Contamination Profile of DDTs in the Shark <Emphasis Type="Italic">Somniosus microcephalus</Emphasis> from Greenland Seawaters

DDT isomers were detected in all the liver and muscle samples of Greenland sharks Somniosus microcephalus (n?=?15) caught in Greenland seawaters. The mean concentrations of ΣDDTs (sum of o,p’ and p,p’ DDT, DDD, and DDE isomers) were 1094?±?818 ng/g lipid weight (lw) in the muscle and 761?±?416 ng/g lw in the liver. The p,p’-DDE accounted for 48%?±?41% and 53%?±?54% of the total DDT residue in the white muscle and liver, respectively. The lipid content was 48%?±?10% in the muscle and 43%?±?17% in the liver. Female sharks showed the highest concentrations of ΣDDTs. The youngest shark showed higher concentrations of ΣDDTs in the liver than the older sharks. To our knowledge, this is one of the few investigations on DDT levels in S. microcephalus where concentrations were correlated to lipid content and sex/size.     

Microinvasive breast cancer: pathological parameters,cancer subtypes distribution,and correlation with axillary lymph nodes invasion. Results of a large single-institution series

Background

Microinvasive breast cancer is a rare entity in which an invasive component not exceeding 1 mm is found, mostly in a ductal carcinoma in situ setting. Its diagnosis can be difficult and must rely upon immunohistochemistry markers. Many studies have analyzed pathological characteristics of this cancer to delineate its biological profile and possibly identify risk factors of axillary lymph nodes infiltration, which might be present and therefore clinically relevant. Starting from a relative large number of cases we aimed to analyze pathological data, cancer subtypes distribution, and their correlation to nodal metastasis, comparing our results to the existing recent literature.

Methods

All cases of microinvasive breast cancer were retrieved from institutional database from 1992 to 2014. Pathological parameters were analyzed for entire cohort. Moreover, cases submitted to standardized sentinel node biopsy in a restricted period, 2000–2014, were selected to correlate pathology and cancer subtype to axillary lymph nodes status.

Results

174 cases (1.4 % of operated breast cancers) were evaluated in the larger period, 1992–2014. Neither specific pathological parameters were expressed nor a peculiar cancer subtype was represented. 126 cases were selected for axillary staging analysis. Eighteen cases (14.3 %) had lymph nodes metastasis, 10 ITCs (7.9 %), 3 micrometastases (2.4 %), and 5 macrometastases (4 %). An associated intraductal component of carcinoma over 20 mm in maximum dimension resulted significant at multivariate analysis, but only if including ITCs, while this risk factor was not reproduced for micro- and macrometastases only.

Conclusions

Microinvasive breast cancer does not seem to have specific pathological and biological traits. An associated intraductal component of carcinoma >20 mm in size is a specific risk factor for ITCs nodal metastasis. Its clinical significance is anyway limited and therefore sentinel node biopsy should be performed case by case and not routinely.

     

Growth hormone response to growth hormone-releasing hormone is reduced in adult asthmatic patients receiving long-term inhaled corticosteroid treatment

BACKGROUND: Some studies have demonstrated that the function of the growth hormone (GH)-insulin-like growth factor (IGF)-1 axis is significantly impaired in patients with oral corticosteroid (CS)-induced osteoporosis. The aim of study was to investigate the effects of long-term therapy with inhaled CSs (ICSs) on the hypothalamic-pituitary-GH axis by the GH response to GH-releasing hormone (GHRH), as well as bone turnover, in adult asthmatic patients. DESIGN: Cross-sectional study. PATIENTS: Twenty-seven adult subjects with mild-to-moderate persistent asthma (long-term ICS therapy [ie, > 1 year], 20 patients; naive to ICS treatment, 7 patients) and 10 control subjects. MEASUREMENTS: Each subject underwent testing with an IV bolus (1 mug/kg) injection of human GHRH, and samples of GH were taken 15 min before the GHRH injection, at 0 min (ie, at the time of GHRH injection), and at 15, 30, 45, 60, and 90 min after injection to obtain values for peak GH and DeltaGH. At baseline, samples of serum IGF-1 and blood-urine were collected for bone turnover markers. RESULTS: The GH response to GHRH was significantly reduced in asthmatic patients receiving ICSs (peak GH, p < 0.05; and DeltaGH, p < 0.01) in comparison with control subjects and asthmatic patients who were naive to ICS therapy (peak GH and DeltaGH, p < 0.01). Baseline IGF-1 levels were similar in the three groups. Serum osteocalcin, a marker of bone formation, was significantly reduced (p < 0.01) and correlated with GH peak (r(2) = 0.34; p = 0.007) in asthmatic patients who were treated with ICSs. CONCLUSIONS: We conclude that GH secretion in response to GHRH is significantly reduced in adult asthmatic patients receiving therapy with ICS and that such inhibition could play a negative role in bone metabolism.     

