Semi Mature Blood Dendritic Cells Exist in Patients with Ductal Pancreatic Adenocarcinoma Owing to Inflammatory Factors Released from the Tumor

Background: Much evidence exists regarding the fact that blood DCs, both myeloid DCs (MDCs) and plasmacytoid DCs (PDCs), are negatively affected in different types of cancer, with both reduced numbers and impaired functionality. Functional impairment of DCs in patients with pancreatic ductal adenocarcinoma (PDAC), may contribute to the poor clinical outcome. The aim of this study was to examine the effects PDAC had on blood DCs and elucidate the underlying mechanism responsible for the DC impairment. Methodology/Principal Findings: We examined the systemic influence PDAC exerted on blood DCs by ex vivo measuring numerous activation and maturation markers expressed on these cells. Furthermore, the effect patient plasma and the inflammatory factors CXCL8 and PGE(2) had on purified MDCs and PDCs from healthy donors was assessed and compared to the DCs existing in PDAC patients. We found a partial maturation of the blood MDCs and PDCs in PDAC patients with significantly enhanced expression of CD83, CD40, B7H3, PDL-1, CCR6, and CCR7 and decreased expression of ICOSL, and DCIR. These changes lead to impairment in their immunostimulatory function. Furthermore, chronic pancreatitis gave rise to DCs with similar semi-mature phenotype as seen in PDAC. Low expression of ICOSL was associated with poor prognosis. We found that the mechanism underlying this semi-maturation of DCs was inflammatory factors existing in the PDAC patients plasma. Of note, PGE2, which is elevated PDAC patient plasma, was one contributing factor to the changes seen in MDCs and PDCs phenotype. Conclusion/Significance: Our findings point to a role for the systemic inflammation in transforming blood MDCs and PDCs into semi-mature cells in PDAC patients and we show a correlation between maturation status and clinical outcome. Thus, means to preserve a functional blood DC compartment in PDAC patients by diminishing the inflammation could facilitate their ability to control the disease and improve survival.Original Publication: Vegard Tjomsland, Anna Spångeus, Per Sandström, Kurt Borch, Davorka Messmer and Marie Larsson, Semi Mature Blood Dendritic Cells Exist in Patients with Ductal Pancreatic Adenocarcinoma Owing to Inflammatory Factors Released from the Tumor, 2010, PLOS ONE, (5), 10. http://dx.doi.org/10.1371/journal.pone.0013441 Licensee: Public Library of Science (PLoS) http://www.plos.org/</p

The Desmoplastic Stroma Plays an Essential Role in the Accumulation and Modulation of Infiltrated Immune Cells in Pancreatic Adenocarcinoma

Tumor microenvironment is composed of tumor cells, fibroblasts, and infiltrating immune cells, which all work together and create an inflammatory environment favoring tumor progression. The present study aimed to investigate the role of the desmoplastic stroma in pancreatic ductal adenocarcinoma (PDAC) regarding expression of inflammatory factors and infiltration of immune cells and their impact on the clinical outcome. The PDAC tissues examined expressed significantly increased levels of immunomodulatory and chemotactic factors (IL-6, TGFβ, IDO, COX-2, CCL2, and CCL20) and immune cell-specific markers corresponding to macrophages, myeloid, and plasmacytoid dendritic cells (DCs) as compared to controls. Furthermore, short-time survivors had the lowest levels of DC markers. Immunostainings indicated that the different immune cells and inflammatory factors are mainly localized to the desmoplastic stroma. Therapies modulating the inflammatory tumor microenvironment to promote the attraction of DCs and differentiation of monocytes into functional DCs might improve the survival of PDAC patients

Технологическая подготовка производства деталей жатки для уборки зерновых культур с разработкой технологического процесса механической обработки детали подвеска КЗР 1502603 и алгоритма оптимизации процесса магнитно-электрического шлифования покрытий

