Background Prostate cancer (PCa) is the second leading cause of cancer-related death in the Western population. The use in oncology of positron emission tomography/computed tomography (PET/CT) with ...emerging radiopharmaceuticals promises accurate staging of primary disease, restaging of recurrent disease and detection of metastatic lesions. Prostate-specific membrane antigen (PSMA) expression, directly related to androgen-independence, metastasis and progression, renders this tumour associate antigen a good target for the development of new radiopharmaceuticals for PET. Aim of this study was to demonstrate in a preclinical in vivo model (PSMA-positive versus PSMA-negative tumours) the targeting specificity and sensitivity of the anti-PSMA single-chain variable fragment (scFv) labelled with .sup.124I. Methods The .sup.124I-labeling conditions of the antibody fragment scFvD2B were optimized and assessed for purity and immunoreactivity. The specificity of .sup.124I-scFvD2B was tested in mice bearing PSMA-positive and PSMA-negative tumours to assess both ex-vivo biodistribution and immune-PET. Results The uptake fraction of .sup.124I-scFvD2B was very high on PSMA positive cells (range 75-91%) and highly specific and immuno-PET at the optimal time point, defined between 15 h and 24 h, provides a specific localization of lesions bearing the target antigen of interest (PSMA positive vs PSMA negative tumors %ID/g: p = 0.0198 and p = 0.0176 respectively) yielding a median target/background ratio around 30-40. Conclusions Preclinical in vivo results of our immuno-PET reagent are highly promising. The target to background ratio is improved notably using PET compared to SPECT previously performed. These data suggest that, upon clinical confirmation of sensitivity and specificity, our anti-PSMA .sup.124I-scFvD2B may be superior to other diagnostic modalities for PCa. The possibility to combine in patients our .sup.124I-scFvD2B in multi-modal systems, such as PET/CT, PET/MR and PET/SPECT/CT, will provide quantitative 3D tomographic images improving the knowledge of cancer biology and treatment. Keywords: PCa, .sup.124I, scFv, Antibody fragment, PET
Abstract Prostate carcinoma is the most common non-cutaneous cancer in developed countries and represents the second leading cause of death. Early stage androgen dependent prostate carcinoma responds ...well to conventional therapies, but relatively few treatment options exist for patients with hormone-refractory prostate cancer. One of the most suitable targets for antibody-mediated approaches is prostate specific membrane antigen (PSMA) which is a well known tumour associated antigen. PSMA is a type II integral cell-surface membrane protein that is not secreted, and its expression density and enzymatic activity are increased progressively in prostate cancer compared to normal prostate epithelium, thereby making PSMA an ideal target for monoclonal antibody imaging and therapy. To obtain a small protein that can better penetrate tissue, we have engineered a single-chain variable fragment (scFv) starting from the variable heavy and light domains of the murine anti-PSMA monoclonal antibody D2B. scFvD2B was analysed in vitro for activity, stability, internalisation ability and in vivo for targeting specificity. Maintenance of function and immunoreactivity as well as extremely high radiolabelling efficiency and radiochemical purity were demonstrated by in vitro assays and under different experimental conditions. Despite its monovalent binding, scFvD2B retained a good strength of binding and was able to internalise around 40% of bound antigen. In vivo we showed its ability to specifically target only PSMA expressing prostate cancer xenografts. Due to these advantageous properties, scFvD2B has the potential to become a good theranostic reagent for early detection and therapy of prostate cancers.
Abstract The relationship between intake of saturated fats and subclinical atherosclerosis, as well as the possible influence of genetic variants, is poorly understood and investigated. We aimed to ...investigate this relationship, with a hypothesis that it would be positive, and to explore whether genetics may modulate it, using data from a European cohort including 3,407 participants aged 54–79 at high risk of cardiovascular disease. Subclinical atherosclerosis was assessed by carotid intima-media thickness (C-IMT), measured at baseline and after 30 months. Logistic regression (OR; 95% CI) was employed to assess the association between high intake of food rich in saturated fat (vs. low) and: (1) the mean and the maximum values of C-IMT in the whole carotid artery (C-IMT mean , C-IMT max ), in the bifurcation (Bif-), the common (CC-) and internal (ICA-) carotid arteries at baseline (binary, cut-point ≥ 75th), and (2) C-IMT progression (binary, cut-point > zero). For the genetic-diet interaction analyses, we considered 100,350 genetic variants. We defined interaction as departure from additivity of effects. After age- and sex-adjustment, high intake of saturated fat was associated with increased C-IMT mean (OR:1.27;1.06–1.47), CC-IMT mean (OR:1.22;1.04–1.44) and ICA-IMT mean (OR:1.26;1.07–1.48). However, in multivariate analysis results were no longer significant. No clear associations were observed between high intake of saturated fat and risk of atherosclerotic progression. There was no evidence of interactions between high intake of saturated fat and any of the genetic variants considered, after multiple testing corrections. High intake of saturated fats was not independently associated with subclinical atherosclerosis. Moreover, we did not identify any significant genetic-dietary fat interactions in relation to risk of subclinical atherosclerosis.
