Atherosclerotic plaque and shear stress in cartotid arteries

The human is a very sophisticated organism in which adaptation is the key to its survival. During a lifetime, the human body is exposed to a wide variety of stimuli. Some of them are self-inflicted while others arise from the environment and nature itself. Communication plays an important role in the response to these stimuli. The main signal transduction in the human body is organized by electrical signals through nerves or by transportation of biomolecular signals through blood vessels. These blood vessels also provide the organs with nutrients and oxygen. When these communication channels are compromised, the human body will try to repair them or find alternative channels. Atherosclerosis is an inflammatory disease affecting the arterial blood vessels. The prevalence of atherosclerosis leading to cardiovascular disease is 36.3% and the disease is at the top of the list of the 15 leading causes of death in the USA. If the carotid arteries (which supply the brain with blood) are affected the disease can lead to a stroke, which is the third most common cause of death and is also responsible for 5 million permanently disabled persons per year world wide. Removal of the obstructing atherosclerotic plaque in the carotid bifurcation has reduced the risk of a stroke, but more knowledge on the development of atherosclerotic disease is required to improve treatment

Study to gather evidence on the working conditions of platform workers VT/2018/032 Final Report 13 December 2019

Platform work is a type of work using an online platform to intermediate between platform workers, who provide services, and paying clients. Platform work seems to be growing in size and importance. This study explores platform work in the EU28, Norway and Iceland, with a focus on the challenges it presents to working conditions and social protection, and how countries have responded through top-down (e.g. legislation and case law) and bottom-up actions (e.g. collective agreements, actions by platform workers or platforms). This national mapping is accompanied by a comparative assessment of selected EU legal instruments, mostly in the social area. Each instrument is assessed for personal and material scope to determine how it might impact such challenges. Four broad legal domains with relevance to platform work challenges are examined in stand-alone reflection papers. Together, the national mapping and legal analysis support a gap analysis, which aims to indicate where further action on platform work would be useful, and what form such action might take

Optimization of combined temozolomide and peptide receptor radionuclide therapy (PRRT) in mice after multimodality molecular imaging studies

Background: Successful treatments of patients with somatostatin receptor (SSTR)-overexpressing neuroendocrine tumours (NET) comprise somatostatin-analogue lutetium-177-labelled octreotate (177Lu-TATE) treatment, also referred to as peptide receptor radionuclide therapy (PRRT), and temozolomide (TMZ) treatment. Their combination might result in additive effects. Using MRI and SPECT/CT, we studied tumour characteristics and therapeutic responses after different (combined) administration schemes in a murine tumour model in order to identify the optimal treatment schedule for PRRT plus TMZ. Methods: We performed molecular imaging studies in mice bearing SSTR-expressing H69 (humane small cell lung cancer) tumours after single intravenous (i.v.) administration of 30 MBq 177Lu-TATE or

FK506 protects against articular cartilage collagenous extra-cellular matrix degradation

Objective: Osteoarthritis (OA) is a non-rheumatologic joint disease characterized by progressive degeneration of the cartilage extra-cellular matrix (ECM), enhanced subchondral bone remodeling, activation of synovial macrophages and osteophyte growth. Inhibition of calcineurin (Cn) activity through tacrolimus (FK506) in invitro monolayer chondrocytes exerts positive effects on ECM marker expression. This study therefore investigated the effects of FK506 on anabolic and catabolic markers of osteoarthritic chondrocytes in 2D and 3D invitro cultures, and its therapeutic effects in an invivo rat model of OA. Methods: Effects of high and low doses of FK506 on anabolic (QPCR/histochemistry) and catabolic (QPCR) markers were evaluated invitro on isolated (2D) and ECM-embedded chondrocytes (explants, 3D pellets). Severe cartilage damage was induced unilaterally in rat knees using papain injections in combination with a moderate running protocol. Twenty rats were treated with FK506 orally and compared to twenty untreated controls. Subchondral cortical and trabecular bone changes (longitudinal microCT) and macrophage activation (SPECT/CT) were measured. Articular cartilage was analyzed exvivo using contrast enhanced microCT and histology. Results: FK506 treatment of osteoarthritic chondrocytes invitro induced anabolic (mainly collagens) and reduced catabolic ECM marker expression. In line with this, FK506 treatment clearly protected ECM integrity invivo by markedly decreasing subchondral sclerosis, less development of subchondral pores, depletion of synovial macrophage activation and lower osteophyte growth. Conclusion: FK506 protected cartilage matrix integrity invitro and invivo. Additionally, FK506 treatment invivo reduced OA-like responses in different articular joint tissues and thereby makes Cn an interesting target for therapeutic intervention of OA

3D fusion of intravascular ultrasound and coronary computed tomography for in-vivo wall shear stress analysis: A feasibility study

Wall shear stress, the force per area acting on the lumen wall due to the blood flow, is an important biomechanical parameter in the localization and progression of atherosclerosis. To calculate shear stress and relate it to atherosclerosis, a 3D description of the lumen and vessel wall is required. We present a framework to obtain the 3D reconstruction of human coronary arteries by the fusion of intravascular ultrasound (IVUS) and coronary computed tomography angiography (CT). We imaged 23 patients with IVUS and CT. The images from both modalities were registered for 35 arteries, using bifurcations as landmarks. The IVUS images together with IVUS derived lumen and wall contours were positioned on the 3D centerline, which was derived from CT. The resulting 3D lumen and wall contours were transformed to a surface for calculation of shear stress and plaque thickness. We applied variations in selection of landmarks and investigated whether these variations influenced the relation between shear stress and plaque thickness. Fusion was successfully achieved in 31 of the 35 arteries. The average length of the fused segments was 36.4 ± 15.7 mm. The length in IVUS and CT of the fused parts correlated excellently (R2= 0.98). Both for a mildly diseased and a very diseased coronary artery, shear stress was calculated and related to plaque thickness. Variations in the selection of the landmarks for these two arteries did not affect the relationship between shear stress and plaque thickness. This new framework can therefore successfully be applied for shear stress analysis in human coronary arteries