The interplay between the tumor cells and the surrounding stroma creates inflammation, which promotes tumor growth and spread. The inflammation is a hallmark for pancreatic adenocarcinoma (PDAC) and is to high extent driven by IL-1α. IL-1α is expressed and secreted by the tumor cells and exerting its effect on the stroma, i.e. cancer associated fibroblasts (CAF), which in turn produce massive amount of inflammatory and immune regulatory factors. IL-1 induces activation of transcription factors such as nuclear factor-κβ (NF-κβ), but also activator protein 1 (AP-1) via the small G-protein Ras. Dysregulation of Ras pathways are common in cancer as this oncogene is the most frequently mutated in many cancers. In contrast, the signaling events leading up to the expression of IL-1α by tumor cells are not well elucidated. Our aim was to examine the signaling cascade involved in the induction of IL-1α expression in PDAC. We found p38MAPK, activated by the K-Ras signaling pathway, to be involved in the expression of IL-1α by PDAC as blocking this pathway decreased both the gene and protein expression of IL-1α. Blockage of the P38MAPK signaling in PDAC also dampened the ability of the tumor cell to induce inflammation in CAFs. In addition, the IL-1α autocrine signaling regulated the migratory capacity of PDAC cells. Taken together, the blockage of signaling pathways leading to IL-1α expression and/or neutralization of IL-1α in the PDAC microenvironment should be taken into consideration as possible treatment or complement to existing treatment of this cancer.Funding Agencies|Swedish Research Council|AI52731|VINNMER (Vinnova)||Medical Research Council of Southeast Sweden||Swedish Society of Medicine||</p

The impact of imaging time and contrast agent dose on screening for osteoporosis with contrast-enhanced CT

Background Screening for osteoporosis with contrast-enhanced computed tomography (CT) is promising for identifying high-risk osteoporotic patients. Our aims were (1) to investigate the estimated volume bone mineral density (vBMD) change over time after contrast injection (CT perfusion imaging, CTPI); and (2) to examine the influence of contrast dose on vBMD. Methods Fifteen patients, aged 71 +/- 9 years (mean +/- standard deviation, range 55-86) underwent a CTPI examination (28 scans within 63 s) of the upper body followed (after a waiting time of 10 min) by a full 4-phase CT examination (4 scans within 4 min). The contrast dose for CTPI was 0.38-0.83 mL/kg, and for 4-phase CT was 0.87-1.29 mL/kg. Vertebrae L1-L3 were analysed totalling 43 vertebrae, using Mindways qCT Pro. Results After contrast injection, vBMD showed a near-horizontal line until 17.5 s (non-contrast phase), followed by a steep increase 17.5-41.5 s after contrast injection, i.e., in the arterial phase, which plateaued 41.5 s after, i.e., in the early venous phase. A higher contrast dose per kg yielded significantly higher vBMD increase in both the arterial and venous phase (p &amp;lt; 0.003). Conclusions Both time from contrast administration and contrast dose per kg affected vBMD results. In arterial phase, the steepness of the curve makes vBMD estimation unsure. However, as values plateaued in the venous phase it might be possible to predict the correct vBMD values. Furthermore, contrast dose is a factor that needs to be adjusted for when using such a formula

Adherence to and persistence with zoledronic acid treatment for osteoporosis-reasons for early discontinuation

This retrospective study reports 81% long-term (&amp;gt; 3 years) adherence to and 77% persistence with zoledronic acid (ZA) treatment in osteoporosis patients, with ZA being costfree for patients. Eight percent of patients discontinued treatment because of adverse events (AEs), with a tendency of higher discontinuation rate in older patients. Purpose This study investigated (1) long-term adherence to and persistence with ZA treatment in a real-world setting, (2) extent to which an adverse reaction to ZA impacted on adherence and persistence, and (3) whether there were sex or age differences in patients that had early treatment termination (ETT) due to AEs and those who adhered to the regimen. Methods All patients treated with ZA at the Endocrinology Department at Linkoping University Hospital, Linkoping, Sweden between 2012 and 2017 were included. ETT was defined as &amp;lt; 3 ZA infusions, which was confirmed from patients medical records. Results A total of 414 patients were treated with ZA, with 81% receiving &amp;gt; 3 ZA infusions. Three-year persistence was 77% for a treatment window of 365 days +/- 90 days (75% with 365 days +/- 60 days window). The most common reason for ETT was AEs (8%), followed by medical conditions (5%), biological aging (3%), and other (e.g., lost to follow-up [3%]). Most patients who discontinued treatment because of AEs reported symptoms of acute-phase reaction, and tended to be older than those who adhered to treatment (74 +/- 9 vs 70 +/- 13 years, p = 0.064). There was no difference in sex ratio between the 2 groups (85% vs 90% females, p = 0.367). Conclusion Rates of long-term adherence to and persistence with ZA treatment were high with a pre-scheduled 3-year treatment regimen in the tax-financed Swedish healthcare system. AEs-mainly acute-phase reaction-were the most common reason for ETT, occurring in nearly 1 out of 10 patients.Funding Agencies|Linkoping University; County council of Ostergotland, Sweden (ALF)</p