Abstract Background and purpose To compare the effects of regular cigarettes (RCs) and light cigarettes (LCs) on brachial artery flow-mediated dilation (FMD) and sublingual glyceryl ...trinitrate-induced dilation (GTN), markers of endothelial dependant and independent function, respectively. Methods 206 subjects (age 51.5 ± 12.8 yr, 122 men) had their smoking habits recorded and FMD and GTN measured by B-mode ultrasound. Cigarettes were categorized as RCs or LCs according to their content of tar, nicotine and CO. The chronic effect was assessed in current smokers of RCs ( n = 85) or LCs ( n = 53) and in never smokers (NS; n = 68). The acute effect was assessed in current smokers by measuring FMD before and 10-min after smoking a single regular ( n = 29) or light ( n = 51) cigarette. Results FMD was significantly lower in consumers of RCs (6.26%, 95% C.I. 5.58, 6.94) or LCs (5.59%, 95% C.I. 4.74, 6.45) compared to NS (8.68%, 95% C.I. 7.92, 9.44) (both P < 0.0001), but did not differ ( P > 0.05) when compared to each other. GTN was similar in the three groups. Analyses adjusted for clinical confounders and for markers involved in oxidative stress, arginine/nitric oxide pathway, and inflammation provided identical results. Smoking a single cigarette, either regular or light, reduced FMD (−0.88% and −1.17%, respectively, both P < 0.05), without significant difference between cigarette type. RCs and LCs produced analogous chronic and acute effects when FMD was calculated with respect to the last 60 s of the low-flow phase (FMD60s ). Conclusions LCs impair endothelial-dependant vasodilation as much as RCs. Thus, smoking LCs cannot be considered an alternative to the only safe choice of a complete and permanent smoking cessation.
Abstract Objective To assess whether the diagnosis ‘metabolic syndrome’ (MS) predicts the degree of subclinical atherosclerosis better than its component parts or the total number of vascular risk ...factors (VRFs) in patients attending a lipid clinic. Methods Carotid intima-media thickness (C-IMT) was measured by B-mode ultrasound in 1804 patients (56 ± 13 years; 52% women). To investigate whether the increased subclinical carotid atherosclerosis often ascribed to MS may be explained by a real interaction between the components or simply by a sum of VRFs, observed C-IMTs were compared with those predicted by the sum of individual components. Values for C-IMT of MS patients were also compared with those of controls matched for number of VRFs or for SCORE predicted risk (SPR). Results Carotid IMT values were significantly higher in patients with MS ( n = 362) than in those not so diagnosed (IMTmean , 1.07 ± 0.37 vs. 0.95 ± 0.33; IMTmax , 1.98 ± 0.93 mm vs. 1.67 ± 0.82 mm, both p < 0.0001), but were not higher than those predicted by the sum of individual risk factors. The linear regression lines of the correlations between C-IMT and total number of VRFs overlapped in patients with and without MS. In patients with and without MS matched for age, sex and total number of VRFs, or matched for age, sex and SPR the C-IMT differences disappeared. Conclusions In patients attending a lipid clinic, ‘metabolic syndrome’ appears not to correlate with C-IMT to a greater extent than what is expected from its component parts or from the patient's total number of VRFs.
