA em solução contendo lacase bruta de Trametes sp., quando comparada com a técnica de HPLC-DAD. Palavras-chave: Dioxano. Espectrofotometria UV Vis derivativa. Interferentes endócrinos. Lignina. Siringol.Abstract: The bisphenol A (BPA) is a monomer widely used in the manufacture of epoxy resins and polycarbonate plastics, and also as an input for other industrial purposes. This compound is classified as an endocrine interferent capable of causing disturbances in the endocrine, immune and nervous system of living beings, besides causing serious environmental disturbances. The physical-chemical treatments for this type of pollutant are quite expensive, so treatments using fungal enzymes, such as laccases, can be a very promising alternative. The objective of this study was to optimize the laccase enzyme production through the cultivation of Trametes sp. fungus, with the addition of crude lignin extracts and chemical inducers, and its application in bioremediation of BPA in water base. The laccase production study began by applying six gross lignin extracts of bracatinga wood, peroba wood, pinus wood, sugarcane bagasse, soybean hull and wheat husk, in a concentration of 1 g L-1 in the experiments. The extracts of peroba wood and sugarcane bagasse presented higher inductive potential compared to the others, so that they were used in the lacase optimization production through a fractional 5-2 factorial experimental design, along with the potential chemical inducers: dioxane, syringol and copper sulphate 1 mmol L-1 concentration. The BPA bioremediation was performed by applying 500 U L-1 crude laccase in buffered medium at pH 5 containing 100 mg L-1 of the contaminant which was quantified by liquid chromatography (HPLC-DAD). The analytical technique of derivative ultraviolet spectrophotometry was evaluated for BPA determination in multicomponent solution. The optimum pH range for the laccase was observed between the values of 4 to 6, in which the enzymatic activity remained stable for a period of 72h. The best inducing effect on laccase production occurred through the interaction of the five inducers reaching an activity of 45.185 + 321 U L-1 in 24 days of cultivation, also a strong inducing effect occurred between the extracts of sugarcane bagasse and peroba together with the CuSO4, and between the peroba extract, dioxane and CuSO4 that obtained results of 35.926 + 642 U L-1 and 35.556 + 1.111 U L-1, respectively. The BPA bioremediation by the crude laccase was efficient, and in the first hour of reaction, about 50% of the initial concentration was reduced, and after 10 hours of reaction it was no longer possible to detect the presence of the contaminant in the aqueous solution. The evaluation of the derivative ultraviolet spectrophotometry technique was satisfactory for the analysis of the BPA in solution containing Trametes sp. crude laccase, when compared with the HPLC-DAD technique. Key-words: Dioxane. Derivative ultraviolet spectrophotometry. Endocrine disruptors. Lignin. Syringol

Phase I study of metformin in combination with carboplatin/paclitaxel chemotherapy in patients with advanced epithelial ovarian cancer

Background Metformin use is associated with reduced cancer risk in epidemiological studies and has preclinical anti-cancer activity in ovarian cancer models. The primary objective of this phase I study was to determine the recommended phase II dose (RP2D) of metformin in combination with carboplatin/paclitaxel in patients with ovarian cancer. Secondary objectives were to describe safety and pharmacokinetics. Methods In this single-center trial the RP2D of metformin in combination with carboplatin area under the concentration-time curve (AUC) 6 and paclitaxel 175 mg/m2 every 3 weeks (q3w) in patients with advanced epithelial ovarian cancer was determined using a 3 + 3 escalation rule at three fixed dose levels: 500 mg three times daily (tds), 850 mg tds and 1000 mg tds. Metformin was commenced on day 3 of cycle 1 and continued until 3 weeks after the last chemotherapy administration. The RP2D was defined as the dose level at which 0 of 3 or ≤ 1 of 6 evaluable subjects experienced a metformin-related dose-limiting toxicity (DLT). Safety was assessed according to CTCAE v4.0. Plasma and serum samples for pharmacokinetic (PK) analyses were collected during treatment cycles 1 and 2. Results Fifteen patients with epithelial ovarian cancer and an indication for neo-adjuvant (n = 5) or palliative (n = 10) treatment were included. No DLTs were observed. Three patients discontinued study treatment during cycle 1 for other reasons than DLT. Six patients were treated at the RP2D of metformin 1000 mg tds. The most frequent low-grade toxicities were anemia, hypomagnesemia and diarrhea. Grade 3 adverse events (AEs) occurred in ten patients, most common were leucopenia (n = 4), thrombocytopenia (n = 3) and increased GGT (n = 3). There were no grade 4 AEs. Metformin increased the platinum (Pt) AUC (Δ22%, p = 0.013) and decreased the Pt clearance (Δ-28%, p = 0.013). Metformin plasma levels were all within the therapeutic range for diabetic patients (0.1-4 mg/L). Conclusion The RP2D of metformin in combination with carboplatin and paclitaxel in advanced ovarian cancer is 1000 mg tds. This is higher than the RP2D reported for combination with targeted agents. A potential PK interaction of metformin with carboplatin was identified.</p