Mobile learning device increased study efficiency for radiology residents but with risk of temporary novelty effect

Background: Digital resources in learning are increasingly available and offer new possibilities in education. Mobile learning devices (MLD) such as tablets provide easy and flexible access for users. Purpose: To investigate whether the introduction of MLDs in radiology education affected time spent on studies over a longer time frame and whether learning behavior and attitudes changed. Material and Methods: The radiology residents employed during 2015–2016 were invited to participate in this 12-month MLD intervention study. Results were evaluated using online questionnaires at six months (6 m) and 12 months (12 m). Results: Thirty-one residents were included, of whom half were in the early stages of residency (&lt;2 years). After the MLD introduction, most participants (91% [6 m] and 83% [12 m]) estimated increased time spent on studies. Of these, 32% stated “a lot more” at 6 m but only 8% at 12 m (P ¼ 0.12). The MLDs showed positive effects on the experience of radiology studies, as a majority of participants stated better quality and effectiveness in their studies (100% [6 m]–92% [12 m]), that MLD facilitated access to educational materials to a high degree (83% [6 m]–75% [12 m]), and that studies had become better and more fun (96% [6 m]–100% [12 m]). Conclusion: The use of MLDs seems to facilitate learning effectively for radiologic residents. However, a larger scale study is required as a trend of decreasing figures in the longer term was seen, but our results did not show a significant reduction of time spent on radiology studies

Computed tomography-based opportunistic osteoporosis assessment : a comparison of two software applications for lumbar vertebral volumetric bone mineral density measurements

Background: We aimed to compare two volumetric bone mineral density (vBMD) analysis programs, regarding (I) agreement of vBMD values based on monoand dual-energy computed tomography (MECT and DECT) scans and (II) suitability for analyzing DECT data obtained at different energies. Methods: We retrospectively analyzed two abdominal CT datasets: one performed in a MECT scan (vertebrae L1-L3) and one in a DECT scan (vertebrae L1-L4). Each dataset included different individuals [MECT 15 patients (45 vertebrae) and DECT 12 patients (48 vertebrae), respectively]. vBMD analysis was conducted using Philips IntelliSpace (IP) and Mindways qCT Pro (MW). Regarding the DECT scans, vBMD analysis was done at three different energies: 80, 150 and synthetic 120 kVp and for MECT scan at 120 kVp. For comparison of vBMD results between different software (aim 1) MECT 120 kVp and DECT synthetic 120 kVp data was used. For analyzing suitability of using different DECT energies for vBMD assessment (aim 2) all three DECT energies were used and results from each software was analyzed separately. Results: vBMD assessed with MW and IP, respectively correlated significantly for both the MECT (r=0.876; P&amp;lt;0.001) and DECT (r=0.837; P&amp;lt;0.001) scans, but the vBMD values were lower in using IP for vBMD assessment (8% and 14% lower for MECT and DECT, respectively; P=0.001). Regarding the different DECT energies, using MW for vBMD assessment showed significant correlations in vBMD results between 120 kVp and the two other energies (r=0.988 and r=0.939) and no significant differences in absolute vBMD values (P 0.05). The IP analysis as well showed significant correlation between 120 kVp and the other energies (r=0.769 and r=0.713, respectively), but differences in absolute vBMD values between the energies (P &amp;lt;= 0.001). Conclusions: We show that the correlations between the vBMD derived from the two investigated software solutions were generally good but that absolute vBMD value did differ and might impact the clinical diagnosis of osteoporosis. Though small, our study data indicate that vBMD might be assessed in energies other than 120 kVp when using MW but not when using IP

Vitamin D status in longstanding type 1 diabetes and controls. Association with upper extremity impairments

