The Endoplasmic Reticulum Chaperone Protein GRP94 Is Required for Maintaining Hematopoietic Stem Cell Interactions with the Adult Bone Marrow Niche

Hematopoietic stem cell (HSC) homeostasis in the adult bone marrow (BM) is regulated by both intrinsic gene expression products and interactions with extrinsic factors in the HSC niche. GRP94, an endoplasmic reticulum chaperone, has been reported to be essential for the expression of specific integrins and to selectively regulate early T and B lymphopoiesis. In GRP94 deficient BM chimeras, multipotent hematopoietic progenitors persisted and even increased, however, the mechanism is not well understood. Here we employed a conditional knockout (KO) strategy to acutely eliminate GRP94 in the hematopoietic system. We observed an increase in HSCs and granulocyte-monocyte progenitors in the Grp94 KO BM, correlating with an increased number of colony forming units. Cell cycle analysis revealed that a loss of quiescence and an increase in proliferation led to an increase in Grp94 KO HSCs. This expansion of the HSC pool can be attributed to the impaired interaction of HSCs with the niche, evidenced by enhanced HSC mobilization and severely compromised homing and lodging ability of primitive hematopoietic cells. Transplanting wild-type (WT) hematopoietic cells into a GRP94 null microenvironment yielded a normal hematology profile and comparable numbers of HSCs as compared to WT control, suggesting that GRP94 in HSCs, but not niche cells, is required for maintaining HSC homeostasis. Investigating this, we further determined that there was a near complete loss of integrin α4 expression on the cell surface of Grp94 KO HSCs, which showed impaired binding with fibronectin, an extracellular matrix molecule known to play a role in mediating HSC-niche interactions. Furthermore, the Grp94 KO mice displayed altered myeloid and lymphoid differentiation. Collectively, our studies establish GRP94 as a novel cell intrinsic factor required to maintain the interaction of HSCs with their niche, and thus regulate their physiology

The Incidence of Pulmonary Embolism and Associated FDG-PET Findings in IV Contrast-Enhanced PET/CT

Rationale and objectivesMost fluorine-18 fluorodeoxyglucose (FDG)-positron emission tomography with computed tomography (PET/CT) studies are performed on cancer patients. These patients are at increased risk of pulmonary embolism (PE). In this retrospective review, we determined the rate of PE, and the prevalence of associated FDG-PET findings on intravenous (IV) contrast-enhanced PET/CT.Materials and methodsWe identified all PET/CT studies performed at our institution with a reported finding of PE between January 2005 and October 2012. The medical record was reviewed for symptoms, which were identified after the diagnosis of PE, and whether the patients received treatment. The prevalence of associated FDG-PET findings was determined.ResultsA total of 65 total cases of PE (of 182,72 total PET/CT examinations) were identified of which 59 were previously unknown. This gives an incidental PE (IPE) rate of 0.32%. Of the patients where sufficient clinical information was available, 34 of 36 (94%) were treated either with therapeutic anticoagulation or inferior vena cava filter, and 30 of 36 (83%) were asymptomatic in retrospect. Of the patients with IPE, we found nine (15.2%) with associated focal pulmonary artery hypermetabolism, three (5.1%) with hypermetabolic pulmonary infarction, and one with increased isolated right ventricular FDG uptake (1.7%). One case of chronic PE demonstrated a focal hypometabolic filling defect in a pulmonary artery on PET.ConclusionsWe found IPE in 0.32% of PET/CT scans. Focal pulmonary artery hypermetabolism or hypometabolism, and hypermetabolic pulmonary artery infarction with the "rim sign" were uncommonly associated with PE. These findings could raise the possibility of IPE in non-IV contrast-enhanced PET/CT studies

The unfolded protein response in immunity and inflammation.

The unfolded protein response (UPR) is a highly conserved pathway that allows the cell to manage endoplasmic reticulum (ER) stress that is imposed by the secretory demands associated with environmental forces. In this role, the UPR has increasingly been shown to have crucial functions in immunity and inflammation. In this Review, we discuss the importance of the UPR in the development, differentiation, function and survival of immune cells in meeting the needs of an immune response. In addition, we review current insights into how the UPR is involved in complex chronic inflammatory diseases and, through its role in immune regulation, antitumour responses.This work was supported by the Netherlands Organization for Scientific Research Rubicon grant 825.13.012 (J.G.); US National Institutes of Health (NIH) grants DK044319, DK051362, DK053056 and DK088199, and the Harvard Digestive Diseases Center (HDDC) grant DK034854 (R.S.B.); National Institutes of Health grants DK042394, DK088227, DK103183 and CA128814 (R.J.K.); and European Research Council (ERC) Starting Grant 260961, ERC Consolidator Grant 648889, and the Wellcome Trust Investigator award 106260/Z/14/Z (A.K.).This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/nri.2016.6

The incidence of pulmonary embolism and associated FDG-PET findings in IV contrast-enhanced PET/CT.

