Development of an automated production process of [64Cu][Cu (ATSM)] for positron emission tomography imaging and theranostic applications

Cyclotron-produced copper-64 radioisotope tracers offer the possibility to perform both diagnostic investigation by positron emission tomography (PET) and radiotherapy by a theranostic approach with bifunctional chelators. The versatile chemical properties of copper add to the importance of this isotope in medicinal investigation. [⁶⁴Cu][Cu (ATSM)] has shown to be a viable candidate for imaging of tumor hypoxia; a critical tumor microenvironment characteristic that typically signifies tumor progression and resistance to chemo-radiotherapy. Various production and radiosynthesis methods of [⁶⁴Cu][Cu (ATSM)] exist in labs, but usually involved non-standardized equipment with varying production qualities and may not be easily implemented in wider hospital settings. [⁶⁴Cu][Cu (ATSM)] was synthesized on a modified GE TRACERlab FXN automated synthesis module. End-of-synthesis (EOS) molar activity of [⁶⁴Cu][Cu (ATSM)] was 2.2–5.5 Ci/μmol (HPLC), 2.2–2.6 Ci/μmol (ATSM-titration), and 3.0–4.4 Ci/μmol (ICP-MS). Radiochemical purity was determined to be >99% based on radio-HPLC. The final product maintained radiochemical purity after 20 h. We demonstrated a simple and feasible process development and quality control protocols for automated cyclotron production and synthesis of [⁶⁴Cu][Cu (ATSM)] based on commercially distributed standardized synthesis modules suitable for PET imaging and theranostic studies.     

Genome-wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer's disease and three causality networks: The GR@ACE project

IntroductionLarge variability among Alzheimer's disease (AD) cases might impact genetic discoveries and complicate dissection of underlying biological pathways.MethodsGenome Research at Fundacio ACE (ef="/cdn-cgi/l/email-protection" class="__cf_email__" data-cfemail="a4e3f6e4e5e7e1">[email protected]) is a genome-wide study of dementia and its clinical endophenotypes, defined based on AD's clinical certainty and vascular burden. We assessed the impact of known AD loci across endophenotypes to generate loci categories. We incorporated gene coexpression data and conducted pathway analysis per category. Finally, to evaluate the effect of heterogeneity in genetic studies, ef="/cdn-cgi/l/email-protection" class="__cf_email__" data-cfemail="17504557565452">[email protected] series were meta-analyzed with additional genome-wide association study data sets.ResultsWe classified known AD loci into three categories, which might reflect the disease clinical heterogeneity. Vascular processes were only detected as a causal mechanism in probable AD. The meta-analysis strategy revealed the <em>ANKRD31em>-rs4704171 and <em>NDUFAF6em>-rs10098778 and confirmed <em>SCIMPem>-rs7225151 and <em>CD33em>-rs3865444.DiscussionThe regulation of vasculature is a prominent causal component of probable AD. ef="/cdn-cgi/l/email-protection" class="__cf_email__" data-cfemail="c1869381808284">[email protected] meta-analysis revealed novel AD genetic signals, strongly driven by the presence of clinical heterogeneity in the AD series.     

Organ-based tube current modulation in chest CT. A comparison of three vendors

IntroductionOrgan-based tube current modulation (OBTCM) is designed for anterior dose reduction in Computed Tomography (CT). The purpose was to assess dose reduction capability in chest CT using three organ dose modulation systems at different kVp settings. Furthermore, noise, diagnostic image quality and tumour detection was assessed.MethodsA Lungman phantom was scanned with and without OBTCM at 80–135/140 kVp using three CT scanners; Canon Aquillion Prime, GE Revolution CT and Siemens Somatom Flash. Thermo-luminescent dosimeters were attached to the phantom surface and all scans were repeated five times. Image noise was measured in three ROIs at the level of the carina. Three observers visually scored the images using a fivestep scale. A Wilcoxon Signed-Rank test was used for statistical analysis of differences.ResultsUsing the GE revolution CT scanner, dose reductions between 1.10 mSv (12%) and 1.56 mSv (24%) (p < 0.01) were found in the anterior segment and no differences posteriorly and laterally. Total dose reductions between 0.64 (8%) and 0.91 mSv (13%) were found across kVp levels (p < 0.00001). Maximum noise increase with OBTCM was 0.8 HU. With the Canon system, anterior dose reductions of 6–10% and total dose reduction of 0.74–0.76 mSv across kVp levels (p < 0.001) were found with a maximum noise increase of 1.1 HU. For the Siemens system, dose increased by 22–51% anteriorly; except at 100 kVp where no dose difference was found. Noise decreased by 1 to 1.5 HU.ConclusionOrgan based tube current modulation is capable of anterior and total dose reduction with minimal loss of image quality in vendors that do not increase posterior dose.Implications for practiceThis research highlights the importance of being familiar with dose reduction technologies.     