[18F]-Florbetaben PET/CT for Differential Diagnosis Among Cardiac Immunoglobulin Light Chain,Transthyretin Amyloidosis,and Mimicking Conditions

ObjectivesThis study aimed to test the diagnostic value of [18F]–florbetaben positron emission tomography (PET) in patients with suspicion of CA.BackgroundDiagnosis of cardiac involvement in immunoglobulin light-chain–derived amyloidosis (AL) and transthyretin-related amyloidosis (ATTR), which holds major importance in risk stratification and decision making, is frequently delayed. Furthermore, although diphosphonate radiotracers allow a noninvasive diagnosis of ATTR, demonstration of cardiac amyloidosis (CA) in AL may require endomyocardial biopsy.MethodsForty patients with biopsy-proven diagnoses of CA (20 ALs, 20 ATTRs) and 20 patients referred with the initial clinical suspicion and later diagnosed with non-CA pathology underwent a cardiac PET/computed tomography scan with a 60-min dynamic [18F]-florbetaben PET acquisition, and 4 10-min static scans at 5, 30, 50, and 110 min after radiotracer injection.ResultsVisual qualitative assessment showed intense early cardiac uptake in all subsets. Patients with AL displayed a high, persistent cardiac uptake in all the static scans, whereas patients with ATTR and those with non-CA showed an uptake decrease soon after the early scan. Semiquantitative assessment demonstrated higher mean standardized uptake value (SUV_mean) in patients with AL, sustained over the whole acquisition period (early SUV_mean: 5.55; interquartile range [IQR]: 4.00 to 7.43; vs. delayed SUV_mean: 3.50; IQR: 2.32 to 6.10; p = NS) compared with in patients with ATTR (early SUV_mean: 2.55; IQR: 1.80 to 2.97; vs. delayed SUV_mean: 1.25; IQR: 0.90 to 1.60; p < 0.001) and in patients with non-CA (early SUV_mean: 3.50; IQR: 1.60 to 3.37; vs. delayed SUV_mean: 1.40; IQR: 1.20 to 1.60; p < 0.001). Similar results were found comparing heart-to-background ratio and molecular volume.ConclusionsDelayed [18F]-florbetaben cardiac uptake may discriminate CA due to AL from either ATTR or other mimicking conditions. [18F]-florbetaben PET/computed tomography may represent a promising noninvasive tool for the diagnosis of AL amyloidosis, which is still often challenging and delayed. (A Prospective Triple-Arm, Monocentric, Phase-II Explorative Study on Evaluation of Diagnostic Efficacy of the PET Tracer [18F]-Florbetaben [Neuraceq] in Patients With Cardiac Amyloidosis [FLORAMICAR2]; EudraCT number: 2017-001660-38)     

The +276 G/T single nucleotide polymorphism of the adiponectin gene is associated with coronary artery disease in type 2 diabetic patients

OBJECTIVE: Two single nucleotide polymorphisms (SNPs) at the adiponectin locus (+45T>G and +276G>T) have been associated with low circulating adiponectin levels, insulin resistance, and type 2 diabetes. We investigated whether these genetic markers are determinants of coronary artery disease (CAD) in type 2 diabetic patients. RESEARCH DESIGN AND METHODS: A total of 376 consecutive type 2 diabetic patients were studied: 142 case subjects with coronary stenosis >50% or previous myocardial infarction and 234 control subjects with no symptoms, no electrocardiogram (ECG) signs of myocardial ischemia, and a normal ECG stress test (n = 189) and/or (n = 45) with coronary stenosis T polymorphism is a determinant of CAD risk in type 2 diabetic patients. This marker may assist in the identification of diabetic individuals at especially high risk of CAD, so that preventive programs can be targeted at these subjects.     

Effects of raloxifene on carotid blood flow resistance and endothelium-dependent vasodilation in postmenopausal women

Raloxifene is one of the most important selective estrogen receptor modulators currently employed for the treatment of postmenopausal osteoporosis. However, it has also been suggested that this compound affects the vascular system. We evaluated both carotid blood flow resistance and endothelium-dependent vasodilation in 50 healthy postmenopausal women randomly assigned to receive, in a double blind design, either raloxifene (60 mg per day; N=25 subjects) or placebo (N=25 subjects) for 4 months. Indices of carotid blood flow resistance, such as the pulsatility index (PI) and resistance index (RI), as well as the flow-mediated brachial artery dilation were measured both at baseline and at the end of treatment. Changes in PI were -1.86+/-2.24 and -2.15+/-2.22% after placebo and raloxifene treatment, respectively, with no significant differences between groups. Changes in RI were -0.77+/-1.72 and -1.81+/-1.54% after placebo and raloxifene treatment, respectively, with no significant differences between groups. At the end of the treatment period, the increments in artery diameter measured after the flow stimulus were 10.79+/-2.39 and 6.70+/-1.23% for placebo and raloxifene, respectively, with no significant differences between groups. These results demonstrate no significant effects of raloxifene on either carotid blood flow resistance or brachial artery flow-mediated dilation in postmenopausal women.     