Rationale and objectivesMost fluorine-18 fluorodeoxyglucose (FDG)-positron emission tomography with computed tomography (PET/CT) studies are performed on cancer patients. These patients are at increased risk of pulmonary embolism (PE). In this retrospective review, we determined the rate of PE, and the prevalence of associated FDG-PET findings on intravenous (IV) contrast-enhanced PET/CT.Materials and methodsWe identified all PET/CT studies performed at our institution with a reported finding of PE between January 2005 and October 2012. The medical record was reviewed for symptoms, which were identified after the diagnosis of PE, and whether the patients received treatment. The prevalence of associated FDG-PET findings was determined.ResultsA total of 65 total cases of PE (of 182,72 total PET/CT examinations) were identified of which 59 were previously unknown. This gives an incidental PE (IPE) rate of 0.32%. Of the patients where sufficient clinical information was available, 34 of 36 (94%) were treated either with therapeutic anticoagulation or inferior vena cava filter, and 30 of 36 (83%) were asymptomatic in retrospect. Of the patients with IPE, we found nine (15.2%) with associated focal pulmonary artery hypermetabolism, three (5.1%) with hypermetabolic pulmonary infarction, and one with increased isolated right ventricular FDG uptake (1.7%). One case of chronic PE demonstrated a focal hypometabolic filling defect in a pulmonary artery on PET.ConclusionsWe found IPE in 0.32% of PET/CT scans. Focal pulmonary artery hypermetabolism or hypometabolism, and hypermetabolic pulmonary artery infarction with the "rim sign" were uncommonly associated with PE. These findings could raise the possibility of IPE in non-IV contrast-enhanced PET/CT studies

Gadoxetate-enhanced Abbreviated MRI for Hepatocellular Carcinoma Surveillance: Preliminary Experience.

To describe a single-center preliminary experience with gadoxetate disodium-enhanced abbreviated MRI for hepatocellular carcinoma (HCC) screening and surveillance in patients with cirrhosis or chronic hepatitis B virus (cHBV). This was a retrospective study of consecutive patients aged 18 years and older with cirrhosis or cHBV who underwent at least one gadoxetate-enhanced abbreviated MRI examination for HCC surveillance from 2014 through 2016. Examinations were interpreted prospectively by one of six abdominal radiologists for clinical care. Clinical, imaging, and other data were extracted from electronic medical records. Diagnostic adequacy was assessed in all patients. Diagnostic accuracy was assessed in the subset of patients who could be classified as having HCC or not having HCC on the basis of a composite reference standard. In this study, 330 patients (93% with cirrhosis; 45% women; mean age, 59 years) underwent gadoxetate-enhanced abbreviated MRI. In the 330 patients, 311 (94.2%) baseline gadoxetate-enhanced abbreviated MRI examinations were diagnostically adequate. Of 141 (43%) of the 330 patients, 91.4% (129 of 141) could be classified as not having HCC and 8.6% (12 of 141) could be classified as having HCC. Baseline gadoxetate-enhanced abbreviated MRI had 0.92 sensitivity (95% confidence interval [CI]: 0.62, 1.00) and 0.91 specificity (95% CI: 0.84, 0.95) for detection of HCC. Of the 330 patients who underwent baseline gadoxetate-enhanced abbreviated MRI, 187 (57%) were lost to follow-up. Gadoxetate-enhanced abbreviated MRI is feasible clinically, has a high diagnostic adequacy rate, and, on the basis of our preliminary experience, accurately depicts HCC in high-risk patients. Strategies to enhance follow-up compliance are needed.© RSNA, 2019Keywords: Abdomen/GI, Cirrhosis, Liver, MR-Imaging, Oncology, ScreeningSupplemental material is available for this article

Anforderungen einer umweltvertraeglichen Erholungsvorsorge an die raeumliche Gesamtplanung aus Bundessicht - Ziele, Massnahmen und Instrumente sowie Handlungsempfehlungen. Mit Anhang Abschlussbericht

Published in two volumesAvailable from TIB Hannover: RN 8908(2000,206): RN 8908(2000,206,Anh.) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEBundesministerium fuer Umwelt, Naturschutz und Reaktorsicherheit, Bonn (Germany)DEGerman

Restriction spectrum imaging: An evolving imaging biomarker in prostate MRI.

Restriction spectrum imaging (RSI) is a novel diffusion-weighted MRI technique that uses the mathematically distinct behavior of water diffusion in separable microscopic tissue compartments to highlight key aspects of the tissue microarchitecture with high conspicuity. RSI can be acquired in less than 5 min on modern scanners using a surface coil. Multiple field gradients and high b-values in combination with postprocessing techniques allow the simultaneous resolution of length-scale and geometric information, as well as compartmental and nuclear volume fraction filtering. RSI also uses a distortion correction technique and can thus be fused to high resolution T2-weighted images for detailed localization, which improves delineation of disease extension into critical anatomic structures. In this review, we discuss the acquisition, postprocessing, and interpretation of RSI for prostate MRI. We also summarize existing data demonstrating the applicability of RSI for prostate cancer detection, in vivo characterization, localization, and targeting.Level of evidence5 J. Magn. Reson. Imaging 2017;45:323-336