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101.
Lena Claesson-Welsh 《Upsala journal of medical sciences》2020,125(3):205
Oxygen is of fundamental importance for most living organisms, and the maintenance of oxygen homeostasis is a key physiological challenge for all large animals. Oxygen deprivation, hypoxia, is a critical component of many human diseases including cancer, heart disease, stroke, vascular disease, and anaemia. The discovery of oxygen sensing provides fundamental knowledge of a stunningly elegant molecular machinery; it also promises development of new therapeutics for serious diseases such as cancer. As a result of their impressive contributions to our understanding of the mechanisms by which cells sense oxygen and signal in hypoxia, Gregg Semenza, Peter Ratcliffe, and William Kaelin were awarded the Nobel Prize in 2019. 相似文献
102.
Marta Lishnevsky Lena C. Young Steven J. Woods Steven D. Groshong Randall J. Basaraba John M. Gilchrist David M. Higgins Mercedes Gonzalez-Juarrero Todd A. Bass William A. Muller Alan R. Schenkel 《Experimental and molecular pathology》2014
Platelet Endothelial Cell Adhesion Molecule 1 (PECAM-1) deficient mice in the FVB/n strain exhibit fatal chronic pulmonary fibrotic disease. The illness occurs in the absence of a detectable pro-inflammatory event. PECAM-1 is vital to the stability of vascular permeability, leukocyte extravasation, clotting of platelets, and clearance of apoptotic cells. We show here that the spontaneous development of fibrotic disease in PECAM-1 deficient FVB/n mice is characterized by early loss of vascular integrity in pulmonary capillaries, resulting in spontaneous microbleeds. Hemosiderin-positive macrophages were found in interstitial spaces and bronchoalveolar lavage (BAL) fluid in relatively healthy animals. We also observed a gradually increasing presence of hemosiderin-positive macrophages and fibrin deposition in the advanced stages of disease, corresponding to the accumulation of collagen, IL-10 expression, and myofibroblasts expressing alpha smooth muscle actin (SMA). Together with the growing evidence that pulmonary microbleeds and coagulation play an active part in human pulmonary fibrosis, this data further supports our hypothesis that PECAM-1 expression is necessary for vascular barrier function control and regulation of homeostasis specifically, in the pulmonary environment. 相似文献
103.
Jenny Bandomir André Schulz Satomi Taguchi Lena Schmitt Hiroyuki Ohno Katrin Sternberg Klaus‐Peter Schmitz Udo Kragl 《Macromolecular chemistry and physics.》2014,215(8):716-724
An easy and efficient route to synthesize gel materials based on polymeric ionic liquids (PILs) is presented. The radical polymerization of imidazolium (Im)‐based ionic liquids (ILs) bearing a vinyl group ([VEIm][Br], [VEIm][Ac], [VBIm][Br], [VBIm][Cl]) with crosslinker (CL) N,N′‐methylenebisacrylamide (Bis) in water results in polyionic liquid hydrogels. Thermal and mechanical properties (tensile and compression tests) are investigated and compared with two different types of hydrogels. One is a polyacrylamide (PAAm) hydrogel having covalent‐type crosslinking. The other is an alginate‐based hydrogel having ionic‐type crosslinking. Prepared IL‐hydrogel materials provide favorable flexibility, adjustable by varying the CL ratio and water content. The higher the CL ratio is, the higher the fragility of the gel matrix. The gelation time of the hydrogels depends on the alkyl chain length, as well as the size of the anion.
104.
Lena Hanberger Niels Birkebaek Ragnar Bjarnason Ann Kristin Drivvoll Anders Johansen Torild Skrivarhaug Arni V. Thorsson Ulf Samuelsson 《Journal of diabetes science and technology》2014,8(4):738-744
Background:In 2008 a Nordic collaboration was established between the quality registries in Denmark, Iceland, Norway, and Sweden to improve quality of care for children with diabetes. This study aimed to describe those registries and confirm that the registry variables are comparable. Selected variables were used to demonstrate outcome measurements.Methods:The organization of the registries and methodology are described. Cross-sectional data for patients between birth and 14.9 years with type 1 diabetes mellitus in 2009 (n = 6523) from 89 centers were analyzed. Variables were age, gender, and diabetic ketoacidosis at onset, together with age, gender, HbA1c, insulin regimen, and severe hypoglycemia at follow-up in 2009.Results:All 4 registries use a standardized registration at the onset of diabetes and at follow-up, conducted at the local pediatric diabetes centers. Methods for measuring HbA1c varied as did methods of registration for factors such as hypoglycemia. No differences were found between the outcomes of the clinical variables at onset. Significant variations were found at follow-up for mean HbA1c, the proportion of children with HbA1c < 57 mmol/mol (NGSP/DCCT 7.4%), (range 15-31%), the proportion with insulin pumps (range 34-55%), and the numbers with severe hypoglycemia (range 5.6-8.3/100 patient years).Conclusions:In this large unselected population from 4 Nordic countries, a high proportion did not reach their treatment target, indicating a need to improve the quality of pediatric diabetes care. International collaboration is needed to develop and harmonize quality indicators and offers possibilities to study large geographic populations, identify problems, and share knowledge. 相似文献
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106.