Peptide receptor radionuclide therapy (PRRT) with [177Lu-DOTA0,Tyr3]octreotate in combination with RAD001 treatment: further investigations on tumor metastasis and response in the rat pancreatic CA20948 tumor model

Background Previously, we reported on the unexpected development of distant metastases in the subcutaneous rat pancreas CA20948 tumor model after 4.5 weeks of treatment with RAD001-only or in combination with [177Lu-DOTA0,Tyr3]octreotate (177Lu-DOTATATE) (Cancer Res. 73:12-8, 2013). Moreover, the combination therapy was less effective compared to 177Lu-DOTATATE-only. In the current study, we address the following questions: (1) Why was the combination therapy less effective? Is 177Lu-DOTATATE tumor uptake affected by pretreatment with RAD001? (2) Could sudden cessation of RAD001 therapy cause the development of distant metastases? (3) Is 177Lu-DOTATATE an effective treatment option for these metastases? Methods Lewis rats (HanHsd or SsNHsd substrain with a slight difference in immune response) bearing subcutaneous CA20948 tumors were treated with either 125 or 275 MBq 177Lu-DOTATATE, RAD001, or their combination. RAD001 was given twice a week for 4.5 or 12 weeks, whereas 177Lu-DOTATATE was given as a single injection. When combined, RAD001 was started either 3 days prior to or 3 days post administration of 177Lu-DOTATATE. SPECT/CT was performed to quantify 177Lu-DOTATATE tumor uptake. Where indicated, primary tumors were surgically removed when tumor size is >6,000 mm3 to enable monitoring for possible metastasis. If metastases were suspected, an 111In-DTPA-octreotide SPECT/CT scan was performed. Seven rats with metastases were treated with 400 MBq 177Lu-DOTATATE. Results Lu-DOTATATE tumor uptake was not significantly affected by RAD001 pretreatment. The occurrence of metastases after RAD001 treatment was not dose dependent in the dose range tested, nor was it related to the duration of RAD001 treatment. In the experiment in which the LEW/SsNsd substrain was used, only 12.5% of RAD001-treated rats showed complete response (CR), compared to 50% tumor regression in the control group. Re-treatment with a high dose of 177Lu-DOTATATE resulted in CR in only two out of seven animals. Conclusion Less effective anti-tumor effects after the combination of RAD001 + 177Lu-DOTATATE could not be explained by reduced 177Lu-DOTATATE tumor uptake after RAD001. Our current data support RAD001-induced immune suppression as the reason for this observation. No evidence was found that cessation of RAD001 treatment caused development of metastases. Metastases appeared to be less sensitive to 177Lu-DOTATATE treatment than primary tumors

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Can DCE-MRI Explain the Heterogeneity in Radiopeptide Uptake Imaged by SPECT in a Pancreatic Neuroendocrine Tumor Model?

Although efficient delivery and distribution of treatment agents over the whole tumor is essential for successful tumor treatment, the distribution of most of these agents cannot be visualized. However, with single-photon emission computed tomography (SPECT), both delivery and uptake of radiolabeled peptides can be visualized in a neuroendocrine tumor model overexpressing somatostatin receptors. A heterogeneous peptide uptake is often observed in these tumors. We hypothesized that peptide distribution in the tumor is spatially related to tumor perfusion, vessel density and permeability, as imaged and quantified by DCE-MRI in a neuroendocrine tumor model. Four subcutaneous CA20948 tumor-bearing Lewis rats were injected with the somatostatin-analog In-111-DTPA-Octreotide (50 MBq). SPECT-CT and MRI scans were acquired and MRI was spatially registered to SPECT-CT. DCE-MRI was analyzed using semi-quantitative and quantitative methods. Correlation between SPECT and DCE-MRI was investigated with 1) Spearman's rank correlation coefficient; 2) SPECT uptake values grouped into deciles with corresponding median DCE-MRI parametric values and vice versa; and 3) linear regression analysis for median parameter values in combined datasets. In all tumors, areas with low peptide uptake correlated with low perfusion/density//permeability for all DCE-MRI-derived parameters. Combining all datasets, highest linear regression was found between peptide uptake and semi-quantitative parameters (R-2>0.7). The average correlation coefficient between SPECT and DCE-MRI-derived parameters ranged from 0.52-0.56 (p<0.05) for parameters primarily associated with exchange between blood and extracellular extravascular space. For these parameters a linear relation with peptide uptake was observed. In conclusion, the 'exchange-related' DCE-MRI-derived parameters seemed to predict peptide uptake better than the 'contrast amount-related' parameters. Consequently, fast and efficient diffusion through the vessel wall into tissue is an important factor for peptide delivery. DCE-MRI helps to elucidate the relation between vascular characteristics, peptide delivery and treatment efficacy, and may form a basis to predict targeting efficiency