Background: Patients with type 1 diabetes have a high prevalence of upper extremity impairments (UEIs), such as frozen shoulder, carpal tunnel syndrome, and trigger finger. The UEIs are strongly associated with activity limitations and impaired quality of life. The etiology of the UEI is not clear. Vitamin D deficiency has been considered to play a role in the pathogenesis of type 1 diabetes and in the development of macro- and microvascular complications in diabetes. Aim: To characterize vitamin D status in a large population of patients with type 1 diabetes, if vitamin D deficiency is associated with metabolic factors and possible association with UEI. Material and methods: Patients who diagnosed before 35 years of age, whose diabetes duration >20 years, and who are not older than 65 years were invited to participate in this cross-sectional case-control, multicenter study. Controls matched for age and sex were obtained from the national population registry. Fasting blood samples were collected and stored at −80°C until analyzed regarding 25-hydroxy-vitamin D (25(OH)D3) by a liquid chromatographic-mass spectrometric method (LC-MS/MS). Results: Vitamin D levels varied with season as expected in the northern hemisphere. The association between 25(OH)D3 and clinical variables was analyzed in a univariate general linear model, which indicated no difference in 25(OH)D3 in men with and without diabetes but higher values in women with diabetes. About 30% of both patients and controls had vitamin D deficiency (≤50 nmol/L). Analyzed by binary logistic regression UEIs was not associated with 25(OH)D3 levels. In both patients and controls, 25(OH)D3 was correlated to apolipoprotein A1 (r = 0.153; 0.220, P < 0.001). Conclusion: In patients with type 1 diabetes and a duration of 20 years or more, vitamin D level is not lower than in nondiabetic controls and is not associated with UEIs

Selection of risk assessment methods for osteoporosis screening in postmenopausal women with low-energy fractures : A comparison of fracture risk assessment tool, digital X-ray radiogrammetry, and dual-energy X-ray absorptiometry

Objectives:Fracture liaison services are designed to identify patients needing osteoporosis treatment after a fracture. Some fracture liaison service designs involve a prescreening step, for example, fracture risk assessment tool (FRAX®). Another possible prescreening tools are bone mass density assessment in the acute setting. The aim of this study was to assess the effectiveness of prescreening tools.Methods:In the present prospective cohort study, women aged &gt;55 years with a radius fracture were included. Patients were recruited at the emergency department after experiencing their fracture. All patients performed fracture risk assessment by fracture risk assessment tool, and bone mass density assessment by digital X-ray radiogrammetry and dual-energy X-ray absorptiometry (prescreening steps) as well as full routine evaluation at the osteoporosis unit (endpoint). The main outcome measures were sensitivity, specificity, predictive values, and area under the curve.Results:Forty-one women were recruited (mean age: 70 ± 8 years). Of these, 54% fulfilled the treatment indication criteria of osteoporosis after a full examination. Fracture risk assessment tool without bone mass density (cutoff ⩾ 15%) for prescreening patients had a high sensitivity (90%) but a low area under the curve (0.50) and specificity (16%). The highest area under the curve (0.73) was found prescreening with bone mass density assessment (dual-energy X-ray absorptiometry or digital X-ray radiogrammetry) having a sensitivity of 59%–86% and specificity of 61%–90%.Conclusion:This study, though small, raises questions regarding the effectiveness of using a prescreening step in fracture liaison services for high-risk individuals. In this cohort, FRAX® without bone mass density had a low precision, with a risk of both underestimating and overestimating patients requiring treatment. Bone mass density assessment in the acute setting could improve the precision of prescreening. Further investigations on the effectiveness and health economics of prescreening steps in fracture liaison services are needed

Trabecular bone microstructure analysis on data from a novel twin robotic X-ray device

Background Bone strength is related to both mineral density (BMD) and the bone microstructure. However, only the assessment of BMD is available in clinical routine care today. Purpose To analyze and study the correlation of trabecular bone microstructure from the imaging data of a prototype Multitom Rax system, using micro-computed tomography (CT) data as the reference method (Skyscan 1176). Material and Methods Imaging data from 14 bone samples from the human radius were analyzed regarding six bone structure parameters, i.e. trabecular nodes, separation, spacing, and thickness as well as bone volume (BV/TV) and structural model index (SMI). Results All six structure parameters showed strong correlations to micro-CT with Spearman correlation coefficients in the range of 0.83-0.93. BV/TV and SMI had a correlation &amp;gt;0.90. Two of the parameters, namely, separation and number, had mean values in the same range as micro-CT. The other four were either over- or underestimated. Conclusion The strong correlation between micro-CT and the clinical imaging system, indicates the possibility for analyzing bone microstructure with potential to add value in fracture assessment using the studied device in a clinical workflow.Funding Agencies|ALF Grants, Region OEstergoetland, Sweden; [ROE-936170]</p