Benoit Desnues Amanda Beatriz Macedo Annie Roussel-Queval Johnny Bonnardel Sandrine Henri Olivier Demaria Lena Alexopoulou 《Proceedings of the National Academy of Sciences of the United States of America》2014,111(4):1497-1502
Systemic lupus erythematosus (SLE) is a complex autoimmune disease with diverse clinical presentations characterized by the presence of autoantibodies to nuclear components. Toll-like receptor (TLR)7, TLR8, and TLR9 sense microbial or endogenous nucleic acids and are implicated in the development of SLE. In mice TLR7-deficiency ameliorates SLE, but TLR8- or TLR9-deficiency exacerbates the disease because of increased TLR7 response. Thus, both TLR8 and TLR9 control TLR7 function, but whether TLR8 and TLR9 act in parallel or in series in the same or different cell types in controlling TLR7-mediated lupus remains unknown. Here, we reveal that double TLR8/9-deficient (TLR8/9−/−) mice on the C57BL/6 background showed increased abnormalities characteristic of SLE, including splenomegaly, autoantibody production, frequencies of marginal zone and B1 B cells, and renal pathology compared with single TLR8−/− or TLR9−/− mice. On the cellular level, TLR8−/− and TLR8/9−/− dendritic cells were hyperesponsive to TLR7 ligand R848, but TLR9−/− cells responded normally. Moreover, B cells from TLR9−/− and TLR8/9−/− mice were hyperesponsive to R848, but TLR8−/− B cells were not. These results reveal that TLR8 and TLR9 have an additive effect on controlling TLR7 function and TLR7-mediated lupus; however, they act on different cell types. TLR8 controls TLR7 function on dendritic cells, and TLR9 restrains TLR7 response on B cells.Systemic lupus erythematosus (SLE) is a complex chronic autoimmune disease that arises spontaneously and is characterized by production of autoantibodies against self-nucleic acids and associated proteins (1). These autoantibodies bind self-nucleic acids released by dying cells and form immune complexes that accumulate in different parts of the body, leading to inflammation and tissue damage. The kidneys, skin, joints, lungs, serous membranes, as well as, the cardiovascular, nervous and musculoskeletal system become targets of inflammation at onset or during the course of the disease (2). The etiology of SLE is unknown, yet genetics, sex, infectious agents, environmental factors, and certain medications may play a role in the initiation of the disease by causing alterations in lymphoid signaling, antigen presentation, apoptosis, and clearance of immune complexes (3, 4).Toll-like receptors (TLRs) detect specific microbial components widely expressed by bacteria, fungi, protozoa, and viruses, and initiate signaling pathways critical for induction of immune responses to infection (5). In contrast to the cell surface TLRs that detect bacterial cell wall components and viral particles, nucleic acid-sensing TLRs are localized mainly within endosomal compartments (6). Human endosomal TLRs consist of TLR3, which senses viral double-stranded RNA (dsRNA) (7), TLR7 and TLR8, which recognize viral single-stranded RNA (8–10), and TLR9, which detects bacterial and viral unmethylated CpG-containing DNA motifs (11). Interestingly, these endosomal TLRs are also able to detect self-nucleic acids (12–14). Although the endosomal localization isolate TLR3, TLR7, TLR8, and TLR9 away from self-nucleic acids in the extracellular space, still self-RNA or -DNA can become a potent trigger of cell activation when transported into TLR-containing endosomes, and such recognition can result in sterile inflammation and autoimmunity, including SLE (4, 15, 16). The connection of the endosomal TLRs with SLE originates mainly from mouse models, where TLR7 signaling seems to play a central role. TLR7 gene duplication is the cause for the development of lupus in mice bearing the Y chromosome-linked autoimmune accelerating (Yaa) locus that harbors 17 genes, including TLR7 (17, 18). In TLR7 transgenic mouse lines, a modest increase in TLR7 expression promotes autoreactive lymphocytes with RNA specificities and myeloid cell proliferation, but a substantial increase in TLR7 expression causes fatal acute inflammatory pathology and profound dendritic cell (DC) dysregulation (17). In addition, studies in several