Immunological Adaptations to Pregnancy in Women with Type 1 Diabetes

Despite adequate glycemic control, pregnancy outcome of women with type 1 diabetes (T1D) is still unfavorable as compared to healthy women. In a rat-model of T1D under normoglycemic conditions, adverse pregnancy outcome was also observed, which was associated with aberrant immunological adaptations to pregnancy. Because similar processes may occur in women with T1D we studied the systemic immune response in non-pregnant and pregnant women with and without T1D. The systemic immune response was assessed by using flow cytometry to evaluate the number and activational status of subpopulations of lymphocytes, Natural Killer cells and monocytes in peripheral blood of non-pregnant and pregnant women with and without T1D. An increased white blood cell count, an increased Th1/Th2 ratio, increased Natural Killer cell expression of CD335 and enhanced activation of intermediate and non-classical monocytes was observed in pregnant women with T1D vs. healthy pregnant women. Also, the pregnancy outcome (i.e. incidence of preterm delivery and macrosomia) of women with T1D was unfavorable as compared to healthy women. This study showed that in T1D, the immunological adaptations to pregnancy are disturbed. In addition to hyperglycemia, these different immunological adaptations may be responsible for the greater frequency of complications in pregnant women with T1D

Cardiovascular Disease in Testicular Cancer Survivors:Identification of Risk Factors and Impact on Quality of Life

PURPOSE: Testicular cancer (TC) treatment is clearly associated with cardiovascular morbidity and mortality. To enable development of preventive strategies for cardiovascular disease (CVD), we assessed cardiometabolic risk factors and quality of life (QoL) in TC survivors.METHODS: Incidence of coronary artery disease, myocardial infarction, and heart failure after TC treatment was assessed in a multicenter cohort comprising 4,748 patients treated at the age of 12-50 years between 1976 and 2007. Patients who had developed CVD and a random sample from the cohort (subcohort) received a questionnaire on cardiometabolic risk factors and QoL. A subgroup of responders in the subcohort additionally underwent clinical evaluation of cardiovascular risk factors.RESULTS: After a median follow-up of 16 years, 272 patients had developed CVD. Compared with orchidectomy only, cisplatin combination chemotherapy was associated with an increased CVD risk (hazard ratio [HR], 1.9; 95% CI, 1.1 to 3.1). Patients who were obese or a smoker at diagnosis (HR, 4.6; 95% CI, 2.0 to 10.0 and HR, 1.7; 95% CI, 1.1 to 2.4, respectively), developed Raynaud's phenomenon (HR, 1.9; 95% CI, 1.1 to 3.6) or dyslipidemia (HR, 2.8; 95% CI, 1.6 to 4.7) or had a positive family history for CVD (HR, 2.9; 95% CI, 1.7 to 4.9) had higher CVD risk. More TC survivors with CVD reported inferior QoL on physical domains than survivors who did not develop CVD. Of 304 TC survivors who underwent clinical evaluation for cardiovascular risk factors (median age at assessment: 51 years), 86% had dyslipidemia, 50% had hypertension, and 35% had metabolic syndrome, irrespective of treatment.CONCLUSION: Cardiovascular events in TC survivors impair QoL. Many TC survivors have undetected cardiovascular risk factors. We advocate early lifestyle adjustments and lifelong follow-up with low-threshold treatment of cardiovascular risk factors, especially in obese and smoking patients treated with platinum-based chemotherapy.</p

Bone mineral density and fractures after risk-reducing salpingo-oophorectomy in women at increased risk for breast and ovarian cancer

AbstractAimRisk-reducing salpingo-oophorectomy (RRSO) reduces ovarian cancer risk in BRCA mutation carriers. RRSO is assumed to decrease bone mineral density (BMD) and increase fracture risk more than natural menopause. We aimed to compare BMD and fracture incidence after premenopausal RRSO to general population data and identify risk factors for low BMD and fractures after RRSO.MethodsIn 212 women with RRSO at premenopausal age, BMD was measured by dual energy X-ray absorptiometry. Fractures and risk factors were assessed by self-administered questionnaire. Fracture incidence after RRSO was compared to general practitioner data by using standardised incidence ratios (SIRs). Risk factors for low standardised BMD-scores and fractures were identified by regression analyses.ResultsMedian age at RRSO was 42years (range 35–65) and duration of follow-up 5years (2–8). Standardised lumbar spine (Z=0.01, p=0.870) and femoral neck BMD (Z=0.15, p=0.019) were not lower than population BMD. Higher age at time of RRSO and use of hormonal replacement therapy were associated with higher, and current smoking with lower standardised BMD-scores. Sixteen women reported 22 fractures. Fracture incidence was not higher than expected from the general population (all fractures: 25–44years: SIR 2.12 [95% confidence interval (CI) 0.85–4.37]; 45–64years: SIR 1.65 [95% CI 0.92–2.72]).ConclusionFive years after RRSO, BMD and fracture incidence were not different than expected from the general population. Based on these data it appears safe not to intensively screen for osteoporosis within five years after RRSO, although prospective research on the long-term effects of RRSO on bone is warranted