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Calcific aortic valve disease (CAVD) is the most common valvular disorder in the elderly, with the incidence of 3% in general population of Western countries. The initial phase of ...CAVD is characterized by leaflet thickening and possible spotty calcification (i.e. aortic valve sclerosis (AVSc)), while advanced stages have leaflets structure degeneration (i.e. aortic valve stenosis (AS)). The pathological cellular and molecular mechanisms, involved in CAVD, are extracellular matrix degradation, aberrant matrix deposition, fibrosis, mineralization, inflammation, lipid accumulation, and neo-angiogenesis. CAVD clinical risk shares considerable overlap with those of atherosclerosis and they include hypertension, smoking habits, and hyperlipidemia. Unfortunately, surgical aortic valve replacement and transcatheter aortic valve implantation are the only available treatments when the disease become severe and symptoms occur. Indeed, no approved pharmacological approach is available for CAVD patients. In this review, we describe the current literature evidence on possible future therapeutic targets for this debilitating and fatal disease such as PCSK9, P2Y2 receptor, cadherin 11, and DDP-4.
Abstract Background and aims Carotid plaque size and the mean common carotid intima-media thickness measured in plaque-free areas (PF CC-IMTmean ) have been identified as predictors of vascular ...events (VEs), but their complementarity in risk prediction and stratification is still unresolved. The aim of this study was to evaluate the independence of carotid plaque thickness and PF CC-IMTmean in cardiovascular risk prediction and risk stratification. Methods The IMPROVE-study is a European cohort (n = 3703), where the thickness of the largest plaque detected in the whole carotid tree was indexed as cIMTmax . PF CC-IMTmean was also assessed. Hazard Ratios (HR) comparing the top quartiles of cIMTmax and PF CC-IMTmean versus their respective 1–3 quartiles were calculated using Cox regression. Results After a 36.2-month follow-up, there were 215 VEs (125 coronary, 73 cerebral and 17 peripheral). Both cIMTmax and PF CC-IMTmean were mutually independent predictors of combined-VEs, after adjustment for center, age, sex, risk factors and pharmacological treatment HR (95% CI) = 1.98 (1.47, 2.67) and 1.68 (1.23, 2.29), respectively. Both variables were independent predictors of cerebrovascular events (ischemic stroke, transient ischemic attack), while only cIMTmax was an independent predictor of coronary events (myocardial infarction, sudden cardiac death, angina pectoris, angioplasty, coronary bypass grafting). In reclassification analyses, PF CC-IMTmean significantly adds to a model including both Framingham Risk Factors and cIMTmax (Integrated Discrimination Improvement; IDI = 0.009; p = 0.0001) and vice-versa (IDI = 0.02; p < 0.0001). Conclusions cIMTmax and PF CC-IMTmean are independent predictors of VEs, and as such, they should be used as additive rather than alternative variables in models for cardiovascular risk prediction and reclassification.
Summary
This study evaluated the peri-implant bone repair in orchiectomized rats receiving intermittently PTH 1-34. The treatment returned the bone quality and quantity of the animals to normal in ...the computerized microtomography, laser confocal microscopy, and histological analysis. The PTH 1-34 promoted marked bone formation with increased volume, improved quality, and greater bone turnover.
Introduction
Osteoporosis can be a problem in implant osseointegration. So this study aimed to evaluate the quantity and quality of peri-implant bone repair in orchiectomized Wistar rats receiving intermittently administered PTH 1-34.
Methods
Animals (
n
= 24) were divided into 3 groups: healthy control (SHAM), orchiectomized (ORQ), and orchiectomized and treated with 0.5 μg/kg/day PTH 1-34 (TERI), and each received an implant in the right and left tibial metaphysis, which was allowed to repair for 60 days. The resultant bone formation was evaluated through computerized microtomography (micro-CT) to compare the percent bone volume (BV/TV), trabecular thickness (Tb.Th), trabecular number and separation (Tb.N, Tb.Sp), and bone implant contact (BIC) through the intersection surface (i.S) between groups. Laser confocal microscopy was used to evaluate fluorochrome areas for mineral apposition rate (MAR) and neoformed bone area (NBA). In addition, histological evaluation of calcified tissues with Stevenel blue and alizarin red staining was performed.
Results
Treatment with PTH 1-34 returned the bone quality and quantity of the osteoporotic animal to normal, as the TERI group presented statistically significant higher values for BV/TV, Tb.Th, and BIC parameters compared with ORQ (
p
< 0.05), but when compared with SHAM (
p
> 0.05), no statistical difference was noted. In addition, in the bone turnover analysis (MAR, NBA) for TERI, the highest results are presented, followed by SHAM, and then ORQ (TERI × ORQ:
p
< 0.05).
Conclusions
Intermittent treatment with PTH 1-34 on orchiectomized animals promoted marked bone formation with increased volume, improved quality, and greater bone turnover in the peri-implant space, returning the bone quality and quantity to the present standard in healthy animals.
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