lupus-prone mouse strains have revealed that TLR7-deficiency ameliorates disease, but TLR9-deficiency exacerbates it. Interestingly, this controversy can be explained by the enhanced TLR7 activity in the TLR9-deficient lupus mice (19, 20). Although murine TLR8 does not seem so far to be able to sense a ligand (21, 22), we have shown previously that it plays an important biological role in controlling TLR7-mediated lupus. Indeed, TLR8-deficiency in mice (on the C57BL/6 background that is not prone to lupus) leads to lupus development because of increased TLR7 expression and signaling in DCs (23). Thus, tight control and regulation of TLR7 is pivotal for avoiding SLE and inflammatory pathology in mice. Recent studies in humans have also revealed that increased expression of TLR7 is associated with increased risk for SLE (24–26).Nucleic acid TLRs are expressed in many cell types, including DCs, plasmacytoid DCs (pDCs) and B cells, all of which play a central role in SLE development. TLR7, TLR8, and TLR9 signal through the adaptor molecule myeloid differentiation primary response gene 88 (MyD88), whereas TLR3 signals via the adaptor TRIF (Toll/IL-1 receptor domain-containing adaptor inducing IFN-β) (5). MyD88-deficiency abrogates most attributes of lupus in several lupus-prone mouse strains (19, 27–29). Moreover, deficiency for Unc93B1, a multipass transmembrane protein that controls trafficking of TLRs from the endoplasmic reticulum to endolysosomes and is required for nucleic acid-sensing TLR function (30), also abrogates many clinical parameters of disease in mouse lupus strains, suggesting that endosomal TLRs are critical in this disease (31). Interestingly, TLR9 competes with TLR7 for Unc93B1-dependent trafficking and predominates over TLR7 (32). TLR9 predominance is reversed to TLR7 by a D34A mutation in Unc93B1 and mice that carry this mutation show TLR7-dependent, systemic lethal inflammation (32).Thus, in mice both TLR8 and TLR9 control TLR7-mediated lupus, but it is unknown if these TLRs act in parallel or in series in the same or different cell types and if they have an additive effect or not in controlling TLR7. To address these issues, we generated double TLR8/TLR9-deficient (TLR8/9−/−) mice and analyzed and compared the lupus phenotype in TLR8−/−, TLR9−/−, and TLR8/9−/− mice. Our data revealed that TLR8/9−/− mice have increased abnormalities characteristic of SLE and that both TLR8 and TLR9 keep TLR7-mediated lupus under control, but they act in different cell types. On DCs TLR7 function is ruled by TLR8, whereas on B cells TLR7 is mastered by TLR9. 相似文献
107.
108.
Lena Nordström Sandra Sernbo Patrik Eden Kirsten Grønbæk Arne Kolstad Riikka Räty Marja‐Liisa Karjalainen Christian Geisler Elisabeth Ralfkiær Christer Sundström Anna Laurell Jan Delabie Mats Ehinger Mats Jerkeman Sara Ek 《British journal of haematology》2014,166(1):98-108
Mantle cell lymphoma (MCL) is an aggressive B cell lymphoma, where survival has been remarkably improved by use of protocols including high dose cytarabine, rituximab and autologous stem cell transplantation, such as the Nordic MCL2/3 protocols. In 2008, a MCL international prognostic index (MIPI) was created to enable stratification of the clinical diverse MCL patients into three risk groups. So far, use of the MIPI in clinical routine has been limited, as it has been shown that it inadequately separates low and intermediate risk group patients. To improve outcome and minimize treatment‐related morbidity, additional parameters need to be evaluated to enable risk‐adapted treatment selection. We have investigated the individual prognostic role of the MIPI and molecular markers including SOX11, TP53 (p53), MKI67 (Ki‐67) and CCND1 (cyclin D1). Furthermore, we explored the possibility of creating an improved prognostic tool by combining the MIPI with information on molecular markers. SOX11 was shown to significantly add prognostic information to the MIPI, but in multivariate analysis TP53 was the only significant independent molecular marker. Based on these findings, we propose that TP53 and SOX11 should routinely be assessed and that a combined TP53/MIPI score may be used to guide treatment decisions. 相似文献
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110.