Mycoplasma pneumoniae multilocus variable-number tandem-repeat analysis genotypes are associated with inflammatory biomarker levels in children with lower respiratory tract infections

European Journal of Clinical Microbiology & Infectious Diseases - The multilocus variable-number tandem-repeat analysis (MLVA) typing method is commonly used in Mycoplasma pneumoniae (M....     

Association of sleep duration with mental health: results from a Spanish general population survey

Sleep and Breathing - The purpose of the present study was to evaluate the association of sleep duration and mental health among the general population. A cross-sectional study was carried out with...     

New advances in Amyotrophic Lateral Sclerosis genetics: Towards gene therapy opportunities for familial and young cases

Due to novel gene therapy opportunities, genetic screening is no longer restricted to familial cases of ALS (FALS) cases but also aplies to the sporadic populations (SALS). Screening of four main genes (<em>C9orf72, SOD1, TARDBPem> and <em>FUSem>) identified the causes in 15% of Amyotrophic Lateral Sclerosis (ALS) patients (two third of the familial cases and 8% of the sporadic ones) but their respective contribution to ALS phenotype varies according the age of disease onset. The genetic overlap between ALS and other diseases is expanding and includes frontotemporal dementia, Paget's Disease of Bone, myopathy for adult cases, HSP and CMT for young cases highlighing the importance of retrieving the exhaustive familial history for each indivdual with ALS. Incomplete disease penetrance, diversity of the possible phenotypes, as well as the lack of confidence concerning the pathogenicity of most identified variants and/or possible oligogenic inheritance are burdens of ALS genetic counseling to be delivered to patients and at risk individuals. The multitude of rare ALS genetic causes identifed seems to converge to similar cellular pathways leading to inapropriate response to stress emphacising new potential therapeutic options for the disease.     

MRI quantification techniques in fatty liver: the diagnostic performance of hepatic T1, T2, and stiffness measurements in relation to the proton density fat fraction

PURPOSENonalcoholic fatty liver disease (NAFLD) can progress to liver cirrhosis and is predicted to become the most frequent indication for liver transplantation in the near future. Noninvasive assessment of NAFLD is important for diagnosis and patient management. This study aims to prospectively determine the liver stiffness and T1 and T2 values in patients with NAFLD and to compare the diagnostic performance of magnetic resonance elastography (MRE) and mapping techniques in relation to the proton density fat fraction (PDFF).METHODSEighty-three patients with NAFLD and 26 participants with normal livers were imaged with a 1.5 T scanner. PDFF measurements obtained from the multiecho Dixon technique were used to quantify the liver fat. MRE, native T1 mapping (modified Look-Locker inversion recovery [MOLLI] schemes 5(3)3, 3(3)3(3)5, and 3(2)3(2)5 and the B1-corrected variable flip angle [VFA] method), and T2 mapping values were correlated with PDFF. The diagnostic performance of MRE and the mapping techniques were analyzed and compared.RESULTST1 values measured with the MOLLI schemes and the B1-corrected VFA (<em>pem> < 0.001), and the stiffness values from MRE (<em>pem> = 0.047) were significantly higher in the NAFLD group. No significant difference was found between the groups in terms of T2 values (<em>pem> = 0.127). In differentiation of the NAFLD and control groups, the B1-corrected VFA technique had slightly higher accuracy and area under the curve (AUC) than the MOLLI schemes. In the NAFLD group, there was a good correlation between the PDFF, MOLLI 3(3)3(3)5 and 3(2)3(2)5, and VFA T1 measurements (r=0.732; r=0.735; r=0.716, <em>pem> < 0.001, respectively).CONCLUSIONLiver T1 mapping techniques have the potential to distinguish steatotic from nonsteatotic livers, and T1 values seem to have a strong correlation with the liver fat content.

Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease, with an estimated worldwide prevalence of around 25% (ef="#b1-dir-27-1-7" rid="b1-dir-27-1-7" class=" bibr popnode">1). It may range from simple steatosis, which is considered a benign condition, to nonalcoholic steatohepatitis (NASH), which can progress to fibrosis, cirrhosis, liver failure, and hepatocellular carcinoma. NAFLD is also known to be associated with metabolic syndrome, which is a risk factor for cardiovascular disease and type II diabetes mellitus (ef="#b2-dir-27-1-7" rid="b2-dir-27-1-7" class=" bibr popnode">2–ef="#b4-dir-27-1-7" rid="b4-dir-27-1-7" class=" bibr popnode">4).The gold standard method for diagnosing NAFLD and distinguishing its different patterns is a liver biopsy which has considerable limitations, including sampling errors, its invasive nature and associated complication risks, small sample size, and inter- and intraobserver variability (ef="#b5-dir-27-1-7" rid="b5-dir-27-1-7" class=" bibr popnode">5, ef="#b6-dir-27-1-7" rid="b6-dir-27-1-7" class=" bibr popnode">6). These drawbacks constrain its utility for clinical monitoring and make it unsuitable as a screening method. Therefore, there is an urgent clinical need for an accurate noninvasive approach in the assessment of NAFLD. Accordingly, both the European Association for the Study of the Liver and the American Association for the Study of Liver Disease propose magnetic resonance imaging (MRI) as a noninvasive diagnostic tool for NAFLD (ef="#b7-dir-27-1-7" rid="b7-dir-27-1-7" class=" bibr popnode">7, ef="#b8-dir-27-1-7" rid="b8-dir-27-1-7" class=" bibr popnode">8). Proton density fat fraction (PDFF)-based MRI and magnetic resonance spectroscopy (MRS) techniques are considered the most accurate noninvasive methods for the quantification of liver fat (ef="#b9-dir-27-1-7" rid="b9-dir-27-1-7" class=" bibr popnode">9–ef="#b12-dir-27-1-7" rid="b12-dir-27-1-7" class=" bibr popnode">12). The PDFF is accepted as a standardized biomarker of hepatic steatosis. Studies suggest that this biomarker is equivalent to the hepatic “signal fat fraction” (FF) after correcting all the confounding factors (ef="#b13-dir-27-1-7" rid="b13-dir-27-1-7" class=" bibr popnode">13). However, PDFF measurement is not suitable for the assessment of any inflammation or fibrosis in NAFLD (ef="#b13-dir-27-1-7" rid="b13-dir-27-1-7" class=" bibr popnode">13). On the other hand, recent studies have shown that other quantitative MRI techniques such as magnetic resonance elastography (MRE) and T1–T2 mapping can be useful in detecting hepatic inflammatory and fibrotic changes (ef="#b14-dir-27-1-7" rid="b14-dir-27-1-7" class=" bibr popnode">14, ef="#b15-dir-27-1-7" rid="b15-dir-27-1-7" class=" bibr popnode">15–ef="#b21-dir-27-1-7" rid="b21-dir-27-1-7" class=" bibr popnode">21). Thus, the application of a multiparametric MRI protocol might be helpful in liver tissue characterization and thereby in the risk stratification and therapeutic management of patients with NAFLD.In this prospective study, we aimed to determine liver stiffness and T1 and T2 values in patients with NAFLD and nonsteatotic subjects and compare the diagnostic performance of MRE and mapping techniques in relation to the FF.