Binding of heparin to human thyroglobulin (Tg) involves multiple binding sites including a region corresponding to a binding site of rat Tg

OBJECTIVE: Binding of thyroglobulin (Tg) to heparin allows efficient Tg interaction with its endocytic receptor, megalin. Rat Tg (rTg) binds to heparin using an exposed carboxyl terminal region (RELPSRRLKRPLPVK, Arg2489-Lys2503) rich in positively charged residues which is, however, not entirely conserved in human Tg (hTg) (Arg2489-Glu2503, REPPARALKRSLWVE). Here, we investigated whether and how this difference affects binding of heparin. DESIGN: To compare binding of heparin to rTg and hTg. To investigate the role of the sequence 2489-2503 using a peptide-based approach. METHODS: Binding of biotin-labeled heparin to rTg, hTg and to Tg peptides was measured in solid phase assays. RESULTS: Heparin bound to rTg with moderately high affinity (K(d): 34.2 nmol/l, K(i): 37.6 nmol/l) and to hTg with lower affinity (K(d): 118 nmol/l, K(i): 480 nmol/l) and to a lower extent. Binding was dose-dependent and saturable, and was reduced by several specific competitors (Tg itself, unlabeled heparin, lactoferrin). Heparin bound to synthetic peptides corresponding to the rat (rTgP) and to the human (hTgP) Tg sequence 2489-2503. Heparin bound to rTgP to a greater extent and with greater affinity than to hTgP. An antibody against hTgP reduced binding of heparin to intact hTg by 30%, suggesting that in hTg this region is, in part, involved in heparin binding, but also that other regions account for most of the binding. Starting from the sequence of rTgP, we designed 6 synthetic 'mutant' peptides by replacing one amino acid residue of rTgP with the corresponding residue of the sequence of hTgP. Heparin bound to 5 of 6 mutant peptides to a lower extent and with lower affinity than to rTgP. CONCLUSIONS: In spite of a reduced binding ability of the sequence 2489-2503, hTg binds to heparin, in part, using alternative, as yet unidentified, binding sites. Substitution of both positive and neutral residues within the sequence 2489-2503 reduced heparin-binding, suggesting that not only charge, but also sequence and/or conformation, may account for the heparin-binding ability of this region of Tg.     

Tumor Targeting <Emphasis Type="Italic">via</Emphasis> Sialic Acid: [<Superscript>68</Superscript>Ga]DOTA-en-pba as a New Tool for Molecular Imaging of Cancer with PET

Purpose

The aim of this study was to demonstrate the potential of Ga-68-labeled macrocycle (DOTA-en-pba) conjugated with phenylboronic vector for tumor recognition by positron emission tomography (PET), based on targeting of the overexpressed sialic acid (Sia).

Procedures

The imaging reporter DOTA-en-pba was synthesized and labeled with Ga-68 at high efficiency. Cell binding assay on Mel-C and B16-F10 melanoma cells was used to evaluate melanin production and Sia overexpression to determine the best model for demonstrating the capability of [⁶⁸Ga]DOTA-en-pba to recognize tumors. The in vivo PET imaging was done with B16-F10 tumor-bearing SCID mice injected with [⁶⁸Ga]DOTA-en-pba intravenously. Tumor, blood, and urine metabolites were assessed to evaluate the presence of a targeting agent.

Results

The affinity of [⁶⁸Ga]DOTA-en-pba to Sia was demonstrated on B16-F10 melanoma cells, after the production of melanin as well as Sia overexpression was proved to be up to four times higher in this cell line compared to that in Mel-C cells. Biodistribution studies in B16-F10 tumor-bearing SCID mice showed blood clearance at the time points studied, while uptake in the tumor peaked at 60 min post-injection (6.36?±?2.41 % ID/g). The acquired PET images were in accordance with the ex vivo biodistribution results. Metabolite assessment on tumor, blood, and urine samples showed that [⁶⁸Ga]DOTA-en-pba remains unmetabolized up to at least 60 min post-injection.

Conclusions

Our work is the first attempt for in vivo imaging of cancer by targeting overexpression of sialic acid on cancer cells with a radiotracer in PET.